We found 41 diseases and 31 genes matching your search

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Dermatoleukodystrophy

Retrieved: 27-07-2015
Source: Orphanet (Original article)

This syndrome is characterised by the association of a progressive leukodystrophy marked by generalised mental and motor impairment with the presence of thickened and wrinkled skin. It has been described in a Japanese brother and sister born to healthy parents. Both patients died in early childhood. Last update: August 2006
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Dermatoleukodystrophy

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Matsuyama et al. (1978) described a 'new' disorder in a Japanese brother and sister, the progeny of normal parents. They were born with thickened wrinkled skin and died in the third year of life with a progressive cerebral disease characterized by generalized mental and motor impairment. Postmortem neuropathologic studies showed a remarkable leukodystrophy with multiple axonal spheroids as the outstanding feature. Ultrastructurally, the spheroids contained granules resembling ceroid-lipofuscin bodies. Similar granules were found in degenerating oligodendrocytes and in Schwann cells. The skin showed hypercellularity and sclerosis. The ears, nose, hands and feet appeared disproportionately large. Striking thickening, wrinkling and creasing of the skin was generalized and gave the face the appearance of an aged person.

Symptoms

Skin: Thickened wrinkled skin; Skin sclerosis; Creased skin

Neuro: Progressive cerebral disease; Mental retardation; Motor impairment

HEENT: Large ears; Large nose; Aged facial appearance

Skel: Large hands and feet

Lab: Leukodystrophy with multiple axonal, oligodendrocytic and Schwann cell spheroids containing granules like ceroid-lipofuscin bodies; Skin hypercellularity

Inheritance: Autosomal recessive
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Patterson pseudoleprechaunism syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Patterson and Watkins (1962) described a 10-month-old boy who they thought had leprechaunism (Donohue syndrome; 246200). Discordant features, however, were normal birth weight (rather than the usual severe intrauterine growth retardation) and marked cutis gyrata of hands and feet as well as a generalized skeletal disorder. Follow-up of this patient at age 7 years by Patterson (1969) made it clear that the disorder is distinct from leprechaunism. The boy had dwarfism, mental retardation, hyperadrenocorticism, and diabetes mellitus. He developed bladder diverticula and died at age 7.5 years from gram-negative sepsis. A main finding at autopsy was marked enlargement of the adrenals, especially of the zona fasciculata (McKusick, 1972). The distinctness of this disorder is further supported by discovery of an identical case in a female whose parents were young and unrelated (David et al., 1981). Findings at age 12 years were premature adrenarche with raised dehydroepiandrosterone and androstenedione levels. There was no clue to the genetics or other etiology of the disorder.

Symptoms

INHERITANCE: Isolated cases

GROWTH: [Weight]; Normal birth weight

HEAD AND NECK: [Ears]; Disproportionately large ears; Normal hearing; [Nose]; Disproportionately large nose

SKELETAL: Marked delay in bone age; Joint swelling (wrist, elbow, knees, ankles) onset late infancy; [Skull]; Thickened cranial vault; Thick maxilla; Thick ethmoid bones; Thick mandibular condyles; [Spine]; Kyphoscoliosis; Irregular, dense end plate; Small, flat cervical vertebrae; Hypoplastic odontoid process; Ovoid thoracic and lumbar vertebrae; [Pelvis]; Flat, irregular acetabular roofs; Failure of ossification of pubic bones, ischii, triradiate cartilages; [Limbs]; Genu valga; Short, deformed tubular bones; Irregular metaphyseal ossification; Sclerotic metaphyseal changes; [Hands]; Disproportionately large hands; [Feet]; Disproportionately large feet; Ankle valgus deformity

SKIN, NAILS, HAIR: [Skin]; Generalized bronze hyperpigmentation (present at birth); Cutis laxa, hands and feet (present at birth); [Hair]; Hirsutism (especially on limbs)

NEUROLOGIC: [Central nervous system]; Severe mental retardation; Seizure

ENDOCRINE FEATURES: Premature adrenarche; Diabetes mellitus; Hyperadrenocorticism

MISCELLANEOUS: Both reported cases survived beyond infancy

Short-rib thoracic dysplasia 13 with or without polydactyly

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-13 with or without polydactyly (SRTD13) is caused by homozygous mutation in the CEP120 gene (613446) on chromosome 5q23.

For a general phenotypic description and discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).Shaheen et al. (2015) described 4 unrelated infants, 3 male and 1 female, with short-rib thoracic dysplasia and polydactyly (SRTD). Two were born of first-cousin Saudi parents, and 1 was born of Swiss parents who were not known to be related but came from the same village; the ethnic or geographic origin of the fourth patient was not noted. All 4 of the affected infants died of respiratory failure within the first week of life, and all had a small thorax with short horizontal ribs, dysplastic pelvis, short long bones, and preaxial polydactyly or synpolydactyly. Extraskeletal features inc...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature at birth

HEAD AND NECK: [Head]; Relative macrocephaly; [Face]; Coarse facies; Midface hypoplasia; Microretrognathia; [Ears]; Large ears; Prominent lobules; [Eyes]; Hypertelorism; Scant eyebrows; [Nose]; Large nose; Prominent nostrils; [Mouth]; Mild cleft lip (notch); Tongue hamartoma (lobulated tongue); Partially bifid tongue; [Teeth]; Natal teeth

CARDIOVASCULAR: [Vascular]; Patent ductus arteriosus

RESPIRATORY: [Lung]; Hypoplastic lungs; Respiratory insufficiency

CHEST: [External features]; Narrow thorax; Bell-shaped thorax; [Ribs, sternum, clavicles, and scapulae]; Short ribs; Horizontal ribs

ABDOMEN: [External features]; Omphalocele

GENITOURINARY: [External genitalia, male]; Ambiguous genitalia; Phallus-like structure; Prominent prepuce; [Internal genitalia, male]; Undescended testes; [Kidneys]; Small kidneys; Increased echogenicity on ultrasound

SKELETAL: [Skull]; Small facial bones; [Pelvis]; Small pelvis; Dysplastic pelvic bone; Flaring of iliac bones; Small, squared iliac bones; Horizontal acetabular roof; Acetabular bony spurs; Narrow sciatic notch; Trident sciatic notch; [Limbs]; Micromelic short limbs; Round-ended femur bones; Small tibia; Small fibula; [Hands]; Synpolydactyly; Preaxial polydactyly; Severely hypoplastic middle and distal phalanges; [Feet]; Synpolydactyly; Hallux deformity

NEUROLOGIC: [Central nervous system]; Unilateral coronal craniosynostosis; Prominent and widened anterior and posterior fontanels; Cerebellar hypoplasia with Dandy-Walker malformation; Vermian hypoplasia with molar-tooth appearance

MISCELLANEOUS: Death occurs early in neonatal period due to respiratory failure; ...
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Say syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Say et al. (1975) described a 'new,' presumably autosomal dominant disorder characterized by cleft palate, short stature, microcephaly, large ears, and hand anomalies. A grandfather, 2 of his 5 daughters, and the son of 1 of the affected daughters were affected. The 2 affected females in the second generation had distally tapering fingers with hypoplastic distal phalanges, ulnar deviation of the middle fingers, and low set thumbs. Both had bilateral acromial dimples. The mother had severe micrognathia, which was surgically corrected during early childhood, and cleft palate. Abu-Libdeh et al. (1993) reported the case of a 13-month-old girl with similar features. Proximal renal tubular acidosis with cystic dysplasia of the kidneys was also present. Cystic renal dysplasia was also present in a new case in one of the discordant monozygotic twins reported by Ashton-Prolla and Felix (1997).

Guion-Almeida et al. (1998) reported a 3-year 7-month-old Brazilian boy with this syndrome whose parents were normal and nonconsanguineous. The child had glossoptosis, seizures, and cerebral anomalies, features which were not observed in previous reports.

Pagnan et al. (1999) reported a 12-month-old boy with cleft palate, large ears, microcephaly, distally tapering fingers, length at the 3rd centile, and delayed bone age. Psychomotor development was normal, and no renal anomalies were identified on ultrasonography. The patient's mother had microcephaly, but no other abnormal features. The authors concluded that this patient had Say syndrome and interpreted the microcephaly in the patient's mother as mild expression of the syndrome.

Symptoms

Mouth: Cleft palate

Growth: Short stature

Head: Microcephaly; Micrognathia

Ears: Large ears

Limbs: Hand anomalies; Distally tapering fingers; Hypoplastic distal phalanges; Ulnar deviation of middle fingers; Low set thumbs

Skin: Acromial dimples

Metabolic: Proximal renal tubular acidosis

GU: Cystic renal dysplasia

Inheritance: Autosomal dominant
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Say syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Say syndrome is a condition characterized by bilateral acromial dimples.

See also

Rud syndrome List of cutaneous conditions
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X-linked intellectual disability, Shashi type

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2, mrxs11

This syndrome is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome. Last update: February 2007
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Mental retardation, x-linked, syndromic 11

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, mrxs11

Clinical features

In a large family from North Carolina, Shashi et al. (2000) studied a seemingly novel X-linked mental retardation syndrome with characteristic facial dysmorphic features. Only males were affected over 4 generations. Clinical findings in the 7 living affected males included a moderate degree of mental retardation, coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, a bulbous nose, prominent lower lip, large ears, obesity, and large testes. Cephalometric measurements suggested that the affected males had a distinctive craniofacial skeletal structure, when compared with normative measurements. Obligate-carrier females had no mental retardation, but the results of cephalometric analysis suggested craniofacial dysmorphism intermediate between that of affected males and that of normative control individuals. Unaffected male relatives showed no clinical or cephalometric resemblance to affected males. The blood-lymphocyte karyotype and the results of DNA analysis for fragile X syndrome (300624) and of other routine investigations were normal.

Castro et al. (2003) described a family with mental retardation in 2 brothers. The pedigree was consistent with either X-linked mental retardation or autosomal recessive inheritance. The diagnosis of Shashi X-linked mental retardation syndrome was suggested by the clinical features of coarse facies, prominent lower lip, large testes, and obesity.

Mapping

By linkage analysis with polymorphic DNA markers spanning the X chromosome in a large family with an X-linked mental retardation syndrome, Shashi et al. (2000) established linkage to Xq26-q27. A maximum lod score of 3.1 was obtained at marker DXS1047 (recombination fraction of 0.0). Shashi et al. (2000) concluded that the features in this family were not consistent with those seen in any previously delineated forms of X-linked mental retardation, including those with a similar phenotype and those that had been mapped in close proximity.

Haplotype analysis in the family with mental retardation described by Castro et al. (2003) was consistent with the localization of Shashi X-linked mental retardation syndrome to chromosome Xq26-q27. Castro et al. (2003) concluded that the family represented a second occurrence of Shashi X-linked mental retardation.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Weight]; Obesity

HEAD AND NECK: [Face]; Coarse facies; [Ears]; Large ears; [Eyes]; Periorbital fullness; Narrow palpebral fissures; [Nose]; Bulbous nose; [Mouth]; Prominent lower lip

GENITOURINARY: [External genitalia, male]; Macroorchidism

SKELETAL: [Skull]; Prominent supraorbital ridges

NEUROLOGIC: [Central nervous system]; Mental retardation, moderate

MISCELLANEOUS: Carrier females show no phenotypic abnormalities, but may have learning difficulties
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Wolff mental retardation syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Wolff et al. (1994) described 2 severely retarded brothers, the only children of consanguineous Italian parents, with severe mental retardation, striking and very similar facial features, and other anomalies. The faces were characterized by a broad nasal bridge, bulbous nose, upward slanting palpebral fissures, microretrognathia, low anterior hairline, and large ears with an incompletely developed upper helix. In addition, both brothers had type II hypospadias, limb contractures, and delayed bone age. Pictures of the patients as infants and as young adults were presented. One brother had a bilateral cleft lip with cleft palate and cryptorchidism, and developed scoliosis during adolescence. The other had bilateral inguinal hernias and strabismus.

Emphysema, congenital, with deafness, penoscrotal web, and mental retardation

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Lynch and Bushby (1997) reported an 8-year-old boy with obesity, mental retardation, downslanting palpebral fissures, large ears, sensorineural deafness, cryptorchidism, and a penoscrotal web. He had congenital emphysema, and the upper lobe of his left lung was removed. He was born to healthy, unrelated parents and had a normal karyotype. Lynch and Bushby (1997) excluded Prader-Willi syndrome (176270). They suggested that this association may be a previously unreported syndrome of multiple congenital abnormalities.
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Mental retardation, autosomal recessive 42

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-42 (MRT42) is caused by homozygous mutation in the PGAP1 gene (611655) on chromosome 2q33. One such family has been reported.Murakami et al. (2014) reported a highly consanguineous Syrian family (MR079) in which 2 sibs had intellectual disability. The children were 4 and almost 3 years of age at the time of the report. Both had neonatal hypotonia and severely delayed psychomotor development (IQ below 35) with some stereotypic movements. One had both major and absence epilepsy. Brain CT scan of 1 patient showed pronounced brain atrophy. Other features included large ears and flattened nasal root.

