X-linked dominant chondrodysplasia punctata: a case report and family studies

Two major types of chondrodysplasia punctata have been delineated; a severe, recessively inherited, rhizomelic form and the less severe, dominantly inherited Conradi-Hünerman form. Clinico-genetic analysis of this latter form of CP uncovered a sub-group characterised by asymmetric involvement with linear or whorled skin patches of ichthyosiform erythroderma or atrophoderma, circumscribed cicatricial alopecia, asymmetrical cataracts and limb shortness. The mosaic pattern of the manifestations and the limitation of reported cases to females suggested an X-linked dominant gene which undergoes Lyonisation in the female and is lethal in the hemizygous male. We report on a family ascertained through a baby girl who had manifestations typical of the X-linked dominant form of CP and whose mother, 2 of 3 maternal aunts, and maternal grandmother all had less severe manifestations. The absence of male offspring for 3 generations and a history of 3 early miscarriages, along with the clinical variability in the affected females, provide further support for X-linked dominant inheritance of this disorder.     

Lethal form of chondrodysplasia punctata with normal plasmalogen and cholesterol biosynthesis

We present a male autopsied case of chondrodysplasia punctata with abnormal face, symmetrical proximal limb shortness, severe psychomotor developmental delay, respiratory muscle weakness, and death at the age of 2 years. Although his clinical manifestations were similar to those of rhizomelic chondrodysplasia punctata (RCDP), biochemical studies using skin fibroblasts did not document the peroxisomal dysfunction described in RCDP. In addition, the sterol profile, for which abnormalities have recently been reported in cases of X-linked dominant form chondrodysplasia punctata (CDPX2), was normal both in the liver and in the fibroblasts. This patient may represent a new lethal form of chondrodysplasia punctata.     

Severe malformations in males from families with osteopathia striata with cranial sclerosis

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the long bones and sclerosis of the craniofacial bones. Affected patients show macrocephaly, ocular hypertelorism, frontal bossing, broad nasal bridge and abnormalities of the palate. Anomalies such as hearing loss, congenital heart defect, vertebral anomalies and mental impairment have also been reported. Pedigree analysis has suggested an autosomal dominant inheritance, but a recent report of a family with significantly more affected males than females suggested the possibility of X-linked inheritance. Here we describe a new family with OS-CS (the twelfth in the literature) with four affected individuals (two males and two females) spanning three generations. The affected male in the third generation was stillborn with multiple congenital anomalies, whereas the other three affected individuals had mild features. This family may represent another example of X-linked OS-CS where the mutated gene(s) is more severe in males.     

Terminal osseous dysplasia and pigmentary defects: clinical characterization of a novel male lethal X-linked syndrome

We describe a new syndrome of distal limb anomalies and pigmentary skin defects in 10 females of a large, four-generation pedigree. The family was ascertained through a 4-month-old infant girl with multiple anomalies, including hypertelorism, iris colobomas, low-set ears, midface hypoplasia, punched-out pigmentary abnormalities over the face and scalp, generalized brachydactyly, and digital fibromatosis. No affected males were identified in this pedigree. Affected females had a lower than normal male-to-female ratio of liveborn offspring, and some of them also had a history of several miscarriages. These findings, together with a significant variability in the phenotype of the affected females, suggest that this condition is inherited in an X-linked dominant fashion, with prenatal male lethality, and that X-inactivation plays an important role in the phenotypic expression of the disease. The syndrome has been described twice in the literature, but only in sporadic cases; it was therefore not recognized as a mendelian entity. Because the most consistent findings are anomalies of the distal skeleton of the limbs and localized pigmentary abnormalities of the skin, we named the syndrome "terminal osseous dysplasia with pigmentary defects." This condition, though rare, can be added to the small group of male lethal X-linked dominant disorders in humans.     

