Chondrodysplasia Punctata 1, X-Linked Recessive

A number sign (#) is used with this entry because of evidence that X-linked recessive chondrodysplasia punctata (CDPX1) is caused by mutation in the arylsulfatase E gene (ARSE; 300180) on chromosome Xp22.

For a general phenotypic description and a discussion of genetic heterogeneity of CDP, see CDPX2 (302960).

Clinical Features

Sheffield et al. (1976) reported 23 patients who presented in infancy with failure to thrive, apparent mental retardation, and atypical facies. Diagnosis was confirmed by finding punctate calcifications in radiographs of the feet and other sites. Seventeen patients were male, and Sheffield et al. (1976) suggested an X-linked recessive inheritance. Four of their patients showed hypoplasia of the distal phalanges, which was ascribed to Dilantin in 2 cases in which the mothers had a history of use of that drug during gestation.

Curry (1979) observed a kindred with 2 affected brothers and 1 of their maternal uncles. She suggested that hypoplasia of the distal phalanges is a distinctive feature. One of the brothers was stillborn and showed nasal hypoplasia and distal phalangeal hypoplasia. The uncle required bilateral choanal tubes during the first weeks of life because of severely hypoplastic nose. At birth the skin was bright red with generalized scales which desquamated in large sheets. The skin lesions subsequently had the appearance of ichthyosis. He was retarded (in the educable range) and deaf. In the family of Curry (1979), the presumed carrier females showed no radiologic abnormality, thus suggesting an X-linked recessive form.

Maroteaux (1989) described 4 cases of chondrodysplasia punctata with hypoplasia of the distal phalanges of the fingers. He designated the disorder brachytelephalangic chondrodysplasia punctata. Growth disturbance was moderate without asymmetry of the limbs, and the facial dysmorphism was similar to that in a condition Maroteaux (1989) referred to as 'Binder's maxillo-facial dysostosis.' Generalized involvement of the vertebral bodies with calcifications was never seen. The cases represented a benign form of chondrodysplasia punctata. The phalangeal anomaly is important to the diagnosis after the second and third years of life, when the epiphyseal stippling is no longer present. Maroteaux (1989) pointed out that the facial features and even the distal phalangeal hypoplasia are similar to those reported by Curry et al. (1984) in cases with a deletion of terminal Xp, and suggested that the affected patients, all males, may have their disorder on the basis of an isolated mutation of the same gene on Xp.

Petit et al. (1990) described a 4-generation family in which chondrodysplasia punctata was found in a boy and one of his maternal uncles. These 2 patients also had short stature, as did all the female members of the family. Petit et al. (1990) emphasized and illustrated the occurrence of short distal phalanges in this condition, especially in the 25-year-old uncle.

Elcioglu and Hall (1998) reported 2 sibs with features consistent with a diagnosis of either chondrodysplasia punctata, metacarpal type or chondrodysplasia, brachytelephalangic type, one of whom was stillborn at 36 weeks and one of whom miscarried at 24 weeks, from a mother with systemic lupus erythematosus (SLE; 152700). Austin-Ward et al. (1998) reported a child with chondrodysplasia punctata (118651) and other congenital anomalies resembling those associated with the use of oral anticoagulants, but with no history of exposure, who was born to a mother with systemic lupus erythematosus. Both Elcioglu and Hall (1998) and Austin-Ward et al. (1998), as well as Toriello (1998) in a commentary on these 2 papers, concluded that there was an association between chondrodysplasia punctata and maternal systemic lupus erythematosus. Kozlowski et al. (2004) described 2 brothers with chondrodysplasia punctata, whose mother had longstanding lupus erythematosus and epilepsy, for which she had been treated with chloroquine and other therapeutic agents during both pregnancies. Kozlowski et al. (2004) pointed to 7 previously reported instances of the association between chondrodysplasia punctata and maternal SLE.

Cytogenetics

Curry et al. (1982) concluded that X-linked chondrodysplasia punctata may be determined by a locus at Xp22.32. Two families were studied, each with 2 affected males. Because atypical ichthyosis was a feature, the steroid sulfatase system was investigated. All 4 had greatly elevated cholesterol sulfate; this measure was normal in carrier females. In both of the males studied, cultured fibroblasts showed steroid sulfatase deficiency. High-resolution cytogenetics showed a small deletion at Xp22.32 in all 4 affected males, their carrier mothers, and several potential carrier females. Curry et al. (1984) reported that the steroid sulfatase (STS; 300747), XG (300879), and MIC2X (313470) loci were also deleted. The women carrying the deletion had normal gonadal function and fertility but were shorter of stature than noncarriers in their families (p less than 0.00001). The skin lesions resembled those of X-linked ichthyosis (308100). The deletion in the family reported by Bick et al. (1989) was larger than that described by Curry et al. (1984) and included the Kallmann gene (KAL1; 300836).

By a study of cases of various deletions of Xp, Ballabio et al. (1989) concluded that CPXR is located just proximal to MIC2 in the most distal portion of Xp, which is pseudoautosomal. Ballabio et al. (1991) described a male infant with short stature, chondrodysplasia punctata, and ichthyosis due to steroid sulfatase deficiency. Deletion of the distal short arm of the X chromosome had been inherited from the mother who had a balanced reciprocal translocation between 9p and Xp. This was evidence of close situation of the STS locus and the CDPX1 locus.

Wulfsberg et al. (1992) described X-linked recessive chondrodysplasia punctata as part of a contiguous Xp gene deletion syndrome including the CDPX1 gene, a nonspecific X-linked mental retardation gene, the STS gene, and the Kallmann syndrome gene.

