Abstract. X-linked dominant chondrodysplasia punctata, (CDPX2 – MIM ) also known as Conradi-. Hünermann-Happle syndrome, is a rare form of. X-linked chondrodysplasia punctata 2 is a disorder characterized by bone, skin, and eye abnormalities. It occurs almost exclusively in females. Although the. Minerva Pediatr. Mar;45(3) [Chondrodysplasia punctata (the Conradi-Hünermann syndrome). A clinical case report and review of the literature ].

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CC HPO: Chondrodysplasia punctata CDP is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form.

CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation summary by Aughton et al. See, and for possible autosomal dominant forms of CDP.

In addition, CDP can be caused by maternal vitamin K deficiency or warfarin teratogenicity see CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts, and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling, and craniofacial defects Derry et al.

A higher ratio of females to males Happle reviewed 35 cases, all female. The phenotype had mosaic features consistent with lyonization. The mother was born with short femora and humeri, the left leg shorter than the right, saddle nose, frontal bossing, flexion contractures at the hips and knees, left talipes equinovarus and hyperkeratosis with erythema of the left side of the body.

The son lived only 1 hour. Happle and Kuchle pictured a sectorial cataract in a woman with X-linked dominant chondrodysplasia punctata and proposed that this reflected lyonization.

Conradi–Hünermann syndrome – Wikipedia

Two of their mothers showed a mild form of cicatricial alopecia. The pathognomonic dermatologic findings in the children included erythematous skin changes and striated ichthyosiform hyperkeratosis during the first months of life. Later, patterned ichthyosis, follicular atrophoderma, coarse lusterless hair, and cicatricial alopecia become evident. The X-linked dominant form of chondrodysplasia punctata is lethal in the hemizygous male and, in females, shows a pattern of skin defects consistent with functional X-chromosomal mosaicism; syndroe variability in severity and conradii marked asymmetry of bone and eye changes may have a similar explanation.

Cerebral involvement does not seem to occur. The X-linked recessive form is clinically mild but has cerebral involvement.

Only after 5 months did the streaky hyperkeratotic pattern characteristic of the disorder appear. Family members bore other stigmata including patchy cicatricial alopecia, coarse hair, follicular atrophoderma, frontal bossing, cataracts, short stature, and short proximal limbs.

Decreased peroxisomal enzyme activity was demonstrated on fibroblast cultures. Three of the affected individuals were females: The fourth affected individual was a male in the second generation who was found to be severely affected but represented the first known male patient with X-linked dominant chondrodysplasia punctata see ‘Affected Males’ below.

Hunerrmann skin changes became evident for the first time during adulthood. Both the ichthyotic and psoriasiform skin lesions followed Blaschko lines. Usually in X-linked dominant chondrodysplasia punctata, punctate epiphyseal calcifications and ichthyotic skin lesions are both transient, resolving during early infancy.

The coexistence of the 2 forms of skin change in the adult was unusual. The mother of 1 of the patients had bone dysplasia consistent with the X-linked dominant form of chondrodysplasia punctata.


She had always been smaller than her peers, and spinal curvature, which had been recognized in early huermann, had progressed.

By adulthood, she had a gross kyphoscoliosis and was cm in height, with relative truncal shortening. Vertebral wedging was maximal in the lower thoracic spine.

The vertebral bodies above and below this cojradi were found to be comparatively normal. The distal end of the left ulna was dysplastic, as was the right femoral head. The left fourth metacarpal was short. A firm diagnosis would not have been possible on the basis of the radiologic findings in the mother alone. In the case of the infant uhnermann had been no maternal exposure to embryopathic agents, and, in particular, no warfarin therapy had been given.

The infant died at approximately 1 hour condadi age. The first girl presented in infancy with asymmetric limb shortening, flat face, saddle nose, and cataracts. She had hyperkeratotic brownish plaques on the lower extremities following the lines of Blaschko and generalized brownish scales sparing the scalp, face, palms, syndrpme, and inguinal area.

Radiographs showed generalized punctate calcifications of the epiphyseal regions of long bones, vertebrae, and the pelvic bone. The second girl first presented at age 13 stndrome. She had short stature, asymmetric limb shortening, postaxial polydactyly, pronounced kyphoscoliosis, dry and scaly skin, sparse hair with areas of alopecia, and conradii. There were atrophic linear skin lesions following the lines of Blaschko mostly on the extremities. Her mother, who also carried the mutation, had sparse hair and atrophic linear skin lesions following the lines of Blaschko.

She did not manifest cataracts, polydactyly, scoliosis, or asymmetric limb shortening. His survival was attributable to syndroke presence of a 47,XXY karyotype. This affected male died at age 31 years due to restricted pulmonary disease secondary to severe kyphoscoliosis. He attained a height of Physical findings showed severe skeletal anomalies, including asymmetric skull with hypoplastic right face, short neck, kyphoscoliosis, shortness of the right upper and lower limbs, short right third digit, and dislocation of the head of the right radius.