Cerebral, cerebellar, and colobomatous anomalies in three related males: Sex-linked inheritance in a newly recognized syndrome with features overlapping with Joubert syndrome

We present a so far unrecognized X-linked mental retardation syndrome with features overlapping with Joubert syndrome (JBS). Two brothers showed hypotonia, mental retardation, ocular abnormalities with impaired vision and colobomas and a breathing pattern compatible with JBS. Neuroimaging revealed cerebellar vermis hypoplasia and ventriculomegaly. A tentative diagnosis of JBS was made, and autosomal recessive inheritance considered most likely. In a subsequent pregnancy that occurred after artificial donor insemination, ultrasound in the 22nd week revealed a Dandy-Walker malformation and hydrocephaly. At autopsy at 34 weeks of gestation, the male infant showed cerebellar vermis aplasia and abnormalities of the brainstem and cerebral cortex. He was considered to have the same disorder as his two half-brothers. This renders the pedigree highly suggestive of X-linked inheritance. The clinical symptoms of this syndrome resemble JBS. However, the absence of the molar tooth sign and the X-linked inheritance do not support JBS. We propose the name X-linked cerebral-cerebellar-coloboma syndrome to distinguish the two disorders. Differentiation of the two disorders is especially important in genetic counseling, where artificial donor insemination may be considered as a means of reducing the recurrence risk, or when female relatives of the patient are concerned.     

New brittle bone disorder: report of a family with six affected individuals.

We report on a family in which four females and two males in three generations had a previously undescribed brittle bone disorder that was dominantly transmitted through a maternal line. The cardinal manifestations of the disorder comprised dolichocephaly with frontal bossing, hypoplasia of the midface, postpubertal prognathism, micromelic short stature, coarse trabeculae of the entire skeleton, and bone fragility of variable degrees. Mild spondylar modification and iliac hypoplasia were other hallmarks that were recognized in childhood. The proband, a 19-year-old male, was most severely affected with multiple wormian bones in the calvaria, repetitive fractures, intractable bowing of the legs and forearms, and pseudofractures of the long bones with metaphyseal narrowing. His male cousin was next severely affected with angular deformity restricted to the forearm. The four females were much less affected without angular deformity. The mode of inheritance was thus consistent with either an autosomal dominant trait with sex-influence or an X-linked semidominant trait. Histological bone examination in the proband showed atrophy and fibrous degeneration of the lamellar trabeculae and disorganized chondro-osseous junction, which implied that the disorder involved both intramembranous and enchondral ossifications.     

A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation

Mutations of the gene coding for emopamil binding protein (EBP) can lead to deficient activity of 3-β-hydroxysteroid Δ(8), Δ(7) isomerase and are most commonly identified in. association with the X-linked dominant (male lethal) chondrodysplasia punctata (CDPX2), also known as Conradi-Hunermann syndrome. Our group has identified a hemizygous EBP mutation in males with a phenotype remarkable for Dandy-Walker malformation, cataracts, collodion skin and cryptorchidism. Additional findings of hydrocephalus, dysplasia of the corpus callosum, cardiovascular, craniofacial and skeletal anomalies were regularly seen in affected males and the family histories were supportive of an X-linked -recessive condition. The regularly reproducible constellation of cardinal features aligns very nicely with other disorders of sterol biosynthesis and is further distinguished by an absence of arty clinical manifestations in obligate carrier females. Biochemical analysis of blood from cases demonstrated markedly increased levels of 8(9)-cholestenol, and 8-dehydroeholesterol and a mildly increased level of 7-dehydrocholesterol; a similar pattern to what is seen in CDPX2. Sequence analysis of EJJP revealed a novel hemizygous missense mutation at position 141, predictive of a tryptophan to cysteine substitution (c.141G>T, p.W47C). The unaffected mothers were heterozygous for the c.141G>T mutation arid showed random X-inactivation pattern upon.     

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

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.     

Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome?

We describe a multiple congenital anomalies (MCA) syndrome dominantly transmitted through three generations. Radial ray abnormalities with wide variability of expression were observed in four female patients. Moreover, a 14-week-gestation male fetus had severe radial ray malformation, anencephaly, unilateral renal agenesis, and a common dorsal mesentery. Results of high-resolution karyotyping were normal in the malformed fetus and his affected mother. Furthermore, several spontaneous abortions of male fetuses had occurred in this pedigree. To our knowledge, a similar association has not been described previously. It could represent a new X-linked dominant MCA syndrome, or an autosomal dominant condition with severe expression limited to males.     

