Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia ... Congenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (summary by Bruchle et al., 2008). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4). For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (161050).
Littman and Levin (1964) reported a 66-year-old woman who had congenital absence of 7 fingernails without any other anomalies. Her nails were normal in her thumbs and left fifth digit, but absent in the other fingers, which had ... Littman and Levin (1964) reported a 66-year-old woman who had congenital absence of 7 fingernails without any other anomalies. Her nails were normal in her thumbs and left fifth digit, but absent in the other fingers, which had only rudimentary matrices and nothing resembling nails had ever been present, according to the patient. Her toenails were normal. Phalanges and patellae were normal to palpation, and bony structures of the thorax, spine, and pelvis were normal on radiographic examination. A 60-year-old brother who lived in East Germany was said to lack 8 fingernails, with nail beds resembling those of the proband, and to have normal thumbnails and toenails. He was in good health based on recent correspondence and had no other known anomalies. There were 19 other unaffected family members, including their parents, suggesting inheritance as an autosomal recessive trait. Mahloudji and Amidi (1971) described a consanguineous Iranian pedigree in which there were 7 affected individuals over 3 generations who had absence of all fingernails and toenails. The 2 affected family members who were examined had normal hair, teeth, and bones with no other anomalies. Normal parents, occurrence in males and females, and frequent consanguinity favored autosomal recessive inheritance. Hopsu-Havu and Jansen (1973) reported a Finnish family in which 4 of 10 children had complete absence of fingernails and toenails since birth. Examination of the 42-year-old female proband showed that the nail bed was present in all fingers and toes, but there were no proper nails; a rudimentary fragile nail plate could be seen in only 2 of the fingers. The proband was 1 of a pair of nonidentical twins, and her twin sister had a different body build and normal nails. Hair, teeth, and bones were normal in the affected sibs, and family members had no other anomalies. The family had lived for hundreds of years on an isolated small island off the Finnish coast, and the local church register revealed that both unaffected parents were descendants of a 17th century clergyman. Al Hawsawi et al. (2002) described a 27-year-old man, born of first-cousin parents, who had absence of all nails of the fingers and toes. His teeth and hair were normal, and he had no significant skin lesions. X-ray of hands and feet showed presence of terminal phalangeal bones. The authors noted that anonychia simplex, as diagnosed in their patient, must be differentiated from anonychia that is associated with absent or hypoplastic distal phalanges (106995). Ozdemir et al. (2004) reported 7-year-old monozygotic twin girls who had absent nails from birth. Physical examination revealed that they lacked all fingernails and toenails, but were otherwise healthy with normal intelligence. X-rays of hands and feet showed normal structures with no dysplasia or hypoplasia. There was no family history of anonychia, suggesting a sporadic mutation.
Blaydon et al. (2006) identified homozygous or compound heterozygous mutations in the RSPO4 gene in 8 affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail ... Blaydon et al. (2006) identified homozygous or compound heterozygous mutations in the RSPO4 gene in 8 affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis. In affected members of a large nonconsanguineous German family with isolated total congenital anonychia mapping to chromosome 20p13, Bergmann et al. (2006) identified compound heterozygosity for mutations in the RSPO4 gene, a frameshift and a nonconservative missense mutation in exon 2 affecting the highly conserved first furin-like cysteine-rich domain. RSPO4 is a member of the R-spondin family of secreted proteins that play a major role in activating the Wnt (see 164820)/beta-catenin (see 116806) signaling pathway. Wnt signaling is evolutionarily conserved and plays a pivotal role in embryonic development, growth regulation of multiple tissues, and cancer development. The findings added to evidence indicating that mesenchymal-epithelial interactions are crucial in nail development and put anonychia on the growing list of congenital malformation syndromes caused by Wnt signaling pathway defects. Bergmann et al. (2006) stated that this was apparently the first gene shown to be responsible for an isolated, nonsyndromic nail disorder. Bruchle et al. (2008) studied 2 unrelated families of Turkish and Kazakh origin, respectively, with congenital nonsyndromic anonychia. Haplotype analysis was compatible with linkage to the RSPO4 gene on 20q13, and sequencing revealed homozygosity for a nonsense mutation (Q101X; 610573.0006) and a missense mutation (R64C; 610573.0007) in affected members of the Kazakh and Turkish family, respectively. Affected individuals had complete absence of fingernails and toenails; the skin in the region of the absent nails was normal,and the nail bed, nail matrix, and fold were present in all fingers and toes of examined patients. In affected members of a large consanguineous Pakistani family segregating an autosomal recessive form of nonsyndromic anonychia with evidence of linkage to the RSPO4 locus, Chisti et al. (2008) identified homozygosity for a missense mutation in the RSPO4 gene (G67R; 610573.0008). Affected individuals had complete absence of fingernails and toenails, with normal skin in the region of the absent nails and nail bed and nail matrix present in all fingers and toes; heterozygous carriers had normal nails.