X‐linked dominant chondrodysplasia punctata: A case report and family studies

Mueller, Rebecca; Crowle, P; Jones, Rachael; Davison, B. C. C.; Opitz, John M.; Reynolds, James F.

doi:10.1002/ajmg.1320200117

Cited by 24 publications

(18 citation statements)

References 10 publications

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“…Typical asymmetric punctate calcifications are present in infancy as well as variable asymmetric proximal limb shortening. Asymmetric cataracts, cicatricial patchy skin changes as well as alopecia or coarse lusterless hair, occasional scoliosis, nasal hypoplasia, frontal bossing, conductive deafness, and laryngomalacia have been described [Silengo et al, 1980;Happle, 1981;Mueller et al, 1985]. Short stature is almost always present.…”

Section: Introductionmentioning

confidence: 95%

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

Milunsky

Maher

Metzenberg

2002

American J of Med Genetics Pt A

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X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.

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Section: Introductionmentioning

confidence: 95%

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

Milunsky

Maher

Metzenberg

2002

American J of Med Genetics Pt A

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“…The primary clinical characteristics of CDPX2, in addition to radiographic stippling, include rhizomelic shortness, skin abnormalities, patchy alopecia, cataracts, and midfacial hypoplasia [Happle, 1979]. Many of the features arise asymmetrically or in a linear pattern, presumably secondary to random X-inactivation of two functionally distinct cell types in females [Happle et al, 1977;Happle, 1985;Mueller et al, 1985].…”

Section: Introductionmentioning

confidence: 99%

X‐linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male

Aughton

Kelley

Metzenberg

et al. 2002

American J of Med Genetics Pt A

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X-linked dominant chondrodysplasia punctata (CDPX2; Happle syndrome) is recognized almost exclusively in females, who display mosaic and asymmetric features, presumed to arise secondary to random X-inactivation. CDPX2 results from mutation of an X-linked gene coding for sterol-delta(8)-delta(7) isomerase (emopamil binding protein). We describe a boy with clinical features of CDPX2 (including those presumed to arise usually secondary to functional mosaicism in females). Biochemical and molecular studies demonstrate that he is mosaic for a sterol-delta(8)-delta(7) isomerase gene mutation. He is the first reported example of single gene mosaicism giving rise to CDPX2 in a male.

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“…In the ensuing years, four additional familial observations of affected females in three generations provided further evidence for the concept of an X-linked dominant gene [Goerttler, 1979;Mueller et al, 1985;Kalter et al, 1989;Traupe et al, 1992a]. Perhaps the most convincing demonstration for the involvement of an X-linked gene in Happle syndrome comes from an observation of Sutphen et al [1995].…”

Section: Delineation Of the Happle Syndromementioning

confidence: 97%

Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko

Traupe

1999

Am. J. Med. Genet.

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In this article, the contribution of Rudolf Happle to the understanding of X-linked skin diseases is reviewed. In 1977 he proposed functional X-chromosomal mosaicism as the genetic mechanism underlying cutaneous anomalies that were seen in a number of X-linked skin diseases such as incontinentia pigmenti or focal dermal hypoplasia. Moreover, he recognized that these cutaneous anomalies followed the lines of Blaschko and thus he could tie in the development of the lines of Blaschko with a datable embryonic event. Convincing proof for the concept of functional X-chromosomal mosaicism was later provided by his group from functional sweat studies in female carriers of the X-linked gene defect hypohidrotic ectodermal dysplasia showing again on the back of the patient a gross, fountain-like mosaic typical of the lines of Blaschko. Moreover, in the years 1977 to 1981 he recognized the mosaic pattern in a syndrome of chondrodysplasia punctata, linear ichthyosis, patchy cicatricial alopecia, unilateral cataracts, and short stature again as a functional X-chromosomal mosaic becoming manifest exclusively in women and proposed that this syndrome, which is today named after him, is because of an X-linked dominant gene defect. Finally, the puzzling molecular genetics of the Happle syndrome are reviewed. Most likely, the Happle syndrome gene is not lethal for hemizygously affected males but rather similar to the example of epilepsy with mental retardation limited to females, the gene actually spares male gene carriers.

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X‐linked dominant chondrodysplasia punctata: A case report and family studies

Cited by 24 publications

References 10 publications

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

X‐linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male

Functional X-chromosomal mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko

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