Molecular genetics

In 2 sibs, born of consanguineous Syrian parents, with MRT42, Murakami et al. (2014) identified a homozygous mutation in the PGAP1 gene (611655.0002). The mutation, which was found by autozygosity mapping and exome sequencing, segregated with the disorder in the family. Lymphoblastoid cells derived from the patients showed normal expression of glycosylphosphatidylinositol (GPI)-anchored proteins, but these proteins were resistant to cleavage by PI-specific phospholipase C. These results indicated abnormal GPI structure due to a loss of PGAP1 enzyme activity early in the remodeling process of GPI-anchored proteins. Expression of the mutation in CHO cells resulted in loss of PI-specific phospholipase C sensitivity, which could be rescued by expression of wildtype PGAP1. Western blot analysis did not detect the mutant protein, indicating that it is unstable.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Ears]; Large ears; [Nose]; Flattened nasal root

MUSCLE, SOFT TISSUE: Neonatal hypotonia

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Seizures (1 patient); Cerebral atrophy; [Behavioral/psychiatric manifestations]; Stereotypic movements

MISCELLANEOUS: One highly consanguineous family has been reported (last curated May 2014)

MOLECULAR BASIS: Caused by mutation in the post-GPI attachment to proteins 1 gene (PGAP1, 611655.0002)
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Abruzzo-erickson syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: tbx22

Clinical features

A number sign (#) is used with this entry because of evidence that Abruzzo-Erickson syndrome (ABERS) is caused by mutation in the TBX22 gene (300307) on chromosome Xq21. One such family has been reported.Abruzzo and Erickson (1977) reported an apparently 'new' syndrome of cleft palate, coloboma, hypospadias, deafness, short stature, and radial synostosis expressed variably in 2 brothers, their mother, and a maternal uncle. Davenport et al. (1986) and Metlay et al. (1987) cited this family as a familial instance of CHARGE syndrome (214800). Abruzzo and Erickson (1989) provided follow-up on the 2 brothers of the family who were children at the time of the first report. Like their mother and maternal uncle, neither had choanal atresia. Both had coronal hypospadias but genital development was otherwise normal. The ears were large and protruding, and hearing impairment required a hearing aid. Wide spacing between the second and third fingers as well as unilateral or bilateral radioulnar synostosis was noted in several members of the family. Mental retardation was not present. The manifestations in the mother, who according to the proposed inheritance as an X-linked disorder would be heterozygous, consisted of large ears and flat malar configuration like her sons and brother and wide spacing between the second and third digits as well as unusual rugosity of the palate. The brothers were below the 5th percentile for height at age 19 and 16, respectively.

Molecular genetics

In the family with an X-linked CHARGE-like syndrome that was originally reported by Abruzzo and Erickson (1977), Pauws et al. (2013) analyzed the candidate gene TBX22 and identified an intronic sequence variant (300307.0011) that segregated with the disease and was not found in the dbSNP database or in 539 control chromosomes. Mutations in TBX22 were also identified in patients with classic X-linked cleft palate phenotypes (CPX; 303400).

Symptoms

HEENT: Cleft palate; Coloboma; Large ears; Protruding ears; Deafness; Flat malar configuration; Palatal rugosity

GU: Hypospadias

Growth: Short stature

Limbs: Radioulnar synostosis; Wide-spaced second and third fingers

Inheritance: X-linked
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Abruzzo–Erickson syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: tbx22
Some characteristics of Abruzzo–Erickson syndrome include deafness, protruding ears, coloboma, a cleft palate or palatal rugosity, and short stature. It was characterized in 1977.

See also

CHARGE syndrome

Mental retardation, autosomal recessive 48

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-48 (MRT48) is caused by homozygous mutation in the SLC6A17 gene (610299) on chromosome 1p13.Iqbal et al. (2015) reported 3 adult sisters, all in their sixties, with severe mental retardation and very poor speech limited to 3-word sentences. All had delayed psychomotor development from birth, but there were no available records of the timing of childhood milestones. Their behavior was characterized by mood instability, aggression, and self-mutilation. Between 40 and 50 years, all developed a progressive essential hand tremor that was not present in their healthy sibs, and all had a waddling gait. Cerebral imaging performed in 1 patient was normal. Mild dysmorphic features included large ears, prominent chin, narrow palpebral fissures, long philtrum, and high, narrow palate. Two sibs from a consanguineous Iranian family had a similar disorder: they had severe mental retardation with no speech development, and onset of progressive hand tremor in the teenage years. They were unable to walk or care for themselves, and showed aggression and poor impulse control. Facial features included large ears, prominent chin, thick eyebrows, and slightly narrow palpebral fissures.

Inheritance

The transmission pattern in the Iranian family with MRT48 reported by Iqbal et al. (2015) was consistent with autosomal recessive inheritance.

Molecular genetics

In 5 affected individuals from 2 unrelated families with MRT48, Iqbal et al. (2015) identified 2 different homozygous missense mutations in the SLC6A17 gene (G162R, 610299.0001 and P633R, 610299.0002). The mutations were found by a combination of homozygosity mapping and exome sequencing. In vitro functional expression studies in mouse embryonic primary hippocampal cells showed that both mutant proteins altered the localization of the protein and/or morphology of the cell compared to wildtype.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Face]; Prominent chin; Long philtrum; [Ears]; Large ears; [Eyes]; Narrow palpebral fissures

SKELETAL: [Hands]; Small hands (family A)

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, severe; Poor or absent speech; Waddling gait (family A); Inability to walk (family B); Essential tremor, progressive; [Behavioral/psychiatric manifestations]; Aggression; Poor impulse control; Self-mutilation; Mood instability

MISCELLANEOUS: Two unrelated families have been reported (last curated March 2015)

MOLECULAR BASIS: Caused by mutation in the solute carrier family 6 (neurotransmitter transporter), member 17 gene (SLC6A16, 610299.0001)
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Hall-Riggs syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

Hall-Riggs syndrome is a very rare syndrome consisting of microcephaly with facial dysmorphism, spondylometaepiphyseal dysplasia and severe intellectual deficit. Eight cases have been reported in the literature in two unrelated families. Dysmorphic features include hypertelorism, depressed nasal bridge, large nose with a large nasal tip, anteverted nostrils and wide mouth with thick lips. Affected patients do not achieve language ability. The condition is probably hereditary, and transmitted as an autosomal recessive trait. Last update: January 2010
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Hall-riggs mental retardation syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Hall and Riggs (1975) reported a family in which 6 of 15 offspring of first-cousin unaffected parents had a characteristic syndrome consisting of severe mental retardation, microcephaly, depressed nasal bridge with anteverted nostrils, large lips, and progressive abnormalities of the bony skeleton. They had unexplained episodes of vomiting in infancy. None of the 6 developed speech even as adults. Scoliosis, flat femoral heads and short femoral necks, relatively short proximal segments of the arms, retarded growth, and flat epiphyses in the fingers and at the ankle were skeletal features. Cataracts, corneal clouding, visceromegaly, joint contractures, and lumbar gibbus were notable for their absence.

Silengo and Rigardetto (2000) reported a second family with Hall-Riggs syndrome. The male and female sibs presented with short stature, microcephaly, hypertelorism, a flat nasal bridge, large nose with a large tip and anteverted nostrils, a wide mouth with thick lips, and severe mental retardation. Radiographs showed mild spondylometaphyseal dysplasia with some epiphyseal involvement. Both children also had cysts in the septum pellucidum and a cavum vergae on MRI scan, and abnormal EEGs.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Other]; Intrauterine growth retardation; Failure to thrive

HEAD AND NECK: [Head]; Microcephaly; [Eyes]; Hypertelorism; Epicanthal folds; [Nose]; Flat nasal bridge; Large nose with large nasal tip; Anteverted nostrils; [Mouth]; Wide, carp-shaped mouth; Thick lips; [Teeth]; Small deciduous teeth; Enamel hypoplasia

ABDOMEN: [Gastrointestinal]; Feeding problems

SKELETAL: Osteoporosis; Delayed bone age; [Spine]; Scoliosis; Kyphosis; Irregular end plates; Platyspondyly; [Limbs]; Mild metaphyseal dysplasia; Epiphyseal hypoplasia; [Hands]; Mild brachydactyly

NEUROLOGIC: [Central nervous system]; Mental retardation; Seizures; Septum pellucidum cyst; Large cavum vergae; Absent speech

VOICE: Absent speech
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Camptodactyly syndrome, guadalajara, type ii

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Cantu et al. (1981, 1985) reported a second Guadalajara camptodactyly syndrome; see 211910 for a description of type I. Two sisters, aged 6 and 3 years, presented the same intrauterine growth retardation-malformation syndrome characterized by low-birth-weight dwarfism and a variety of dysmorphic features including camptodactyly of all fingers, bilateral hallux valgus, short toes 2, 4 and 5, patella hypoplasia, short neck, low-set ears, microcephaly, cuboid vertebral bodies, and others.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature; [Other]; Intrauterine retardation

HEAD AND NECK: [Head]; Microcephaly; [Face]; Micrognathia; Long philtrum; [Ears]; Large ears; Low-set ears; [Eyes]; Hypotelorism; [Neck]; Short neck

CHEST: [External features]; Wide-spaced nipples; [Ribs, sternum, clavicles, and scapulae]; Pectus excavatum

GENITOURINARY: [External genitalia, female]; Labial hypoplasia

SKELETAL: Osteopenia; [Spine]; Cuboid vertebral bodies [Pelvis]; Pelvis hypoplasia; [Limbs]; Patellar hypoplasia; Slender long bones; [Hands]; Simian creases; Camptodactyly, all fingers; Second phalanx hypoplasia; [Feet]; Hallux valgus; Brachydactyly, toes 2,4, and 5; Talipes equinovarus

MUSCLE, SOFT TISSUE: Gluteal hypoplasia
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Histidinuria due to a renal tubular defect

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Sabater et al. (1976) described 2 brothers, aged 9 and 11 years, with mild mental retardation and histidinuria despite normal blood levels. Histidine loading showed impaired intestinal absorption. The inheritance is presumably autosomal recessive because both parents showed intermediate intestinal absorption. Holmgren et al. (1974) had reported 1 patient with renal histidinuria associated with myoclonic seizures. Kamoun et al. (1981) likewise reported 1 patient with associated histidinuria and myoclonic seizures. Nyhan and Hilton (1992) described a 7-year-old boy with histidinuria without histidinemia. Low concentrations of histidine in plasma were consistent with impaired intestinal and renal tubular absorption of histidine. The patient was developmentally delayed and had some minor anomalies: bilateral nerve deafness of moderate severity; protuberant large and somewhat simple oracles; very short thick fingers and toes with hypoplasia of the toenails; and broad nasal bridge with long shallow philtrum and thin upper lip. Roentgenograms showed that the shortness of the 5th digit resulted from a short rounded middle phalanx that was abnormal in shape. All 5 patients who have been reported have been male.

Symptoms

Neuro: Mental retardation; Myoclonic seizures

GI: Impaired histidine intestinal absorption

GU: Impaired histidine renal tubular absorption

HEENT: Nerve deafness; Protuberant ears; Broad nasal bridge; Long shallow philtrum; Thin upper lip; Large ears; Simple auricles

Limbs: Short thick fingers; Short thick toes; Hypoplastic toenails

Radiology: Short, rounded, abnormal-shaped middle phalanges

Lab: Histidinuria

Inheritance: Autosomal recessive
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Mental retardation, x-linked 101

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-101 (MRX101) is caused by mutation in the MID2 gene (300204) on chromosome Xq22. One such family has been reported.Geetha et al. (2014) reported a large family from northern India in which 11 males spanning 3 generations had mental retardation. All 6 patients evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had long face, prominent ears, and squint or strabismus. Two had seizures. Most also had hyperactivity, often with aggressive outbursts.

Inheritance

The transmission pattern in the family with MRX101 reported by Geetha et al. (2014) was consistent with X-linked recessive inheritance.

Molecular genetics

In affected members of a family with MRX101, Geetha et al. (2014) identified a hemizygous missense mutation in the MID2 gene (R347Q; 300204.0001). The mutation was found using a combination of linkage analysis and targeted next-generation sequencing. Carrier females in the family were unaffected. Transfection of the mutation in HEK293T cells showed abnormal localization of the mutant protein, which was found in aggregate form or enclosed in vesicles in the cytoplasm rather than being bound to microtubules. By direct sequencing of the coding exons of the MID2 gene among 480 patients with intellectual disability, Geetha et al. (2014) identified an individual with a missense mutation (N343S); however, functional assays indicated that this mutation may not be disease causing.

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Face]; Long face (in some patients); [Ears]; Large ears (in some patients); [Eyes]; Squint; Strabismus

NEUROLOGIC: [Central nervous system]; Global developmental delay; Impaired cognition; Mental retardation; Poor speech; Lack of speech; Seizures (in some patients); [Behavioral/psychiatric manifestations]; Hyperactivity; Aggressive outbursts

MISCELLANEOUS: Onset at birth; One family from Punjab, India has been reported (last curated August 2014)

MOLECULAR BASIS: Caused by mutation in the midline 2 gene (MID2, 300204.0001)
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Iridogoniodysgenesis and skeletal anomalies

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Garcia-Cruz et al. (1990) reported 3 sisters, born of nonconsanguineous parents, with congenital glaucoma, distinctive facies (large eyes, wide forehead, thin nasal bridge, and broad nose with large tip), large ears, short neck, wide thorax, umbilicated nipples, cubitus valgus, and short big toes. Radiologic examination revealed mild skeletal anomalies characterized by slender long bones with wide metaphyses and thin cortices, cuboid-shaped vertebral bodies, enlarged transverse apophysis of the seventh vertebral body, narrowed vertebral canal and decreased interpedicular distance at the lumbar segments, and generalized osteopenia. Ophthalmologic examination was suggestive of iridogoniodysgenesis, but presurgical gonioscopic data were not available. There was no family history of glaucoma or any other ophthalmologic disorder. Garcia-Cruz et al. (1990) suggested that the disorder represented a newly recognized congenital glaucoma syndrome with possible autosomal recessive inheritance.

Rodriguez-Rojas et al. (2004) described a sister and 2 brothers with congenital glaucoma, skeletal anomalies, and a peculiar facial appearance whose clinical and radiologic features were identical to those of the 3 sisters reported by Garcia-Cruz et al. (1990), except for the absence of large ears and cubitus valgus, and the presence of undeveloped frontal sinuses. Ophthalmologic examination in the proposita revealed megalocornea, wide anterior chambers, concave iris with stromal atrophy, and nasal corectopia in both eyes with no evidence of posterior embryotoxon, associated with congenital glaucoma. Radiologic and ophthalmologic examination including gonioscopy in the healthy, nonconsanguineous parents and 2 unaffected sibs were normal. There was no family history of glaucoma or other ophthalmologic anomalies. Rodriguez-Rojas et al. (2004) concluded that these 2 families had a distinct iridogoniodysgenesis syndrome with probable autosomal recessive inheritance.

