Anonychia-Onychodystrophy With Hypoplasia Or Absence Of Distal Phalanges

Description

Familial anonychia/onychodystrophy with hypoplasia or absence of distal phalanges (ODP) is a rare disorder characterized by onychodystrophy, anonychia, brachydactyly of the fifth finger, and digitalization of the thumbs, with absence or hypoplasia of the distal phalanges of the hands and feet. Generally the nails of the first to third digits are progressively deformed with total anonychia in the last 2 digits and in all toes (summary by Genzer-Nir et al., 2010).

A syndrome has been described in which affected females display juvenile hypertrophy of the breast (JHB; 113670) in association with ODP, whereas males have only ODP (mammary-digital-nail syndrome; 613689).

Clinical Features

Santos et al. (1981) described an 8-generation Portuguese family in which 12 members had brachydactyly and nail dysplasia. The disorder was characterized by brachydactyly of all fingers and toes except the thumb and big toe and absence of distal phalanges and nails in all fingers and toes. The affected members of the family also had a peculiar shape of the nose. Santos et al. (1981) suggested that this family had a type B brachydactyly of Bell classification (or 8 of Fitch) and that the transmission was autosomal dominant.

Cooks et al. (1985) described a kindred in which 7 individuals in 2 generations with one instance of male-to-male transmission had a disorder characterized by onychodystrophy, anonychia, brachydactyly of the fifth finger, and digitalization of the thumbs, with absence or hypoplasia of the distal phalanges of the hands and feet. Cooks et al. (1985) stated that the disorder differed from autosomal dominant anonychia-onychodystrophy (107000) in which there is progressive nail hypoplasia from the fifth digit to the thumb, with anonychia often present in the second and third digits whereas in their family they observed nail hypoplasia in the thumb progressing to total nail absence in the fourth and fifth digits. Moreover, in dominant anonychia-onychodystrophy, no bone changes had been described. In autosomal dominant brachydactyly with absence of middle phalanges and hypoplastic nails (112900), the changes in the middle phalanges are distinctive. Relatively bizarre, asymmetric digital anomalies, including absence of one or more digits, distinguish anonychia with ectrodactyly (106900). In '20-nail dystrophy' (161050), dystrophy of the nails progresses with age, whereas in the family of Cooks et al. (1985) the nail findings were present from birth.

Houlston and Temple (1994) raised the question of a distinctive facial appearance associated with type B brachydactyly in an English family with at least 11 affected members in 4 generations. Affected members showed wide-spaced, downslanting palpebral fissures, a prominent nose with bulbous tip, and a short philtrum.

Nevin et al. (1995) described what they considered to be the second reported family with Cooks syndrome. For members in 3 successive generations, with an instance of male-to-male transmission, had bilateral nail hypoplasia of digits 1-3, with absence of nails of digits 4-5 of the hands, and total absence of toenails. In addition, there was absence/hypoplasia of the distal phalanges of the hands and feet.

De Ravel et al. (1999) reported a sib pair with a distinct facies, absence/hypoplasia of the distal phalanges of the hands, feet, and nails, and bulbous digit tips, and suggested that these patients had features of both classic type B brachydactyly (BDB; 113000) and Cooks syndrome.

Castori et al. (2007) reported a 2-year-old Caucasian girl with Cooks syndrome. She had slightly shortened fingers with hypoplastic distal flexion creases. Nails were absent on fingers 2 and 3, severely hypoplastic on fingers 1 and 4, and moderately shortened on fingers 5. Her feet showed absent or severely hypoplastic nails on 5 digits total. The digits without nails appeared bulbous-ended with tumor-like soft tissue hypertrophy. Cutaneous syndactyly of toes 2 and 3 and toes 2, 3, and 4 was evident on the left and right foot, respectively. Radiographic examination of the hands showed symmetrical shortening of the distal phalanges with clinodactyly of the fifth digit. Metacarpals were grossly normal. Feet radiographs showed only 2 phalanges in the toes and hypoplastic distal phalanges. There were no facial anomalies. Molecular analysis excluded a mutation in the ROR2 gene (602337). A paternal grandfather had cutaneous syndactyly of the fourth and fifth toes of the right foot. Castori et al. (2007) concluded that Cooks syndrome is distinct from classic brachydactyly type B because the former affects dorsoventral patterning and the latter affects early differentiation of skeletal precursor structures. The authors suggested that the large family reported by Kumar and Levick (1986) (106990) may have had Cooks syndrome.

Kurth et al. (2009) reported 4 families with symmetric brachydactyly of the hands and feet, along with hyponychia or anonychia. The phenotype was consistent with Cooks syndrome. Radiographs showed missing middle phalanges and elongated terminal and proximal phalanges. There were no other skeletal anomalies, and sexual development was normal.

Inheritance

The transmission pattern in the families reported by Santos et al. (1981), Cooks et al. (1985), and Nevin et al. (1995) is consistent with autosomal dominant inheritance of this disorder.

Molecular Genetics

In affected members of 4 unrelated families with a phenotype consistent with Cooks syndrome, Kurth et al. (2009) identified overlapping duplications in a 2-Mb interval on chromosome 17q24.3, with a minimal critical area of 1.2 Mb. The region encompassed a large gene desert between KCNJ2 (600681) and SOX9 (608160). The duplications were confirmed by quantitative PCR and were not detected in more than 400 control DNA samples. The duplications occurred de novo in 2 families. Kurth et al. (2009) suggested that the duplications involved putative regulatory elements of SOX9 and may induce SOX9 misexpression and/or overexpression at specific time points during development, resulting in abnormal digit and nail development. In mouse embryo, Sox9 was strongly expressed in the distal mesenchymal condensations that develop into terminal phalanges.