Microphthalmia, Syndromic 6

A number sign (#) is used with this entry because microphthalmia with brain and digital anomalies (MCOPS6) is caused by heterozygous mutation in the gene encoding bone morphogenetic protein-4 (BMP4; 112262) on chromosome 14q22.

Clinical Features

Bennett et al. (1991) described a 21-week female fetus with histologically confirmed bilateral anophthalmia, retrognathia, brachycephaly, fleshy low-set angular ears, bilateral in-curving of the fifth digit with short middle phalanges and flexion of the thumbs, underdeveloped external genitalia, and hypoplastic kidneys. Brain anomalies included a small cerebellum and the absence of optic nerves, chiasma and tracts, geniculate bodies, and pituitary stalk and gland.

Elliott et al. (1993) reported a 4-year-old boy with bilateral clinical anophthalmia and dysmorphic features including micrognathia, extremely small tongue, high-arched palate, developmental and growth retardation, undescended testes with micropenis, and hypothyroidism believed to be secondary to a pituitary abnormality.

Phadke et al. (1994) reported a 5-day-old male infant with bilateral clinical anophthalmia, micrognathia, cleft palate, hypospadias, and bifid scrotum.

Lemyre et al. (1998) described a 21-month-old girl with bilateral clinical anophthalmia, absent left auditory canal, facial asymmetry, microretrognathia, hypotonia, and psychomotor retardation. X-rays revealed lambdoid craniosynostosis, a very small sella turcica, and cervical vertebral anomalies, and MRI revealed absence of the optic chiasm, hypoplasia of the pituitary gland, and cortical atrophy.

Bakrania et al. (2008) reported 2 patients with bilateral clinical anophthalmia, partial callosal agenesis, and other developmental anomalies including hypothyroidism and central vermis hypoplasia in 1 patient and microcephaly, sensorineural deafness, cryptorchidism, and cerebellar and pituitary abnormalities in the other. They also described 2 additional patients with anophthalmia-microphthalmia and digital and brain anomalies. One had right clinical anophthalmia and left microanterior segment, iris and chorioretinal coloboma, retinal dystrophy of both rods and cones, learning difficulties, partial callosal agenesis, and postaxial polydactyly of feet. This patient's grandmother had a similar brain phenotype, polydactyly, and finger webbing; both the grandmother and mother had high myopia but no anophthalmia-microphthalmia. The other had bilateral microphthalmia, broad hands, low thumbs, dysplastic nails, simple prominent ears, cryptorchidism, brain anomalies, seizures, and developmental delay. The patient's father did not have anophthalmia-microphthalmia but demonstrated some mild inferior pigmentation of both retinas, which was considered a possible forme fruste coloboma.

Cytogenetics

Using cultured tissue from a female fetus with bilateral anophthalmia and pituitary anomalies, Bennett et al. (1991) identified a small deletion of chromosome 14q22-q23. Using a fibroblast cell line from the female fetus reported by Bennett et al. (1991), Gallardo et al. (1999) localized the deletion to chromosome 14q22.3-q23 and showed that regulatory and coding regions of the SIX6 gene (606326) were included within the deletion. Analysis of microsatellite markers and sequencing data were compatible with SIX6 haploinsufficiency.

In a 4-year-old boy with bilateral clinical anophthalmia, hypogonadism, and suspected pituitary abnormality, Elliott et al. (1993) identified an interstitial deletion on chromosome 14, del14(q22.1-q22.3). The findings suggested that haploinsufficiency of genes in this region might account for the phenotype.

Lemyre et al. (1998) identified an interstitial deletion of the long arm of chromosome 14, del(14)(q22.1q23.2), in a 21-month-old girl with bilateral anophthalmia and pituitary hypoplasia. Noting that 2 other patients had been reported with similar deletions (Bennett et al., 1991 and Elliott et al., 1993), Lemyre et al. (1998) suggested that the region 14q22 is important for eye and pituitary development and noted that the BMP4 gene may play a role.

Ahmad et al. (2003) described a family in which the proband, his 3 sisters, and 2 of his 3 sons had uni- or bilateral clinical anophthalmia and preaxial polydactyly in the right hand. Karyotyping of the proband and 1 affected son showed deletion of 14q22-q23; the deletion was not present in his unaffected son. No pituitary anomaly was found in the proband or his affected son.