Microcephaly, cerebellar hypoplasia, and cardiac conduction defect syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

The Zaki-Gleeson syndrome is an autosomal recessive neurodevelopmental disorder characterized by profound mental retardation, severe microcephaly, poor growth, cerebellar hypoplasia, and second-degree cardiac conduction defects (summary by Zaki et al., 2011).

Clinical features

Zaki et al. (2011) reported a consanguineous Egyptian family in which 3 sibs and a first cousin had a syndromic disorder apparent at birth and characterized by profound mental retardation, severe microcephaly (-8 to -11 SD), poor growth, dysmorphic facial features, cerebellar hypoplasia, and second-degree atrioventricular heart block. All showed severe psychomotor retardation, with no speech, sitting only with support, inability to grasp objects or feed themselves, and lack of sphincter control. They were hypotonic with brisk reflexes, truncal ataxia, intention tremor, and dystonic movements. The 3 older children showed autistic behavior. Dysmorphic facial features included broad forehead, thin long eyebrows, upslanting palpebral fissures, prominent nose, long philtrum, thin vermilion of the upper lip, prominent lower lip, and large ears with prominent antihelix. Hands and feet showed long fusiform fingers with bilateral campto- and clinodactyly of fifth fingers and crowded toes. Physical examination showed bradycardia and second-degree cardiac conduction defects, as well as vasomotor instability with prolonged capillary refill, skin mottling, and acrocyanosis. Brain imaging showed cerebellar hypoplasia, thin corpus callo...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Other]; Failure to thrive; Poor growth

HEAD AND NECK: [Head]; Microcephaly, progressive, severe (-8 to -11 SD); [Face]; Broad forehead; Long philtrum; [Ears]; Large ears; Prominent antihelix; [Eyes]; Thin, long eyebrows; [Nose]; Prominent nose; [Mouth]; Thin vermilion of the upper lip; Prominent lower lip

CARDIOVASCULAR: [Heart]; Bradycardia; Second degree atrioventricular heart block; [Vascular]; Vasomotor instability

SKELETAL: [Hands]; Long tapered fingers; Fifth finger clinodactyly; Fifth finger camptodactyly; [Feet]; Crowded toes

SKIN, NAILS, HAIR: [Skin]; Skin mottling due to poor perfusion; Prolonged capillary refill; Acrocyanosis; [Hair]; Thin, long eyebrows

NEUROLOGIC: [Central nervous system]; Mental retardation, profound; Hypotonia; Hyperreflexia; Dystonia; Intention tremor; Truncal ataxia; Lack of independent ambulation; Unable to grasp objects; Absent speech; Simplified gyral pattern; Cerebellar hypoplasia; Thin corpus callosum; White matter abnormalities; [Behavioral/psychiatric manifestations]; Autistic features

ENDOCRINE FEATURES: Diabetes mellitus, insulin-dependent (1 patient); Impaired glucose tolerance

MISCELLANEOUS: One consanguineous Egyptian family with 4 affected individuals has been reported (as of December 2011)
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Mental retardation, autosomal recessive 39

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: tti2

Clinical features

A number sign (#) is used with this entry because autosomal recessive mental retardation-39 (MRT39) is caused by homozygous mutation in the TTI2 gene (614426) on chromosome 8p12.Langouet et al. (2013) reported 3 sibs, born of consanguineous Algerian parents, with mental retardation and behavioral problems. All had a normal neonatal period, but showed delayed psychomotor development and severe speech delay. Examination at ages 30 to 36 years revealed microcephaly (-3 to -4 SD), short stature, kyphoscoliosis, and dysmorphic facial features, including sloping forehead, deep-set eyes, synophrys, prominent nose, anteverted large ears, and dental anomalies. Behavioral abnormalities included hyperactivity, aggression, and stereotypic movements. Seizures were not reported. Laboratory analysis showed mild lymphopenia of naive T cells, but increased susceptibility to infection was not reported.

Inheritance

The transmission pattern in the family with mental retardation reported by Langouet et al. (2013) was consistent with autosomal recessive inheritance.

Molecular genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M100, they identified homozygosity for a missense mutation in the TTI2 gene (P367L; 614426.0001) in 4 sibs with moderate nonsyndromic mental retardation. The parents were first cousins and had 4 healthy children.

In 3 sibs, born of consanguineous Algerian parents, with mental retardation and dysmorphic features, Langouet et al. (2013) identified a homozygous missense mutation in the TTI2 gene (I436N; 614426.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed almost undetectable levels of mutant TTI2 compared to controls, although mRNA levels wer...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Microcephaly (-3 to -4 SD); [Face]; Sloping forehead; [Ears]; Anteverted ears; Large ears; [Eyes]; Deep-set eyes; Strabismus; Synophrys; [Nose]; Prominent nose; [Teeth]; Malposition of the teeth

SKELETAL: [Spine]; Kyphoscoliosis

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Speech delay, severe; [Behavioral/psychiatric manifestations]; Hyperactivity; Aggression; Stereotyped behavior

IMMUNOLOGY: Decreased circulating naive T cells (1 family)

MISCELLANEOUS: Onset in infancy; Dysmorphic facial features reported in 1 family; Two unrelated families have been reported (last curated November 2013)

MOLECULAR BASIS: Caused by mutation in the TELO2-interacting protein 2 gene (TTI2, 614426.0001)

Digitorenocerebral syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: tbc1d24

DOOR syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: tbc1d24
DOOR (Deafness, Onychdystrophy, Osteodystrophy, and Mental Retardation) Syndrome is a genetic disease which is inherited in an autosomal recessive fashion. DOOR syndrome is characterized by mental retardation, sensorineural deafness, abnormal nails and phalanges of the hands and feet, and variable seizures. A similar deafness-onychodystrophy syndrome is transmitted as an autosomal dominant trait and has no mental retardation. Some authors have proposed that it may be the same as Eronen Syndrome, but since both disorders are extremely rare it is hard to make a determination.

Symptoms

Not all of the DOOR symptoms are consistently present. They can vary in severity, and additional features can be noted in individuals affected by DOOR syndrome. Some of these additional features are: Polyhydramnios (increased amniotic fluid during pregnancy) and increased nuchal fold during pregnancy Specific facial features such as a large nose Severe and sometimes refractory seizures, abnormalities on the magnetic resonance imaging of the brain Increased 2-oxoglutaric acid in the blood and urine - this compound is made or used by several enzymes Finger-like thumbs Visual impairment Peripheral neuropathy (nerves conducting sensation from extremities to the brain) and insensivity to pain Intellectual impairment is present in all reported cases, but the severity can vary widely. The prognosis in terms of survival also varies greatly from early childhood till adulthood.

Etiology

The recurrence of DOOR in siblings and the finding of DOOR syndrome in a few families with consanguinity suggest that the condition is an autosomal recessive genetic condition. Mutations in TBC1D24 have been identified in 9 families.

References

DOOR Syndrome Website

Deafness onychodystrophy osteodystrophy and mental retardation syndrome

Retrieved: 27-07-2015
Source: GARD (Original article)
Associated genes: tbc1d24

Deafness onychodystrophy osteodystrophy and mental retardation syndrome

Deafness onychodystrophy osteodystrophy and mental retardation (DOOR) syndrome is a rare genetic disorder that is usually recognized shortly after birth. The term DOOR is an acronym with each letter representing a common feature in affected individuals: (D)eafness due to a defect of the inner ear or auditory nerve; (O)nychodystrophy or malformation of the nails; (O)steodystrophy, meaning malformation of certain bones; and mild to profound mental (R)etardation, which is now referred to as intellectual disability. In some cases, individuals may also experience seizures. This condition is inherited in an autosomal recessive fashion; the exact genetic cause is unknown

Microcephaly, severe, with skeletal anomalies including posterior rib-gap defects

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Duval et al. (1998) described a possibly 'new' autosomal recessive syndrome in 2 female fetuses conceived by a nonconsanguineous couple. The pregnancies were interrupted at 31 and 26 weeks of gestation, respectively, because of severe microcephaly. Postmortem x-ray and autopsy studies showed in both fetuses: (1) severe intrauterine growth retardation; (2) facial anomalies characterized by severe microcephaly, sloping forehead, low-set and posteriorly angulated ears, prominent eyes, downslanting palpebral fissures, large nose, small mouth with full lips, and mild microretrognathia; (3) severe brain hypoplasia that was more pronounced in the second fetus; (4) severe rib hypoplasia with posterior rib-gap defects and, in case 2, hypoplasia of several bones (right clavicle, right radius and ulna, several phalanges of hands and feet); and (5) contracture at large joints. No other visceral malformations were observed, and chromosomes were normal in patient 2 and in the parents.
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Mcdonough syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Neuhauser and Opitz (1975) described a family with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome consisting of mental retardation, peculiar facies, kyphoscoliosis, diastasis recti, cryptorchidism, and congenital heart defect. They called it McDonough syndrome. Three of 5 sibs were affected, leading to a suggestion of autosomal recessive inheritance. The authors considered it coincidental that the youngest affected sib had a chromosomal complement 47,XXY and the father was a mosaic 46,XY/47,XXY. Garcia-Sagredo et al. (1984) reported a second family in which 2 of 3 sibs (a girl and a boy) were affected. It was considered coincidental that the affected boy and the unaffected mother had a balanced X;20 translocation. The father had ptosis, which was also considered coincidental.

Symptoms

Neuro: Mental retardation

HEENT: Peculiar facies; Synophrys; Strabismus; Upslanted palpebral fissures; Hypertelorism; Ptosis; Large nose; Short philtrum; Grooved tongue; Prognathism; Micrognathia; Malocclusion; Anteverted auricles

Skin: Sparse hair; Bristly hair

Growth: Short stature

Skel: Kyphoscoliosis; Pectus carinatum; Pectus excavatum

Limbs: Single transverse palmar crease; Hypoplastic toenails; Clinodactyly

Abdomen: Diastasis recti

GU: Cryptorchidism

Cardiac: Congenital heart defect; Atrial septal defect; Ventricular septal defect; Pulmonic stenosis; Aortic stenosis

Inheritance: Autosomal recessive
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McDonough syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

McDonough syndrome belongs to the group of multiple congenital anomalies/mental retardation (MCA/MR) syndromes and is characterised by intellectual deficit, distinctive facies (upward slanting palpebral fissures, squint), kyphoscoliosis, diastasis recti, cryptorchidism, and a congenital heart defect. Two families have been reported. Autosomal recessive inheritance was suggested. Last update: October 2006
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Microhydranencephaly

Retrieved: 27-07-2015
Source: GARD (Original article)
Associated genes: cyp11b2, mhac, nde1

Microhydranencephaly

Microhydranencephaly (MHAC) is a severe abnormality of brain development characterized by both microcephaly and hydranencephaly. Signs and symptoms may include severe microcephaly, scalp rugae (a series of ridges), and profound developmental delay. Familial occurrence of the condition is very rare but it has been reported in a few families. It has been suggested that MHAC is possibly inherited in an autosomal recessive manner
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BIDS syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

This disease has been moved to Trichothiodystrophy
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Disorder of sex development - intellectual disability

Retrieved: 27-07-2015
Source: Orphanet (Original article)

Verloes-Gillerot-Fryns syndrome is a rare association of malformations. It has been described in only three patients, including two sibs. The first patient had profound intellectual deficit. His general aspect clearly resembled that of individuals with Borjeson-Forssman-Lehmann syndrome, a rare X-linked recessive disorder. Clinical features included short stature, coarse face, deep set eyes, microphthalmia, large ears, gynoid obesity, imperforate anus, sacral spina bifida, pseudovaginal perineoscrotal hypospadias, persistence of Mullerian structures, and low gonadotrophin levels. His XY sib was raised as a girl. She was slightly mentally impaired and had microphthalmia and large ears, and short stature. She had a complete uterus with tubae and a single intraabdominal gonad with testicular organization at birth. These were removed during infancy. The third patient had severe hearing loss, ocular colobomata, hypogonadism of central origin, distinct craniofacial features resembling those of the Borjeson-Forssman-Lehmann syndrome and skeletal anomalies with cervical spina bifida, hyperkyphosis and thoracic deformity. All patients had a normal 46, XY karyotype. Inheritance could be either autosomal recessive or X-linked. Last update: February 2006
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Macdermot-winter syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

MacDermot and Winter (1989) described a seemingly 'new' syndrome with facial anomalies, microcephaly, hypoplastic genitalia, and failure of psychomotor development. The 2 brothers were from a consanguineous Moslem family. They showed prenatal onset of growth deficiency and had convulsions from birth. Atypical anomalies consisted of a prominent glabella, arched eyebrows, a low upswept frontal hairline, large posteriorly rotated ears with overfolded upper helices, partial camptodactyly, and wide-spaced nipples. Death occurred at 21 days and 7 months, respectively. Postmortem examination showed dilated cerebral ventricles and hydronephrosis.

Symptoms

HEENT: Facial anomalies; Microcephaly; Prominent glabella; Arched eyebrows; Low upswept frontal hairline; Large ears; Posteriorly rotated ears; Folded helix

GU: Hypoplastic genitalia; Hydronephrosis

Growth: Prenatal growth deficiency

Neuro: Psychomotor development failure; Seizures; Dilated cerebral ventricles

Limbs: Partial camptodactyly

Thorax: Wide-spaced nipples

Misc: Death in infancy

Inheritance: Autosomal recessive
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Microcephaly with chemotactic defect and transient hypogammaglobulinemia

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

Say et al. (1986) reported 2 brothers with microcephaly, dysmorphic facies, developmental delay, and hypoglobulinemia. Their facial similarity was striking, with sloping forehead, beaked nose, large and protruding ears, micrognathia, and high-arched palate. One brother had craniosynostosis. Both brothers had hypogonadism, flexion contractures, hypoplastic patellae, and scoliosis. They also showed low levels of serum gammaglobulins in infancy reaching normal levels by 3.5 years and 15 months, respectively. Defective chemotaxis and recurrent infections were present from the beginning and persisted to age of report, age 7 in the older brother. Carpenter et al. (1996) provided a brief follow-up of the patients reported by Say et al. (1986) at ages 18 and 19 years. Both boys had recurrent infections since birth, and they also developed skeletal changes consistent with multiple epiphyseal dysplasia and the autoimmune phenomena of recurrent panniculitis and erythema nodosum. Treatment with gammaglobulin every 3 weeks improved their condition. Linkage analysis showed that the brothers both inherited the same maternal alleles at Xp22.2-p21.2, suggesting X-linked inheritance.

