Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014). Clinical Features Brautigam et al. (2002) described twins, born of first-cousin parents, who were born at 29 weeks' gestation and suffered from birth from severe convulsions, myoclonus, rotatory eye movements, sudden clonic contractions, burst suppression electroencephalogram (EEG), hypoglycemia, and acidosis. ... Biochemical abnormalities in CSF and urine were as for AADC deficiency with the additional features of raised glycine (in all 5), threonine (4 of 5), taurine (4 of 5), histidine (all 5), and low arginine (3 of 5). ... INHERITANCE - Autosomal recessive GROWTH Other - Failure to thrive HEAD & NECK Head - Microcephaly, progressive Eyes - Eye movement abnormalities ABDOMEN Gastrointestinal - Feeding problems NEUROLOGIC Central Nervous System - Neonatal epileptic encephalopathy (NEE) - Global developmental delay, variable severity - Burst suppression on EEG - Seizures - Myoclonus - Partial response to pyridoxine - Response to pyridoxal phosphate - Hypotonia, truncal - Hypertonia - Unsteady gait METABOLIC FEATURES - Metabolic acidosis HEMATOLOGY - Anemia PRENATAL MANIFESTATIONS Delivery - Preterm delivery - Low APGAR scores LABORATORY ABNORMALITIES - Increased blood lactate - Hypoglycemia - Normal to increased plasma glycine - Normal to increased plasma threonine - Decreased plasma arginine - Increased urine vanillactic acid (VLA) - Decreased CSF homovanillic acid (HVA) - Decreased CSF 5-hydroxyindoleacetic acid (5HIAA) - Increased CSF 3-methoxytyrosine (3-MT) - Increased CSF glycine - Increased CSF threonine - Increased CSF taurine - Increased CSF histidine - Decreased CSF arginine - Decreased CSF pyridoxal 5-prime-phosphate (PLP) MISCELLANEOUS - Onset 0-12 hours after birth - Variable features and severity MOLECULAR BASIS - Caused by mutation in the pyridoxamine 5-prime-phosphate oxidase gene (PNPO, 603287.0001 ) ▲ Close

., 2019), suggesting significant clinical variability of this disorder. Clinical Features Edvardson et al. (2013) reported 3 sibs, born of consanguineous Arab-Palestinian parents, with early infantile epileptic encephalopathy, global developmental delay, and cerebellar atrophy. ... EEG was consistent with epileptic encephalopathy and later evolved to slow background with multifocal spike and slow-wave discharges. Additional features included brisk reflexes and choreiform movements. ... Brain imaging showed cerebellar atrophy; dysmorphic features were not noted. Clinical Variability Valence et al. (2019) reported a 20-year-old man (P12), born of consanguineous Portuguese parents, with cerebellar ataxia. ... INHERITANCE - Autosomal recessive HEAD & NECK Face - Dysmorphic facial features (1 patient) Eyes - Abnormal eye movements - Nystagmus - Strabismus - Poor eye contact MUSCLE, SOFT TISSUES - Axial hypotonia - Peripheral hypertonia NEUROLOGIC Central Nervous System - Epileptic encephalopathy (in most patients) - Global developmental delay (in most patients) - Inability to walk (in most patients) - Seizures, refractory, early-onset - Multifocal discharges seen on EEG - Background slowing seen on EEG - Photoparoxysmal response seen on EEG - Ataxic gait - Ataxia - Dysmetria - Dysarthria - Choreiform movements - Dyskinetic movements - Cerebellar vermis atrophy MISCELLANEOUS - Onset in infancy - Variable severity - One patient with only a single seizure and normal cognitive development has been reported MOLECULAR BASIS - Caused by mutation in the calcium channel, voltage-dependent, alpha-2/delta subunit 2 gene (CACNA2D2, 607082.0001 ) ▲ Close

