Nance-Horan Syndrome

A number sign (#) is used with this entry because Nance-Horan syndrome (NHS) is caused by mutation in the NHS gene (300457) on chromosome Xp22.

Description

Nance-Horan syndrome is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation (summary by Burdon et al., 2003).

Clinical Features

Affected males have dense nuclear cataracts and frequently microcornea. Carrier females may show posterior Y-sutural cataracts with small corneas and only slightly reduced vision. Horan and Billson (1974) described a family in which 2 brothers had sutural cataracts like those known to be X-linked (302200) in association with Hutchinsonian incisors (but no evidence of syphilis). Two sisters and the mother, despite normal vision, showed punctate opacities surrounding the posterior Y-suture and dental changes similar to those in the brothers. The mother's maternal uncle had surgery for cataract at age 3 years. Nance et al. (1974) described an extensively affected family in which males and carrier females with cataract and heterozygote lens changes, respectively, had dental anomalies, whereas persons without lens changes did not. Affected males had microcornea. Two had had mesiodens (a supernumerary centrally situated upper incisor) removed in childhood and others had had other supernumerary teeth removed. Screwdriver incisors were found in heterozygotes. Affected males had prominent, anteverted pinnae and short metacarpals. Another family with the Nance-Horan syndrome was reported by van Dorp and Delleman (1979). They emphasized the association of large, anteverted pinnae and of dental anomalies (irregular diastema, cone-shaped incisors, and in some cases supernumerary teeth). Bergen (1997) concluded that the family reported by Waardenburg et al. (1961) was the same as the family reported by van Dorp and Delleman (1979).

Bixler et al. (1984) reported 2 additional kindreds. In one of these, the heterozygous female was blind in one eye and reportedly had had supernumerary central incisors removed. Whether the syndrome is the same as that (302200) in the families reported by Walsh and Wegman (1937) is not completely certain. Maumenee (1988) suggested that they are the same disorder. Walpole et al. (1990) pictured affected mother and son and pointed out large, prominent ears and nose and high nasal bridge. They suggested that intellectual handicap or developmental delay is a feature in over a fifth of affected males.

Li et al. (2015) reported a Chinese family in which 10 members (4 males and 6 females) over 3 generations had Nance-Horan syndrome. The ocular manifestation in the 4 males consisted of bilateral and severe early-onset cataract with microcornea. Obligate heterozygous females had a variable phenotype from total opacity to clear lenses, with bilateral lens opacity observed in most and microcornea in 2. Severe visual impairment led to nystagmus and strabismus in most of the affected males and female carriers. All affected males had similar facial features, including large anteverted pinnae and widely spaced teeth with notched or serrated incised edges. In obligate carrier females, dental abnormalities were generally less severe.

Mapping

Stambolian et al. (1989) found a suggestion of linkage of NHS to 2 DNA markers (DXS43 and DXS84) located on Xp. Further linkage studies may help resolve the question of the relationship of these 2 forms of X-linked cataract. Both appear to be on Xp. Stambolian et al. (1989, 1990) demonstrated linkage with several DNA markers in the region Xp22.3-p21.1. A lod score of 7.07 was obtained for linkage with DXS41 at theta = 0.0. They suggested that NHS in the human may be homologous to the Xcat locus in the mouse. The Xcat mutation causes total lens opacity both in hemizygous males and in homozygous females (Favor and Pretsch, 1987, 1990). The fact that the mouse locus is closely linked to the hypophosphatemia locus as well as the fact that both human hypophosphatemia and NHS are tightly linked to DXS41 suggests a conserved block of syntenic genes in this region of the X chromosome. Using backcross progeny carrying the Xcat mutation obtained from an interspecific cross, Stambolian et al. (1994) subjected genomic DNA to Southern and PCR analyses to identify RFLPs and simple sequence length polymorphisms, respectively. Thereby, they refined the location of the Xcat gene to a 2-cM region, eliminated several genes from consideration as the Xcat mutation, and suggested candidate genes.