Perandones et al. (1996) reported a 13-year-old boy with severe microcephaly, mental retardation, short stature, and recurrent infections. Dysmorphic features included a sloping forehead, metopic suture synostosis, abnormal hairlines, sparse eyebrows, hypertelorism, upslanting palpebral fissures, prominent nasal bridge, high-arched palate, irregular dental implantation, multiple caries, micrognathia, and low-set, posteriorly rotated ears. He also had flexion contractures of the limbs, ulnar deviation of the fingers with clinodactyly of the fifth fingers, dislocated hips, hypoplastic and displaced patellae, scoliosis, hypogonadism, cryptorchidism, and eczematous skin. Laboratory studies showed defective neutrophil chemotaxis. Perandones et al. (1996) suggested that this patient had the same syndrome as that described by Say et al. (1986).

Carpenter et al. (2000) stated that the 2 brothers reported by Say et al. (1986) developed macular degeneration and pigmented retinal lesions resembling retinitis pigmentosa. Laboratory studies showed normal IgG levels but IgG subclass deficiencies and decreased cellular immunity. Nijmegen syndrome (NBS; 251260), ADA deficiency (102700), cartilage-hair hypoplasia (CHH; 250250), and Lowry-Wood syndrome (226960) were excluded. Carpenter et al. (2000) suggested that their patients had the disorder reported by Roifman (1999) (300258). In a reply, however, Roifman (2000) noted several phenotyp...

Symptoms

HEENT: Microcephaly; Sloping forehead; Beaked nose; Large ears; Protruding ears; Micrognathia

Immunology: Newborn gammaglobulin deficiency; Defective chemotaxis; Recurrent infections

GU: Hypogonadism

Skel: Flexion contractures; Hypoplastic patellae; Scoliosis

Inheritance: Autosomal recessive
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Arterial tortuosity syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Arterial tortuosity syndrome

Clinical features

A number sign (#) is used with this entry because of evidence that the arterial tortuosity syndrome is caused by loss-of-function mutations in the gene encoding glucose transporter GLUT10 (SLC2A10; 606145).From Ankara, Turkey, Ertugrel (1967) described a 10-year-old girl with generalized tortuosity and elongation of all major arteries including the aorta. Telangiectases of the cheeks, high palate, aortic regurgitation and histologic fragmentation of the internal elastic membrane of arteries were noted. Three brothers were well. The parents were also healthy. No comment on consanguinity was made. The same condition may have been present in the boy reported by Beuren et al. (1969). Multiple pulmonary artery stenoses were present. The child reported by Lees et al. (1969) had tortuous systemic arteries and multiple pulmonary artery stenoses, but the skin was considered excessively stretchable, consistent with the Ehlers-Danlos syndrome (EDS; see 130000). The sibs reported by Welch et al. (1971) had features suggesting cutis laxa (219100) with arterial tortuosity of severe degree. The parents were consanguineous. The father and many of his relatives had joint laxity interpreted as the benign hypermobile form of EDS (130020).

Franceschini et al. (2000) described a mal...

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Face]; Long face; Long philtrum; Micrognathia; [Eyes]; Downslanting palpebral fissures; Blepharophimosis; Hypertelorism; Keratoconus (less common); [Nose]; Beaked nose; [Mouth]; High-arched palate

CARDIOVASCULAR: [Heart]; Ventricular hypertrophy; [Vascular]; Arterial tortuosity (large and medium-sized arteries including aorta); Elongated arteries (large and medium-sized arteries including aorta); Arterial aneurysms; Aortic stenosis; Pulmonary artery stenosis; Arterial vessels show fragmentation of the internal elastic membrane; Arterial vessels show disruption of the elastic fibers of the tunica media; Increased risk of thrombosis; Hypertension

CHEST: [External features]; Pectus excavatum; Pectus carinatum; [Diaphragm]; Diaphragmatic hernia; Hiatal hernia; Sliding hernia; Gastric hernia

ABDOMEN: [External features]; Inguinal hernia; Umbilical hernia; [Gastrointestinal]; Diverticulitis; Hiatal hernia; Bowel necrosis due to thrombosis

SKELETAL: Joint laxity; Joint contractures; [Hands]; Arachnodactyly; [Feet]; Archnodactyly

SKIN, NAILS, HAIR: [Skin]; Hyperextensibility of the skin; Soft, doughy skin; No increased bruisability

NEUROLOGIC: [Central nervous system]; Ischemic stroke; Mental retardation (some); Hypotonia (less common)

MISCELLANEOUS: Onset at birth; Increased risk of early death

MOLECULAR BASIS: Caused by mutation in the solute carrier family 2 (facilitated glucose transporter), member 10 gene (SLC2A10, 606145.0001)
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Ogden syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: naa10

Clinical features

A number sign (#) is used with this entry because of evidence that Ogden syndrome (OGDNS) is caused by mutation in the NAA10 gene (300013) on chromosome Xq28.Rope et al. (2011) reported 2 families segregating an X-linked recessive condition characterized by postnatal growth failure with severe delays and dysmorphic features characterized by wrinkled forehead, prominent eyes, widely opened anterior and posterior fontanels, downsloping palpebral fissures, thickened lids, large ears, flared nares, hypoplastic alae, short columella, protruding upper lip, and microretrognathia. There were also delayed closing of fontanels and broad great toes. Skin was characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals, all males. Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Arrhythmias included torsade de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernia, and the majority had unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scol...

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Other]; Postnatal growth failure

HEAD AND NECK: [Face]; Wrinkled forehead; [Ears]; Large ears; [Eyes]; Prominent eyes; Downslanting palpebral fissures; Thick eyelids; Sparse eyebrows; [Nose]; Flared nares; Hypoplastic alae nasai; Short columella; [Mouth]; Protruding upper lip; Microretrognathia

CARDIOVASCULAR: [Heart]; Ventral septal defect (VSD); Atrial septal defect (ASD); Arrhythmias; Torsade de pointes; Premature ventricular contraction (PVC); Premature atrial contraction (PAC); Supraventricular tachycardia (SVtach); Ventricular tachycardia (Vtach); [Vascular]; Pulmonary artery stenosis

GENITOURINARY: [Internal genitalia, male]; Cryptorchidism; Inguinal hernia

SKELETAL: [Skull]; Delayed closure of fontanels; [Spine]; Scoliosis (in some patients); [Feet]; Broad great toes

SKIN, NAILS, HAIR: [Skin]; Cutis laxa; Redundant skin; Wrinkled forehead; Cutaneous capillary malformations; [Hair]; Fine hair (in some patients); Sparse eyebrows

MUSCLE, SOFT TISSUE: Minimal subcutaneous fat

NEUROLOGIC: [Central nervous system]; Hypotonia progressing to hypertonia; Cerebral atrophy

MISCELLANEOUS: Death usually associated with cardiogenic shock preceded by arrhythmia

MOLECULAR BASIS: Caused by mutation in the NatA catalytic subunit N-alpha-acetyltransferase-10 gene (NAA10, 300013.0001)
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Ogden Syndrome

Retrieved: 27-07-2015
Source: WIKIPEDIA (Original article)
Associated genes: naa10
Ogden Syndrome, also known as n-terminal acetyltransferase deficiency (NATD), is an x-linked disorder of infancy comprising a distinct combination of distinctive craniofacial features producing an aged appearance, growth failure, hypotonia, global developmental delays, cryptorchidism, and acquired cardiac arrhythmias. The first family was identified in Ogden, Utah, with five affected boys in two generations of family members. A mutation was identified as a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NatA). This same mutation was identified in a second unrelated family, with three affected boys in two generations. This X-linked Malformation and Infantile Lethality Syndrome has provisionally been named Ogden Syndrome, in honor of the hometown where the first family resides.

History

Ogden Syndrome was discovered in 2011 by a team of researchers led by Gholson J. Lyon, consisting of: Alan F. Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J. Johnston, Jeffrey J. Swensen, W. Evan Johnson, Barry Moore, Chad D. Huff, Lynne M. Bird, John C. Carey, John M. Opitz, Cathy A. Stevens, Tao Jiang, Christa Schank, Heidi Deborah Fain, Reid J. Robison, and 10 others.

Clinical Summary

This is an X-linked condition affecting males and characterized by postnatal growth failure with developmental delays and dysmorphic features characterized by wrinkled forehead, anterior and posterior fontanels, prominent eyes, large down-slanting palpebral fissures, thickened or hooded eyelids, large ears, flared nares, hypoplastic alae nasi, short columella, protruding upper lip, and microretrognathia. There is also delayed closing of fontanelle, and the boys also have broad great toes. Skin is characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals. Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Arrhythmias at the time of death included torsade de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernias, and the majority had, at least, unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to 2 years in all cases and prior to 1 year in the majority. There are extensive clinical details for each child reported in the original publication

Molecular Genetics

A mutation in an enzyme involved in N-terminal acetylation of proteins has thus far been associated with this distinct X-linked phenotype in two families, with 8 males who carried the hypomorphic hNaa10p p.Ser37P...
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Asparagine synthetase deficiency

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: asns

Description

A number sign (#) is used with this entry because of evidence that asparagine synthetase deficiency (ASNSD) is caused by homozygous or compound heterozygous mutation in the ASNS gene (108370) on chromosome 7q21.ASNS deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (summary by Ruzzo et al., 2013).

Clinical features

Ruzzo et al. (2013) reported 9 patients from 4 unrelated families with a similar phenotype characterized by congenital and progressive microcephaly (up to -7 SD), lack of or severely delayed psychomotor development, appendicular hypertonia and hyperreflexia, and decreased cerebral volume. Two families were Iranian Jewish, 1 was Bangladeshi, and 1 was French Canadian. Patients in 3 of the families developed early-onset seizures, including tonic, myoclonic, generalized tonic-clonic, and partial complex seizures associated with multiple independent spike foci or suppression burst patterns on EEG. Three sibs had hypsarrhythmia. Three sibs in the fourth family did not have overt seizures, but showed hyperekplexia and jitteriness with disorganized background activity on EEG. Brain imaging showed decreased cerebral volume with enlarged lateral ventricles. Some patients had cerebellar hypoplasia, pontine hypoplasia, thin corpus callosum, simplified gyral pattern, cortical dysgenesis, and/or delayed myelination. Other more variable features included dysmorphism, such as micrognathia, receding forehead, and large ears, axial hypotonia, and cortical blindness. Most had...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Other]; Failure to thrive

HEAD AND NECK: [Head]; Microcephaly, progressive (up to -7 SD); [Face]; Receding forehead; Micrognathia; [Ears]; Large ears; [Eyes]; Cortical blindness

RESPIRATORY: Respiratory insufficiency

ABDOMEN: [Gastrointestinal]; Poor feeding

SKELETAL: [Hands]; Large hands; [Feet]; Large feet

NEUROLOGIC: [Central nervous system]; Encephalopathy, progressive; Delayed psychomotor development, profound; Axial hypotonia; Appendicular hypertonia; Spastic tetraplegia; Hyperreflexia; Seizures; Jitteriness; Hyperekplexia; Burst suppression pattern seen on EEG; Multiple independent spike foci; Hypsarrhythmia; Brain imaging shows cortical atrophy; Enlarged ventricles; Pontine hypoplasia; Cerebellar hypoplasia; Thin corpus callosum; Delayed myelination; Cortical dysplasia; Simplified gyral pattern

LABORATORY ABNORMALITIES: Decreased asparagine levels (in some patients)

MISCELLANEOUS: Onset in utero or at birth; Progressive disorder; Death usually in infancy

MOLECULAR BASIS: Caused by mutation in the asparagine synthetase gene (ASNS, 108370.0001)

Peroxisomal fatty acyl-coa reductase 1 disorder

Retrieved: 27-07-2015
Source: OMIM (Original article)

Description

A number sign (#) is used with this entry because of evidence that peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is caused by homozygous or compound heterozygous mutation in the FAR1 gene (616107) on chromosome 11p15.Peroxisomal fatty acyl-CoA reductase-1 disorder is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, 215100), although the characteristic skeletal abnormalities observed in RCDP are absent (summary by Buchert et al., 2014).

