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Chondrodysplasia Punctata 1, X-Linked

Synonym: Arylsulfatase E Deficiency

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

Author Information

Initial Posting: ; Last Update: October 15, 2020.

Estimated reading time: 17 minutes

Summary

Clinical characteristics.

X-linked chondrodysplasia punctata 1 (CDPX1) 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 involvement, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability.

Diagnosis/testing.

The diagnosis of CDPX1 is established in a male proband with typical clinical and radiographic findings and a hemizygous ARSL pathogenic variant identified by molecular genetic testing. Testing of ARSL enzymatic activity is not currently available on a clinical basis.

Management.

Treatment of manifestations: Treatment of respiratory difficulty as per ENT and/or pulmonologist including nasal stents and oxygen as needed. 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. Decompression for cervical spine stenosis as needed. Hearing aids and pressure equalization tubes may be needed for hearing loss. Therapies and individualized education plan for those with developmental delay and/or learning disorder. Standard treatment for vision issues and cardiac anomalies.

Surveillance: Routine monitoring for growth deficiency, scoliosis, hearing loss, developmental delay, and ocular abnormalities. Assess for cervical spine instability by flexion-extension radiographs every six to twelve months until growth is completed.

Agents/circumstances to avoid: In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided. In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure.

Genetic counseling.

CDPX1 is inherited in an X-linked manner. If the mother of a proband has the ARSL pathogenic variant identified in the proband, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and thus far have not been affected. Males with CDPX1 pass the pathogenic variant 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 ARSL pathogenic variant has been identified in the family.

Diagnosis

Suggestive Findings

X-linked chondrodysplasia punctata 1 (CDPX1) should be suspected in a male proband with the following clinical and radiographic findings.

Clinical findings

  • Brachytelephalangy (shortening of the distal phalanges)
  • Nasomaxillary hypoplasia
    • Hypoplasia of the anterior nasal spine
    • Flattened nasal base
    • Reduced nasal tip protrusion with short columella
    • Crescent-shaped nostrils
    • Vertical grooves within the alae nasi (in some individuals)
  • Postnatal short stature

Radiographic findings

  • Chondrodysplasia punctata (stippled epiphyses) are observed on skeletal x-rays in infancy, usually of 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 age dependent and cannot be seen after normal epiphyseal ossification at age two to three years.
  • Calcifications can also occur in the larynx, 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, cervical stenosis, and atlantoaxial instability.

Laboratory findings. Normal clotting function (PT and PTT) and clotting factors II, VII, IX, and X (See Differential Diagnosis.)

Establishing the Diagnosis

The diagnosis of CDPX1 is established in a male proband with suggestive findings and a hemizygous pathogenic variant in ARSL identified by molecular genetic testing (see Table 1).

Note: (1) Identification of a hemizygous ARSL variant of uncertain significance does not establish or rule out the diagnosis of this disorder. (2) Testing of ARSL enzymatic activity is not currently available on a clinical basis.

Molecular genetic testing approaches can include the following:

  • If an Xp deletion syndrome is suspected (see Genetically Related Disorders), chromosomal microarray analysis (CMA) to detect genome-wide large deletions/duplications (including ARSL) that cannot be detected by sequence analysis
  • Single-gene testing. Sequence analysis of ARSL to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes ARSL and other genes of interest (see Differential Diagnosis) can be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ARSL (formerly ARSE)Sequence analysis 3, 488% 5
Gene-targeted deletion/duplication analysis 612% 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

5.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

Affected Males

The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are chondrodysplasia punctata (CDP), brachytelephalangy, and nasomaxillary hypoplasia. 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.

To date, approximately 50 individuals with a pathogenic variant in ARSL have been reported in the literature. The following description of the phenotypic features associated with this condition is based on the case series from Nino et al [2008] and Matos-Miranda et al [2013].

Table 2.

