Mammary-digital-nail syndrome is a novel phenotypic association consisting of anonychia onychodystrophy with hypoplasia or absence of distal phalanges in males and females, accompanied by juvenile hypertrophy of the breast in affected females. This newly described genetic trait presents an autosomal dominant inheritance pattern, with either reduced penetrance or germ-line mosaicism. Analysis of the pedigree, linkage studies followed by a genome-wide screen and by haplotype analysis defined the locus for the phenotype within a 12 cM (4.3 Mb) interval on chromosome 22q12.3-13.1. This chromosomal region has not been implicated before in genetic disorders of the mammary tissue or limbs. These data suggest a possibly novel signaling pathway affecting the organogenesis of limbs and mammary glands in humans.