Clinical features

Buchert et al. (2014) reported 3 patients from 2 families with a severe disorder comprising intellectual disability, growth retardation, and early-onset epilepsy. Two sibs, born of consanguineous Syrian parents, showed neonatal hypotonia, delayed psychomotor development, and onset of well-controlled seizures around age 13 months. At ages 5 and 3 years, both had significant microcephaly (-6.6 and -8.7 SD, respectively) and were small for their age. One sib had bilateral cataracts, developed spasticity of the upper and lower extremities, and showed a Dandy-Walker variant on brain imaging. One sib was reported to have mild dysmorphic facial features, including long philtrum, high-arched eyebrows, large ears, and flattened nasal root. The third patient, born of unrelated parents, had a complex medical and neurodevelopmental history. In infancy, he showed significant growth delay with microcephaly (-4 to -5 SD), nuclear cataracts, and generalized and complex seizures that were difficult to control. Dysmorphic facial features included hypertelorism, short nose, long and smooth philtrum, high-arched eyebrows, and thin upper lip. He later developed progressive spastic quadriparesis with contractures, had symmetric short stature, and never achieved inde...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Other]; Growth retardation

HEAD AND NECK: [Head]; Microcephaly; [Face]; Dysmorphic facial features, mild; Coarse facies; Long philtrum; [Ears]; Large ears; [Eyes]; Cataracts; High-arched eyebrows; [Nose]; Flattened nasal root; [Mouth]; Thin upper lip

MUSCLE, SOFT TISSUE: Hypotonia

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development, severe; Mental retardation; Spasticity; Seizures; Cerebellar atrophy (1 patient); Cerebral white matter lesions (1 patient)

LABORATORY ABNORMALITIES: Decreased plasmalogen

MISCELLANEOUS: Onset in early infancy; Three patients from 2 families have been reported (last curated December 2014)

MOLECULAR BASIS: Caused by mutation in the fatty acyl CoA reductase 1 gene (FAR1, 616107.0001)
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Genitopatellar syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: kat6b, lmx1b

This syndrome is characterized by the association of absent patellae, genital anomalies, dysmorphic features (coarse face, large nose, microcephaly), renal anomalies (multicystic kidneys or hydronephrosis), and intellectual deficit. It has been described in seven children (six boys and one girl) from five unrelated families. Constant skeletal manifestations include flexion deformities of the knees and hips, club feet, and absent patellae. Boys present with scrotal hypoplasia and cryptorchidism. This condition is transmitted as an autosomal recessive syndrome. Prenatal ultrasound detection of microcephaly and renal anomalies is feasible. Prognosis is poor. Last update: December 2006
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Momo syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Momo syndrome

Clinical features

In 2 unrelated patients, a boy and a girl, Moretti-Ferreira et al. (1993) described an overgrowth syndrome characterized by macrocrania, obesity, ocular abnormalities (retinal coloboma and nystagmus), downward slant of the palpebral fissures, mental retardation, and delayed bone maturation. The parents were not consanguineous. The authors suggested that this syndrome is caused by a de novo autosomal mutation.

Zannolli et al. (2000) described a possible case of MOMO syndrome in a 5-year-old girl with mild mental retardation, macrocephaly, high and broad forehead with frontal bossing, hypertelorism, right optic disc coloboma, left choroidal coloboma, a large nose with broad nasal root, thick upper and lower lips, a high palate, dental malocclusion, short neck, severe obesity, slightly delayed bone maturation, short stature, and recurvation of the femur. Zannolli et al. (2000) suggested that tall stature, which was a feature in the patients reported by Moretti-Ferreira et al. (1993), may not be a diagnostic criterion for the disorder.

Giunco et al. (2008) described a 29-year-old man with macrosomia, obesity, macrocephaly, ocular anomalies (downslanting palpebral fissures, microphthalmia, nystagmus, convergent strabismus, hypertelorism), short neck, large nose with broad nasal root, macroglossia, high palate, large hands and feet, psychomotor delay, epileptic seizures since age 11 months, and the classic features of autism (see 209850). Giunco et al. (2008) suggested that this was the fourth reported case of MOMO syndrome and the first associated with autism.

Wallerstein and Sugalski (2010) described what they considered to be the fourth reported case of MOMO syndrome in a 6-year-old boy with macrosomia, obesity, macrocephaly, ocular anomalies (retinochoroidal coloboma, microphthalmia), cognitive delay, tactile defensiveness, and acute sensitivity to noise.

Symptoms

INHERITANCE: Autosomal dominant

GROWTH: [Height]; Height >90th percentile; [Weight]; Obesity; [Other]; Overgrowth

HEAD AND NECK: [Head]; Macrocephaly; Brachycephaly; [Face]; High, broad forehead; Frontal bossing; Long, smooth philtrum; [Ears]; Simplified helices; [Eyes]; Retinal coloboma; Nystagmus; Downslanting palpebral fissures; Glaucoma; Hypertelorism; Blindness; Epicanthal folds; Strabismus; Eyelid coloboma; [Nose]; Broad nasal root; [Mouth]; Thick lips; High-arched palate; [Teeth]; Dental malocclusion; Taurodontia; Delayed dental eruption; [Neck]; Short neck

CHEST: [Ribs, sternum, clavicles, and scapulae]; Short sternum

SKELETAL: Delayed bone age; [Skull]; Macrocrania; [Hands]; Large hands; [Feet]; Large feet

SKIN, NAILS, HAIR: [Skin]; Cutis marmorata; [Nails]; Hyperconvex nails

NEUROLOGIC: [Central nervous system]; Mental retardation

MISCELLANEOUS: MOMO is an acronym - Macrosomia, Obesity, Macrocrania, Ocular abnormalities
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Ohdo syndrome, x-linked

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: opa1

Clinical features

A number sign (#) is used with this entry because X-linked Ohdo syndrome is caused by mutation in the MED12 gene (300188) on chromosome Xq13.Maat-Kievit et al. (1993) described a boy (patient 2) with low weight, blepharophimosis, ptosis, wide depressed nasal bridge, long flat philtrum, thin vermilion, microstomia, micrognathia, cryptorchidism, scrotum hypoplasia, joint hyperextensibility, clinodactyly, overriding third toes, cafe-au-lait spots, developmental delay, deafness, and feeding problems. The authors diagnosed the patient with Ohdo blepharophimosis syndrome.

Verloes et al. (2006) reported the 9-month-old maternal nephew of the patient reported by Maat-Kievit et al. (1993), who had died at age 25 years of metastatic carcinoma. The nephew had a similar phenotype. Verloes et al. (2006) classified the disorder in these patients as a distinct blepharophimosis-mental retardation syndrome, MKB (Maat-Kievit-Brunner) type, and suggested X-linked inheritance. They noted that whereas the MKB phenotype in infancy resembled that of the SBBYS variant of Ohdo syndrome (603736), the phenotype in adulthood was clearly distinct, with coarse facial features, thick alae nasi, triangular face, and a different gestalt from that in the SBBYS type.

Molecular genetics

Vulto-van Silfhout et al. (2013) performed exome sequencing in 2 families segregating X-linked Ohdo syndrome, including the family originally studied by Maat-Kievit et al. (1993) and another family with 2 affected males, and identified hemizygous missense mutations in the MED12 gene (300188.0003-300188.0004) that segregated with the disorder in each family. By analysis of an additional cohort of 9 simplex male patients with Ohdo syndrome, they identified another MED12 missense mutation (300188.0005) in 1 patient.

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Weight]; Low weight

HEAD AND NECK: [Face]; Coarse facial features; [Ears]; Deafness; [Eyes]; Blepharophimosis; Ptosis; [Nose]; Wide nasal bridge; Depressed nasal bridge; Large nose; Bulbous nose; [Mouth]; Long philtrum; Flat philtrum; Thin vermillion; Microstomia; Micrognathia

ABDOMEN: [Gastrointestinal]; Feeding problems

GENITOURINARY: [Internal genitalia, male]; Cryptorchidism; Scrotal hypoplasia

SKELETAL: [Limbs]; Joint hyperextensibility; [Hands]; Clinodactyly; [Feet]; Overriding 3rd toes

SKIN, NAILS, HAIR: [Skin]; Cafe-au-lait spots

NEUROLOGIC: [Central nervous system]; Developmental delay; Mental retardation

MOLECULAR BASIS: Caused by mutation in the homolog of the S. cerevisiae mediator of RNA polymerase II transcription, subunit 12 (MED12, 300188.0003)
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Borjeson-forssman-lehmann syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: phf6, fgf2

Clinical features

A number sign (#) is used with this entry because Borjeson-Forssman-Lehmann syndrome is caused by mutation in the PHF6 gene (300414).The features of this syndrome, described in a single kindred by Borjeson et al. (1962), are severe mental defect, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, and large but not deformed ears. Three females who might be carriers had moderate mental retardation. Brun et al. (1974) extended the observations of Borjeson et al. (1962). Baar and Galindo (1965) described a single case they thought represented the same entity. Robinson et al. (1983) observed a Saudi Arabian sibship with a severely affected male and a more mildly affected pair of female monozygotic twins. They pointed to a report of cases by Weber et al. (1978) as well as others.

Ardinger et al. (1984) studied 5 affected males in 2 unrelated families. The authors were impressed with a characteristic facial appearance which included prominent superciliary ridges, deep-set eyes, ptosis, and large ears. They could find no reliable means of identifying heterozygotes. The differential diagnosis includes Prader-Willi (176270), Coffin-Lowry (303600), and Bardet-Biedl (209900) syndromes.

Turner et al. (2004) reviewed the clinical features of affected males in 9 families with BFLS in which mutation in the PHF6 gene had been identified (Lower et al., 2002). The clinical history and physical findings in the affected males indicated that the phenotype is milder and ...

Symptoms

INHERITANCE: X-linked recessive

GROWTH: [Height]; Short stature; [Weight]; Moderate obesity; [Other]

HEAD AND NECK: [Head]; Microcephaly; [Face]; Coarse facies; Prominent supraorbital ridges; [Ears]; Large ears; [Eyes]; Deep-set eyes; Nystagmus; Ptosis; Poor vision; Narrow palpebral fissures

CHEST: [Breasts]; Gynecomastia, postpubertal

GENITOURINARY: [External genitalia, male]; Small penis; [Internal genitalia, male]; Small, atrophic testes; Cryptorchidism; Hypoplastic prostate

SKELETAL: [Skull]; Thick calvarium; [Spine]; Narrow cervical spinal canal; Mild scoliosis; Kyphosis; Scheuermann-like vertebral changes; [Hands]; Hypoplastic distal and middle phalanges; Soft, fleshy hands; Tapering fingers; [Feet]; Short toes; Widely spaced and flexed toes

NEUROLOGIC: [Central nervous system]; Severe mental retardation (IQ 10-40); Hypotonia; Abnormal EEG (poor alpha rhythms); Seizures

ENDOCRINE FEATURES: Delayed puberty

MISCELLANEOUS: Majority of female carriers have skewed X-inactivation (inactivation of chromosome containing the PHF6 (300414) mutation); Some female heterozygotes express phenotypic features (e.g., coarse facies, mild mental retardation)

MOLECULAR BASIS: Caused by mutations in the PHD finger protein 6 gene (PHF6, 300414.0001)
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Monosomy 18p

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: cyp11b2

Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18. The incidence is estimated to be about 1:50,000 live-born infants. In the commonest form of the disorder, the dysmorphic syndrome is very moderate and non-specific. The main clinical features are short stature, round face with short philtrum, palpebral ptosis and large ears with detached pinnae. Intellectual deficiency is mild to moderate. A small subset of patients, about 10 to 15 percent of cases, present with severe brain/facial malformations evocative of holoprosencephaly spectrum disorders. In two-thirds of the cases, the 18p- syndrome is due to a mere terminal deletion occurring de novo. In the remaining cases the following are possible: a de novo translocation with loss of 18p, missegregation of a parental translocation or inversion, or a ring chr18. Parental transmission of the 18p- syndrome has been reported. Cytogenetic analysis is necessary to make a definite diagnosis. Differential diagnosis may include a wide number of syndromes with short stature and mild intellectual deficiency. In young children, deletion 18p syndrome may be vaguely evocative of either Turner syndrome or trisomy 21 (see these terms). Recurrence risk for siblings is low for de novo deletions and translocations, but is significant if a parental rearrangement is present. Deletion 18p can be detected prenatally by amniocentesis or chorionic villus sampling and cytogenetic testing. No specific treatment exists but speech therapy and early educational programs may help to improve the performances of the children. Except for the patients with severe brain malformations, the life expectancy does not seem significantly reduced. Expert reviewer(s) Dr Catherine TURLEAU Last update: February 2008
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X-linked intellectual disability - cerebellar hypoplasia

Retrieved: 27-07-2015
Source: Orphanet (Original article)
Associated genes: ophn1

X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities. OPHN1 syndrome is very rare. To date, up to 12 families have been reported. Affected male patients present moderate to severe intellectual disability, hypotonia, severe developmental delay, early-onset complex partial or tonic-clonic seizures, strabismus, dysmetria and occasionally ataxia. Cryptorchidism and genital hypoplasia have been reported. Some patients have abnormal behavior and a characteristic facial phenotype (long face, prominent forehead, infraorbital creases, deep-set eyes, upturned philtrum and large ears). Carrier females have been reported to have mild learning disabilities, mild cognitive impairment, strabismus, and subtle facial changes. Various mutations including deletions and splice site mutations in the OPHN1 gene (Xq12) have been reported in patients with this syndrome. Neuroradiological findings include posterior vermis dysgenesis, vermian parasagittal cleft, cerebellar hypoplasia, cortical atrophy, and enlargement of the cerebral ventricles. Molecular genetic testing is needed to confirm diagnosis. Transmission appears to follow an X-linked semi-dominant pattern. Expert reviewer(s) Dr Ginevra ZANNI Last update: February 2013
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Galloway-Mowat syndrome

Retrieved: 27-07-2015
Source: Orphanet (Original article)

Galloway syndrome is characterized by the association of nephrotic syndrome and central nervous system anomalies. Approximately 40 cases have been reported since it was first described in 1968 in two siblings with early-onset nephrotic syndrome, microcephaly and hiatus hernia. The nephrotic syndrome is discovered at a mean age of 3 months (ranging from birth to 34 months). Renal biopsy may show minimal glomerular lesions, mesangial proliferation, focal segmental hyalinosis or diffuse mesangial sclerosis. Neurological symptoms include microcephaly, psychomotor retardation, convulsions, hypotonia, abnormal cerebral giri and sulci, cortical atrophy, hydrocephalus due to aqueductal stenosis, porencephaly or encephalomalacia. Histological analyses reveal anomalies of neuron migration. Facial dysmorphology and large ears have been reported, as well as hiatus hernia, which is responsible for vomiting after the first feed. Other symptoms have been described such as arachnodactyly with contractures and anterior cleavage syndrome of the eye. Galloway syndrome is an autosomal recessive disorder. The genetic defect is still unknown. The nephrotic syndrome does not respond to any form of treatment (steroid therapy or immunosuppressive drugs) and progresses to end-stage renal failure. Expert reviewer(s) Pr Patrick NIAUDET Last update: February 2007
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Mental retardation, x-linked 93

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: brwd3

Clinical features

A number sign (#) is used with this entry because of evidence that this form of X-linked mental retardation is caused by mutation in the BRWD3 gene (300553).Field et al. (2007) identified 3 families with X-linked mental retardation (XLMR) associated with macrocephaly. The first family included a nephew and an uncle with mild to moderate metal retardation and an aunt with mild cognitive difficulties during early childhood. The height, weight, and head circumference of the nephew were consistently greater than the 97th percentile. His height at age 17 years was 190 cm and head circumference was 62 cm. The right testis was undescended and was brought down by orchiopexy at age 13 months. Muscular hypotonia was noted in early life. Facial features included a long face, pointed chin, and large, prominent ears. The uncle's height was 187 cm and head circumference was 59 cm, with frontal bossing, large and prominent ears, and a pointed chin. His build was thin, with midthoracic kyphosis and minimal pectus excavatum. The second family included 2 half-brothers who shared the same mother, who was reported to have an intellectual disability and head circumference at the 97th percentile. The elder had an undescended testis; the younger had mild muscular hypotonia. Evaluated at ages 13 and 9 years, both had head circumference at greater than the 97th percentile, frontal bossing, pointed chin, and prominent ears with cupped helices. The third family was originally reported by Gedeon et al. (1994) (as family 'E') and included 3 brothers, a cousin, and an uncle, all with borderline to mild mental retardation. None of the affected males had macrocephaly or tall stature in childhood. They had large, prominent ears, triangular face, and pointed chin.

