Oculodentodigital Dysplasia

A number sign (#) is used with this entry because autosomal dominant oculodentodigital dysplasia (ODDD) is caused by heterozygous mutation in the connexin-43 gene (GJA1; 121014) on chromosome 6q22.

Description

Oculodentodigital syndrome is characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding (summary by Judisch et al., 1979).

Neurologic abnormalities are sometimes associated (Gutmann et al., 1991), and lymphedema has been reported in some patients with ODDD (Brice et al., 2013). See review by De Bock et al. (2013).

Genetic Heterogeneity of Oculodentodigital Syndrome

An autosomal recessive form of ODDD (257850) is also caused by mutation in the GJA1 gene, but the majority of cases are autosomal dominant.

Clinical Features

Gillespie (1964) described a brother and sister with bilateral microphthalmia, abnormally small nose, hypotrichosis, dental anomalies, fifth finger camptodactyly, syndactyly of the fourth and fifth fingers, and missing toe phalanges. Gillespie (1964) noted that similar features had been reported in 2 unrelated patients by Meyer-Schwickerath et al. (1957), who called the disorder oculodentodigital dysplasia and noted some phenotypic overlap with the Francois dyscephalic syndrome (Hallermann-Streiff syndrome; 234100).

ODDD was probably first described by Lohmann (1920). Lightwood and Lewis (1963) reported affected father and son.

The condition reported as acrocephalosyndactyly by Mohr (1939) and characterized by bilateral syndactyly of the fourth and fifth fingers is probably the same condition. The father and 5 of his children (including 3 sons) presented craniofacial deformity and complete syndactyly of the fourth and fifth fingers.

In 2 unpublished pedigrees, Renwick (1967) found that a constant and characteristic feature of the syndrome is the absence of the middle phalanx of those toes (second through fifth) that normally have 3 phalanges.

Rajic and De Veber (1966) reported a family with many affected members in 3 generations but no male-to-male transmission. Eye features included microphthalmia, microcornea, and glaucoma. The teeth were small with what was termed enamelogenesis imperfecta. The phalanges and metacarpals were widened and syndactyly of fingers 4 and 5 was present. Reisner et al. (1969) reported the syndrome in a mother and 3 of her 4 children.

Jones et al. (1975) found evidence of paternal age effect in new mutations for this disorder.

Fara and Gorlin (1981) found orbital (bony) hypotelorism in about 40% of cases. The distance between the inner canthi was not altered. Thus, the length of the palpebral slit was markedly diminished.

Gorlin (1985) suggested that ODDD was the true diagnosis in the family reported as metaphyseal dysplasia by David and Palmer (1958).

Patton and Laurence (1985) reported 3 new cases. With photographs they traced the development of the facial features. Conductive deafness was present in 1 of the 3 and had been reported in 6 previous cases.

Opjordsmoen and Nyberg-Hansen (1980) described a family from northern Norway with spastic paraplegia and type III syndactyly. The 2 traits were transmitted together through 3 generations and 9 affected persons. The spastic paraplegia was of unusual type: neurogenic bladder was the earliest manifestation. Indeed, the spastic paraplegia easily escaped attention.

Gutmann et al. (1991) pointed out that some previously reported patients manifested spastic quadriparesis and described a sporadic case of ODDD with progressive spastic paraparesis. MRI of the brain demonstrated abnormal white matter, specifically, diffuse, abnormally high signal intensity in the subcortical white matter bilaterally.

Norton et al. (1995) described a 2-generation family with ODDD and progressive paraplegia associated with leukodystrophic changes documented by MRI. The presence of abnormal white matter changes in both sporadic and inherited forms of ODDD suggested that the phenotype of this disorder should be expanded to include spastic paraparesis. Schrander-Stumpel and Franke (1996) highlighted neurologic findings in their previously described 3-generation family (Schrander-Stumpel et al., 1993). They reviewed other reports about neurologic defects in this syndrome and concluded that brain abnormalities may be a manifestation of the syndrome.

Loddenkemper et al. (2002) pointed out that neurologic symptoms are frequent in ODDD and include spasticity, gaze palsy and squinting, bladder and bowel dysfunction, visual and hearing loss, ataxia, and nystagmus. Cognitive impairment was seen in some patients. Subcortical white matter lesions and basal ganglia changes are seen on MRI. Loddenkemper et al. (2002) recommended that a full neurologic evaluation and brain MRI be performed in patients with features suggestive of ODDD.

