Alternative titles; symbols
SNOMEDCT: 438504004; ORPHA: 568; DO: 0111799;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Microphthalmia, syndromic 1 | 309800 | X-linked | 3 | NAA10 | 300013 |
A number sign (#) is used with this entry because of evidence that syndromic microphthalmia-1 (MCOPS1) is caused by mutation in the NAA10 gene (300013) on chromosome Xq28.
Syndromic microphthalmia-1 (MCOPS1) is an X-linked disorder characterized by unilateral or bilateral microphthalmia or anophthalmia. The most common extraocular features are impaired intellectual development, large and dysplastic ears with skin tags, high-arched or cleft palate, dental anomalies, urogenital anomalies, and skeletal manifestations including lordosis or scoliosis, clinodactyly, syndactyly, brachydactyly, and abnormal thumbs. There is considerable variation in severity among reported families (Slavotinek et al., 2005).
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; MCOPS15 (615145), caused by mutation in the TENM3 gene (610083) on chromosome 4q; and MCOPS16 (611038), caused by mutation in the RAX gene (601881) on chromosome 18q21.
A form of syndromic microphthalmia also maps to chromosome 6q21 (MCOPS8; 601349). A form of microphthalmia associated with progressive brain atrophy has been reported (MCOPS10; 611222).
A form of syndromic microphthalmia, formerly designated MCOPS4, has been found to be the same entity as MCOPS1.
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).
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.'
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.
In 2 generations of a family from Northern Ireland, Graham et al. (1991) described 7 males with clinical anophthalmia, 3 of whom were deceased at the time of study. Clinically affected males with bilateral disease had fusion of the eyelid margins (ankyloblepharon) and radiologically demonstrable underdevelopment of the bony orbits. All males had mental retardation (IQ less than 50) and 1 male was born with preauricular skin tags and a cleft soft palate. No deafness was present, and the lack of limb, hand, dental, and urogenital abnormalities appeared to exclude the diagnosis of Lenz microphthalmia syndrome. This family had originally been reported by Graham et al. (1988).
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.
Slavotinek et al. (2005) reported a 4-generation family in which 4 males had anophthalmia. Only 1 patient (III-5) was available for examination. His medical history included unilateral right anophthalmia, colorblindness, and bilateral hearing loss that had developed in adulthood following frequent ear infections. Examination at age 50 years showed prominent supraorbital ridges with a right-sided ocular prosthesis, minimal development of the right upper and lower eyelids, small right orbit, and right epicanthal fold. The left eye was normal. Skeletal findings included mild fifth-finger clinodactyly bilaterally, pes planus, and bilateral partial syndactyly between the second and third toes, but no scoliosis. His sister had a male infant who was stillborn and had microphthalmia and a horseshoe-shaped kidney. The proband also had an affected male cousin (III-3) who was reported to have right anophthalmia, colorblindness, and deafness in the left ear following an ear infection at age 41 years. The cousin's mother (II-2) was examined and had valgus deviation of the right thumb and pes planus, which the authors attributed to likely carrier status. Both cousins had normal intelligence and had completed university educations. Their maternal grandfather was reported to have had colorblindness, 6 toes, and pes planus, but no known microphthalmia or anophthalmia.
Johnston et al. (2019) restudied the family (family 1) originally reported by Graham et al. (1991), noting that an additional affected male (IV-3) had since been born with a large open neural tube defect; he also had right anophthalmia, bilateral 2-3 cutaneous syndactyly of the toes, and irregular teeth. However, he did not exhibit developmental delay or behavioral problems, as had been observed in his affected uncles. Another male family member (II-18), who was initially considered unaffected, was noted to have cleft soft palate and a single ear tag. Johnston et al. (2019) also reported an unrelated boy (family 3) who was born with spina bifida and had widely spaced eyes, unilateral phthisis bulbi, downturned corners of the mouth, small penis, and small feet with upturned nails. He underwent repair of myelomeningocele, and evaluation at 8 months of age showed hydrocephalus with ventriculoperitoneal shunt. Brain MRI revealed ventriculomegaly with Chiari type 2 malformation, but he had normal developmental milestones. In addition, he had left grade 2 vesicoureteric reflux with a normal renal ultrasound. A maternal uncle was reported to have had anencephaly.
