Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004).
- Genetic Heterogeneity of Brittle Cornea ... Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). - Genetic Heterogeneity of Brittle Cornea Syndrome Brittle cornea syndrome-2 (BCS2; 614170) is caused by mutation in the PRDM5 gene (614161) on chromosome 4q25-q26.
Stein et al. (1968) reported brittle cornea associated with blue sclera in 2 Tunisian Jewish brothers with consanguineous parents, indicating autosomal recessive inheritance. Hyams et al. (1969) reported an affected Tunisian Jewish boy who may have been related ... Stein et al. (1968) reported brittle cornea associated with blue sclera in 2 Tunisian Jewish brothers with consanguineous parents, indicating autosomal recessive inheritance. Hyams et al. (1969) reported an affected Tunisian Jewish boy who may have been related to the patients of Stein et al. (1968) because 'the two families come from the same town in Tunisia.' Badtke (1941) reported 2 sisters, born of consanguineous parents, with blue sclerae and keratoconus from south Tyrol. Tucker (1959) reported the disorder in a brother and sister with first-cousin parents, and Arkin (1964) described an affected 17-year-old boy. The features included blue sclerae; large, cloudy, thin, bulging cornea, noted from early in life, and mimicking buphthalmos but accompanied by normal intraocular pressure; fragility of the cornea with repeated rupture; dental abnormalities somewhat like those of osteogenesis imperfecta; abnormal proclivity to fracture of bones; long, slender, hyperextensible fingers; and hernia. The Tunisian cases of Stein et al. (1968) and Hyams et al. (1969) had red hair, a sufficiently unusual finding in this group to suggest to the authors that it was a part of the syndrome. In keratoglobus the thinning of the cornea is generalized or in the periphery, whereas in keratoconus it is mainly central. Greenfield et al. (1973) reported 2 affected sibs with first-cousin parents. Judisch et al. (1976) studied 2 brothers with fragilitas oculi and other abnormalities and found normal lysyl hydroxylase activity, thus distinguishing the disorder from EDS VIA. Cadle et al. (1985) studied 3 sisters with EDS VI phenotype but normal lysyl hydroxylase and the additional feature of macrocephaly. On review it was concluded that the 2 sibs reported by Judisch et al. (1976) also had macrocephaly, and Cadle et al. (1985) suggested that macrocephaly and EDS VI phenotype was a recessive entity. Ticho et al. (1980) described a brother and sister, aged 16 and 8 years, with red hair, blue sclera, uniform keratoglobus, and extremely thin corneae with several leucomata from previous spontaneous perforations. No systemic manifestations were found, and blood examinations were normal. Their 3 sibs and their parents, first cousins of Tunisian Jewish origin, had dark hair and no abnormality of the eyes. Zlotogora et al. (1990) identified 2 groups of patients with the brittle cornea syndrome. The first group, composed of 5 families of Tunisian Jewish origin, was characterized by red hair in all affected individuals. In the second group, 9 families from various ethnic origins showed a normal distribution of hair color in the affected persons. Zlotogora et al. (1990) suggested that the locus for the gene may be closely linked to the locus for a gene responsible for hair color, with linkage disequilibrium in Tunisian Jews. Royce et al. (1990) described brittle cornea and blue sclerae in association with red hair in the 4-year-old daughter of healthy, consanguineous Syrian parents. Other features included joint hyperextensibility, soft skin, and dysplastic auricles with unusually soft cartilage. Electron microscopy showed dramatic ultrastructural alterations in the dermis: distributed over its whole thickness were 20-60 micron wide 'holes' or fiber-free spaces, filled with amorphous material. Al-Hussain et al. (2004) described 23 patients with brittle cornea syndrome from 13 Middle Eastern families (9 from Saudi Arabia, 2 from Syria, 1 from Jordan, and 1 from Yemen). A total of 28 events of corneal rupture were noted in 17 patients; 9 of these patients had bilateral ruptures. By age 4 years, 50% of patients had experienced corneal rupture. Blue sclerae were present in all 22 patients examined, and 20 patients had