Agematsu et al. (1988) described mother and son who were carrying an extra piece on the short arm of the X chromosome, identified as having derived from the long arm of the Y chromosome by means of in situ hybridization with a Y-chromosome-specific DNA probe. The son had punctate epiphyseal calcifications, mildly short limbs, flattened nasal bridge, and mental retardation. The mother was somewhat short of stature and was said to have mildly short arms but no punctate calcifications. It is difficult to suggest that the mother was affected. During the early weeks of life, the son suffered from severe respiratory distress attributed to the small nasal airway and laryngomalacia with stippling of the laryngeal cartilages.

Maroteaux (1989) reported that DNA molecular analysis of pseudoautosomal and Xp22.3-specific loci showed an interstitial deletion that cosegregated with the phenotypic abnormalities. The deletion lay at the boundary of the pseudoautosomal region. The fact that the patients had neither ichthyosis nor Kallmann syndrome indicates that these loci are located more proximally.

Seidel et al. (2001) described an 8-year-old male with mesomelic shortening of forearms and legs, brachytelephalangy, and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome. Fluorescence in situ hybridization and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene and demonstrated deletions of steroid sulfatase, arylsulfatase E, and short stature homeobox (SHOX; 312865) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the ARSE gene; however, no stippled epiphyses were seen in the neonatal radiograph. Brachytelephalangy was the only result of ARSE gene deletion in this patient. The patient's mother had dwarfism and showed Madelung deformity of the forearms. She was shown to be a carrier of the same aberrant X chromosome. Her son did not show Madelung deformity, demonstrating that the Leri-Weill syndrome phenotype may be incomplete in children with SHOX gene deletion.

Mapping

Van Maldergem et al. (1991) confirmed the assignment of the CDPX1 gene to Xp22.3 by demonstrating the existence of a reciprocal X-Y translocation involving the region distal to Xp22.3. Weil et al. (1993) studied a 13-year-old male with a 45,X karyotype and many stigmata of Turner syndrome. Y-chromosome material had been transposed to the X chromosome, which was partially deleted. The deletions on the X and Y chromosomes allowed Weil et al. (1993) to map the genes responsible for most features of the Turner syndrome to the segment between DXS432 and Xqter. Since the patient had no clinical or radiographic signs of chondrodysplasia punctata, they concluded from the molecular analysis that this locus can be narrowed to an interval of 1.5 Mb between DXS432 and DXS31.

Molecular Genetics

Franco et al. (1995) cloned the genomic region within Xp22.3 where the gene related to CDPX is located and isolated 3 adjacent genes showing highly significant homology to the sulfatase gene family: arylsulfatase D (300002), arylsulfatase E (ARSE), and arylsulfatase F (300003). Point mutations in ARSE were identified in 5 patients with CDPX (300180.0001-300180.0005). Expression of the gene in COS cells resulted in a heat-labile arylsulfatase activity that is inhibited by warfarin. Franco et al. (1995) demonstrated a deficiency of a heat-labile arylsulfatase activity in patients with deletions spanning the CDPX region. Thus, Franco et al. (1995) determined that CDPX is caused by an inherited deficiency of a novel sulfatase. It is likely that warfarin embryopathy involves drug-induced inhibition of the same enzyme. ARSD lies telomeric to ARSE and both are transcribed toward the telomere. The authors noted that ancient duplications may be responsible for the contiguous location of genes of closely similar sequence and structure. Franco et al. (1995) granted the possibility that mutations in the ARSD or ARSF genes may also cause CDPX. Another member of the arylsulfatase family, ARSC, also known as steroid sulfatase, is deficient in X-linked ichthyosis. ARSA (607574) is deficient in metachromatic leukodystrophy (250100); ARSB (611542) is deficient in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; 253200).

Sheffield et al. (1998) reported mutation analysis on 16 males and 2 females with what they classified as the symmetric type of chondrodysplasia punctata, including individuals from 3 multigeneration families. Mutations in ARSE were found in 3 males. No mutations were detected in the ARSD gene. Family studies showed segregation of the mutations with phenotype, establishing X-linked inheritance in the families. Asymptomatic females and males were found in these studies. Sheffield et al. (1998) concluded that clinical presentation varied not only between unrelated affected males but also between affected males within the same family, and that the clinical diagnosis of chondrodysplasia punctata in adults can be difficult. Sheffield et al. (1998) also discussed the nosology of the chondrodysplasia punctata group.

In 16 male patients with CDPX1, Brunetti-Pierri et al. (2003) performed direct sequencing of the ARSE gene and identified mutations in 12 of them (see 300180.0007-300180.0008). Clinical variability was observed among the patients, including severe presentation with early lethality in one, and unusual features such as cataracts, sensorineural deafness, and respiratory distress.

Nino et al. (2008) evaluated the ARSE gene in 11 patients with a suspected clinical diagnosis of CDPX1 based on the diagnostic criteria of male sex, nasomaxillary hypoplasia, brachytelephalangy, and radiologic evidence of chondrodysplasia punctata. Mutations were identified in 7. Three of the remaining 4 individuals had underlying maternal conditions, including maternal pancreatitis and autoimmune disease involving several organs, that further expand the phenocopy group. Nino et al. (2008) compared the clinical features of 31 patients with documented ARSE deficiency and 27 patients with presumed phenocopies of CDPX1. Distinguishing features included the increased occurrence of maternal complications, preterm delivery, and infant demise in the phenocopy group.

Matos-Miranda et al. (2013) reported the results of a Collaboration Education and Test Translation (CETT) program for CDPX1 from 2008 to 2010. Of 29 male probands identified, 17 had ARSE mutations (58%) including 10 novel missense alleles and 1 single-codon deletion. All mutant alleles had negligible ARSE activity, and there were no obvious genotype-phenotype correlations. Maternal etiologies were not reported in most patients.