A number sign (#) is used with this entry because posterior amorphous corneal dystrophy (PACD) is a chromosome 12q21.33 contiguous gene deletion syndrome. Clinical Features Carpel et al. (1977) observed a posterior corneal dystrophy characterized by irregular sheetlike areas of opacification with involvement of the Descemet membrane and, in some instances, alterations of the normal endothelial mosaic. ... Family members manifested this rare abnormality in both its centroperipheral and peripheral forms. Additional features found in these patients included hyperopia, flattened corneal topography, anterior iris surface and stromal abnormalities, fine iris processes extending to the Schwalbe line for 350 degrees, and extension of the opacity to the limbus. ... Reexamination at 1 year of age showed a decrease in the stromal haze and sharper delineation of the posterior sheetlike opacity, and there was an increase in his hypermetropia to +7.5D bilaterally. Other features in the boy included left intraventricular hemorrhage at 5 days of life with midline shift and ventricular enlargement, for which he underwent placement of ventriculoperitoneal shunts due to progressive hydrocephalus. ... In addition, Kim et al. (2014) noted that loss-of-function mouse models involving the Lum and Kera genes showed phenotypic features consistent with those observed in the PACD families.

Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; 614199). Clinical Features Pierson et al. (1963) reported 2 sisters with congenital nephrotic syndrome and peculiar eye abnormalities. The renal disorder manifested in the newborn period with severe nephrotic syndrome followed by early-onset end-stage renal disease; both sisters died in the first 2 weeks of life. Ocular features included extreme nonreactive narrowing of the pupils (microcoria) due to aplasia or atrophy of the dilatator pupillae muscle. ... The fourth patient had a milder phenotype with regard to ocular features and renal disease, normal development, no neurologic abnormalities, and absence of muscle hypotonia, suggesting that she had residual protein function. ... Genotype/Phenotype Correlations Hasselbacher et al. (2006) stated that homozygosity or compound heterozygosity for LAMB2 mutations conferring complete loss of function (e.g., truncating mutations) appear to be associated consistently with the typical features of Pierson syndrome, including neonatal renal failure, severe ocular abnormalities, and neurologic impairment in long-term survivors, whereas patients with nontruncating (missense) LAMB2 mutations may display variable phenotypes ranging from a milder variant of Pierson syndrome to isolated congenital nephrotic syndrome.

For a discussion of genetic heterogeneity of temporal lobe epilepsy, see ETL1 (600512). Clinical Features Berkovic et al. (1996) reported 38 individuals from 13 unrelated families with familial temporal lobe epilepsy. ... The disease phenotype was characterized by temporal lobe epilepsy, no deja vu or auditory or visual hallucinations, a high incidence of febrile seizures, mean age at onset of afebrile seizures of 8 years, low incidence of epileptic features on electroencephalography, no hippocampal sclerosis, and a usually good prognosis. ... Seizures were generalized tonic-clonic, although 2 patients had febrile seizures with focal features. Gurnett et al. (2007) emphasized that none of the individuals manifested clear evidence of temporal lobe epilepsy. Biochemical Features In hippocampal tissue from 10 patients with intractable temporal lobe epilepsy, Henshall et al. (2004) found increased DAP kinase (600831) expression and phosphorylation compared to controls.

A number sign (#) is used with this entry because X-linked cleft palate with or without ankyloglossia (CPX) is caused by mutation in the TBX22 gene (300307) on chromosome Xq21. Clinical Features In a British Columbia Indian family, Lowry (1970) found 12 males with incomplete cleft of the secondary palate. ... Palatopharyngeal incompetence was a leading feature. The pedigree pattern suggested X-linked recessive inheritance. ... Cleft palate was the sole presenting feature in 6% of female carriers. Not all female carriers escaped a cleft, which affected 16% regardless of tongue phenotype. ... Sponenberg and Bowling (1985) described a similar disorder in Australian shepherd dogs; the features were cleft palate, syndactyly, polydactyly, tibiofibular shortening, brachygnathism, and often scoliosis.

Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. ... Other Forms of Hypophosphatemic Rickets For a discussion of other forms of hypophosphatemic rickets, see ADHR (193100). Clinical Features Kitanaka et al. (1998) reported 4 unrelated Japanese patients with vitamin D-dependent rickets confirmed by genetic analysis. ... INHERITANCE - Autosomal recessive GROWTH Other - Failure to thrive - Poor growth - Growth retardation HEAD & NECK Head - Frontal bossing Teeth - Delayed tooth eruption - Enamel hypoplasia CHEST Ribs Sternum Clavicles & Scapulae - Enlargement of the costochondral junction - 'Bulging' of the costochondral junction - Deformed rib cage ABDOMEN External Features - Protuberant abdomen due to muscle weakness SKELETAL - Rickets - Increased fractures - Bone pain - Sparse bone trabeculae - Thin bony cortex Skull - Widened cranial sutures - Posterior flattening of the skull Limbs - Delayed opacification of the epiphyses - Widened, distorted epiphyses - 'Bulging' epiphyses - Frayed, irregular metaphyses - Curvatures of the femur, tibia, fibula - Lower limb deformities - Bowing of the legs - Enlargement of the wrists - Enlargement of the ankles - Subperiosteal erosions due to secondary hyperparathyroidism MUSCLE, SOFT TISSUES - Hypotonia - Muscle weakness - Difficulty walking - Difficulty standing NEUROLOGIC Central Nervous System - Delayed motor development - Seizures due to hypocalcemia Behavioral Psychiatric Manifestations - Irritability ENDOCRINE FEATURES - Secondary hyperparathyroidism LABORATORY ABNORMALITIES - Hypocalcemia - Hypophosphatemia - Increased serum parathyroid hormone (PTH) - Increased serum alkaline phosphatase - Generalized aminoaciduria - Markedly decreased or absent serum 1,25-dihydroxyvitamin D3 - Normal serum 25-hydroxyvitamin D3 MISCELLANEOUS - Clinical onset within first 2 years of life - Can be treated with physiologic levels of 1,25-dihydroxyvitamin D3 or 1-alpha-hydroxyvitamin D3 - Increased frequency among French-Canadians from the Charlevoix-Saguenay-Lac Saint Jean area of Quebec (carrier rate 1 in 26) MOLECULAR BASIS - Caused by mutations in the 25-hydroxyvitamin D3-1-alpha-hydroxylase gene (CYP27B1, 609506.0001 ). ▲ Close

Description Schmid-type metaphyseal chondrodysplasia is characterized by short stature and bowing of the long bones; radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora (summary by Makitie et al., 2005). Clinical Features Stephens (1943) reported a Mormon kindred in which over 40 members of 4 generations were affected with what he considered to be achondroplasia. ... They suggested that the condition was often overdiagnosed. Significant radiologic features included an enlarged capital femoral epiphysis in early childhood, coxa vara, greater involvement of the distal femoral metaphysis than the proximal, anterior rib changes, and a normal spine. ... Elliott et al. (2005) concluded that mild hand involvement that appears to resolve with age is a common feature of MCDS and should not exclude the diagnosis in young patients.

Patients with homozygous or compound heterozygous mutations in this gene have a more severe phenotype. Clinical Features Ichthyosis is one of the most frequent single-gene disorders in humans. ... The disorder in the mother was clinically and histologically of the dominant type, whereas the affected sons showed features of both the autosomal dominant and X-linked recessive forms. The authors concluded that the mother was heterozygous for both forms. Biochemical Features Anton-Lamprecht (1978) pointed out that electron microscopy is particularly revealing in dominant disorders in which structural abnormality of a protein is likely to be found, whereas biochemistry is more likely to be revealing in recessive disorders. ... The association of ichthyosis vulgaris with atopic diathesis is well established; 37 to 50% of people with ichthyosis vulgaris have atopic diseases, and roughly 8% of patients with atopic dermatitis (603165) have classic features of ichthyosis vulgaris. Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese patients with ichthyosis vulgaris from 4 unrelated families who were negative for the R501X and 2282del4 mutations, and identified heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA (135940.0004), respectively.

