Microphthalmia, Syndromic 1

A number sign (#) is used with this entry because of evidence that Lenz microphthalmia syndrome (MCOPS1) is caused by mutation in the NAA10 gene (300013) on chromosome Xq28. One such family has been reported.

Description

Lenz microphthalmia syndrome is a rare multisystem condition defined by the canonical features of unilateral or bilateral microphthalmia or anophthalmia and defects in the skeletal and genitourinary systems. Anomalies of the digits, teeth, and ears are also hallmarks of the syndrome. Intellectual disability ranges from mild to severe, with self-mutilating behaviors and seizures in severely affected individuals (summary by Esmailpour et al., 2014).

Genetic Heterogeneity

Other forms of syndromic microphthalmia include MCOPS2 (300166), caused by the BCOR gene (300485) on chromosome Xp11; MCOPS3 (206900), caused by mutation in the SOX2 gene (184429) on chromosome 3q26; MCOPS5 (610125), caused by mutation in the OTX2 gene (600037) on chromosome 14q22; MCOPS6 (607932), caused by mutation in the BMP4 gene (112262) on chromosome 14q22; MCOPS7 (309801), caused by mutation in the HCCS gene (300056) on chromosome Xp22; MCOPS9 (601186), caused by mutation in the STRA6 gene (610745) on chromosome 15q24; MCOPS11 (614402), caused by mutation in the VAX1 gene (604294) on chromosome 10q25; MCOPS12 (615524), caused by mutation in the RARB gene (180220) on chromosome 3p24; MCOPS13 (300915), caused by mutation in the HMGB3 gene (300193) on chromosome Xq28; MCOPS14 (615877), caused by mutation in the MAB21L2 gene (604357) on chromosome 4q31; and MCOPS15 (615145), caused by mutation in the TENM3 gene (610083) on chromosome 4q.

Syndromic microphthalmia has also been mapped to chromosome Xq27-q28 (MCOPS4; 301590) and to chromosome 6q21 (MCOPS8; 601349). A form of microphthalmia associated with progressive brain atrophy has been reported (MCOPS10; 611222).

Williamson and FitzPatrick (2014) reviewed genes associated with microphthalmia, anophthalmia, and/or coloboma phenotypes. They noted that when exon sequencing is combined with detection of gene deletions via aCGH and high-resolution analysis of intragenic microdeletions and microduplications, approximately 75% of cases of bilateral anophthalmia or severe microphthalmia are found to carry heterozygous mutations in the SOX2 (184429) or OTX2 (600037) genes, or biallelic mutations in the STRA6 gene (610745) (see also MCOPS5, 610125 and MCOPS9, 601186).

Nomenclature

The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.'

Clinical Features

The eye anomaly was unilateral in some of the affected persons in the remarkable pedigree described by Lenz (1955). Narrow shoulders, double thumbs, other skeletal anomalies, and dental, urogenital and cardiovascular malformations were observed. The mother of the proband, a 13-year-old boy born blind, had a deformity of the fifth finger, suggesting mild expression.

Herrmann and Opitz (1969) described an affected 11-year-old boy. Features were physical and mental retardation, hypospadias and bilateral cryptorchidism, renal dysgenesis and hydroureters, left microphthalmos, agenesis of upper lateral incisors and irregular lower incisors, long cylindrical thorax with sloping shoulders and exaggerated lumbar lordosis, and cutaneous clubbing of the right third and fourth toes. The mother was short and had a small head circumference.

In 6 males in 4 sibships connected through females, Dinno et al. (1976) described moderate microphthalmos, microcornea, and large bilateral colobomas of the optic disc, choroid, ciliary body, and iris. The shoulders were sloping, with underdeveloped clavicles. Height was about 168 cm. The patients had normal intelligence. None had children.

Ozkinay et al. (1997) reported a 15-year-old affected male who, in addition to features suggestive of Lenz microphthalmia, had dysgenesis of the corpus callosum and dilatation of the lateral cerebral ventricles. Ozkinay et al. (1997) pointed out similarities common to this condition, Goltz syndrome (305600), and Aicardi syndrome (304050).

Hornby et al. (2000) correlated visual function with clinical features and biometric findings in the eyes of children with coloboma. Of the 196 eyes with colobomatous malformations, 11 had microphthalmos with cyst (251505), and 185 eyes had coloboma (associated with microcornea in 155 eyes and with normal corneal diameter in 30 eyes). The visual prognosis depended on the phenotype of the more normal eye. Microphthalmos with cyst had the worst prognosis (all worse than 20/400). Microcornea with microphthalmos had a worse prognosis than microcornea without microphthalmos. For microcornea with microphthalmos, 67% saw worse than 20/400. Of the children with microcornea without microphthalmos, 76% saw better than 20/400. Simple coloboma (without microcornea or microphthalmos) had the best visual prognosis: only 7% saw 20/400 or worse. A corneal diameter of less than 6 mm had a poor visual prognosis, whereas a corneal diameter of more than 10 mm had a good prognosis.

Forrester et al. (2001) reported 3 brothers (aged 15 years, 9 years, and 18 months) and a maternal uncle (aged 27 years) with congenital clinical anophthalmia, delayed motor development, hypotonia, and moderate to severe mental retardation. They also had abnormally modeled ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads of the digits, scoliosis, and cardiac and renal abnormalities. An obligate carrier had abnormally modeled ears and syndactyly of toes 2 and 3 bilaterally.

Esmailpour et al. (2014) reexamined the 3 brothers with Lenz microphthalmia syndrome who were originally studied by Forrester et al. (2001), noting significant intrafamilial variation. All 3 sibs developed scoliosis to varying degrees, and 2 of them underwent surgery. Two of the brothers developed body hair to an uncomfortable degree, requiring frequent shaving. One of the brothers, who had previously been energetic, outgoing, and physically strong, showed loss of energy, increasing muscle stiffness, loss of short-term memory, and worsening autism-like behavior. He had 2 strokes, and MRI showed 50% narrowing of the carotid artery. Another brother, who was the most severely affected and had a seizure disorder, never developed words and relied on sign language to communicate. Histology of his skeletal muscle showed degeneration, and he also required surgical lengthening of his heel cord.

Okumus et al. (2008) reported a sporadic case of Lenz microphthalmia syndrome in a male infant who had additional features including macrophallus, broad chest with widely spaced nipples, and a wide gap between the first and second toes.

Mapping

By linkage and haplotype analysis in a family with Lenz microphthalmia syndrome, Forrester et al. (2001) mapped the disorder to a 17.65-cM region on Xq27-q28. This region overlaps that of the MCOPS4 locus (301590), which Graham et al. (1991) tentatively mapped to Xq27-q28.

Molecular Genetics

In 3 affected brothers with Lenz microphthalmia syndrome, originally studied by Forrester et al. (2001), Esmailpour et al. (2014) performed exome sequencing and identified a splice site mutation in the NAA10 gene (300013.0002) on chromosome Xq28. The mutation was confirmed by Sanger sequencing in the 3 sibs and their obligate heterozygote mother, as well as in a maternal aunt and her daughter, but was not found in 4 unaffected family members. The 3 heterozygotes had cutaneous syndactyly between the second and third toes and also displayed short terminal phalanges; because these manifestations were not seen in the mutation-negative family members, Esmailpour et al. (2014) suggested that the condition could be considered X-linked with reduced expressivity in heterozygotes. Analysis of the NAA10 gene in 11 male patients with microphthalmia and 'atypical Lenz syndrome' revealed no mutations.