Microphthalmia With Limb Anomalies

A number sign (#) is used with this entry because of evidence that microphthalmia with limb anomalies (MLA) is caused by homozygous mutation in the SMOC1 gene (608488) on chromosome 14q24.

Clinical Features

In 5 children of 2 different families with consanguineous parents, Richieri-Costa et al. (1983) described the association of bilateral (in 4) or unilateral (in 1) clinical anophthalmia with multiple other congenital abnormalities, mainly in the distal parts of the limbs. Traboulsi et al. (1984), who attributed the first description to Waardenburg (1961), reported affected brother and sister and affected first cousin once removed. The parents were consanguineous in the case of each affected sibship. The proband had bilateral syndactyly of the fourth and fifth toes, synostosis of the fourth and fifth metatarsals on the left, and absence of the right fifth metatarsal. Another sister had cleft lip and fused toes without anophthalmia and another sister had bilateral toe fusion deformities. Le Merrer et al. (1988) described 2 consanguineous sibships with 3 children and 2 children with this syndrome, respectively. The distal abnormalities of the limbs included syndactyly IV-V, fusion of metacarpals IV-V, absence of the fifth toes, and, in the second family, hypoplasia of the fibula with short femur or tibia.

Sayli et al. (1995) reported the cases of 2 brothers from a consanguineous family who had bilateral clinical anophthalmia, partial synostosis of metatarsals IV and V, and basal synostosis of the fourth and fifth toes on the right only in the older sib.

Suyugul et al. (1996) reported the cases of 2 girls, the offspring of consanguineous Turkish parents, who had bilateral clinical anophthalmia, upper and lower limb abnormalities, and mental retardation. They reported an affected boy with consanguineous parents from a second Turkish family and reviewed features of some of the reported cases. This disorder was also described by Pallotta and Dallapiccola (1984).

Megarbane et al. (1998) described a 12-day-old male infant, born of consanguineous Lebanese parents, with clinical anophthalmia, split hand, oligodactyly, syndactyly, and polydactyly. The authors stated that these features were consistent with ophthalmoacromelic syndrome (OAS), but noted that this was the first report of 2/3 syndactyly of the fingers, metacarpal polydactyly, or lobster-claw hand deformity in OAS.

Tekin et al. (2000) reported an additional patient with ophthalmoacromelic syndrome. The parents were of Turkish ancestry and were reportedly distant relatives. The patient had bilateral clinical anophthalmia and typical limb malformations. In addition, the patient had interruption of the inferior vena cava with azygos continuation, the first report of internal organ abnormalities in this condition.

Cogulu et al. (2000) reported an 8-year-old Turkish girl, born of consanguineous parents, who had bilateral clinical anophthalmia, syndactyly of the fourth and fifth fingers, and absence of the fifth toes. Psychomotor development was normal. X-ray examination revealed proximal fourth and fifth metacarpal synostosis, hypoplasia of the fifth finger, coalition of capitate and hamate, and absence of the fifth metatarsals and toes.

Garavelli et al. (2006) described an Italian boy, born of second-cousin gypsy parents, who had bilateral clinical anophthalmia, fused fourth and fifth metacarpals bilaterally with fifth fingers set at the base of the fourth, presence of 4 toes with 2-3 syndactyly, and undescended right testis. Abdominal ultrasound and renal scintigraphy revealed horseshoe kidney; the authors stated that this was the first report of a renal malformation in this disorder.

Teiber et al. (2007) described a 15-month-old girl with ophthalmoacromelic syndrome. She had an asymmetric face, left unilateral microphthalmia, short, hypoplastic fifth fingers with a single interphalangeal crease, and proximal implantation of the second and third toes. Radiographs of the hands revealed synostosis of the fourth and fifth metacarpals. Spine x-rays demonstrated cervical fusion and hemivertebrae. The authors stated that this was the first report of vertebral anomalies in this disorder.

Mapping

Hamanoue et al. (2009) performed homozygosity mapping in 2 unrelated consanguineous Lebanese families with ophthalmoacromelic syndrome, 1 of which had been previously reported by Megarbane et al. (1998), and identified a 422-kb common region on chromosome 10p11.23 between STS9 and STS12. Analysis of the 2 Lebanese families as well as a nonconsanguineous Japanese OAS family with 2 affected sibs yielded a maximum multipoint lod score of 3.9863 near STS9; the maximum 2-point lod score was 2.9444 (theta = 0.0) at STS10. No causative mutations were found on screening of MPP7 (610973), the only gene located in the critical interval. All 3 families had different haplotypes in the 422-kb segment.

In the 3 families with microphthalmia and limb anomalies (MLA) previously studied by Hamanoue et al. (2009) and an additional Turkish MLA family, previously reported by Cogulu et al. (2000), Okada et al. (2011) performed homozygosity mapping and haplotype analysis but did not detect any regions common to all 4 families. Analysis to identify common regions in any 3 of the 4 families yielded a lod score of 3.9 at chromosome 14q24.1-q24.2 in the Japanese and Turkish families and 1 of the Lebanese families. Fine mapping narrowed the region to a 3.0-Mb interval containing 24 genes.

In a consanguineous Egyptian family in which 2 sisters had MLA, Abouzeid et al. (2011) performed homozygosity mapping and identified 3 homozygous regions larger than 1 Mb, the largest of which was a 14-Mb interval at chromosome 14q23.

Molecular Genetics

In 3 families with microphthalmia and limb anomalies mapping to chromosome 14q24.1-q24.2, Okada et al. (2011) analyzed 14 candidate genes and identified homozygosity for a nonsense and 2 different splice site mutations in the SMOC1 gene, respectively (see, e.g., 608488.0001-608488.0003). The mutations segregated with disease in each of the families and were not found in ethnically matched controls. No mutations were found in a fourth MLA family, in which the proband was a Lebanese boy originally reported by Megarbane et al. (1998); the disease in that consanguineous family was unlinked to the 14q24.1-q24.2 locus.

In 2 sisters with MLA from a consanguineous Egyptian family, Abouzeid et al. (2011) identified a splice site mutation in the SMOC1 gene (608488.0003). The mutation was detected in heterozygosity in the unaffected parents, but was not found in 556 control chromosomes from individuals of Egyptian, North African, and European descent.

Genetic Heterogeneity

In the Lebanese boy with MLA who was originally described by Megarbane et al. (1998) and was found to be negative for mutation in the SMOC1 gene by Okada et al. (2011), Kondo et al. (2013) performed whole-exome sequencing and identified homozygosity for a missense variant in the FNBP4 gene (T228M; see 615265.0001). Although Kondo et al. (2013) demonstrated substantial FNBP4 expression in human fetal and adult eye tissues, the causative nature of the T228M variant has not been confirmed.

Animal Model

Okada et al. (2011) studied Smoc1-null mice and observed recapitulation of the human microphthalmia and limb anomalies phenotype, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed.

Nomenclature

See 309800 for discussion of the misuse of the term 'anophthalmia' in the medical literature.