joint laxity. Most patients also had skin hyperelasticity without excessive fragility. All 19 patients examined biochemically showed normal lysyl hydroxylase activity. Christensen et al. (2010) restudied a brother and sister with brittle cornea syndrome who were originally reported by Bertelsen (1968) as having 'dysgenesis mesodermalis corneae et sclerae.' Both sibs, born to first-cousin Norwegian parents, had markedly blue sclerae and thin cornea. In the girl, rupture of the cornea occurred in both eyes after slight indirect trauma. Megalocornea, deep anterior chambers, and severe myopia were present. Christensen et al. (2010) examined 8 members in 3 generations of the family. At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced bone mineral density (BMD), dental anomalies, hearing loss, and minor cardiac defects. Christensen et al. (2010) concluded that BCS is a disorder that affects a variety of connective tissues. The authors noted that reduced BMD and atypical dental crown morphology had not previously been reported in this disorder. The sibs, who were the only members of the family to have red hair, were found to be homozygous for the common red hair variant R151C in the MC1R gene (155555.0004). Christensen et al. (2010) suggested that the association with red hair in some individuals with BCS is likely to occur by chance. Khan et al. (2010) reported a consanguineous Syrian family in which 2 sibs had brittle cornea syndrome and 1 sib had blue sclerae only. The older affected sib was a 13-year-old boy who had blue sclerae noted at birth and suffered bilateral corneal rupture at 2 years of age due to minor trauma, with multiple corneal operations resulting in phthisis. Examination revealed bilateral phthisical eyes with blue sclerae. His skin was thin and velvety with prominent subcutaneous veins and scattered small scars on all extremities, but there was no abnormal elasticity or joint hypermobility. He also had a slightly arched palate, bilateral valgus foot and hallux valgus, and normal bone density. His 8-year-old sister had blue sclerae and keratoglobus; slit-lamp examination revealed thin corneas and corneal haze in the left eye due to an earlier Descemet membrane detachment. She had thin velvety skin with prominent subcutaneous veins but no abnormal elasticity or scarring, and she had significant joint hypermobility. In addition, she displayed frontal bossing, arched palate, pectus carinatum, lumbar lordosis, and bilateral talipes valgus; radiography confirmed irregular calvaria, exaggerated lumbar lordosis, and bilateral talipes valgus, with normal bone densities. A 4-year-old sister had blue sclerae noted at birth, but ocular examination was normal, and physical examination was unremarkable.
Abu et al. (2008) analyzed the candidate gene ZNF469 in 4 Tunisian Jewish families, one of which was the family originally reported by Ticho et al. (1980), and 1 Palestinian family with brittle cornea syndrome-1 and identified homozygosity ... Abu et al. (2008) analyzed the candidate gene ZNF469 in 4 Tunisian Jewish families, one of which was the family originally reported by Ticho et al. (1980), and 1 Palestinian family with brittle cornea syndrome-1 and identified homozygosity for 2 different 1-bp deletions (612078.0001 and 612078.0002, respectively) that were not found in ethnically matched controls. In a brother and sister with brittle cornea syndrome who were originally reported by Bertelsen (1968), Christensen et al. (2010) identified a homozygous mutation in the ZNF469 gene that affected the fourth of 5 zinc finger domains (612078.0003). In affected sibs from a consanguineous Syrian family with brittle cornea syndrome (BCS1), Khan et al. (2010) identified homozygosity for a nonsense mutation in the ZNF469 gene (612078.0004). Burkitt Wright et al. (2011) noted that the phenotypic spectrum in BCS patients with mutations in either the ZNF469 or PRDM5 (614161) genes is extremely similar if not identical (see BCS2, 614170), suggesting that the 2 genes act within the same developmental pathway. Quantitative PCR of mutant fibroblasts from BCS1 and BCS2 patients showed that mutation in either ZNF469 or PRDM5 causes significant downregulation of genes encoding molecules involved in extracellular matrix development and maintenance compared to controls.