Chondrodysplasia Punctata 1, X-Linked: Frequency of Select Features

FeatureProportion of Persons w/Feature 1Comment
Chondrodysplasia punctata (CDP)45/46 2CDP typically not visible on radiographs after age 3 yrs
Nasomaxillary hypoplasia42/42
Brachytelephalangy33/35
Short stature (height <5th %ile)12/16Postnatal onset
Significant respiratory abnormalities17/23Frequent respiratory infections, asthma, central apnea, tachypnea, neonatal respiratory distress, mechanical ventilation, tracheotomy, chronic nasal obstruction, nasal stents
Mixed conductive & sensorineural hearing loss13/18
Significant cervical spine abnormalities10/16Dysplasia or hypoplasia of cervical vertebrae, C1–C2 anterior subluxation, kyphosis, cervical cord compression, spinal canal stenosis
Delayed cognitive development5/6
1.

From Nino et al [2008], Matos-Miranda et al [2013]. Note: These studies may have an ascertainment bias towards more severely affected children.

2.

A child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [Casarin et al 2009].

Nasomaxillary hypoplasia. Hypoplasia of the anterior nasal spine results in a characteristic flattened nasal base, reduced nasal tip protrusion with short columella, and in some individuals vertical grooves within the alae nasi. The nostrils are crescent shaped.

Brachytelephalangy. The shortening of the distal phalanges is typically seen in newborns in both hands and feet. Brachytelephalangy persists in the fingers over the life span of individuals with CDPX1 but may become less apparent with age.

Growth measurements tend to be normal at birth; short stature usually develops postnatally but only some affected adults have short stature.

Respiratory insufficiency. Respiratory compromise caused by severe nasal hypoplasia or extensive punctate calcifications along the tracheobronchial tree may require choanal stents, tracheostomy, or tracheal reconstruction [Wolpoe et al 2004].

Hearing loss. Conductive and sensorineural hearing loss have been reported.

Cervical spine abnormalities. Abnormal ossification of the cervical vertebrae can result in cervical spine stenosis and/or instability and spinal cord compression [Garnier et al 2007, Vogel & Menezes 2012].

Developmental delay / intellectual disability. Cognitive delay has been reported in some individuals.

Other. Less frequently seen findings:

  • Ophthalmologic abnormalities (e.g., cataracts, optic disc atrophy, small optic nerves)
  • Cardiac anomalies (e.g., patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis)
  • Gastroesophageal reflux
  • Feeding difficulties

Prognosis. Affected individuals most often have a normal life span; however, some males experience severe morbidity and early mortality due to respiratory compromise, cervical spine stenosis, and/or cervical instability [Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].

Heterozygotes

Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some heterozygous females may have smaller-than-expected stature [Sheffield et al 1998, Brunetti-Pierri et al 2003].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance may be incomplete. ARSL pathogenic variant p.Gly137Ala was identified in an affected proband and his unaffected maternal grandfather [Sheffield et al 1998]. A deletion of exons 7-10 was identified in an affected proband and his asymptomatic maternal grandfather [Casarin et al 2009]. Considering that physical features of CDPX1 improve with age, it is uncertain whether such instances represent non-penetrance.

Nomenclature

CDPX1 refers specifically to a deficiency of ARSL 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 at 1:500,000 [Malou et al 2001], but it is likely more common.

CDPX1 is pan ethnic.

Differential Diagnosis

Genetic Disorders

Table 3a.

Disorders with Brachytelephalangic Chondrodysplasia Punctata (BCDP) in the Differential Diagnosis of CDPX1

Gene(s)DisorderMOIAdditional Overlapping FeatureFindings Distinguishing the Disorder from CDPX1
GGCX
VKORC1
Combined deficiency of vitamin K-dependent clotting factor 1 (OMIM 277450) & factor 2 (OMIM 607473)ARNasal hypoplasiaBleeding disorder due to variably ↓ levels of coagulation factors II, VII, IX, & X, & protein C, protein S, & protein Z
MGPKeutel syndrome (OMIM 245150)ARMore diffuse & progressive calcification of cartilage incl nose, auricles, & respiratory tract

AR = autosomal recessive; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI = mode of inheritance

Table 3b.