Ioan et al. (2002) described the full clinical manifestations of ODDD in a 9.5-year-old female whose father had mild manifestations, namely type III syndactyly.

Abnormalities of the skin, hair, and nails have been recognized in ODDD but are often overlooked. Kelly et al. (2006) described an ODDD patient with curly hair, early trichorrhexis nodosa, and discrete keratoderma. Molecular genetic studies revealed a novel GJA1 mutation (121014.0014) affecting the N terminus of the CX43 protein.

Feller et al. (2008) reported a black South African boy with ODDD confirmed by genetic analysis. The patient presented at 11 years of age with a dental abscess. He had multiple dental anomalies, including small, discolored teeth, hypoplastic enamel, multiple caries, and enlarged pulp chambers of the permanent teeth. He also had taurodontism, characterized by lack of normal cervical constriction and elongation of the waist of the tooth, resulting in a rectangular block-like configuration. Characteristic facial features were also noted.

Brice et al. (2013) reported a family segregating autosomal dominant ODDD and lymphedema. The proband was a 40-year-old woman who had the characteristic facial features of ODDD, with a flat face, pinched nose, hypoplastic alae nasi, mild bilateral ptosis, and small, crowded teeth. She was born with bilateral syndactyly of the fourth and fifth fingers, which was surgically corrected. In addition, she had bilateral lower limb edema from age 30 years, which initially fluctuated but then remained constant despite overnight leg elevation. Her upper limbs showed no clinically visible edema. Her father was reported to have syndactyly but no lymphedema; a paternal aunt also had syndactyly and lymphedema, and the affected aunt's daughter had bilateral syndactyly of the fourth and fifth fingers, microphthalmia, microdontia, and poor enamel, as well as bilateral lower limb edema presenting at age 14 years. Lymphoscintigraphy in the proband confirmed primary edema of both lower extremities, with impaired drainage in the left upper extremity as well.

Clinical Variability

O'Rourk and Bravos (1969) observed the sporadic case of a boy with an oculodentodigital dysplasia probably distinct from that described above and therefore tentatively designated ODD syndrome II. Rather than syndactyly of fingers 4 and 5 the patient showed unilateral preaxial polydactyly of the hand, laterally curved fifth finger on the right, fifth finger camptodactyly on the left, and absent terminal phalanges of right fingers 2 and 5.

Vingolo et al. (1994) described a large kindred with 14 persons in 4 generations affected with bilateral microphthalmia without other ocular or systemic signs. Autosomal dominant inheritance with complete penetrance was suggested. All the patients had microcornea. Vingolo et al. (1994) concluded that the family had a form of nanophthalmos characterized by ultrasonographic reduction of the posterior segment of the eye and a normal anterior segment. On clinical reexamination of the family reported by Vingolo et al. (1994), Vitiello et al. (2005) found extraocular signs that were suggestive of ODDD. In particular, some patients had thin hypoplastic nose, dental color anomalies, inverted palate, fifth finger camptodactyly, and fine, dry hair. None of the patients had hand or foot syndactyly or any neurologic signs. Identification of a mutation in the GJA1 gene (121014.0013) led Vitiello et al. (2005) to conclude that this family had an atypical form of ODDD.

Gabriel et al. (2011) described 2 patients with typical findings of autosomal dominant ODDD and the additional findings of optic nerve and retinal dysplasia in both and ciliary body cysts in one. Gabriel et al. (2011) suggested that retinal and optic nerve dysplasia may be more common than previously appreciated and may be associated with reduced vision and that ciliary body cysts may exacerbate glaucoma or complicate its management.

Mapping

In linkage studies of 6 families with ODDD, Gladwin et al. (1997) mapped the locus to 6q22-q24 (pairwise maximum lod = 9.37 at theta = 0.001). One of the ODDD families was the atypical family reported by Brueton et al. (1990); see type III syndactyly (186100). The family showed type III syndactyly, but none of the ophthalmologic, dental, or skeletal features commonly reported in ODDD. This suggested to Gladwin et al. (1997) that isolated type III syndactyly and ODDD may be caused by mutation in the same gene.

