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 ... 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.
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), ... 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.
X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the enzyme arylsulfatase E (ARSE)....
DiagnosisClinical DiagnosisX-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the enzyme arylsulfatase E (ARSE).CDPX1 is suspected in a male with the following clinical findings:Chondrodysplasia punctata (CDP) (stippled epiphyses) (see Radiographic Findings)Brachytelephalangy (shortening of the distal phalanges)Nasomaxillary hypoplasia in which hypoplasia of the anterior nasal spine results in a characteristic flattened nasal base, reduced nasal tip protrusion with short columella, and in some cases vertical grooves within the alae nasi. The nostrils are crescent-shaped. It may appear as if the child’s nose is pressed flat against a window.Note: Coagulopathy should be explicitly ruled out by measurement of clotting function (PT and PTT) and clotting factors II, VII, IX, and X (see Differential Diagnosis).The diagnosis is confirmed by molecular genetic testing.Radiographic FindingsStippled epiphyses are observed on skeletal x-rays in infancy, usually in the ankle and distal phalanges, although they can be more generalized to include epiphyses of long bones, vertebrae, hips, costochondral junctions, and hyoid bone. An inverted triangular shape of the distal phalanges with lateral stippling at the apex is characteristic. Stippling is usually symmetric and tends to disappear radiologically after age two to three years when the epiphyses ossify.Calcifications can also occur in the trachea and main stem bronchi, structures that do not normally ossify, and cause stenosis. Vertebral abnormalities are common and include dysplastic and hypoplastic vertebrae and coronal or sagittal clefts. Cervical vertebral abnormalities can cause cervical kyphosis and atlantoaxial instability.TestingCytogenetic analysis. Routine karyotype analysis reveals Xp deletions or rearrangements that include ARSE in approximately 25% of individuals with features of CDPX1. To identify these individuals, karyotype analysis or chromosomal microarray (CMA) should be performed. Smaller interstitial deletions are evaluated by CMA [Hou 2005].Molecular Genetic TestingGene. Mutations in ARSE are the only known genetic cause of CDPX1.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked RecessiveView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier FemalesARSESequence analysisSequence variants 260%-75% 3, 4, 5, 6>50%-65% 7Clinical Exonic, multiexonic, and whole-gene deletions0% 7Deletion / duplication analysis 8Exonic, multiexonic, and whole-gene deletions10% 9Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Non-genetic phenocopies contribute to some cases in which ARSE sequence analysis does not identify a mutation [Brunetti-Pierri et al 2003, Eash et al 2003, Nino et al 2008].4. Franco et al [1995], Parenti et al [1997], Sheffield et al [1998], Brunetti-Pierri et al [2003], Garnier et al [2007], Nino et al [2008]5. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 6. Includes the mutation detection frequency using deletion/duplication analysis7. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysisInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a male probandCDP, brachytelephalangy, and nasomaxillary hypoplasia should be present on clinical examination.Perform molecular genetic testing for mutations in ARSE, including sequence analysis followed by deletion/duplication analysis. If no mutation is identified, chromosomal microarray (CMA) is indicated to detect possible duplications missed on sequence analysis. If an Xp deletion syndrome is suspected (see Genetically Related Disorders), perform karyotype analysis or CMA before molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygous females who are not known to be at risk of manifesting clinical findings of CDPX1. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersContiguous Xp gene deletions that include ARSE have additional phenotypic features that may include ichthyosis, hypogonadotropic hypogonadism, anosmia, cataracts, intellectual disability, and autism. Affected males have Xp terminal deletions, interstitial deletions, or translocations, most involving SHOX or ARSC (STS). (See also SHOX-Related Haploinsufficiency Disorders.) In one of the more well-characterized deletion syndromes, the presence of ichthyosis, cataracts, anosmia, and hypogonadotropic hypogonadism reflects associated deletions of ARSC (STS) and KAL1. (See also Kallmann Syndrome.)
Affected males. The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are CDP, brachytelephalangy, and nasomaxillary hypoplasia. Of note, a child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [Casarin et al 2009]....
