Meier-Gorlin Syndrome 1

A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-1 (MGORS1) is caused by homozygous or compound heterozygous mutation in the ORC1 gene (601902) on chromosome 1p32.

Description

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011).

Genetic Heterogeneity of Meier-Gorlin Syndrome

Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12.

An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22.

Clinical Features

Gorlin et al. (1975) described this condition in a teenaged male in whom microtia, absent patellae, and micrognathia were the significant features. Camptodactyly of the fingers was noted, as well as Blount osteochondritis dissecans and bilateral aseptic necrosis of the lateral femoral condyles. The family history was unremarkable and parental consanguinity was denied. Gorlin et al. (1975) pointed to a single case report by Meier and Rothschild (1959) of what appeared to be the same disorder; the parents were consanguineous.

Cohen et al. (1991) used the designation ear, patella, short stature syndrome (EPS) for a condition they observed in 2 sisters who had bilateral microtia, absent patellae, short stature, poor weight gain, and characteristic facial features. Other skeletal anomalies included complete habitual dislocation of the elbow, slender ribs and long bones, abnormal modeling of the glenoid fossas with hooked clavicles, and clinodactyly. Bone age was significantly delayed and there was flattening of the epiphyses. Similarities to the findings in the 2 unrelated males reported by Hurst et al. (1988) were noted. Bongers et al. (2005) presented pictures indicating the change in facial appearance of the Meier-Gorlin syndrome during aging. Pictures at ages 14 years and 20 years of the same individual reported by Cohen et al. (1991) were presented.

Boles et al. (1994) described this disorder in 2 daughters of phenotypically normal, African American parents who showed severe proportional dwarfism with microcephaly, peculiar craniofacial anomalies (maxillary and mandibular hypoplasia, full lips, small mouth), microtia, absent patellae, and joint hyperextensibility.

Lacombe et al. (1994) provided follow-up on the male patient originally reported by Gorlin et al. (1975). Family history was unremarkable, and the patient had 3 healthy sibs. As an infant he was observed to have bilateral microtia, micrognathia, bilateral talipes equinovarus, an arthrogryposis-like condition, and unilateral cryptorchidism. Absent patellae were later noted, together with short stature, mild scoliosis, and fifth-finger camptodactyly. On examination as an adult, he had degeneration of the knees due to absent patellae, with bilateral aseptic necrosis of the lateral femoral condyles. He had normal mental status.

Loeys et al. (1999) reported 2 brothers with Meier-Gorlin syndrome, the younger of whom was more severely affected. Both patients had severe deafness and congenital labyrinthine anomalies, which had not previously been described as features of this syndrome. Unusual craniofacial appearance and hypoplastic genitalia were demonstrated by photographs. The neuromotor and mental development of these patients was adversely affected by late diagnosis, deafness, and their sociocultural environment, but their cognitive ability fell within the range observed in other Meier-Gorlin patients. Loeys et al. (1999) recommended neuroradiographic imaging and functional inner ear investigations in the diagnostic workup of this rather specific, probably autosomal recessive mental retardation syndrome with multiple congenital anomalies.

Bongers et al. (2001) reported 6 female and 2 male patients from 7 families with Meier-Gorlin syndrome and reviewed the literature on this condition. Most of their patients had bilateral small ears, patellar aplasia/hypoplasia, and short stature, except for monozygotic twins who had normal patellae on physical examination. Radiographic studies of the patellae were recommended in patients with this condition to understand the patellar abnormality better. Bongers et al. (2001) also described differences in facial features between patients reported in early infancy (micrognathia, microstomia, and full lips) and those described at older age (high vertical forehead, narrow nose, and high nasal bridge). One of their male patients had hypoplasia of the corpora cavernosa and the medial segment of the urethra, which had not previously been reported in this condition. Bongers et al. (2005) presented pictures of the Meier-Gorlin syndrome in a 5-year-old boy with small and simply formed ears and full lips.

Terhal et al. (2000) reported 2 patients who had disproportionate short stature and breast hypoplasia in addition to the typical features of EPS.

Cohen et al. (2002) described an Italian boy with the triad of microtia, absent patellae, and growth retardation of prenatal onset. At the age of 18.5 years, he was 44 cm tall. Recombinant growth hormone therapy had no beneficial effect. At the age of 15 years, the patient had urgent surgery for acute torsion of the left spermatic cord, a condition related to a congenital defect of the tunica vaginalis.

Shalev and Hall (2003) reported a 25-year-old woman with Meier-Gorlin syndrome. Her phenotypic evolution was characterized by severe growth retardation with decelerated growth of the head and subsequently a relatively small head, normal intelligence, alteration of the facial features to a more proportionate appearance, improvement of joint function, and incomplete breast development. Other characteristics of her phenotype in adulthood included a cheerful personality, a high forehead and accentuated nasolabial folds, very small ears, hypoplastic breasts, and normal menstruation.