Zhu et al. (1990) found a lod score of 1.662 at theta = 0.16 for linkage with a probe from locus DXS85 on Xp22.3-p22.2. See also Lewis et al. (1990). In a Dutch family previously studied by van Dorp and Delleman (1979), Bergen et al. (1994) found close linkage to 3 Xp markers, DXS207, DXS43, and DXS365. Multipoint linkage analysis suggested that the gene lies near DMD (300377) proximally and STS (300747) distally.

Toutain et al. (2002) performed linkage analysis in 11 multiplex NHS families, which showed that the disease-causing gene mapped to the Xp22 region in all families tested, and a combined maximum 2-point lod score of 9.94 at theta = 0.00 was obtained at the RS1 locus (312700). A recombination with the marker DXS1195 was observed in 2 independent families, refining the localization of the NHS gene on the telomeric side. These results combined with previous data reduced the NHS gene interval to around 1 Mb between DXS1195 on the telomeric side and DXS999 on the centromeric side in the Xp22.13 region. Direct sequencing or SSCP analysis of the coding exons of 5 genes (SCML1, 300227; SCML2, 300208; STK9, 300203; RS1, 312700; and PPEF1, 300109), located in the critical interval, failed to detect any mutation in 12 unrelated NHS patients, making it highly unlikely that these genes are implicated in NHS.

Molecular Genetics

Studying the extended Australian family in which Horan and Billson (1974) first identified Nance-Horan syndrome, Burdon et al. (2003) confirmed localization of the disease locus to a 1.3-Mb interval on Xp22.13. In that family and 4 others with NHS, they identified protein-truncating mutations in a novel gene, which they called NHS (see 300457.0001-300457.0004).

Ramprasad et al. (2005) reported a 4-generation family containing 8 affected males who inherited X-linked developmental lens opacity and microcornea. Some members of the family had mild to moderate nonocular clinical features suggestive of Nance-Horan syndrome. By fine mapping, the authors localized the disease gene to Xp22.13. Mutational screening revealed a truncating mutation in the NHS gene (Q39X; 300457.0005) in all affected males and carrier females but not in unaffected family members or controls. The authors concluded that families with X-linked cataract should be carefully examined for both ocular and nonocular features, to exclude Nance-Horan syndrome. RT-PCR analysis did not suggest nonsense-mediated mRNA decay as the possible mechanism for clinical heterogeneity.

In affected members of the family reported by van Dorp and Delleman (1979), Florijn et al. (2006) identified a mutation in the NHS gene (300457.0006). Florijn et al. (2006) also identified mutations in the NHS gene in 3 additional NHS families.

In affected members of a Chinese family with Nance-Horan syndrome, Li et al. (2015) identified a frameshift mutation in the NHS gene (300457.0009) that segregated with the disorder in the family and was not found in 100 matched controls.

Cytogenetics

Van Esch et al. (2007) reported a 10-month old male infant with severe encephalopathy, congenital cataracts, and tetralogy of Fallot who had a hemizygous de novo 2.8-Mb microdeletion at chromosome Xp22.2-Xp22.13, including the CDKL5 (300203) and NHS genes. He had microphthalmia, refractory myoclonic seizures, and hypotonia. The clinical features were consistent with both Nance-Horan syndrome and early infantile epileptic encephalopathy-2 (EIEE2; 300672), which is caused by mutation in the CDKL5 gene.

Liao et al. (2011) reported 2 Taiwanese brothers with a clinical diagnosis of Nance-Horan syndrome associated with a 915-kb deletion at chromosome Xp22.13 inherited from their mother. The boys had congenital cataracts, delayed psychomotor development, mental retardation, long face, prominent nose, screwdriver-shaped incisors, and widely spaced teeth. Both also had pedis planus and hallux valgus. One had incomplete cryptorchidism, and the other had autistic features. The mother had normal intelligence, localized posterior subcapsular cataract in the right eye, and mild nuclear sclerosis in the left eye. The deleted region spanned from 16,853,030 to 17,768,574 and included the REPS2 (300317), NHS, SCML1 (300227), and RAI2 (300217) genes. The findings indicated that genomic rearrangements involving the NHS gene can cause Nance-Horan syndrome, and suggested that deletion of other genes in this region contributed to the severe phenotype and additional clinical features observed in these patients.