Chondrodysplasia Punctata 1, X-Linked

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.

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 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

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

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].

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.

Genetic Disorders

Table 3a.

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

Table 3b.

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

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.

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

Treatment of Manifestations

Table 5.

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

Surveillance

Table 6.

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

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.

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

• The father of an affected male will not have the disorder nor will he be hemizygous for the ARSL (formerly ARSE) pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the ARSL pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo ARSL pathogenic variant, in which case the mother is not a carrier.
• To date, CDPX1 caused by a de novo ARSL pathogenic variant has not been reported. All mothers of males with a detectable ARSL pathogenic variant tested to date were found to be carriers [Nino et al 2008, Matos-Miranda et al 2013].

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 sex, 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.

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.

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

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

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