Natural HistoryAffected males. The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are CDP, brachytelephalangy, and nasomaxillary hypoplasia. Of note, a child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [Casarin et al 2009].Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability. Growth measures tend to be normal at birth; short stature usually develops postnatally but only some affected adults have small stature. The shortening of the distal phalanges may become less apparent with age such that older individuals may show brachytelephalangy only in some digits. Affected individuals have been thought to have a normal life span; however, recent descriptions have identified persons with more severe morbidity and mortality. These complications include the following:Respiratory compromise caused by severe nasal hypoplasia or extensive punctate calcifications along the tracheobronchial tree requiring choanal stents, tracheostomy, or tracheal reconstruction [Wolpoe et al 2004]Abnormal ossification of the cervical vertebrae that leads to cervical spine stenosis and instability and spinal cord compression [Garnier et al 2007]These complications have led to early death in some cases [Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].In a retrospective review of clinical features associated with CDPX1 and proven mutations in ARSE, the following were observed [Nino et al 2008]:Significant respiratory abnormalities (30%)Mixed conductive and sensorineural hearing loss (~25%)Significant cervical spine abnormalities (20%)Delayed cognitive development (16%)Less frequently seen findings included the following:Ophthalmologic abnormalities (cataracts, optic disc atrophy, small optic nerves)Cardiac abnormalities (PDA, VSD, ASD)Gastroesophageal reflux Feeding difficultiesHeterozygotes. Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some carrier females may have smaller than expected stature [Sheffield et al 1998, Brunetti-Pierri et al 2003].
The absence of common mutations precludes identifying correlations between genotype and phenotype....
Genotype-Phenotype Correlations The absence of common mutations precludes identifying correlations between genotype and phenotype.The severity of the phenotype differed significantly between two brothers with the missense allele p.Ile40Ser, demonstrating variable intrafamilial disease expression [Nino et al 2008].Thus far, affected individuals with intragenic deletions do not appear to be more severely affected than those with missense alleles.
Stippled calcifications are observed in a wide variety of disorders including single gene disorders, chromosomal abnormalities, and intrauterine infections, maternal illnesses, or drug exposure (for a review see Patel et al [1999]). A number of those disorders with radiographic stippling are also associated with shortening of the distal phalanges....
Differential DiagnosisBrachytelephalangic Chondrodysplasia Punctata (BCDP)Stippled calcifications are observed in a wide variety of disorders including single gene disorders, chromosomal abnormalities, and intrauterine infections, maternal illnesses, or drug exposure (for a review see Patel et al [1999]). A number of those disorders with radiographic stippling are also associated with shortening of the distal phalanges.Genetic conditions associated with BCDPKeutel syndrome. This autosomal recessive disorder has features that overlap with X-linked chondrodysplasia punctata 1 (CDPX1), but with more diffuse and progressive calcification of cartilage including nose, auricles, and respiratory tract. Peripheral pulmonic stenosis is also observed. Defects in the vitamin K-dependent matrix Gla protein (MGP) cause Keutel syndrome [Munroe et al 1999].Deficiency of vitamin K epoxide reductase subunit 1 (VKORC1) and gamma-glutamyl carboxylase (GGCX). Mutations in VKORC1 cause both warfarin resistance and multiple coagulation factor deficiency type 2, an autosomal recessive disorder that also may include BCDP [Pauli et al 1987, Rost et al 2004]. Mutations in GGCX cause multiple coagulation factor deficiency type 1, an autosomal recessive disorder that also includes BCDP [Brenner et al 1990].Xp contiguous deletion syndromes. See Genetically Related Disorders.Multiple sulfatase deficiency is a rare autosomal recessive disorder characterized by impaired activity of all known sulfatases including ARSE [Cosma et al 2003].Teratogenic conditions associated with BCDP. Both male and female infants with BCDP have been described. In the case of an affected male, no