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 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.

Clinical Description

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.

Genetic Disorders

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.

Treatment of Manifestations

Surveillance

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