A number sign (#) is used with this entry because of evidence that Caffey disease is caused by heterozygous mutation in the alpha-1 collagen type I gene (COL1A1; 120150) on chromosome 17q21. Clinical Features Infantile cortical hyperostosis has somewhat unusual features for a hereditary disorder. ... Postmortem radiographs, autopsy, and histologic study showed typical features of a severe form of prenatal cortical hyperostosis. ... None of the affected individuals or obligate carriers in any of the families had clinical signs of the major type I collagen disorder, osteogenesis imperfecta (see 166200); however, in 2 of the 3 families, individuals carrying the mutation did have joint hyperlaxity, hyperextensible skin, and inguinal hernias, features seen in Ehlers-Danlos syndrome (see 130000), some forms of which are caused by mutations in COL1A1.

., 2011, and Popova et al., 2013). Clinical Features Wiesner et al. (2011) reported 2 unrelated families with autosomal dominant inheritance of a skin tumor predisposition syndrome. ... Some of the neoplasms showed atypical features such as high cellularity or nuclear pleomorphism, and were classified as 'neoplasms of uncertain malignant potential;' these individuals were managed as if they had melanoma. ... None of the affected individuals had intellectual disabilities or dysmorphic features, or lung or breast cancer. Testa et al. (2011) reported 2 unrelated families with multiple cases of malignant mesothelioma apparently transmitted in an autosomal dominant pattern. ... INHERITANCE - Autosomal dominant HEAD & NECK Eyes - Uveal melanoma RESPIRATORY Lung - Mesothelioma, malignant, after asbestos exposure - Lung adenocarcinoma SKIN, NAILS, & HAIR Skin - Melanocytic skin tumors/papules, skin-colored to reddish-brown, dome-shaped or pedunculated, well circumscribed with an average size of 5 mm (in 2 families) - Cutaneous melanoma Skin Histology - Dermal tumors composed of epithelioid melanocytes - Abundant cytoplasm - Prominent nucleoli - Melanocytes contain large vesicular nuclei with varying shapes - Some show atypical features, such as nuclear pleomorphism NEUROLOGIC Central Nervous System - Meningioma NEOPLASIA - Mesothelioma, malignant, after asbestos exposure - Uveal melanoma - Cutaneous melanoma - Meningioma - Renal cell carcinoma, usually clear cell type MISCELLANEOUS - Tumor predisposition syndrome MOLECULAR BASIS - Caused by mutation in the BRCA1-associated protein 1 (BAP1, 603089.0001 ) ▲ Close

Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008). Clinical Features Families with multiple cases of disseminated atypical mycobacteriosis, a rare disorder, were reported by Engbaek (1964) and Uchiyama et al. (1981). ... Genotype/Phenotype Correlations Dorman et al. (2004) compared the clinical features of recessive and dominant IFNGR1 deficiencies using a worldwide cohort of patients. ... Dorman et al. (2004) concluded that there is a strong correlation between the IFNGR1 genotype, clinical disease features, and the cellular responsiveness to IFNG.

Spheroid body myopathy (182920) is an allelic disorder with overlapping features. Description Myofibrillar myopathy refers to a genetically heterogeneous group of muscular disorders characterized by a pathologic morphologic pattern of myofibrillar degradation and abnormal accumulation of proteins involved with the sarcomeric Z disc (summary by Foroud et al., 2005). ... Straub et al. (2018), on behalf of the LGMD workshop study group, reclassified LGMD1A as a form of myofibrillar myopathy. Clinical Features Gilchrist et al. (1988) reported a large family from southeastern West Virginia diagnosed with autosomal dominant limb-girdle muscular dystrophy. ... One patient had a brother with distal leg weakness and another patient had an affected brother and an affected son, suggesting autosomal dominant inheritance. The main features included progressive distal muscle weakness and peripheral neuropathy with hyporeflexia. ... INHERITANCE - Autosomal dominant CARDIOVASCULAR Heart - Cardiomyopathy SKELETAL Feet - Achilles tendon contractures MUSCLE, SOFT TISSUES - Muscle weakness, distal, progressive - Muscle atrophy, distal - Proximal muscle involvement may occur - Muscle stiffness or aching - EMG shows myopathic and neurogenic changes - Muscle biopsy shows myofibrillar myopathy - Abnormal muscle fibers with amorphous, granular, or hyaline deposits - Congophilic staining - Increased staining for myotilin, dystrophin, desmin - Electron microscopy shows dense material emanating from the Z-disk - Phagocytic vacuoles with degraded membranous material NEUROLOGIC Peripheral Nervous System - Peripheral neuropathy - Hyporeflexia/areflexia in lower limbs LABORATORY ABNORMALITIES - Increased serum creatine kinase MISCELLANEOUS - Adult onset (mean 60 years) - Slowly progressive disorder - Limb-girdle muscular dystrophy 1A (LGMD1A, 159000 ) is an allelic disorder with overlapping clinical features MOLECULAR BASIS - Caused by mutations in the titin immunoglobulin domain protein gene (TTID, 604103.0002 ). ▲ Close