specific clinical features distinguished CDPX1 from these non-genetic conditions [Nino et al 2008].Prenatal exposure to warfarin. BCDP is well described in infants born to mothers receiving warfarin in early gestation [Hall et al 1980]. Warfarin interferes with the recycling of vitamin K.Reduced intestinal absorption of vitamin K. BCDP was reported in infants whose mothers had presumed vitamin K deficiency as a result of severe hyperemesis gravidarum [Brunetti-Pierri et al 2007], small intestinal obstruction [Eash et al 2003], postoperative small bowel syndrome [Menger et al 1997, Khau Van Kien et al 1998], untreated celiac disease [Menger et al 1997], pancreatitis [Herman et al 2002], and cholelithiasis [Jaillet et al 2005]. Maternal vitamin K deficiency was indirectly documented in two cases [Khau Van Kien et al 1998, Alessandri et al 2010] and suspected in the others. In one of these cases ARSE molecular analysis was negative [Eash et al 2003].Hydantoins. Both stippling and brachytelephalangy have been reported after exposure to hydantoins [Howe et al 1995]. It is unclear whether this is a result of the known effect of hydantoins on vitamin K cycling.Alcohol. Occasionally, infants with other evidence for intrauterine consequences of maternal alcoholism have stippled epiphyses similar to that seen in BCDP [Leicher-Düber et al 1990].Note: Prenatal exposure to warfarin, fetal vitamin K deficiency, and vitamin K epoxide reductase deficiency has been associated with brain malformation [Menger et al 1997, Van Driel et al 2002, Puetz et al 2004, Brunetti-Pierri et al 2007]. However, brain abnormalities have not been reported to date in persons with ARSE mutations.Maternal autoimmune disease. BCDP was reported in infants born to mothers with systemic lupus erythematosus (SLE), Sjogren syndrome, mixed connective tissue disease, scleroderma, and unclassified autoimmune disorders [Kozlowski et al 2004, Kirkland et al 2006, Shanske et al 2007, Chitayat et al 2008, Nino et al 2008, Schulz et al 2010, Tim-aroon et al 2011]. It was proposed that antibodies against ARSE or a component of the biochemical pathway are causative.Non-Brachytelephalangic CDP / Other CDP Conditions Clinically Distinguishable from BCDPX-linked chondrodysplasia punctata 2 (CDPX2) [Herman et al 2002] and CHILD syndrome (congenital hemidysplasia, ichthyosis, and limb defects) [Konig et al 2000] are a result of defects in cholesterol synthesis; they are X-linked dominant and typically lethal in males:CDPX2 (Conradi-Hünermann syndrome, Happle syndrome) is caused by defects in sterol 8-isomerase (encoded by EBP). Affected females have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, and atrophoderma. Rare males with a 47,XXY karyotype or mosaic for defects in EBP have been reported [Aughton et al 2003].CHILD syndrome (see NSDHL-Related Disorders) results from defects in the NAD(P)-dependent steroid dehydrogenase-like enzyme. Affected females have unilateral distribution of ichthyosis, limb defects, CDP, and visceral anomalies.Rhizomelic chondrodysplasia punctata is an autosomal recessive disorder caused by a deficiency of the peroxisomal step of ether phospholipid synthesis [Braverman et al 2002] (see Rhizomelic Chondrodysplasia Punctata Type 1).Tibial-metacarpal type CDP (CDP-TM) is inherited in an autosomal dominant manner; the gene in which mutation is causative is unknown [Savarirayan et al 2004].Humeral-metacarpal type CDP may include brachytelephalangy as well as hypoplasia of the humeri and metacarpals [Fryburg & Kelly 1996]. All instances have been sporadic.Toriello-type CDP is a rare and presumably autosomal recessive disorder with multiple dysmorphic features, colobomata, short stature, and stippling of the proximal humeral epiphyses [Toriello et al 1993].Smith-Lemli-Opitz syndrome, resulting from a defect in conversion of 7-dehydrocholesterol to cholesterol, can also present with stippled calcifications.Peroxisome biogenesis disorders (PBD), Zellweger syndrome spectrum can have stippling in the knees and hips.Stippling is occasionally present in GM1 gangliosidosis, mucolipidosis II, mucopolysaccharidosis type III [Irving et al 2008], trisomy 18, and trisomy 21. Nasomaxillary DysplasiaBinder phenotype, a term describing nasomaxillary dysplasia similar to that observed in CDPX1, does not represent a single nosologic entity. A subset of individuals with Binder syndrome may have mutations in ARSE; this has yet to be determined [Carach et al 2002, Cuillier et al 2005].