Evidence of postzygotic mosaicism in a transmitted form of Conradi-Hunermann-Happle syndrome associated with a novel EBP mutation.

BACKGROUND X-linked dominant chondrodysplasia punctata, also known as Conradi-Hünermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. Conradi-Hünermann-Happle syndrome is caused by mutations in the gene EBP encoding Δ(8)-Δ(7) sterol isomerase emopamil-binding protein. Random X-inactivation could account for the intrafamilial variability of the phenotype of X-linked dominant chondrodysplasia punctata. OBSERVATIONS We describe a girl with clinical features of X-linked dominant chondrodysplasia punctata. Biochemical analysis showed an abnormal sterol profile consistent with a defect in Δ(8)-Δ(7) sterol isomerase. Molecular studies confirmed the diagnosis by identifying a novel heterozygous missense EBP mutation (c.199C>T; p.Cys67Arg). The mutation was not detectable on genomic DNA extracted from blood lymphocytes in both parents. The mother presented with an erythematous and ichthyosiform skin lesion. EBP analysis of DNA extracted from a lesional skin biopsy revealed the presence of p.Cys67Arg mutation. CONCLUSION To our knowledge, we report the first molecular confirmation of postzygotic mosaicism on an ichthyosiform skin lesion in the mother of a girl with X-linked dominant chondrodysplasia punctata associated with a novel EBP mutation.

[1]  M. Krempf,et al.  PCSK9 Dominant Negative Mutant Results in Increased LDL Catabolic Rate and Familial Hypobetalipoproteinemia , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[2]  P. Tanpaiboon,et al.  Two novel EBP mutations in Conradi-Hünermann-Happle syndrome. , 2008, European journal of dermatology : EJD.

[3]  P. Steijlen,et al.  Novel EBP gene mutations in Conradi–Hünermann–Happle syndrome , 2007, The British journal of dermatology.

[4]  F. Chevy,et al.  Sterol profiling of amniotic fluid: a routine method for the detection of distal cholesterol synthesis deficit , 2005, Prenatal diagnosis.

[5]  R. Happle.  Lyonization and the lines of Blaschko , 2004, Human Genetics.

[6]  R. Pauli,et al.  X‐linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male , 2003, American journal of medical genetics. Part A.

[7]  M. Krempf,et al.  Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia , 2002, Human Genetics.

[8]  U. Seedorf,et al.  Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hünermann-Happle syndrome. , 2002, The Journal of investigative dermatology.

[9]  N. Tanaka,et al.  Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata , 2002, Human Genetics.

[10]  C. Has,et al.  The Conradi-Hünermann-Happle syndrome is caused by mutations in the gene that encodes a 8- 7 sterol isomerase and is biochemically related to the CHILD syndrome. , 2000, European journal of dermatology : EJD.

[11]  C. Has,et al.  The Conradi-Hünermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. , 2000, Human molecular genetics.

[12]  J. Derry,et al.  Mutations in a Δ8-Δ7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata , 1999, Nature Genetics.

[13]  A. Moser,et al.  Mutations in the gene encoding 3β-hydroxysteroid-Δ 8,Δ7-isomerase cause X-linked dominant Conradi-Hünermann syndrome , 1999, Nature Genetics.

[14]  J. Derry,et al.  Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com. , 1999, Nature genetics.

[15]  R. Sutphen,et al.  XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome) , 1995, American journal of medical genetics.