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 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.     

New brittle bone disorder: Report of a family with six affected individuals

We report on a family in which four females and two males in three generations had a previously undescribed brittle bone disorder that was dominantly transmitted through a maternal line. The cardinal manifestations of the disorder comprised dolichocephaly with frontal bossing, hypoplasia of the midface, postpubertal prognathism, micromelic short stature, coarse trabeculae of the entire skeleton, and bone fragility of variable degrees. Mild spondylar modification and iliac hypoplasia were other hallmarks that were recognized in childhood. The proband, a 19-year-old male, was most severely affected with multiple wormian bones in the calvaria, repetitive fractures, intractable bowing of the legs and forearms, and pseudofractures of the long bones with metaphyseal narrowing. His male cousin was next severely affected with angular deformity restricted to the forearm. The four females were much less affected without angular deformity. The mode of inheritance was thus consistent with either an autosomal dominant trait with sex-influence or an X-linked semidominant trait. Histological bone examination in the proband showed atrophy and fibrous degeneration of the lamellar trabeculae and disorganized chondro-osseous junction, which implied that the disorder involved both intramembranous and enchondral ossifications. Am. J. Med. Genet. 84:320–329, 1999. © 1999 Wiley-Liss, Inc.     

Terminal osseous dysplasia with pigmentary defects: clinical description of a new family

Terminal osseous dysplasia with pigmentary defects is an extremely rare condition characterized by the triad of pigmentary anomalies of the skin, skeletal abnormalities of the limbs and recurring digital fibromatosis of childhood, with considerable interfamilial and intrafamilial variability of expression. It has recently been added to the small group of X-linked dominant disorder with prenatal male lethality on the basis of a four-generation pedigree in which only females were affected, male progeny was decreased and the number of spontaneous abortions was increased. In this clinical report, we describe a 2-year-old girl with full expression of the syndrome including skin defects, skeletal anomalies and recurrent fibromatosis of fingers and toes and her mother who presents with only multiple hypertrophic oral frenula. As previously demonstrated, our patients also show an extremely skewed X-inactivation on blood cells, strongly suggesting that there is selective disadvantage for cells carrying the mutated gene on their active X chromosome. Terminal osseous dysplasia with pigmentary defects could represent an additional example of extreme intrafamilial variability as already described for other X-linked dominant disorders.     

A family of oculofaciocardiodental syndrome (OFCD) with a novel BCOR mutation and genomic rearrangements involving NHS

Oculofaciocardiodental syndrome (OFCD) is an X-linked dominant disorder associated with male lethality, presenting with congenital cataract, dysmorphic face, dental abnormalities and septal heart defects. Mutations in BCOR (encoding BCL-6-interacting corepressor) cause OFCD. Here, we report on a Korean family with common features of OFCD including bilateral 2nd-3rd toe syndactyly and septal heart defects in three affected females (mother and two daughters). Through the mutation screening and copy number analysis using genomic microarray, we identified a novel heterozygous mutation, c.888delG, in the BCOR gene and two interstitial microduplications at Xp22.2-22.13 and Xp21.3 in all the three affected females. The BCOR mutation may lead to a premature stop codon (p.N297IfsX80). The duplication at Xp22.2-22.13 involved the NHS gene causative for Nance-Horan syndrome, which is an X-linked disorder showing similar clinical features with OFCD in affected males, and in carrier females with milder presentation. Considering the presence of bilateral 2nd-3rd toe syndactyly and septal heart defects, which is unique to OFCD, the mutation in BCOR is likely to be the major determinant for the phenotypes in this family.     

Oto-Palato-Digital syndrome in four generations of a larqe family

A new large family, affected by O-P-D syndrome is reported. Nine members in four consecutive generations have been studied. Computerized tomography study of spine and skull showed abnormalities to be confined to mesodermal derivates, while nervous structures were normal. Transmission pattern may be X-linked with intermediate expression in the female or autosomal dominant with sex limitation of expression.     