Disorders with Non-Brachytelephalangic Chondrodysplasia Punctata and Cervical Spine Anomalies in the Differential Diagnosis of CDPX1

Gene(s)DisorderMOIFindings Distinguishing the Disorder from CDPX1
Clinical FeaturesBiochemical Findings
AGPS
GNPAT
PEX5
PEX7
RDCP1, 2, 3, & 5 (OMIM PS215100)AR
  • Rhizomelia, profound growth restriction, congenital cataract
  • Absence of nasal hypoplasia
Deficiency of peroxisomal plasmalogen (measured in erythrocytes) is diagnostic.
EBPCDPX2 1XL
  • Asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis, & atrophoderma
  • Affected individuals are typically female
  • Absence of nasal hypoplasia
↑ 8(9)-cholestenol & 8-dehydrocholesterol levels in plasma
NSDHL 2CHILD syndrome (See NSDHL-Related Disorders.)XL
  • Male lethal, unilateral CDP, rhizomelia, polydactyly, skin findings; one side of the body affected
  • Absence of nasal hypoplasia
↑ 4-methyl- & carboxysterols levels in cultured lymphoblasts (but only occasionally in plasma) 2

AR = autosomal recessive; CDP = chondrodysplasia punctata; CDPX = X-linked chondrodysplasia punctata; CHILD = congenital hemidysplasia, ichthyosis, limb defects; MOI = mode of inheritance; RCDP = rhizomelic chondrodysplasia punctata; XL = X-linked

1.

Also referred to as Conradi-Hünermann syndrome and Happle syndrome.

2.

NSDHL encodes a cholesterol biosynthetic 4-methylsterol dehydrogenase. The enzyme, part of a 4-methylsterol demethylase complex, occurs one step proximal to the EBP sterol isomerase.

Teratogen Exposures

Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to CDPX1 with especially severe hypoplasia of the nasal bone ("Binder anomaly"), distal phalangeal abnormalities, and punctata of the axial skeleton.

BCDP was reported in infants whose mothers had presumed vitamin K deficiency as a result of severe hyperemesis gravidarum [Brunetti-Pierri et al 2007], Crohn disease [Toriello et al 2013], 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], cholelithiasis [Jaillet et al 2005], and liver fibrosis due to transfusional iron overload [Xie et al 2013]. Maternal vitamin K deficiency was indirectly documented in three instances [Khau Van Kien et al 1998, Alessandri et al 2010, Xie et al 2013] and suspected in the others. Molecular genetic testing did not identify an ARSL pathogenic variant in the infant described by Eash et al [2003].

Maternal autoimmune disease (systemic lupus erythematosus) [Blask et al 2018, Alkhunaizi et al 2020], mixed connective tissue disease, and scleroderma [Chitayat et al 2008, Schulz et al 2010] can cause CDP with rhizomelic limb shortening.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Chondrodysplasia Punctata 1, X-Linked

System/ConcernEvaluationComment
RespiratoryAssessment of upper & lower airways by ENT & pulmonologistIf stridor is present
Obstructive sleep
apnea
PolysomnographyIf sleep apnea is suspected
Skeletal
  • Growth assessment
  • Skeletal survey
  • Assessment for scoliosis
To determine extent of CDP & skeletal anomalies
Cervical spine
instability
Flexion, neutral, & extension lateral radiographs of the cervical spine
  • Cervical spine MRI if clinical evidence of cervical myelopathy or significant instability on radiographs
  • Special consideration when performing this study in flexion & extension positions as spinal cord compression may only occur w/these movements (i.e., normal neutral cervical spine MRI does not rule out dynamic compression).
  • Consider brain MRI at time of cervical spine MRI. 1
AudiologyHearing assessmentTo assess for sensorineural & conductive hearing loss
Developmental delayDevelopmental assessment
Ophthalmologic
abnormalities
Ophthalmologic evalTo evaluate for cataracts, optic disc atrophy, & small optic nerves
Cardiac anomaliesEchocardiogramTo evaluate for patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonary artery stenosis
Genetic counselingBy genetics professionals 2To inform patients & families re nature, MOI, & implications of CDPX1 in order to facilitate medical & personal decision making
Family support/
resources
Assess:

CDP = chondrodysplasia punctata; CDPX1 = chondrodysplasia punctata 1, X-linked; MOI= mode of inheritance

1.