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CDPX1, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the following evaluations are recommended:Full skeletal surveyFlexion, neutral, and extension lateral views of the C-spine in every patient. If clinical evidence suggests cervical myelopathy or if significant instability is demonstrated radiographically, a cervical MRI should be performed. Special consideration should be given to performing this study in flexion and extension positions as spinal cord compression may only occur with these movements (i.e., a normal neutral cervical MRI does not rule out dynamic compression).Growth measuresDevelopmental assessmentHearing assessmentAssessment of upper and lower airways if stridor is presentPolysomnography if clinical findings suggest increased upper-airway resistance, disordered breathing in sleep, or apneaOphthalmologic evaluationCardiac ultrasound examinationBrain imaging studiesGenetics consultationTreatment of ManifestationsManagement is supportive.Respiratory difficulty can require frequent monitoring, nasal stents, and oxygen.Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals [Carach et al 2002].Instability of the cervical spine may require a cervical collar or spinal fusion.SurveillanceSurveillance of the following is according to recommended pediatric practice, with closer follow-up recommended if abnormalities are identified:HearingGrowthDevelopmentThoracic and lumbar spine (for scoliosis)Evaluation of Relatives at RiskSee Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Chondrodysplasia Punctata 1, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDARSEXp22.33Arylsulfatase EARSE @ LOVDARSEData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Chondrodysplasia Punctata 1, X-Linked (View All in OMIM) View in own window 300180ARYLSULFATASE E; ARSE 302950CHONDRODYSPLASIA PUNCTATA 1, X-LINKED RECESSIVE; CDPX1Normal allelic variants. ARSE spans 29.5 kb of genomic DNA and contains 11 exons and ten introns. It encodes a 2.2-kb full-length transcript. Several polymorphic variations occur in the coding region. ARSE is located in Xp22.3, close to the pseudoautosomal boundary within a cluster of evolutionarily related sulfatase genes that include ARSD, ARSF, ARSG, and ARSC (STS), which encodes steroid sulfatase. These genes escape X inactivation and have a pseudogene on the Y chromosome [Sardiello et al 2005].Pathologic allelic variants. See Table 2. Eighteen unique mutations, two partial deletions, and three complete gene deletions have thus far been identified in 30 probands. A few recurrent mutations were reported in two unrelated probands: p.Gly137Ala, p.Thr481Met, and p.Pro578Ser. The nonsense mutation p.Trp581X was reported in five probands. The Gly137 residue was also mutated to Val (p.Gly137Val) in another individual [Franco et al 1995, Sheffield et al 1998, Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].Table 2. Selected ARSE Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.119T>Gp.Ile40SerNM_000047.2 NP_000038.2c.410G>Cp.Gly137Alac.410G>Tp.Gly137Valc.1442C>Tp.Thr481Metc.1732C>Tp.Pro578Serc.1743G>Ap.Trp581XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The protein encoded by ARSE comprises 589 amino acid residues. Sulfatase enzymes hydrolyze sulfate ester bonds in glycosaminoglycans, sulfolipids, steroid sulfates, and other compounds. All sulfatases undergo a post-translational processing event by the enzyme SUMF1, in which a C-alpha-formylglycine (FGly), the catalytic residue in the active site, is generated from a cysteine [Cosma et al 2003]. The ARSE protein has been studied in an in vitro expression system in COS7 cells, where it localized to Golgi membranes [Daniele et al 1998]. Although its physiologic substrate has not yet been identified, ARSE enzyme hydrolyzes the fluorogenic artificial substrate, 4-methylumbelliferyl (4-MU) sulfate. It is active at neutral pH, heat labile, and inactive toward steroid sulfates [Daniele et al 1998]. ARSE enzyme activity is inhibited in vitro by warfarin, an anticoagulant that inhibits VKORC1, and therefore the regeneration of active vitamin K [Rost et al 2004]. Given the well-documented phenotypic similarities between CDPX1 and warfarin embryopathy, it was proposed that ARSE was the vitamin K-dependent protein inhibited by warfarin. Alternatively, ARSE could act downstream of a vitamin K-dependent metabolic pathway.Abnormal gene product. Several missense alleles were experimentally evaluated and shown to have reduced function [Daniele et al 1998, Brunetti-Pierri et al 2003].