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.
Cheng et al. (2019) reported an 11-year-old boy (patient 23) with global developmental delay, severely impaired intellectual development, generalized hypotonia, microcornea, and microphthalmia. MRI showed agenesis of the corpus callosum and craniosynostosis.
In a 2-generation family from Northern Ireland with clinical anophthalmia segregating in a pattern consistent with X-linked recessive inheritance, Graham et al. (1991) performed multipoint linkage analysis that suggested that the gene was localized to the Xq27-q28 region (maximum lod, 1.9 at theta = 0.08). The authors noted that although some early reports of 'anophthalmos' were probably instances of Norrie disease (310600), the linkage mapping would exclude that possibility in this family, since the Norrie disease gene is located at Xp11.4.
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 overlapped that to which Graham et al. (1991) had tentatively mapped a similar disorder in a family from Northern Ireland.
In a 4-generation family with unilateral clinical anophthalmia, Slavotinek et al. (2005) performed linkage analysis and obtained the highest 2-point lod score (0.73, theta = 0) with markers DXS1205 and DXS1227 on chromosome Xq27, in a region overlapping the ANOP1 locus. Recombination events in 2 affected cousins (III-3 and III-5) excluded the MCOPS2 locus, and mutation analysis of the SOX3 gene (313430) did not reveal any sequence alterations.
Johnston et al. (2019) repeated multimarker analysis in the Irish family (family 1) originally studied by Graham et al. (1991) and obtained a peak lod score of 2.19 with 75% penetrance, 2.46 with 50% penetrance, and 3.31 assuming gonadal mosaicism. Haplotype analysis revealed a recombination event that restricted the possible linkage region telomeric to chrX:144,028,513 (GRCh37), a region including the HMGB3 and NAA10 genes. Reexamination of linkage data from a 5-generation family (family 2) originally reported by Slavotinek et al. (2005) and family 1 showed overlapping regions near Xqtel consistent with linkage.
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.
By trio exome sequencing in an Irish family (family 1) with clinical anophthalmia that was previously studied by Graham et al. (1991), Johnston et al. (2019) identified a mutation in the 3-prime UTR of the NAA10 gene (300013.0006) that altered the polyadenylation sequence (PAS). The variant segregated fully with disease and was not found in the gnomAD database. Targeted Sanger sequencing in a 5-generation family (family 2) originally reported by Slavotinek et al. (2005) identified another mutation in the 3-prime UTR (300013.0007) that was present in 2 affected male cousins and 5 carrier females, and was not found in 2 unaffected males. In an unrelated proband with unilateral phthisis bulbi (family 3), targeted sequencing of 41 genes associated with several eye malformations revealed a third variant in the NAA10 3-prime UTR (300013.0008). Targeted sequencing of the NAA10 PAS in 250 unrelated patients with microphthalmia/anophthalmia/coloboma and in 126 male patients with developmental eye disorders did not reveal any additional variants. Analysis of X inactivation showed greater than 90% skewing in 4 of 11 carrier females; however, carrier females did not show consistent skewing of X inactivation. The authors noted that all 3 families with mutations in NAA10 manifested microphthalmia/anophthalmia with variable additional features, and family 1 also exhibited variable expressivity, ranging from microphthalmia/anophthalmia associated with severe intellectual disability to isolated cleft palate and an ear tag.
In an 11-year-old boy (patient 23) with Lenz microphthalmia syndrome, Cheng et al. (2019) identified a frameshift mutation in the NAA10 gene (300013.0009).
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