Adult Syndrome

A number sign (#) is used with this entry because of evidence that ADULT syndrome is caused by heterozygous mutation in the TP63 gene (603273) on chromosome 3q28.

Allelic disorders with overlapping features include EEC3 (604292), limb-mammary syndrome (LMS; 603543), AEC syndrome (106260), Rapp-Hodgkin syndrome (RHS; 129400), and SHFM4 (605289)

Clinical Features

Propping and Zerres (1993) described a family with at least 7 living members who were affected by a hitherto undescribed syndrome with variable expression, which bore a close resemblance to the EEC syndrome. Features included ectrodactyly, syndactyly, finger- and toenail dysplasia, hypoplastic breasts and nipples, intensive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and loss of permanent teeth.

Slavotinek et al. (2005) reported a patient with ADULT syndrome with phenotypic overlap with ulnar-mammary syndrome (UMS; 181450). At age 15 years, the patient had sparse, fine, white blond hair, incomplete fusion of the right inner canthus, high and broad nasal bridge, midface hypoplasia, and hypodontia with small and peg-shaped incisors. Other features included fair skin with extensive freckling over sun-exposed areas, onychodystrophy, and absent nipples. The patient also had brachydactyly with bilateral fifth finger clinodactyly and camptodactyly and ulnar ray hypoplasia, suggesting UMS. Clinical history included surgical repair of an imperforate anus and nasolacrimal duct stenosis, and reduced axillary sweating. Genetic analysis identified a mutation in the TP63 gene (603273.0020).

Rinne et al. (2006) reported 3 unrelated families with ADULT syndrome of Finnish, Italian, and Danish origin, respectively. Clinical features included ectrodactyly and syndactyly, atrophic skin, dry skin, photosensitive skin, dermatitis, lacrimal duct obstruction, thin, sparse, blond hair, dysplastic nails, and hypoplastic breasts and/or nipples. Freckling was a variable feature.

De Almeida et al. (2010) examined an 11-year-old boy who presented with nail dystrophy, athelia, freckling of sun-exposed areas, and dystrophic teeth. Ophthalmologic examination revealed obstruction of the lacrimal ducts; light microscopy of a skin biopsy showed normal eccrine sweat glands. His mother had similar changes, as well as hypoplastic mammillae. A mutation in the p63 gene was identified in the boy and his mother (R298Q; 603273.0014); in addition, his 2 older sisters and a nephew were affected. The sisters mentioned that they had problems with fingerprinting for identification documentation, and close examination revealed adermatoglyphia of all affected individuals, which was not found in unaffected relatives. De Almeida et al. (2010) noted that adermatoglyphia had been described in other forms of ectodermal dysplasia, and suggested that it may have been overlooked in previously reported cases of ADULT syndrome.

Mapping

Because of the phenotypic similarity between the family reported by Propping and Zerres (1993) and a family with limb-mammary syndrome (LMS; 603543), which had been mapped to chromosome 3q27, Propping et al. (2000) genotyped 21 members of the ADULT family with 19 polymorphic markers from this chromosome region. Their studies placed the ADULT locus in the same chromosome region as the LMS locus, suggesting that these 2 conditions are allelic.

Inheritance

Amiel et al. (2001) and Duijf et al. (2002) reported families with autosomal dominant inheritance of ADULT syndrome.

Molecular Genetics

Amiel et al. (2001) reported a missense mutation in the TP63 gene (N6H; 603273.0011), located at chromosome 3q27, in an isolated ADULT syndrome case. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome. Amiel et al. (2001) considered incomplete penetrance as the most likely explanation.

In affected members of a 2-generation family with ADULT syndrome, Duijf et al. (2002) identified a heterozygous mutation in the TP63 gene (R298Q; 603273.0014).

Rinne et al. (2006) identified the R298Q mutation in affected members of 2 unrelated families with ADULT syndrome; 1 was Italian, and the other was Dutch. A third family of Finnish origin had a different mutation at the same codon (R298G; 603273.0022).

In a mother and daughter with ADULT syndrome, Reisler et al. (2006) identified an R227Q mutation in the TP63 gene (603273.0024). The R227Q mutation had previously been found in 3 families with EEC3 (see 604292 and van Bokhoven et al., 2001); Reisler et al. (2006) suggested that there may be considerable overlap between the EEC and ADULT syndromes.

In a Dutch mother and daughter with minimal manifestations of ADULT syndrome, including hypothelia and palmar hyperlinearity, van Zelst-Stams and van Steensel (2009) identified heterozygosity for a missense mutation in the C-terminal end of the proline-rich domain of TP63 (P127L; 603273.0026). The authors noted that mutations in this domain have primarily been reported to cause limb-mammary syndrome.

In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular dysplasia, who did not have the skin and limb manifestations of ADULT syndrome, Valenzise et al. (2008) identified the R298Q mutation in the TP63 gene. The mutation was also found in his mother, who had only hypodontia and athelia. Valenzise et al. (2008) noted that their findings highlighted the clinical overlapping of TP63-related ectodermal dysplasias and the difficulty of establishing unequivocal genotype-phenotype correlations.