Mammary-Digital-Nail Syndrome

Clinical Features

Govrin-Yehudain et al. (2004) reported a 3-generation Druze pedigree in which 4 females presented with juvenile hypertrophy of the breast (JHB; see 113670) and congenital anonychia. They developed rapid and massive breast enlargement at ages 13 to 14 years, before menarche, and underwent breast reduction surgery. Three required subsequent surgery after recurrence of breast enlargement. All were related through their fathers, who had congenital anonychia of the hands and feet, but no other abnormalities. The mothers and sisters of the 4 patients had normal breasts and normal nails.

Genzer-Nir et al. (2010) examined 11 affected members, 6 males and 5 females, from the 3-generation Druze pedigree with JHB and congenital anonychia originally reported by Govrin-Yehudain et al. (2004), and proposed the designation 'mammary-digital-nail syndrome.' All affected individuals presented with congenital onychodystrophy and/or anonychia and abnormalities of the distal phalanges (see Cooks syndrome, 106995), involving digitalization of thumbs, hypoplasia of the distal phalanges of the second to fourth digits, total absence of distal phalanx of the fifth digit, bilateral absence of all distal creases of the second to fifth digits, and hypoplasia and complete absence of distal phalanges and nails of the great toes. The JHB phenotype presented only in females, and in the 4 affected postpubertal females, the breasts enlarged dramatically during a 3-month period before and shortly after menarche, reaching enormous proportions. The 4 females had regular menses, normal laboratory evaluation, and no exposure to drug or hormonal therapy. An additional 40 members of the family were examined, including secondary sex characteristics, but no further abnormalities were found.

Mapping

Genzer-Nir et al. (2010) performed linkage analysis under an assumption of autosomal dominant inheritance with full penetrance in the 3-generation Druze pedigree with mammary-digital-nail syndrome and obtained a maximum lod score of 4.27 at 3 continuous loci, D22S1154, D22S277, and D22S283, within a 30-cM (19.3-Mb) interval on chromosome 22q12.3-q13.1. Haplotype analysis narrowed the critical interval to 12.5 cM (4.3 Mb). Noting that 9 of 30 unaffected family members examined carried the same haplotype as affected individuals, including 3 unaffected offspring of the founding father, Genzer-Nir et al. (2010) suggested that the founder was a germline mosaic for a dominant mutation. Reanalysis of the genotypes under a germline-mosaic model generated a maximum lod score of 4.87 (theta = 0.0) for 4 continuous markers (D22S277, D22S1142, D22S683, and D22S283) in the 12.5-cM critical interval.

Molecular Genetics

In a 3-generation Druze pedigree with mammary-digital-nail syndrome mapping to chromosome 22q12.3-q13.1, originally reported by Govrin-Yehudain et al. (2004), Genzer-Nir et al. (2010) found no mutations in any of 38 candidate genes selected for sequence analysis.