Faqeih et al. (2005) reported a girl, born of nonconsanguineous parents belonging to an endogamous tribe in Saudi Arabia, who exhibited the classic Meier-Gorlin triad of bilateral small ears, patellar aplasia, and short stature, as well as delayed bone age. At birth, she was diagnosed with congenital left upper lobe emphysema (see 130710) and underwent left upper lobectomy and subsequent right middle lobectomy; a chest x-ray also showed a soft tissue density posterior to the distal sternum, suggestive of Morgagni hernia. She was found to have growth hormone (GH) deficiency and was started on recombinant GH at age 6, but at age 10 she was still below the fifth percentile for height and weight.

Inheritance

Parental consanguinity and the occurrence of affected sibs of normal parents indicate autosomal recessive inheritance (Cohen et al., 1991; Boles et al., 1994).

Mapping

In a consanguineous Saudi Arabian family in which 2 children had a form of microcephalic primordial dwarfism resembling Meier-Gorlin syndrome, Bicknell et al. (2011) performed genomewide homozygosity mapping and identified a single homozygous region on chromosome 1p32 that was refined by microsatellite genotyping to a 15.6-cM region.

Molecular Genetics

In 2 affected sibs from a consanguineous Saudi Arabian family with a form of microcephalic primordial dwarfism resembling Meier-Gorlin syndrome mapping to chromosome 1p32, Bicknell et al. (2011) identified homozygosity for a missense mutation in the candidate gene ORC1 (601902.0001). Screening of 204 additional individuals with microcephalic primordial dwarfism identified a further 3 probands with biallelic missense mutations in ORC1 (601902.0002-601902.0004). All 5 mutation-positive individuals had very marked growth retardation with proportionate microcephaly and 3 had relatively small ears; however, in the 3 patients who underwent skeletal analysis, patellae were present, although 1 patient had hyperextended dislocated knees at birth.

In a follow-up study, Bicknell et al. (2011) analyzed the ORC1 gene in 2 brothers with a complex lethal developmental syndrome involving profound growth retardation and microcephaly and identified compound heterozygosity for a missense (R105Q; 601902.0003) and a frameshift mutation (601902.0005). Both brothers also had microtia, and 1 had absent patellae. Subsequent sequencing of ORC1 in 33 individuals with an established diagnosis of Meier-Gorlin syndrome revealed 2 probands who were compound heterozygous for R105Q and a splice site mutation (601902.0006) in the ORC1 gene, 1 of whom was the male patient originally described by Gorlin et al. (1975) and the other, a 23-year-old English woman previously reported by Bongers et al. (2001).

In a woman with Meier-Gorlin syndrome who was previously reported by Shalev and Hall (2003), Guernsey et al. (2011) independently identified compound heterozygosity for missense mutations in the ORC1 gene (601902.0003 and 601902.0007).

Exclusion Studies

Because the Meier-Gorlin syndrome had been suggested as the human equivalent of the 'short ear' mouse (Lacombe et al., 1994), Cohen et al. (2002) performed a mutation analysis of the BMP5 (112265) gene, which is mutant in the mouse disorder, in a patient with Meier-Gorlin syndrome; no mutation was found. The LMX1B (602575) and the SHOX (312865) genes were evaluated because of the absent patellae and short stature, respectively, and were found to be normal as well.

Genotype/Phenotype Correlations

De Munnik et al. (2012) studied 45 patients from 35 families with Meier-Gorlin syndrome, including 27 females and 18 males with ages ranging from 3 months to 47 years, most of whom had previously been reported (Bongers et al., 2001; Bicknell et al., 2011; Bicknell et al., 2011; Guernsey et al., 2011). Thirty-five patients from 26 families had mutations in 1 of the 5 known pre-replication complex genes, including 10 (29%) with mutations in ORC1, 7 (20%) in ORC4, 7 (20%) in ORC6, 10 (29%) in CDT1, and 1 (3%) in CDC6; 10 patients from 9 families did not have a definitive molecular diagnosis. The classic triad of microtia, absent or hypoplastic patellae, and short stature was observed in 82% of these patients. Additional manifestations included mammary hypoplasia, which was present in all 13 postpubertal females (10 mutation-positive and 3 without molecular diagnosis) and abnormal genitalia, which was present in 42% and consisted predominantly of cryptorchidism and hypoplastic labia majora/minora. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumference than individuals with mutations in the 4 other genes and individuals without definitive molecular diagnosis. No other clear genotype/phenotype correlation was detected, although compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation with mutations in ORC4 and more frequent pulmonary emphysema with mutations in CDT1, and a lethal phenotype was observed in 4 compound heterozygous individuals, 2 with mutations in ORC1 and 2 with mutations in CDT1.