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Chondrodysplasia Punctata 1, X-Linked

Synonyms: CDPX1, Arylsulfatase E Deficiency

, MS, MD, , MD, PhD, , MD, and , MS, CGC.

Author Information
, MS, MD
Departments of Human Genetics and Pediatrics
McGill University - Montreal Children's Hospital Research Institute
Montreal, Quebec, Canada
, MD, PhD
Skeletal Dysplasia Program
AI DuPont Hospital for Children
Wilmington, Delaware
, MD
Telethon Institute of Genetics and Medicine
Naples, Italy
, MS, CGC
Genetic Counselor, McKusick-Nathans Institute of Genetic Medicine
Johns Hopkins Medical Center
Baltimore, Maryland

Initial Posting: ; Last Update: November 3, 2011.

Summary

Disease characteristics. X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the Golgi enzyme arylsulfatase E (ARSE). It is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory compromise, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and abnormal cognitive development.

Diagnosis/testing. In approximately 25% of individuals with features of CDPX1, routine karyotype analysis reveals deletions or rearrangements of the short arm of the X chromosome (Xp) that include ARSE. Chromosomal microarray (CMA) can be used to evaluate for smaller interstitial deletion syndromes. Sequence analysis of ARSE identifies mutations in up to 60% to 75% of males who meet clinical diagnostic criteria.

Management. Treatment of manifestations: Respiratory difficulty can require frequent monitoring, nasal stents, and oxygen. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine may require a cervical collar or spinal fusion.

Surveillance: Routine monitoring of hearing, growth, development, and cervical spine instability.

Genetic counseling. CDPX1 is inherited in an X-linked manner. If the mother of a proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and thus far have not been affected. Males with CDPX1 pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for at-risk pregnancies are possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

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).

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 Findings

Stippled 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.

Testing

Cytogenetic 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 Testing

Gene. Mutations in ARSE are the only known genetic cause of CDPX1.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked Recessive

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected MalesCarrier Females
ARSESequence analysisSequence variants 260%-75% 3, 4, 5, 6>50%-65% 7
Exonic, multiexonic, and whole-gene deletions0% 7
Deletion / duplication analysis 8Exonic, multiexonic, and whole-gene deletions10% 9Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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. For issues to consider in interpretation of sequence analysis results, click here.

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 analysis

7. Sequence analysis of genomic DNA cannot detect (multi)exonic 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 analysis

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a male proband

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.

Clinical Description

Natural History

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].

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 difficulties

Heterozygotes. 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].

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.

Penetrance

Penetrance appears to be complete; however, in one report, the mutation p.Gly137Ala was identified in a proband and his maternal grandfather, the latter of whom was considered asymptomatic [Sheffield et al 1998]. This missense substitution involving a conserved amino acid was identified in a second unrelated, clinically affected proband [Nino et al 2008], implicating it as pathologic. In a second, similar case [Casarin et al 2009] a deletion of exons 7-10 was identified in a proband and his asymptomatic maternal grandfather. Considering that physical features of CDPX1 improve with age, it is uncertain if such cases represent non-penetrance.

Nomenclature

CDPX1 refers specifically to a deficiency of ARSE enzyme activity.

Brachytelephalangic chondrodysplasia punctata (BCDP) is a descriptive term associated with CDPX1 and its non-genetic phenocopies.

Prevalence

The prevalence of CDPX1 is unknown; in one study it was estimated to be 1:500,000 [Malou et al 2001], but it is likely more common.

CDPX1 is pan ethnic.

Differential Diagnosis

Brachytelephalangic 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 BCDP

  • Keutel 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 BCDP

X-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 Dysplasia

Binder 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the following evaluations are recommended:

  • Full skeletal survey
  • Flexion, 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 measures
  • Developmental assessment
  • Hearing assessment
  • Assessment of upper and lower airways if stridor is present
  • Polysomnography if clinical findings suggest increased upper-airway resistance, disordered breathing in sleep, or apnea
  • Ophthalmologic evaluation
  • Cardiac ultrasound examination
  • Brain imaging studies
  • Genetics consultation

Treatment of Manifestations

Management 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.

Surveillance

Surveillance of the following is according to recommended pediatric practice, with closer follow-up recommended if abnormalities are identified:

  • Hearing
  • Growth
  • Development
  • Thoracic and lumbar spine (for scoliosis)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked chondrodysplasia punctata 1 (CDPX1) is inherited in an X-linked manner.

