Father-to-daughter transmission of focal dermal hypoplasia associated with nonrandom X-inactivation: support for X-linked inheritance and paternal X chromosome mosaicism

Am J Med Genet. 1991 Sep 1;40(3):332-7. doi: 10.1002/ajmg.1320400317.


Focal dermal hypoplasia (FDH) is a rare syndrome of severe developmental anomalies of the tissues and organs derived from ectoderm and mesoderm. Though data have suggested that FDH is an X-linked dominant trait associated with male hemizygote lethality, a hypothesis supported by the observation of three unrelated infants with FDH manifestations and de novo chromosome rearrangements involving Xp22, observations of father-to-daughter transmission have suggested possible genetic heterogeneity and autosomal dominant inheritance with sex limitation. We hypothesize that, if FDH is an X-linked disorder, cells expressing an active disease locus might experience a selective disadvantage resulting in a nonrandom pattern of X-inactivation in patient tissue. To test this hypothesis, we studied one of the two previously described families demonstrating father-to-daughter inheritance of FDH. To determine if the affected daughter had a skewed pattern of X-inactivation consistent with X-linked inheritance of FDH, somatic cell hybrids were constructed by fusing hypoxanthine phosphoribosyl transferase (HPRT)-deficient rodent fibroblasts with either patient dermal fibroblasts or peripheral white blood cells (WBCs); hybrid clones retaining an active X chromosome were analyzed to determine the parental origin of the active X chromosome. Analyses of resulting hybrid clones showed that while hybrids constructed from skin fibroblasts contained an active X chromosome inherited from either of the patient's parents, hybrids constructed from WBCs showed a skewed pattern of X-inactivation; 11 of 11 hybrids contained an active maternal X chromosome (chi 2 = 12.2, P = .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cells, Cultured
  • DNA
  • Dosage Compensation, Genetic*
  • Female
  • Focal Dermal Hypoplasia / genetics*
  • Genes, Dominant
  • Genetic Linkage
  • Humans
  • Infant, Newborn
  • Male
  • Middle Aged
  • Mosaicism
  • Parents
  • Skin / pathology
  • X Chromosome*


  • DNA