For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000). Clinical Features Ghezzi et al. (2011) reported 4 Italian patients with mitochondrial complex III deficiency. ... A fourth patient from southern Italy had normal psychomotor development until age 42 years, when he developed subacute, rapidly progressive neurologic failure resulting in death at age 45. Features included weakness with fasciculations, apraxia, dysarthria, bradykinesia, dystonia, paraparesis, and behavioral changes. ... Nogueira et al. (2013) reported 4 Portuguese sibs, born of parents who were likely related, with a complex neurodegenerative disease associated with significant psychiatric features. The age at onset varied between 12 and 34 years, but followed a relentlessly progressive course in each patient, resulting in death in 2 patients between ages 30 and 49 years. ... Some patients had extrapyramidal signs. The psychiatric features progressed to include major depression, psychosis, and extremely poor social interactions.

Homozygous mutation in the titin gene causes the more severe limb-girdle muscular dystrophy type 2J (LGMD2J; 608807). Clinical Features Markesbery et al. (1974) reported a late adult-onset, autosomal dominant form of distal myopathy with onset in the anterior compartment of the legs rather than in the hands, which is the presenting feature of Welander myopathy (604454). ... Heterogeneity Genetic Heterogeneity Felice et al. (1999) reported a family with autosomal dominant distal myopathy spanning 4 generations in whom linkage to Nonaka distal myopathy (605820) on 9p, MPD1 (160500) on 14q, Miyoshi myopathy on 2p13, and TMD on 2q31 was excluded. Clinical features included onset in the second to third decade of foot drop, difficulty in stair climbing, and progressive leg weakness. ... INHERITANCE - Autosomal dominant MUSCLE, SOFT TISSUES - Weakness of the muscles in the anterior compartment of the lower leg (particularly the tibialis anterior muscle) - Atrophy of the muscles in the anterior compartment of the lower leg - 'Steppage' gait - Reduced ankle dorsiflexion - Replacement of affected muscle tissue with fatty tissue - Biopsy shows rimmed vacuoles, central nuclei, and variation in fiber size - Myopathy seen on EMG MISCELLANEOUS - Adult onset (after age 35 years) - Slow progression without marked disability - Incomplete penetrance - Cardiomyopathy is not a feature MOLECULAR BASIS - Caused by heterozygous mutation in the titin gene (TTN, 188840.0004 ) ▲ Close

For a general description and a discussion of genetic heterogeneity of ALPS, see 601859. Clinical Features Salzer et al. (2013) reported a 12-year-old boy, born of consanguineous Turkish parents, with a primary immune deficiency syndrome characterized by B-cell deficiency and severe autoimmunity. ... By age 3 years, he had hepatosplenomegaly and generalized lymphadenopathy associated with low-grade herpes viremia. Additional autoimmune features included polychondritis and antiphospholipid syndrome, with antinuclear, anti-dsDNA, and anticardiolipin IgG antibodies. ... The patient's sister and brother presented at ages 10 and 6 years, respectively, with features of SLE, including rash, arthritis, and glomerulonephritis, but without a frank lymphoproliferative disorder. ... In a follow-up of the patients reported by Andre et al. (2007), Belot et al. (2013) noted that none of them presented with features of early-onset immunodeficiency, although 1 died at age 13 years of septic shock.