Molecular genetics

In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic XLMR, Field et al. (2007) identified 2 families with truncating mutations in BRWD3. In both families, the mutation segregated with the phenotype in affected males. In a family in which an uncle and nephew had XLMR with macrocephaly, Field et al. (2007) described a splice site mutation in the BRWD3 gene (300553.0001). Three carrier females were identified and all 3 of the chromosomes carrying the mutation were preferentially inactivated. In a family in which 2 half-brothers had LXMR with macrocephaly, Field et al. (2007) identified a 1-bp insertion in the BRWD3 gene (300553.0002). In the fa...

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Head]; Macrocephaly; [Face]; Prominent forehead; Long face; [Ears]; Large ears; Cupped ears

GENITOURINARY: [Internal genitalia, male]; Cryptorchidism

SKELETAL: [Feet]; Pes planus

NEUROLOGIC: [Central nervous system]; Mental retardation, mild-moderate; Hypotonia; Speech delay

MOLECULAR BASIS: Caused by mutation in the bromodomain-and WD repeat domain-containing protein 3 gene (BRWD3, 300553.0001)
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Mental retardation, x-linked, syndromic 32

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: clic2

Clinical features

A number sign (#) is used with this entry because of evidence that syndromic X-linked mental retardation-32 (MRXS32) is caused by mutation in the CLIC2 gene (300138) on chromosome Xq28. One such family has been reported.Takano et al. (2012) reported a family in which 2 brothers had profound mental retardation. Both had delayed psychomotor development beginning in infancy and had little or no speech development. Both also had seizures, large joint contractures, and abnormal positioning of the thumbs. One patient had hydrocephalus and 1 had spastic quadriplegia as an adult. Both patients were confined to a residential institution in childhood. Cardiac problems became apparent during the forties. Both had an enlarged heart resulting in congestive heart failure and valvular insufficiency, and 1 patient had atrial fibrillation. The patients did not have apparent abnormalities of skeletal muscles.

Inheritance

The transmission pattern in the family with MRXS32 reported by Takano et al. (2012) was consistent with X-linked recessive inheritance.

Molecular genetics

Using exome capture and deep sequencing of genes on the X chromosome in a family with X-linked syndromic mental retardation, Takano et al. (2012) identified a missense mutation in the CLIC2 gene (H101Q; 300138.0001). The mother, who carried the mutation in heterozygous state, had learning difficulties. In vitro functional expression studies showed that the mutant protein had increased thermal stability compared to wildtype and caused an increase in both the skeletal RYR1 (180901) and cardiac RYR2 (180902) channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with excess potential firing in those cells.

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Ears]; Large ears

CARDIOVASCULAR: [Heart]; Cardiomegaly; Congestive heart failure; Valvular insufficiency; Atrial flutter (rare)

GENITOURINARY: [External genitalia, male]; Macroorchidism

SKELETAL: [Spine]; Kyphoscoliosis (rare); [Limbs]; Contractures of the large joints; [Hands]; Abnormal positioning of the thumbs

NEUROLOGIC: [Central nervous system]; Global developmental delay; Mental retardation, profound; Lack of speech; Seizures; Spasticity (rare); Hydrocephalus (rare)

MISCELLANEOUS: One family with 2 affected brothers has been reported (last curated November 2012); Female carriers may show mild learning disabilities

MOLECULAR BASIS: Caused by mutation in the chloride intracellular channel 2 gene (CLIC2, 300138.0001)
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Forsythe-wakeling syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: cyp11b2, fws

Clinical features

Forsythe et al. (2009) reported 4 sibs, born of consanguineous Pakistani parents, with microcephaly, postnatal growth retardation, and global developmental delay with poor speech. All had similar dysmorphic features, including frontal bossing, sunken eyes, high nasal bridge, and large, prominent, low-set ears. During childhood, 3 patients developed persistent thrombocytopenia and steroid-nonresponsive nephrotic syndrome, resulting in death in 2 children. The fourth child had similar dysmorphic features and developmental delay, but did not have nephrotic syndrome or thrombocytopenia by age 25 months. The oldest child developed steroid-unresponsive nephrotic syndrome at age 7 years, with a renal biopsy showing glomerulosclerosis, tubular atrophy, interstitial fibrosis, and hyaline thickening of the arteriolar wall. He also had thrombocytopenia, generalized osteoporosis, and delayed bone age. There was no history of photosensitivity, poor vision, or deafness in any of the children, but 2 had keratinized, purple, nodular skin lesions. Studies of skin fibroblasts of 2 of the patients showed an intermediate recovery of RNA synthesis following UV irradiation. Forsythe et al. (2009) considered the dysmorphic features and fibroblast findings to be reminiscent of Cockayne syndrome (see, e.g., 133540).

Inheritance

The family reported by Forsythe et al. (2009) was consanguineous, suggesting autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a Pakistani family with an autosomal recessive disorder characterized by microcephaly, poor growth, developmental delay, dysmorphic features, nephrotic syndrome, and thrombocytopenia, Forsythe et al. (2009) identified a 27-Mb interval of shared homozygosity on chromosome 1p33-p31.1 between dbSNP rs2354462 and dbSNP rs718883 (maximum multipoint lod score of 2.4).

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature; [Weight]; Low weight; [Other]; Poor growth

HEAD AND NECK: [Head]; Microcephaly; [Face]; Frontal bossing; [Ears]; Large ears; Low-set ears; [Eyes]; Sunken eyes; [Nose]; High nasal bridge

GENITOURINARY: [Kidneys]; Nephrotic syndrome, steroid-nonresponsive

SKELETAL: Delayed bone age; Osteoporosis

SKIN, NAILS, HAIR: [Skin]; Keratinized, purple, nodular skin lesions (in 2 of 4 patients)

NEUROLOGIC: [Central nervous system]; Global developmental delay; Speech delay

HEMATOLOGY: Thrombocytopenia

LABORATORY ABNORMALITIES: Intermediate level of cellular sensitivity to UV light

MISCELLANEOUS: Onset of dysmorphic features and developmental delay in infancy; Onset of nephrotic syndrome and thrombocytopenia in mid-childhood; One family has been reported (as of October 2010)
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Warburg micro syndrome 2

Retrieved: 27-07-2015
Source: OMIM (Original article)
Associated genes: rab3gap2

Clinical features

A number sign (#) is used with this entry because Warburg Micro syndrome-2 (WARBM2) can be caused by homozygous mutation in the RAB3GAP2 gene (609275) on chromosome 1q41.

Martsolf syndrome (212720), a clinically overlapping but milder disorder, is also caused by mutation in the RAB3GAP2 gene.

For a general phenotypic description and a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118.Borck et al. (2011) reported a girl from a consanguineous Turkish family with Warburg Micro syndrome who presented with congenital cataracts, microphthalmia, absent visual evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay.

Molecular genetics

In a girl from a consanguineous Turkish family with Warburg Micro syndrome, Borck et al. (2011) identified homozygosity for a small in-frame deletion in the RAB3GAP2 gene (609275.0002). The parents were heterozygous carriers of the mutation, which was not found in 188 Turkish and 170 German control chromosomes. Analysis of RAB3GAP2 in 10 additional unrelated children with suspected Warburg Micro syndrome who were negative for mutation in the RAB3GAP1 (602536) gene revealed no further mutations.

In affected individuals from 7 families with the typical features of Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for mutations in the RAB3GAP2 gene (see, e.g., 609275.0004-609275.0006).

GENOTYPE/

Phenotype correlations

Handley et al. (2013) reviewed brain MRI findings in 17 patients with mutations in the RAB3GAP1, RAB3GAP2, and RAB18 (602207) genes. While brain findings were remarkably similar among the patients, the overall impression...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Postnatal growth retardation

HEAD AND NECK: [Head]; Postnatal microcephaly; Brachycephaly; [Face]; Low anterior hairline; [Ears]; Large ears; Asymmetric ears; [Eyes]; Congenital cataracts, bilateral; Microphthalmia; Microcornea; Atonic pupils; Optic nerve atrophy; Absent visual evoked potentials; [Nose]; Short nose; Prominent nasal root

GENITOURINARY: [External genitalia, male]; Micropenis; Scrotal hypoplasia; [External genitalia, female]; Hypoplasia of labia majora; [Internal genitalia, male]; Cryptorchidism

SKELETAL: [Skull]; Microcephaly, postnatal; [Limbs]; Contractures; [Feet]; Overlapping toes

SKIN, NAILS, HAIR: [Hair]; Low anterior hairline

NEUROLOGIC: [Central nervous system]; Global developmental delay; Severe mental retardation; Minimal to absent speech; Axial hypotonia; Progressive spastic diplegia to quadriplegia; Generalized brain atrophy; Frontotemporal polymicrogyria; Wide Sylvian fissures; Hypoplastic corpus callosum; Increased subdural space around frontal lobes

MOLECULAR BASIS: Caused by mutation in the RAB3 GTPase-activating protein (noncatalytic) subunit 2 gene (RAB3GAP2, 609275.0002)
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Bangstad syndrome

Retrieved: 27-07-2015
Source: OMIM (Original article)

Clinical features

Bangstad et al. (1989) described 2 sibs, a 26-year-old male and his 16-year-old sister, born of nonconsanguineous Norwegian parents, who had primordial bird-headed dwarfism, progressive ataxia, goiter, primary gonadal insufficiency, and insulin-resistant diabetes mellitus. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon, and insulin, all hormones working through cell membrane receptors, were elevated. Bangstad et al. (1989) suggested that a generalized cell membrane defect was responsible for the pathophysiologic abnormality in these patients.

Symptoms

Head: Small

Growth: Dwarfism, 'low birth weight' type

Eyes: Large

Nose: Beaklike protrusion

Face: Narrow

Mandible: Receding

Neck: Goiter

Endocrine: Primary gonadal insufficiency

Metabolic: Insulin-resistant diabetes mellitus

Lab: Elevated plasma TSH, PTH, LH, FSH, ACTH, glucagon, and insulin

Neuro: Progressive ataxia; Mental retardation; Brain very small

Misc: Chromosome instability

Heme: Pancytopenia

Inheritance: Autosomal recessive

Retrieved: 27-07-2015
Source: Orphanet (original)

This syndrome is characterised by the association of a progressive leukodystrophy marked by generalised mental and motor impairment with the presence of thickened and wrinkled skin. It has been described in a Japanese brother and sister born to healthy parents. Both patients died in early childhood. Last update: August 2006


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

Patterson and Watkins (1962) described a 10-month-old boy who they thought had leprechaunism (Donohue syndrome; 246200). Discordant features, however, were normal birth weight (rather than the usual severe intrauterine growth retardation) and marked cutis gyrata of hands and feet as well as a generalized skeletal disorder. Follow-up of this patient at age 7 years by Patterson (1969) made it clear that the disorder is distinct from leprechaunism. The boy had dwarfism, mental retardation, hyperadrenocorticism, and diabetes mellitus. He developed bladder diverticula and died at age 7.5 years from gram-negative sepsis. A main finding at autopsy was marked enlargement of the adrenals, especially of the zona fasciculata (McKusick, 1972). The distinctness of this disorder is further supported by discovery of an identical case in a female whose parents were young and unrelated (David et al., 1981). Findings at age 12 years were premature adrenarche with raised dehydroepiandrosterone and androstenedione levels. There was no clue to the genetics or other etiology of the disorder.

Symptoms

INHERITANCE: Isolated cases

GROWTH: [Weight]; Normal birth weight

HEAD AND NECK: [Ears]; Disproportionately large ears; Normal hearing; [Nose]; Disproportionately large nose

SKELETAL: Marked delay in bone age; Joint swelling (wrist, elbow, knees, ankles) onset late infancy; [Skull]; Thickened cranial vault; Thick maxilla; Thick ethmoid bones; Thick mandibular condyles; [Spine]; Kyphoscoliosis; Irregular, dense end plate; Small, flat cervical vertebrae; Hypoplastic odontoid process; Ovoid thoracic and lumbar vertebrae; [Pelvis]; Flat, irregular acetabular roofs; Failure of ossification of pubic bones, ischii, triradiate cartilages; [Limbs]; Genu valga; Short, deformed tubular bones; Irregular metaphyseal ossification; Sclerotic metaphyseal changes; [Hands]; Disproportionately large hands; [Feet]; Disproportionately large feet; Ankle valgus deformity

SKIN, NAILS, HAIR: [Skin]; Generalized bronze hyperpigmentation (present at birth); Cutis laxa, hands and feet (present at birth); [Hair]; Hirsutism (especially on limbs)

NEUROLOGIC: [Central nervous system]; Severe mental retardation; Seizure

ENDOCRINE FEATURES: Premature adrenarche; Diabetes mellitus; Hyperadrenocorticism

MISCELLANEOUS: Both reported cases survived beyond infancy


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-13 with or without polydactyly (SRTD13) is caused by homozygous mutation in the CEP120 gene (613446) on chromosome 5q23.