Although not reported in individuals with CDPX1, cortical dysplasia was reported in two infants with brachytelephalangic chondrodyspalsia punctata due to maternal vitamin K deficiency [Brunetti-Pierri et al 2007, Bhoj et al 2013]. It is suspected that cortical dysplasia could occur in individuals with CDPX1 [Author, personal observation].

2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Chondrodysplasia Punctata 1, X-Linked

Manifestation/ConcernTreatment
Respiratory difficultyTreatment per ENT/pulmonologist incl nasal stents & oxygen
Severe maxillary hypoplasia
or maxillary retrognathia
Reconstructive surgery in older individuals as needed 1
Cervical spine instabilityCervical collar or spinal fusion as needed
Cervical spine stenosisDecompression as needed
Hearing loss
  • Hearing aids
  • Pressure equalization tube placement as needed
Developmental delays
  • Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified developmental delays
  • Individualized education plans for learning disorders & school performance issues
Vision issuesTreatment per ophthalmologist
Cardiac anomaliesTreatment per cardiologist

OT = occupational therapy; PT = physical therapy

1.

Surveillance

Table 6.

Recommended Surveillance for Individuals with Chondrodysplasia Punctata 1, X-Linked

System/ConcernEvaluationFrequency
Short statureGrowth assessmentAnnually
ScoliosisClinical assessment of thoracic & lumbar spineAs needed
Cervical spine
instability
  • Flexion-extension radiograph
  • Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
  • Every 6-12 mos until growth is completed & prior to anesthesia to asses for cervical spine instability
  • Note: Some patients have developed cervical spine instability later in the disease course [Vogel & Menezes 2012].
Hearing lossHearing assessmentAs needed
Developmental delayMonitor developmental progress & educational needs.
Ocular abnormalitiesOphthalmologic eval

Agents/Circumstances to Avoid

In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.

In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk male relatives of an individual with CDPX1 in order to identify as early as possible those who would benefit from evaluation for cervical spine instability and early screening for cardiac anomalies, ophthalmologic abnormalities, and hearing loss.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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 a male proband

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has an ARSL pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and have thus far not been affected (see Clinical Description, Heterozygotes).
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the ARSL pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.

Offspring of a male proband. Males with CDPX1 transmit the ARSL pathogenic variant to:

  • All of their daughters, who will be carriers (heterozygotes) and will not be expected to have clinical manifestations of CDPX1 (affected carrier females have not been reported to date);
  • 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.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the ARSL pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) prior identification of the ARSL pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk male relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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 affected, are carriers, or 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ARSL pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CDPX1 are possible.

Ultrasound examination. Abnormal spinal curvature [He et al 2019] as well as hypoplastic nose and nasal bone [Nino et al 2008] have been identified on prenatal ultrasound examination in trimesters two and three in affected male fetuses.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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
  • BabyHearing.org
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • 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
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
    Email: Salon@mednet.ucla.edu

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ARSLXp22​.33Arylsulfatase LARSE @ LOVDARSLARSL

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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

Molecular Pathogenesis

ARSL encode arylsulfatase L (ARSE), a sulfatase that localizes to Golgi membranes [Daniele et al 1998]. 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) is generated from a cysteine [Cosma et al 2003].

Although its physiologic substrate has not yet been identified, ARSE enzyme activity is inhibited in vitro by the anticoagulant warfarin [Rost et al 2004]. Given the well-documented phenotypic similarities between CDPX1 and warfarin embryopathy, ARSE may be the enzyme inhibited by warfarin.