Risk to Family Members

Parents of the proband

Sibs of the proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and have thus far not been affected.
  • If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with CDPX1 will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the ARSE mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • CDPX1 Family Support Group
    Email: thegillums@cox.net
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ARSEXp22​.33Arylsulfatase EARSE @ LOVDARSE

Data 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)

300180ARYLSULFATASE E; ARSE
302950CHONDRODYSPLASIA PUNCTATA 1, X-LINKED RECESSIVE; CDPX1

Normal 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.Trp581* 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

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.119T>Gp.Ile40SerNM_000047​.2
NP_000038​.2
c.410G>Cp.Gly137Ala
c.410G>Tp.Gly137Val
c.1442C>Tp.Thr481Met
c.1732C>Tp.Pro578Ser
c.1743G>Ap.Trp581*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

References

Literature Cited

  1. Alessandri JL, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19:85–7. [PubMed: 20177377]
  2. Aughton DJ, Kelley RI, Metzenberg A, Pureza V, Pauli RM. X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet A. 2003;116A:255–60. [PubMed: 12503102]
  3. Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002;20:284–97. [PubMed: 12325024]
  4. Brenner B, Tavori S, Zivelin A, Keller CB, Suttie JW, Tatarsky I, Seligsohn U. Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants. Br J Haematol. 1990;75:537–42. [PubMed: 2145029]
  5. Brunetti-Pierri N, Andreucci MV, Tuzzi R, Vega GR, Gray G, McKeown C, Ballabio A, Andria G, Meroni G, Parenti G. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet A. 2003;117A:164–8. [PubMed: 12567415]
  6. Brunetti-Pierri N, Hunter JV, Boerkoel CF. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency? Am J Med Genet A. 2007;143:200–4. [PubMed: 17163521]
  7. Carach B, Woods M, Scott P. Maxillonasal dysplasia (Binder syndrome): a lateral cephalometric assessment. Aust Orthod J. 2002;18:82–91. [PubMed: 12462685]
  8. Casarin A, Rusalen F, Doimo M, Trevisson E, Carraro S, Clementi M, Tenconi R, Baraldi E, Salviati L. X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple. Am J Med Genet A. 2009;149A:2464–8. [PubMed: 19839041]
  9. Chitayat D, Keating S, Zand DJ, Costa T, Zackai EH, Silverman E, Tiller G, Unger S, Miller S, Kingdom J, Toi A, Curry CJ. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases. Am J Med Genet A. 2008;146A:3038–53. [PubMed: 19006208]
  10. Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003;113:445–56. [PubMed: 12757706]
  11. Cuillier F, Cartault F, Lemaire P, Alessandri JL. Maxillo-nasal dysplasia (binder syndrome): antenatal discovery and implications. Fetal Diagn Ther. 2005;20:301–5. [PubMed: 15980645]
  12. Daniele A, Parenti G, d'Addio M, Andria G, Ballabio A, Meroni G. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata. Am J Hum Genet. 1998;62:562–72. [PMC free article: PMC1376941] [PubMed: 9497243]
  13. Eash DD, Weaver DD, Brunetti-Pierri N. Cervical spine stenosis and possible vitamin K deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system. Am J Med Genet A. 2003;122A:70–5. [PubMed: 12949976]
  14. Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA, Andria G, Petit C, Ballabio A. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995;81:15–25. [PubMed: 7720070]
  15. Fryburg JS, Kelly TE. Chondrodysplasia punctata, humero-metacarpal type: a second case. Am J Med Genet. 1996;64:493–6. [PubMed: 8862628]
  16. Garnier A, Dauger S, Eurin D, Parisi I, Parenti G, Garel C, Delbecque K, Baumann C. Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases. Eur J Pediatr. 2007;166:327–31. [PubMed: 16937129]
  17. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980;68:122–40. [PubMed: 6985765]
  18. Herman GE, Kelley RI, Pureza V, Smith D, Kopacz K, Pitt J, Sutphen R, Sheffield LJ, Metzenberg AB. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med. 2002;4:434–8. [PubMed: 12509714]
  19. Hou JW. Detection of gene deletions in children with chondrodysplasia punctata, ichthyosis, Kallmann syndrome, and ocular albinism by FISH studies. Chang Gung Med J. 2005;28:643–50. [PubMed: 16323556]
  20. Howe AM, Lipson AH, Sheffield LJ, Haan EA, Halliday JL, Jenson F, David DJ, Webster WS. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Am J Med Genet. 1995;58:238–44. [PubMed: 8533825]
  21. Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol. 2008;17:229–41. [PubMed: 18978650]