Nolen et al. (2006) reported a 5-year-old boy with clinical anophthalmia and absence of the optic nerves, chiasm, and tracts as well as pituitary gland hypoplasia on MRI who had an apparently balanced de novo chromosomal translocation t(3,14)(q28;q23.2). Translocation breakpoint analysis revealed a 9.66-Mb deletion at chromosome 14q22-q23. At birth the patient exhibited facial dysmorphism and abnormal ears, with small, triangular pinnae, small external auditory canals, and uplifted earlobes; he also had undescended testes, small scrotum, hypoplastic foreskin, and syndactyly of the hands and feet. Echocardiogram and renal sonograms were normal. Audiologic assessment at age 2 years revealed high frequency hearing loss bilaterally. At 5 years of age, the patient exhibited hypotonia and global developmental delay, with no expressive language. Nolen et al. (2006) noted that several genes are located within the 9.66-Mb deleted region, including OTX2 (600037), SIX6 (606326), and BMP4 (112262).

In 2 patients with bilateral clinical anophthalmia and partial callosal agenesis, Bakrania et al. (2008) detected interstitial deletion of 14q22-q23. One deletion, del(14)(q22.3q23.2), was found in a female patient with the additional features of hypothyroidism and cerebellar vermis hypoplasia. The other deletion, del(14)(q22.2-q23.1), was carried by a male patient with sensorineural deafness, cryptorchidism, and cerebellar and pituitary anomalies. MLPA analysis showed that both the BMP4 and OTX2 genes were deleted. No anomalies of the digits were reported for these 2 patients.

Molecular Genetics

Deletions in 14q22-q23 are associated with anophthalmia-microphthalmia, brain, pituitary, and ear anomalies including structural defects and hearing loss, hypothyroidism, poly- and/or syndactyly, clinodactyly, high-arched palate, cryptorchidism, and developmental delay (e.g., Ahmad et al., 2003, Bennett et al., 1991). Although the OTX2 gene (600037) had been identified as a causative gene for anophthalmia-microphthalmia within this region (see MCOPS5, 610125), Bakrania et al. (2008) suggested that it may not account for all cases and did not appear to explain a complex phenotype that includes hypopituitarism and digital anomalies because OTX2 is not expressed in the pituitary gland or digits during development. Bakrania et al. (2008) considered BMP4 (112262), also located at 14q22-q23, as a candidate gene and screened 215 individuals with ocular defects, mainly microphthalmia, for cytogenetic defects by chromosomal analysis, for gene deletions by multiplex ligation-dependent probe amplification (MLPA), and for mutations in the BMP4 gene by direct sequencing. They identified 2 individuals with a 14q22-q23 deletion associated with anophthalmia-microphthalmia, 1 with associated pituitary anomaly. Sequence analysis of the BMP4 gene identified 2 mutations: a frameshift mutation (112262.0001) in a family with anophthalmia-microphthalmia, retinal dystrophy, myopia, poly- and syndactyly, and brain anomalies, and a missense mutation (112262.0002) in an individual with anophthalmia-microphthalmia and brain and digital anomalies. Bakrania et al. (2008) remarked that although the SIX6 gene, which resides in the same 14q22-q23 region as BMP4 and OTX2, is expressed in pituitary and so could potentially explain the hypopituitarism in a contiguous gene syndrome, it does not appear to be important in human anophthalmia-microphthalmia (Aijaz et al., 2004).

Reis et al. (2011) analyzed the BMP4 coding region in 133 patients with various ocular conditions, including 60 with clinical anophthalmia/microphthalmia (34 syndromic), 38 with anterior segment anomalies, 16 with cataract, 4 with coloboma, 5 with high myopia, and 10 with other disorders. In 3 probands with syndromic microphthalmia, they identified heterozygosity for a 158-kb deletion involving only the BMP4 gene (112262.0006), a nonsense mutation (R198X; 112262.0007), and a frameshift mutation (112262.0008), respectively; the affected sister of the proband with the frameshift mutation carried both the frameshift and a missense mutation (H121R; 112262.0009).

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.'