For a general phenotypic description and discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).Shaheen et al. (2015) described 4 unrelated infants, 3 male and 1 female, with short-rib thoracic dysplasia and polydactyly (SRTD). Two were born of first-cousin Saudi parents, and 1 was born of Swiss parents who were not known to be related but came from the same village; the ethnic or geographic origin of the fourth patient was not noted. All 4 of the affected infants died of respiratory failure within the first week of life, and all had a small thorax with short horizontal ribs, dysplastic pelvis, short long bones, and preaxial polydactyly or synpolydactyly. Extraskeletal features inc...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature at birth

HEAD AND NECK: [Head]; Relative macrocephaly; [Face]; Coarse facies; Midface hypoplasia; Microretrognathia; [Ears]; Large ears; Prominent lobules; [Eyes]; Hypertelorism; Scant eyebrows; [Nose]; Large nose; Prominent nostrils; [Mouth]; Mild cleft lip (notch); Tongue hamartoma (lobulated tongue); Partially bifid tongue; [Teeth]; Natal teeth

CARDIOVASCULAR: [Vascular]; Patent ductus arteriosus

RESPIRATORY: [Lung]; Hypoplastic lungs; Respiratory insufficiency

CHEST: [External features]; Narrow thorax; Bell-shaped thorax; [Ribs, sternum, clavicles, and scapulae]; Short ribs; Horizontal ribs

ABDOMEN: [External features]; Omphalocele

GENITOURINARY: [External genitalia, male]; Ambiguous genitalia; Phallus-like structure; Prominent prepuce; [Internal genitalia, male]; Undescended testes; [Kidneys]; Small kidneys; Increased echogenicity on ultrasound

SKELETAL: [Skull]; Small facial bones; [Pelvis]; Small pelvis; Dysplastic pelvic bone; Flaring of iliac bones; Small, squared iliac bones; Horizontal acetabular roof; Acetabular bony spurs; Narrow sciatic notch; Trident sciatic notch; [Limbs]; Micromelic short limbs; Round-ended femur bones; Small tibia; Small fibula; [Hands]; Synpolydactyly; Preaxial polydactyly; Severely hypoplastic middle and distal phalanges; [Feet]; Synpolydactyly; Hallux deformity

NEUROLOGIC: [Central nervous system]; Unilateral coronal craniosynostosis; Prominent and widened anterior and posterior fontanels; Cerebellar hypoplasia with Dandy-Walker malformation; Vermian hypoplasia with molar-tooth appearance

MISCELLANEOUS: Death occurs early in neonatal period due to respiratory failure; ...


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Say et al. (1975) described a 'new,' presumably autosomal dominant disorder characterized by cleft palate, short stature, microcephaly, large ears, and hand anomalies. A grandfather, 2 of his 5 daughters, and the son of 1 of the affected daughters were affected. The 2 affected females in the second generation had distally tapering fingers with hypoplastic distal phalanges, ulnar deviation of the middle fingers, and low set thumbs. Both had bilateral acromial dimples. The mother had severe micrognathia, which was surgically corrected during early childhood, and cleft palate. Abu-Libdeh et al. (1993) reported the case of a 13-month-old girl with similar features. Proximal renal tubular acidosis with cystic dysplasia of the kidneys was also present. Cystic renal dysplasia was also present in a new case in one of the discordant monozygotic twins reported by Ashton-Prolla and Felix (1997).

Guion-Almeida et al. (1998) reported a 3-year 7-month-old Brazilian boy with this syndrome whose parents were normal and nonconsanguineous. The child had glossoptosis, seizures, and cerebral anomalies, features which were not observed in previous reports.

Pagnan et al. (1999) reported a 12-month-old boy with cleft palate, large ears, microcephaly, distally tapering fingers, length at the 3rd centile, and delayed bone age. Psychomotor development was normal, and no renal anomalies were identified on ultrasonography. The patient's mother had microcephaly, but no other abnormal features. The authors concluded that this patient had Say syndrome and interpreted the microcephaly in the patient's mother as mild expression of the syndrome.

Symptoms

Mouth: Cleft palate

Growth: Short stature

Head: Microcephaly; Micrognathia

Ears: Large ears

Limbs: Hand anomalies; Distally tapering fingers; Hypoplastic distal phalanges; Ulnar deviation of middle fingers; Low set thumbs

Skin: Acromial dimples

Metabolic: Proximal renal tubular acidosis

GU: Cystic renal dysplasia

Inheritance: Autosomal dominant


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: cyp11b2, mrxs11

This syndrome is characterised by moderate intellectual deficit, obesity, macroorchidism and a characteristic facies (large ears, a prominent lower lip and puffy eyelids). It has been described in nine boys from two families. Transmission is X-linked and the causative gene has been localised to the q21.3-q27 region of the X chromosome. Last update: February 2007


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Wolff et al. (1994) described 2 severely retarded brothers, the only children of consanguineous Italian parents, with severe mental retardation, striking and very similar facial features, and other anomalies. The faces were characterized by a broad nasal bridge, bulbous nose, upward slanting palpebral fissures, microretrognathia, low anterior hairline, and large ears with an incompletely developed upper helix. In addition, both brothers had type II hypospadias, limb contractures, and delayed bone age. Pictures of the patients as infants and as young adults were presented. One brother had a bilateral cleft lip with cleft palate and cryptorchidism, and developed scoliosis during adolescence. The other had bilateral inguinal hernias and strabismus.


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Lynch and Bushby (1997) reported an 8-year-old boy with obesity, mental retardation, downslanting palpebral fissures, large ears, sensorineural deafness, cryptorchidism, and a penoscrotal web. He had congenital emphysema, and the upper lobe of his left lung was removed. He was born to healthy, unrelated parents and had a normal karyotype. Lynch and Bushby (1997) excluded Prader-Willi syndrome (176270). They suggested that this association may be a previously unreported syndrome of multiple congenital abnormalities.


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-42 (MRT42) is caused by homozygous mutation in the PGAP1 gene (611655) on chromosome 2q33. One such family has been reported.Murakami et al. (2014) reported a highly consanguineous Syrian family (MR079) in which 2 sibs had intellectual disability. The children were 4 and almost 3 years of age at the time of the report. Both had neonatal hypotonia and severely delayed psychomotor development (IQ below 35) with some stereotypic movements. One had both major and absence epilepsy. Brain CT scan of 1 patient showed pronounced brain atrophy. Other features included large ears and flattened nasal root.

Molecular genetics

In 2 sibs, born of consanguineous Syrian parents, with MRT42, Murakami et al. (2014) identified a homozygous mutation in the PGAP1 gene (611655.0002). The mutation, which was found by autozygosity mapping and exome sequencing, segregated with the disorder in the family. Lymphoblastoid cells derived from the patients showed normal expression of glycosylphosphatidylinositol (GPI)-anchored proteins, but these proteins were resistant to cleavage by PI-specific phospholipase C. These results indicated abnormal GPI structure due to a loss of PGAP1 enzyme activity early in the remodeling process of GPI-anchored proteins. Expression of the mutation in CHO cells resulted in loss of PI-specific phospholipase C sensitivity, which could be rescued by expression of wildtype PGAP1. Western blot analysis did not detect the mutant protein, indicating that it is unstable.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Ears]; Large ears; [Nose]; Flattened nasal root

MUSCLE, SOFT TISSUE: Neonatal hypotonia

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Seizures (1 patient); Cerebral atrophy; [Behavioral/psychiatric manifestations]; Stereotypic movements

MISCELLANEOUS: One highly consanguineous family has been reported (last curated May 2014)

MOLECULAR BASIS: Caused by mutation in the post-GPI attachment to proteins 1 gene (PGAP1, 611655.0002)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: tbx22

Clinical features

A number sign (#) is used with this entry because of evidence that Abruzzo-Erickson syndrome (ABERS) is caused by mutation in the TBX22 gene (300307) on chromosome Xq21. One such family has been reported.Abruzzo and Erickson (1977) reported an apparently 'new' syndrome of cleft palate, coloboma, hypospadias, deafness, short stature, and radial synostosis expressed variably in 2 brothers, their mother, and a maternal uncle. Davenport et al. (1986) and Metlay et al. (1987) cited this family as a familial instance of CHARGE syndrome (214800). Abruzzo and Erickson (1989) provided follow-up on the 2 brothers of the family who were children at the time of the first report. Like their mother and maternal uncle, neither had choanal atresia. Both had coronal hypospadias but genital development was otherwise normal. The ears were large and protruding, and hearing impairment required a hearing aid. Wide spacing between the second and third fingers as well as unilateral or bilateral radioulnar synostosis was noted in several members of the family. Mental retardation was not present. The manifestations in the mother, who according to the proposed inheritance as an X-linked disorder would be heterozygous, consisted of large ears and flat malar configuration like her sons and brother and wide spacing between the second and third digits as well as unusual rugosity of the palate. The brothers were below the 5th percentile for height at age 19 and 16, respectively.

Molecular genetics

In the family with an X-linked CHARGE-like syndrome that was originally reported by Abruzzo and Erickson (1977), Pauws et al. (2013) analyzed the candidate gene TBX22 and identified an intronic sequence variant (300307.0011) that segregated with the disease and was not found in the dbSNP database or in 539 control chromosomes. Mutations in TBX22 were also identified in patients with classic X-linked cleft palate phenotypes (CPX; 303400).

Symptoms

HEENT: Cleft palate; Coloboma; Large ears; Protruding ears; Deafness; Flat malar configuration; Palatal rugosity

GU: Hypospadias

Growth: Short stature

Limbs: Radioulnar synostosis; Wide-spaced second and third fingers

Inheritance: X-linked


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-48 (MRT48) is caused by homozygous mutation in the SLC6A17 gene (610299) on chromosome 1p13.Iqbal et al. (2015) reported 3 adult sisters, all in their sixties, with severe mental retardation and very poor speech limited to 3-word sentences. All had delayed psychomotor development from birth, but there were no available records of the timing of childhood milestones. Their behavior was characterized by mood instability, aggression, and self-mutilation. Between 40 and 50 years, all developed a progressive essential hand tremor that was not present in their healthy sibs, and all had a waddling gait. Cerebral imaging performed in 1 patient was normal. Mild dysmorphic features included large ears, prominent chin, narrow palpebral fissures, long philtrum, and high, narrow palate. Two sibs from a consanguineous Iranian family had a similar disorder: they had severe mental retardation with no speech development, and onset of progressive hand tremor in the teenage years. They were unable to walk or care for themselves, and showed aggression and poor impulse control. Facial features included large ears, prominent chin, thick eyebrows, and slightly narrow palpebral fissures.

Inheritance

The transmission pattern in the Iranian family with MRT48 reported by Iqbal et al. (2015) was consistent with autosomal recessive inheritance.

Molecular genetics

In 5 affected individuals from 2 unrelated families with MRT48, Iqbal et al. (2015) identified 2 different homozygous missense mutations in the SLC6A17 gene (G162R, 610299.0001 and P633R, 610299.0002). The mutations were found by a combination of homozygosity mapping and exome sequencing. In vitro functional expression studies in mouse embryonic primary hippocampal cells showed that both mutant proteins altered the localization of the protein and/or morphology of the cell compared to wildtype.

Symptoms

INHERITANCE: Autosomal recessive

HEAD AND NECK: [Face]; Prominent chin; Long philtrum; [Ears]; Large ears; [Eyes]; Narrow palpebral fissures

SKELETAL: [Hands]; Small hands (family A)

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, severe; Poor or absent speech; Waddling gait (family A); Inability to walk (family B); Essential tremor, progressive; [Behavioral/psychiatric manifestations]; Aggression; Poor impulse control; Self-mutilation; Mood instability

MISCELLANEOUS: Two unrelated families have been reported (last curated March 2015)

MOLECULAR BASIS: Caused by mutation in the solute carrier family 6 (neurotransmitter transporter), member 17 gene (SLC6A16, 610299.0001)


Retrieved: 27-07-2015
Source: Orphanet (original)

Hall-Riggs syndrome is a very rare syndrome consisting of microcephaly with facial dysmorphism, spondylometaepiphyseal dysplasia and severe intellectual deficit. Eight cases have been reported in the literature in two unrelated families. Dysmorphic features include hypertelorism, depressed nasal bridge, large nose with a large nasal tip, anteverted nostrils and wide mouth with thick lips. Affected patients do not achieve language ability. The condition is probably hereditary, and transmitted as an autosomal recessive trait. Last update: January 2010


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Cantu et al. (1981, 1985) reported a second Guadalajara camptodactyly syndrome; see 211910 for a description of type I. Two sisters, aged 6 and 3 years, presented the same intrauterine growth retardation-malformation syndrome characterized by low-birth-weight dwarfism and a variety of dysmorphic features including camptodactyly of all fingers, bilateral hallux valgus, short toes 2, 4 and 5, patella hypoplasia, short neck, low-set ears, microcephaly, cuboid vertebral bodies, and others.