Single-gene testing (sequence analysis of GRIN2A, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found may be considered first in individuals with features that are highly suggestive of GRIN2A -related speech disorder and epilepsy. However, because many of these features overlap with those of other genetic epileptic encephalopathies, multigene panels or comprehensive genomic testing are often performed in lieu of single-gene testing. ... Development ranges from normal to severely impaired. Mild dysmorphic features may be present in individuals with a contiguous gene deletion. ... Reutlinger et al [2010] described three individuals with 16p13 deletions involving multiple genes and complete or partial heterozygous deletion of GRIN2A . All had mild dysmorphic features, intellectual disability, and epilepsy involving the rolandic region. ... Pathogenic variants in RBFOX1 and RBFOX3 may play a contributory role in some cases [Lal et al 2013, Turner et al 2015b]. At present, no clinical features differentiate GRIN2A -related EAS from EAS of other genetic causes.

Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics, Neurologic Features). Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis. ... The proportion of individuals with suggestive features of RVCL-S who do not have an identifiable heterozygous pathogenic variant in TREX1 has not been systematically studied. 5. ... Clinical course of RVCL-S Adapted from Pelzer et al [2019] Ophthalmologic Features Symptoms Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course. ... Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy. Neurologic Features Symptoms Focal neurologic symptoms were reported in 40/72 individuals. ... Penetrance Penetrance of RVCL-S is age dependent; however, it is thought that all individuals with a heterozygous pathogenic TREX1 variant will develop features of this condition if they live long enough.

Mutation in the ZFPM2 gene (603693) has been identified in patients with DORV. Clinical Features In a study of the families of children with cardiac malformations, Pierpont et al. (1988) found that conotruncal malformations carry a higher recurrence risk than other cardiac defects and proposed a monogenic mode of inheritance. ... Le Marec et al. (1989) had raised the question of autosomal recessive inheritance of truncus arteriosus. Typical facial features of conotruncal anomaly face syndrome (CAFS) are ocular hypertelorism (with increased interpupillary distance due to increased separation of the inner canthi), short palpebral fissures, 'bloated' eyelids, a low nasal bridge, a small mouth, and minor ear lobe anomalies. These features are almost always associated with nasal voice (often associated with cleft palate/submucosal cleft palate/bifid uvula) and mild mental retardation (frequently associated with developmental retardation and, occasionally, dwarfism), and often associated with cardiovascular anomalies. ... In a study of the origin of the deletion using microsatellite analyses in 48 de novo patients, the mother was shown to be the source in 65% of CAFS patients, while the father was the source in 64% of DGA patients. In addition to the major features of CAFS, other notable extracardiac anomalies were susceptibility to infection, schizophrenia, atrophy or dysmorphism of the brain, thrombocytopenia, short stature, facial palsy, anal atresia, and mild limb abnormalities. ... All patients with the deletion showed additional clinical features of the velocardiofacial syndrome.

See HYC1 (236600) for a discussion of nonsyndromic autosomal recessive forms of hydrocephalus. Clinical Features The hydrocephalus may become arrested and the principal manifestations may be mental deficiency and spastic paraplegia. ... Schrander-Stumpel et al. (1995) reported 5 families with definite hydrocephalus accompanied by various features, including macrocephaly, mental retardation, spastic paraplegia, adducted thumbs, and agenesis of the corpus callosum. ... Diagnosis Sajid and Copple (1968) found basilar impression (109500) as an associated feature in 2 brothers and suggested its usefulness in diagnosis. ... Schrander-Stumpel et al. (1990) noted that similar linkage of HSAS and the MASA syndrome (303350) to Xq28 and overlapping features of the two disorders suggested that they may be allelic. ... Okamoto et al. (1997) identified a mutation in the L1CAM gene (308840.0012) in a child with features of X-linked hydrocephalus (307000) who also had Hirschsprung disease and cleft palate.