He also had patchy cicatricial alopecia, right cataract, and right esotropia. Intelligence was borderline; his IQ was 83 at age 5 years and 77 at age 11 years. Although Sutphen et al.

Contrasting with the XXY male reported by Sutphen et al. Additional features included coarse, dry hair with spotty congadi alopecia, mild nasal depression, mild midface flattening, and cutaneous linear streaky hypotrophy. He did not have cataracts, and cognition was normal. Laboratory studies showed increased levels of plasma 8-dehydrocholesterol and 8 9 -cholestenol.

He also had patchy alopecia of the scalp and follicular atrophoderma of the knees. No skeletal hhunermann ocular abnormalities were noted, and no neurologic abnormalities were reported. Karyotype analysis showed 46,XY, and Arnold et al. They found abnormal plasma or tissue sterol conadi characterized by increased levels of 8-dehydrocholesterol and 8 9 -cholestenol, suggesting a deficiency of 3-beta-hydroxysteroid-delta 8 ,delta 7 -isomerase, a principal enzyme of cholesterol biosynthesis.

The authors concluded that abnormal cholesterol ssyndrome is a characteristic of some syndromes with rhizomelic shortening and chondrodysplasia punctata. Herman reviewed the cholesterol biosynthetic pathway and the 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: The assignment of the EBP gene to Xp None of the mutations were identical to those found by Derry et al.

No correlation between the nature of the mutation and the phenotype was evident. Mutations in the EBP gene conrai identified in 22 of the 26 females studied, including 20 of the 22 patients who demonstrated an abnormal sterol profile.


Thirteen of the mutations were novel. Affected females had typical skin manifestations and all but 1 had skeletal dysplasia. Sheffield traced the legitimacy of a tripartite eponym conrafi this disorder: Heterozygous females are small and at 4 to 5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults Uwechue et al. Craniofacial anomalies and twisted toes have also been observed in some affected females.

A potential second allele of Td was described by Seo et al.

Florida Zoo Gives Girl with Conradi-Hünermann Syndrome an Unforgettable Day

The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata as well as another X-linked semidominant mouse mutation, ‘bare patches’ Bpa. The location of the Bpa gene in the mouse suggested that the human counterpart is in the Xq28 region.

Multiple recombinations appeared to exclude the Xq28 region as the site of the gene. Surprisingly, multiple crossovers were also found with 26 other markers distributed over the rest of the X chromosome. Two-point linkage analysis and analysis of recombination chromosomes seemed to exclude the gene from the entire X chromosome.

Rare Disease Database

They considered 3 mechanisms that might explain the apparent exclusion of the X-linked gene from the X chromosome by linkage analysis. A second possibility is syhdrome of metabolic interference as proposed by Johnson This hypothesis would suggest that only hunernann manifest the disorder and that it would segregate in a manner mimicking X-linked dominant transmission.

However, males could receive and transmit the abnormal gene but could not exhibit the abnormal phenotype. Such nonpenetrant males would be scored as recombinants. Metabolic interference would predict that all daughters of a nonpenetrant male gene carrier would be affected; transmission of the gene via an unaffected male has not been observed in the families with Happle syndrome. In the 3 kindreds studied, only females were affected in successive generations. This explanation would account for the unexpected sex ratio M: One expects with an X-linked dominant male-lethal gene to find a ratio of 1: An unstable premutation would also explain the striking clinical variability of the phenotype, including stepwise increases in disease expression in successive generations.

Traupe recounted difficulties in mapping the gene for X-linked dominant chondrodysplasia punctata or, as he called it, Happle syndrome.

Because of presumed homology to the mouse mutant ‘bare patches,’ on Xq28, they tested for linkage in that region cornadi excluded it. Indeed, multiple crossovers were found, with hunerman other markers spread along the rest of the X chromosome. The linkage of the gene seemed to be excluded for the entire X chromosome by 2-point linkage analysis. On reexamination of the pedigree, they realized that in contrast to their expectation of a gene that is lethal for hemizygous males and thus results in a preponderance of females, they actually observed a close-to-even sex ratio M: This result suggested that the assumption that males with a mutant gene for Happle syndrome die in utero could be wrong.

The disorder studied by Ryan et al. Craniofrontonasal dysplasia CFND; is another X-linked dominant disorder synddome which females are consistently affected more hhunermann than males, although male carriers show xyndrome phenotypic abnormalities Kapusta et al. X-linked dominant chondrodysplasia punctata CDPX2 caused by single gene mosaicism in a male.