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature; [Other]; Intrauterine retardation

HEAD AND NECK: [Head]; Microcephaly; [Face]; Micrognathia; Long philtrum; [Ears]; Large ears; Low-set ears; [Eyes]; Hypotelorism; [Neck]; Short neck

CHEST: [External features]; Wide-spaced nipples; [Ribs, sternum, clavicles, and scapulae]; Pectus excavatum

GENITOURINARY: [External genitalia, female]; Labial hypoplasia

SKELETAL: Osteopenia; [Spine]; Cuboid vertebral bodies [Pelvis]; Pelvis hypoplasia; [Limbs]; Patellar hypoplasia; Slender long bones; [Hands]; Simian creases; Camptodactyly, all fingers; Second phalanx hypoplasia; [Feet]; Hallux valgus; Brachydactyly, toes 2,4, and 5; Talipes equinovarus

MUSCLE, SOFT TISSUE: Gluteal hypoplasia


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Sabater et al. (1976) described 2 brothers, aged 9 and 11 years, with mild mental retardation and histidinuria despite normal blood levels. Histidine loading showed impaired intestinal absorption. The inheritance is presumably autosomal recessive because both parents showed intermediate intestinal absorption. Holmgren et al. (1974) had reported 1 patient with renal histidinuria associated with myoclonic seizures. Kamoun et al. (1981) likewise reported 1 patient with associated histidinuria and myoclonic seizures. Nyhan and Hilton (1992) described a 7-year-old boy with histidinuria without histidinemia. Low concentrations of histidine in plasma were consistent with impaired intestinal and renal tubular absorption of histidine. The patient was developmentally delayed and had some minor anomalies: bilateral nerve deafness of moderate severity; protuberant large and somewhat simple oracles; very short thick fingers and toes with hypoplasia of the toenails; and broad nasal bridge with long shallow philtrum and thin upper lip. Roentgenograms showed that the shortness of the 5th digit resulted from a short rounded middle phalanx that was abnormal in shape. All 5 patients who have been reported have been male.

Symptoms

Neuro: Mental retardation; Myoclonic seizures

GI: Impaired histidine intestinal absorption

GU: Impaired histidine renal tubular absorption

HEENT: Nerve deafness; Protuberant ears; Broad nasal bridge; Long shallow philtrum; Thin upper lip; Large ears; Simple auricles

Limbs: Short thick fingers; Short thick toes; Hypoplastic toenails

Radiology: Short, rounded, abnormal-shaped middle phalanges

Lab: Histidinuria

Inheritance: Autosomal recessive


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-101 (MRX101) is caused by mutation in the MID2 gene (300204) on chromosome Xq22. One such family has been reported.Geetha et al. (2014) reported a large family from northern India in which 11 males spanning 3 generations had mental retardation. All 6 patients evaluated had global developmental delay. Facial dysmorphism was not prominent, but several patients had long face, prominent ears, and squint or strabismus. Two had seizures. Most also had hyperactivity, often with aggressive outbursts.

Inheritance

The transmission pattern in the family with MRX101 reported by Geetha et al. (2014) was consistent with X-linked recessive inheritance.

Molecular genetics

In affected members of a family with MRX101, Geetha et al. (2014) identified a hemizygous missense mutation in the MID2 gene (R347Q; 300204.0001). The mutation was found using a combination of linkage analysis and targeted next-generation sequencing. Carrier females in the family were unaffected. Transfection of the mutation in HEK293T cells showed abnormal localization of the mutant protein, which was found in aggregate form or enclosed in vesicles in the cytoplasm rather than being bound to microtubules. By direct sequencing of the coding exons of the MID2 gene among 480 patients with intellectual disability, Geetha et al. (2014) identified an individual with a missense mutation (N343S); however, functional assays indicated that this mutation may not be disease causing.

Symptoms

INHERITANCE: X-linked recessive

HEAD AND NECK: [Face]; Long face (in some patients); [Ears]; Large ears (in some patients); [Eyes]; Squint; Strabismus

NEUROLOGIC: [Central nervous system]; Global developmental delay; Impaired cognition; Mental retardation; Poor speech; Lack of speech; Seizures (in some patients); [Behavioral/psychiatric manifestations]; Hyperactivity; Aggressive outbursts

MISCELLANEOUS: Onset at birth; One family from Punjab, India has been reported (last curated August 2014)

MOLECULAR BASIS: Caused by mutation in the midline 2 gene (MID2, 300204.0001)


Retrieved: 27-07-2015
Source: OMIM (original)

Clinical features

Garcia-Cruz et al. (1990) reported 3 sisters, born of nonconsanguineous parents, with congenital glaucoma, distinctive facies (large eyes, wide forehead, thin nasal bridge, and broad nose with large tip), large ears, short neck, wide thorax, umbilicated nipples, cubitus valgus, and short big toes. Radiologic examination revealed mild skeletal anomalies characterized by slender long bones with wide metaphyses and thin cortices, cuboid-shaped vertebral bodies, enlarged transverse apophysis of the seventh vertebral body, narrowed vertebral canal and decreased interpedicular distance at the lumbar segments, and generalized osteopenia. Ophthalmologic examination was suggestive of iridogoniodysgenesis, but presurgical gonioscopic data were not available. There was no family history of glaucoma or any other ophthalmologic disorder. Garcia-Cruz et al. (1990) suggested that the disorder represented a newly recognized congenital glaucoma syndrome with possible autosomal recessive inheritance.

Rodriguez-Rojas et al. (2004) described a sister and 2 brothers with congenital glaucoma, skeletal anomalies, and a peculiar facial appearance whose clinical and radiologic features were identical to those of the 3 sisters reported by Garcia-Cruz et al. (1990), except for the absence of large ears and cubitus valgus, and the presence of undeveloped frontal sinuses. Ophthalmologic examination in the proposita revealed megalocornea, wide anterior chambers, concave iris with stromal atrophy, and nasal corectopia in both eyes with no evidence of posterior embryotoxon, associated with congenital glaucoma. Radiologic and ophthalmologic examination including gonioscopy in the healthy, nonconsanguineous parents and 2 unaffected sibs were normal. There was no family history of glaucoma or other ophthalmologic anomalies. Rodriguez-Rojas et al. (2004) concluded that these 2 families had a distinct iridogoniodysgenesis syndrome with probable autosomal recessive inheritance.


Retrieved: 27-07-2015
Source: OMIM (original)

Description

The Zaki-Gleeson syndrome is an autosomal recessive neurodevelopmental disorder characterized by profound mental retardation, severe microcephaly, poor growth, cerebellar hypoplasia, and second-degree cardiac conduction defects (summary by Zaki et al., 2011).

Clinical features

Zaki et al. (2011) reported a consanguineous Egyptian family in which 3 sibs and a first cousin had a syndromic disorder apparent at birth and characterized by profound mental retardation, severe microcephaly (-8 to -11 SD), poor growth, dysmorphic facial features, cerebellar hypoplasia, and second-degree atrioventricular heart block. All showed severe psychomotor retardation, with no speech, sitting only with support, inability to grasp objects or feed themselves, and lack of sphincter control. They were hypotonic with brisk reflexes, truncal ataxia, intention tremor, and dystonic movements. The 3 older children showed autistic behavior. Dysmorphic facial features included broad forehead, thin long eyebrows, upslanting palpebral fissures, prominent nose, long philtrum, thin vermilion of the upper lip, prominent lower lip, and large ears with prominent antihelix. Hands and feet showed long fusiform fingers with bilateral campto- and clinodactyly of fifth fingers and crowded toes. Physical examination showed bradycardia and second-degree cardiac conduction defects, as well as vasomotor instability with prolonged capillary refill, skin mottling, and acrocyanosis. Brain imaging showed cerebellar hypoplasia, thin corpus callo...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Other]; Failure to thrive; Poor growth

HEAD AND NECK: [Head]; Microcephaly, progressive, severe (-8 to -11 SD); [Face]; Broad forehead; Long philtrum; [Ears]; Large ears; Prominent antihelix; [Eyes]; Thin, long eyebrows; [Nose]; Prominent nose; [Mouth]; Thin vermilion of the upper lip; Prominent lower lip

CARDIOVASCULAR: [Heart]; Bradycardia; Second degree atrioventricular heart block; [Vascular]; Vasomotor instability

SKELETAL: [Hands]; Long tapered fingers; Fifth finger clinodactyly; Fifth finger camptodactyly; [Feet]; Crowded toes

SKIN, NAILS, HAIR: [Skin]; Skin mottling due to poor perfusion; Prolonged capillary refill; Acrocyanosis; [Hair]; Thin, long eyebrows

NEUROLOGIC: [Central nervous system]; Mental retardation, profound; Hypotonia; Hyperreflexia; Dystonia; Intention tremor; Truncal ataxia; Lack of independent ambulation; Unable to grasp objects; Absent speech; Simplified gyral pattern; Cerebellar hypoplasia; Thin corpus callosum; White matter abnormalities; [Behavioral/psychiatric manifestations]; Autistic features

ENDOCRINE FEATURES: Diabetes mellitus, insulin-dependent (1 patient); Impaired glucose tolerance

MISCELLANEOUS: One consanguineous Egyptian family with 4 affected individuals has been reported (as of December 2011)


Retrieved: 27-07-2015
Source: OMIM (original)
Associated genes: tti2

Clinical features

A number sign (#) is used with this entry because autosomal recessive mental retardation-39 (MRT39) is caused by homozygous mutation in the TTI2 gene (614426) on chromosome 8p12.Langouet et al. (2013) reported 3 sibs, born of consanguineous Algerian parents, with mental retardation and behavioral problems. All had a normal neonatal period, but showed delayed psychomotor development and severe speech delay. Examination at ages 30 to 36 years revealed microcephaly (-3 to -4 SD), short stature, kyphoscoliosis, and dysmorphic facial features, including sloping forehead, deep-set eyes, synophrys, prominent nose, anteverted large ears, and dental anomalies. Behavioral abnormalities included hyperactivity, aggression, and stereotypic movements. Seizures were not reported. Laboratory analysis showed mild lymphopenia of naive T cells, but increased susceptibility to infection was not reported.

Inheritance

The transmission pattern in the family with mental retardation reported by Langouet et al. (2013) was consistent with autosomal recessive inheritance.

Molecular genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M100, they identified homozygosity for a missense mutation in the TTI2 gene (P367L; 614426.0001) in 4 sibs with moderate nonsyndromic mental retardation. The parents were first cousins and had 4 healthy children.

In 3 sibs, born of consanguineous Algerian parents, with mental retardation and dysmorphic features, Langouet et al. (2013) identified a homozygous missense mutation in the TTI2 gene (I436N; 614426.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed almost undetectable levels of mutant TTI2 compared to controls, although mRNA levels wer...

Symptoms

INHERITANCE: Autosomal recessive

GROWTH: [Height]; Short stature

HEAD AND NECK: [Head]; Microcephaly (-3 to -4 SD); [Face]; Sloping forehead; [Ears]; Anteverted ears; Large ears; [Eyes]; Deep-set eyes; Strabismus; Synophrys; [Nose]; Prominent nose; [Teeth]; Malposition of the teeth

SKELETAL: [Spine]; Kyphoscoliosis

NEUROLOGIC: [Central nervous system]; Delayed psychomotor development; Mental retardation, moderate to severe; Speech delay, severe; [Behavioral/psychiatric manifestations]; Hyperactivity; Aggression; Stereotyped behavior

IMMUNOLOGY: Decreased circulating naive T cells (1 family)

MISCELLANEOUS: Onset in infancy; Dysmorphic facial features reported in 1 family; Two unrelated families have been reported (last curated November 2013)

MOLECULAR BASIS: Caused by mutation in the TELO2-interacting protein 2 gene (TTI2, 614426.0001)


Retrieved: 27-07-2015
Source: Orphanet (original)
Associated genes: tbc1d24



Retrieved: 27-07-2015
Source: OMIM (original)

Description

Duval et al. (1998) described a possibly 'new' autosomal recessive syndrome in 2 female fetuses conceived by a nonconsanguineous couple. The pregnancies were interrupted at 31 and 26 weeks of gestation, respectively, because of severe microcephaly. Postmortem x-ray and autopsy studies showed in both fetuses: (1) severe intrauterine growth retardation; (2) facial anomalies characterized by severe microcephaly, sloping forehead, low-set and posteriorly angulated ears, prominent eyes, downslanting palpebral fissures, large nose, small mouth with full lips, and mild microretrognathia; (3) severe brain hypoplasia that was more pronounced in the second fetus; (4) severe rib hypoplasia with posterior rib-gap defects and, in case 2, hypoplasia of several bones (right clavicle, right radius and ulna, several phalanges of hands and feet); and (5) contracture at large joints. No other visceral malformations were observed, and chromosomes were normal in patient 2 and in the parents.


Retrieved: 27-07-2015
Source: OMIM (original)

Description

Neuhauser and Opitz (1975) described a family with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome consisting of mental retardation, peculiar facies, kyphoscoliosis, diastasis recti, cryptorchidism, and congenital heart defect. They called it McDonough syndrome. Three of 5 sibs were affected, leading to a suggestion of autosomal recessive inheritance. The authors considered it coincidental that the youngest affected sib had a chromosomal complement 47,XXY and the father was a mosaic 46,XY/47,XXY. Garcia-Sagredo et al. (1984) reported a second family in which 2 of 3 sibs (a girl and a boy) were affected. It was considered coincidental that the affected boy and the unaffected mother had a balanced X;20 translocation. The father had ptosis, which was also considered coincidental.

Symptoms

Neuro: Mental retardation

HEENT: Peculiar facies; Synophrys; Strabismus; Upslanted palpebral fissures; Hypertelorism; Ptosis; Large nose; Short philtrum; Grooved tongue; Prognathism; Micrognathia; Malocclusion; Anteverted auricles

Skin: Sparse hair; Bristly hair

Growth: Short stature

Skel: Kyphoscoliosis; Pectus carinatum; Pectus excavatum

Limbs: Single transverse palmar crease; Hypoplastic toenails; Clinodactyly

Abdomen: Diastasis recti

GU: Cryptorchidism

Cardiac: Congenital heart defect; Atrial septal defect; Ventricular septal defect; Pulmonic stenosis; Aortic stenosis

Inheritance: Autosomal recessive