  22. Jaillet J, Robert-Gnansia E, Till M, Vinciguerra C, Edery P. Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency. Birth Defects Res A Clin Mol Teratol. 2005;73:188–93. [PubMed: 15751048]
  23. Khau Van Kien P, Nievelon-Chevallier A, Spagnolo G, Douvier S, Maingueneau C. Vitamin K deficiency embriopathy. Am J Med Genet. 1998;79:66–8. [PubMed: 9738872]
  24. Kirkland V, Sundaram UT, Brookshire G, Nino M, Bober M, Braverman N. Chondrodysplasia punctata in infants of mothers with autoimmune diseases. Abstract 518/A. New Orleans, LA: American Society of Human Genetics 56th Annual Meeting; 2006.
  25. Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet. 2000;90:339–46. [PubMed: 10710235]
  26. Kozlowski K, Basel D, Beighton P. Chondrodysplasia punctata in siblings and maternal lupus erythematosus. Clin Genet. 2004;66:545–9. [PubMed: 15521983]
  27. Leicher-Düber A, Schumacher R, Spranger J. Stippled epiphyses in fetal alcohol syndrome. Pediatr Radiol. 1990;20:369–70. [PubMed: 2190164]
  28. Malou E, Gekas J, Troucelier-Lucas V, Mornet E, Razafimanantsoa L, Cuvelier B, Mathieu M, Thepot F. X-linked recessive chondrodysplasia punctata. Cytogenetic study and role of molecular biology. Arch Pediatr. 2001;8:176–80. [PubMed: 11232459]
  29. Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet. 1997;72:129–34. [PubMed: 9382132]
  30. Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet. 1999;21:142–4. [PubMed: 9916809]
  31. Nino M, Matos-Miranda C, Maeda M, Chen L, Allanson J, Armour C, Greene C, Kamaluddeen M, Rita D, Medne L, Zackai E, Mansour S, Superti-Furga A, Lewanda A, Bober M, Rosenbaum K, Braverman N. Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet A. 2008;146A:997–1008. [PubMed: 18348268]
  32. Parenti G, Buttitta P, Meroni G, Franco B, Bernard L, Rizzolo MG, Brunetti-Pierri N, Ballabio A, Andria G. X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene. Am J Med Genet. 1997;73:139–43. [PubMed: 9409863]
  33. Patel MS, Callahan JW, Zhang S, Chan AK, Unger S, Levin AV, Skomorowski MA, Feigenbaum AS, O'Brien K, Hellmann J, Ryan G, Velsher L, Chitayat D. Early-infantile galactosialidosis: prenatal presentation and postnatal follow-up. Am J Med Genet. 1999;85:38–47. [PubMed: 10377011]
  34. Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet. 1987;41:566–83. [PMC free article: PMC1684308] [PubMed: 3499071]
  35. Puetz J, Knutsen A, Bouhasin J. Congenital deficiency of vitamin K-dependent coagulation factors associated with central nervous system anomalies. Thromb Haemost. 2004;91:819–21. [PubMed: 15045146]
  36. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41. [PubMed: 14765194]
  37. Sardiello M, Annunziata I, Roma G, Ballabio A. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Hum Mol Genet. 2005;14:3203–17. [PubMed: 16174644]
  38. Savarirayan R, Boyle RJ, Masel J, Rogers JG, Sheffield IJ. Long-term follow-up in chondrodysplasia punctata, tibial metacarpal type, demonstrating natural history. Am J Med Genet A. 2004;124A:148–57. [PubMed: 14699613]
  39. Schulz SW, Bober M, Johnson C, Braverman N, Jimenez SA. Maternal mixed connective tissue disease and offspring with chondrodysplasia punctata. Semin Arthritis Rheum. 2010;39:410–6. [PMC free article: PMC2844477] [PubMed: 19110299]
  40. Shanske AL, Bernstein L, Herzog R. Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics. 2007;120:e436–41. [PubMed: 17671048]
  41. Sheffield LJ, Osborn AH, Hutchison WM, Sillence DO, Forrest SM, White SJ, Dahl HH. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. J Med Genet. 1998;35:1004–8. [PMC free article: PMC1051512] [PubMed: 9863597]
  42. Tim-aroon T, Jaovisidha S, Wattanasirichaigoon D. A new case of maternal lupus-associated chondrodysplasia punctata with extensive spinal anomalies. Am J Med Genet A. 2011;155A:1487–91. [PubMed: 21567922]
  43. Toriello HV, Higgins JV, Miller T. Provisionally unique autosomal recessive chondrodysplasia punctata syndrome. Am J Med Genet. 1993;47:797–9. [PubMed: 8267015]
  44. Van Driel D, Wesseling J, Sauer PJ, Touwen BC, van der Veer E, Heymans HS. Teratogen update: Fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology. 2002;66:127–40. [PubMed: 12210474]
  45. Wolpoe ME, Braverman N, Lin SY. Severe tracheobronchial stenosis in the X-linked recessive form of chondrodysplasia punctata. Arch Otolaryngol Head Neck Surg. 2004;130:1423–6. [PubMed: 15611404]

Chapter Notes

Revision History

  • 3 November 2011 (me) Comprehensive update posted live
  • 22 April 2008 (me) Review posted live
  • 16 November 2007 (nb) Original submission
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