Mechanism of disease causation. The majority of missense variants studied showed negligible activity using a gene expression system and the artificial substrate, fluorogenic 4-methylumbelliferyl (4-MU) sulfate [Daniele et al 1998, Brunetti-Pierri et al 2003, Matos-Miranda et al 2013]. Individuals with ARSL gene deletions, nonsense variants, or missense variants present with indistinguishable phenotypes, supporting loss of function as the disease mechanism [Matos-Miranda et al 2013].

ARSL-specific laboratory technical considerations. ARSL has a pseudogene on the Y chromosome, which may complicate detection of exon-level deletions for some exons.

Table 7.

Notable ARSL Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000047​.2
NP_000038​.2
c.410G>Cp.Gly137AlaIncomplete penetrance reported in one family [Sheffield et al 1998]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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

Chapter Notes

Author History

Michael B Bober, MD, PhD (2008-present)
Nancy E Braverman, MS, MD (2008-present)
Nicola Brunetti-Pierri, MD (2008-present)
Gretchen L Oswald, MS, CGC; Johns Hopkins Medical Center (2008-2020)
Sharon F Suchy, PhD (2020-present)

Revision History

  • 15 October 2020 (sw) Comprehensive update posted live
  • 20 November 2014 (me) Comprehensive update posted live
  • 3 November 2011 (me) Comprehensive update posted live
  • 22 April 2008 (me) Review posted live
  • 16 November 2007 (nb) Original submission

References

Literature Cited

  • Alkhunaizi E, Unger S, Shannon P, Nishimura G, Blaser S, Chitayat D. Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants. Am J Med Genet A. 2020;182:1807–11. [PubMed: 32506814]
  • 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]
  • Bhoj E, Dubbs H, McDonald-McGinn D, Zackai E. Late-onset partial complex seizures secondary to cortical dysplasia in a patient with maternal vitamin K deficient embryopathy: comments on the article by Toriello et al [2013] and first report of the natural history. Am J Med Genet A. 2013;161A:2396–8. [PubMed: 23897629]
  • Blask AR, Rubio EI, Chapman KA, Lawrence AK, Bulas DI. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018;48:979–91. [PMC free article: PMC6365632] [PubMed: 29572747]
  • 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]
  • 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;143A:200–4. [PubMed: 17163521]
  • Carach B, Woods M, Scott P. Maxillonasal dysplasia (Binder syndrome): a lateral cephalometric assessment. Aust Orthod J. 2002;18:82–91. [PubMed: 12462685]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • He G, Yin Y, Zhao J, et al. Prenatal findings in a fetus with X-linked recessive type of chondrodysplasia punctata (CDPX1): a case report with novel mutation. BMC Pediatr. 2019;19:250. [PMC free article: PMC6647267] [PubMed: 31337364]
  • 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]
  • 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]
  • 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]
  • 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]
  • Matos-Miranda C, Nimmo G, Williams B, Tysoe C, Owens M, Bale S, Braverman N. A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies. Genet Med. 2013;15:650–7. [PubMed: 23470839]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Toriello HV, Erick M, Alessandri JL, Bailey D, Brunetti-Pierri N, Cox H, Fryer A, Marty D, McCurdy C, Mulliken JB, Murphy H, Omlor J, Pauli RM, Ranells JD, Sanchez-Valle A, Tobiasz A, Van Maldergem L, Lin AE. Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease. Am J Med Genet A. 2013;161A:417–29. [PubMed: 23404932]
  • Vogel TW, Menezes AH. Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy. Childs Nerv Syst. 2012;28:609–19. [PubMed: 22274407]
  • 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]
  • Xie Y, Pivnick EK, Cohen HL, Adams-Graves PE, Pourcyrous M, Aygun B, Hankins JS. Phenocopy of warfarin syndrome in an infant born to a mother with sickle cell anemia and severe transfusional iron overload. J Pediatr Hematol Oncol. 2013;35:e265–8. [PubMed: 23018567]
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