Zimmermann-Laband Syndrome 2

A number sign (#) is used with this entry because of evidence that Zimmermann-Laband syndrome-2 (ZLS2) is caused by heterozygous mutation in the ATP6V1B2 gene (606939) gene on chromosome 8p21.

For a general phenotypic description and a discussion of genetic heterogeneity of Zimmermann-Laband syndrome, see ZLS1 (135500).

Clinical Features

Abo-Dalo et al. (2008) studied a boy with Zimmerman-Laband syndrome (patient 6), who at birth was noted to have hypertrichosis and dysmorphic facies, with a broad nasal bridge, large fleshy nose, full lips, and synophrys. At 10 years of age, he had a coarse facial appearance with thick eyebrows and eyelashes, bulbous flat nose with bifid nasal tip, thick lips, and macroglossia. In addition, he exhibited total congenital anonychia, as well as aplasia of the distal phalanges of the second and fifth fingers of the left hand and the fifth finger of the right hand, and aplasia of the terminal phalanges of the second to fifth toes. Other features included axial and peripheral hypotonia, kyphosis, and valgus deformity of the feet. Kortum et al. (2015) restudied this patient (as patient 7) and reported the additional features of unilateral total deafness and global developmental delay with severe intellectual disability.

Castori et al. (2013) reported a 5.5-year-old Italian girl who was born with generalized hypotonia, coarse face, enlarged alveolar ridges, hirsutism, and partial anonychia of the hands and feet. X-rays of the hands and feet at 2 months of age showed bilateral absence of the distal phalanx of the second, fourth, and fifth fingers, with absence or severe hypoplasia of the distal phalanx of the third fingers; tapering of the middle phalanx of the second through fifth fingers and distal phalanx of the thumbs; absence of the distal phalanx of the second through fifth toes and the middle phalanx of the fifth toe; and hypoplasia of the middle phalanx of the second through fourth toes and the distal phalanx of the great toe. Psychomotor development was delayed, and at age 5 the patient was found to have borderline cognitive delay with an IQ of 74. Hearing was intact. Examination at 5.5 years of age showed a widow's peak, thick and laterally flared eyebrows, long eyelashes, mildly upslanting palpebral fissures, prominent nasal septum with hypoplastic alae nasi and a vertical cutaneous-cartilaginous ridging on the nasal tip, prominent philtrum, and thick helices and lobules of the ears. She had gingival hypertrophy of the upper and lower alveoli with normally erupted deciduous teeth. Cartilage of the nose and ears was extremely soft to palpation. The patient had a short neck as well as complete anonychia of the hands and feet except for a small nail remnant on the right third finger. The second through fourth fingers and toes were shortened, whereas the thumbs appeared elongated, and finger pads were present. She also displayed mild hypotonia and generalized joint hypermobility.

Molecular Genetics

By whole-exome sequencing in the male patient with ZLS originally reported by Abo-Dalo et al. (2008) as patient 6 and the Italian girl with ZLS studied by Castori et al. (2013), Kortum et al. (2015) identified heterozygosity for the same de novo missense mutation in the ATP6V1B2 gene (R485P; 606939.0002) in both patients. The mutation was not found in the unaffected parents from either family, or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or Exome Aggregation Consortium databases.