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

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. Am. J. Med. Genet. 85:324–329, 1999. © 1999 Wiley-Liss, Inc.     

Clinical and genetic heterogeneity in keratosis follicularis spinulosa decalvans

Keratosis follicularis spinulosa decalvans (KFSD) is an uncommon genodermatosis mainly characterized by follicular hyperkeratosis, progressive cicatricial alopecia and photophobia. Although an excess of affected males and linkage studies strongly suggest an X-linked pattern of inheritance, an apparently rarer autosomal dominant form with prominent follicular inflammation has also been postulated. We report on a three-generation family with five affected individuals and male-to-male transmission. In addition to widespread keratosis pilaris, cicatricial alopecia and eye involvement, our patients show diffuse facial erythema, recurrent folliculitis, enamel hypoplasia, and thickened nails. A literature review of the last 50 years identified 43 additional KFSD cases. X-linked inheritance is demonstrated in two pedigrees by linkage studies and suspected in five. An autosomal dominant pattern is confirmed in three families, including ours, by male-to-male transmission and considered likely in four. Marked facial erythema, extensive folliculitis, onychodystrophy and multiple caries are frequently reported in the autosomal dominant variant, while palmo-plantar keratoderma and early onset seem more typical of the X-linked form. Moreover, three sporadic male patients showing additional multisystemic abnormalities might be explained by an X-linked contiguous-gene syndrome.     

The Conradi-Hünermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism

The Conradi-Hünermann-Happle (CHH) syndrome (X-chromosomal dominant chondrodysplasia punctata type II; MIM 302960) is an X-linked dominant disorder that is characterized by ichthyosis, chondrodysplasia punctata, cataracts and short stature. The disease occurs almost exclusively in females and shows increased disease expression in successive generations (anticipation). Recently, causative mutations in the emopamil binding protein (EBP) have been identified. To better appreciate the genetics of this syndrome we analyzed the EBP gene in seven independent families using PCR, conformation-sensitive gel electrophoresis, direct sequencing and restriction enzyme analysis. We found five novel mutations: three nonsense mutations in exon 2 and exon 3 and two frameshift mutations, one deletion in exon 4 and an insertion in exon 5. In two families, known mutations affecting exon 2 were identified. Surprisingly, we failed to detect the mutation in a grandmother exhibiting minor disease symptoms such as sectorial cataract and attribute this to gonadal and somatic mosaicism. Gonadal mosaicism appeared also to be involved in the case of healthy parents having two affected girls, one of whom died due to the disease. We conclude that gonadal mosaicism has to be considered when dealing with seemingly sporadic cases.     

Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion

We report on a male infant with X-linked ichthyosis, X-linked Kallmann syndrome, and X-linked recessive chondrodysplasia punctata (CPXR). Chromosome analysis showed a terminal deletion with a breakpoint at Xp22.31, inherited maternally. This patient confirms the localization of XLI, XLK, and CPXR to this region of the X chromosome and represents an example of a "contiguous gene syndrome." A comparison of the manifestations of patients with CPXR, warfarin embryopathy, and vitamin K epoxide reductase deficiency shows a remarkable similarity. However, vitamin K epoxide reductase deficiency does not appear to be the cause of CPXR. We propose that CPXR may be due to a defect in a vitamin K-dependent bone protein such as vitamin K-dependent bone carboxylase, osteocalcin, or matrix Gla protein.     

X-linked dominant chondrodysplasia punctata: A peroxisomal disorder?

X-linked dominant chondrodysplasia punctata is characterised by resolving irregular punctate calcifications of epiphyses, variable ichthyosis and atrophoderma, short stature, and cataracts. We report on a patient with this syndrome who had transiently abnormal peroxisomal function tests. We review the literature and propose that X-linked dominant chondrodysplasia punctata is a peroxisomal disorder and that its phenotype can be explained by X chromosome lyonisation and the relative proliferation of cells expressing the normal X allele. Am. J. Med. Genet. 78:300–302, 1998. © 1998 Wiley-Liss, Inc.     

Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes.

Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.