Molecular Genetics

Paznekas et al. (2003) analyzed the connexin-43 gene (GJA1; 121014) as a candidate for ODDD and identified mutations in all 17 families studied (see 121014.0003-121014.0007). Sixteen different missense mutations and 1 codon duplication were detected. These mutations may cause misassembly of channels or alter channel conduction properties. Expression patterns and phenotypic features of Gja1 mutant animals, reported by others, were considered compatible with the pleiotropic clinical presentation of ODDD.

Kjaer et al. (2004) described a 5-generation Danish family with ODDD in which all affected members had a val96-to-met (121014.0009) substitution in GJA1. The authors noted that in available photographs, 7 of 9 affected subjects had curly hair and 8 unaffected relatives did not, suggesting that curly hair is part of the pleiotropic phenotype.

In affected members of the family reported by Vingolo et al. (1994) as having simple microphthalmia without syndactyly, Vitiello et al. (2005) identified a heterozygous mutation in the GJA1 gene (121014.0013). The findings confirmed the highly variable phenotype associated with GJA1 mutations.

Paznekas et al. (2009) reported 18 new GJA1 mutations in 28 ODDD cases, and reviewed the 62 known mutations in GJA1 as well as the phenotypic information available on 177 affected individuals from 54 genotyped families. The characteristic facies was seen in 92% of the families, with ocular, dental, and digital manifestations present in 68%, 70%, and 80% of the families, respectively; 78% of families displayed features from more than 2 of these categories. Neurologic manifestations were seen in 30% of families, conductive hearing loss in 26%, and hair with poor growth in 26%. Secondary features observed more frequently in these ODDD patients than in the general population included cleft palate (3% versus 0.05%), glaucoma (16% versus 1.86%), and conductive hearing loss (10% versus 0.8%). Paznekas et al. (2009) noted that phenotypic variability occurred even among family members with the same mutation, and stated that making genotype/phenotype correlations was difficult, since there were no predominant mutations and mutations were equitably distributed throughout most protein domains.

In 2 patients with typical features of ODDD and the additional features of optic nerve and retinal dysplasia in both and ciliary body cysts in 1, Gabriel et al. (2011) identified heterozygous mutations in the GJA1 gene (121014.0019-121014.0020).

In 4 affected members of a family with ODDD and lymphedema, Brice et al. (2013) identified heterozygosity for a missense mutation in the GJA1 gene (K206R; 121014.0022). The mutation was not found in an unaffected family member or in 600 controls. Brice et al. (2013) noted that mutation in a related gene, GJC2 (608803), had been associated with 4-limb edema (613480) with a similar pattern on lymphoscintigraphy.

Genotype/Phenotype Correlations

In a Dutch kindred with ODDD and palmoplantar keratoderma, van Steensel et al. (2005) identified a 2-bp deletion in the GJA1 gene (121014.0010). The authors stated that this was the first reported mutation affecting the C-terminal loop, and suggested that the mutation might explain the presence of skin symptoms.

Vreeburg et al. (2007) reported another Dutch woman with ODDD and palmar hyperkeratosis with a 2-bp deletion in the GJA1 gene (121014.0015) resulting in truncation of the protein and absence of a significant portion of the C-terminal domain. The findings suggested a genotype/phenotype correlation between pronounced palmoplantar keratoderma and mutations that truncate the C terminus of the GJA1 protein.

Animal Model

Kalcheva et al. (2007) created a mouse model of ODDD by generating mice heterozygous for the human I130T mutation, previously identified by Paznekas et al. (2003) in a family with ODDD and an increased incidence of cardiac arrhythmias. Kalcheva et al. (2007) found that the I130T mutation interfered with posttranslational processing, resulting in diminished cell-cell coupling, slowing of impulse propagation, and a proarrhythmic substrate.

To understand causal links between GJA1 mutations and glaucoma in individuals with ODDD, Tsui et al. (2011) examined the ocular phenotype of Gja1(Jrt/+) mice harboring a Cx43 G60S mutation. Decreased Cx43 protein levels were evident in whole eyes from mutant mice compared with those of wildtype mice at postnatal day 1. Cx43 immunofluorescence in ciliary bodies of mutant mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wildtype mice. Intraocular pressure (IOP) in the mutant mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wildtype eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in the mutant mice of all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of mutant mice, split irides, and alterations in the number and distribution of nuclei in the retina. Tsui et al. (2011) concluded that detailed phenotyping of the eyes of Gja1(Jrt/+) mice offered a framework for elucidating human ODDD ocular disease mechanisms and for evaluating new treatments.