Chondrodysplasia punctata 1, X-linked recessive

Other Names: Chondrodysplasia punctata 1 X-linked recessive; CDPX1; CPXR; Arylsulfatase E deficiency; Chondrodysplasia punctata, brachytelephalangic; Chondrodysplasia punctata brachytelephalangic

Chondrodysplasia punctata 1, X-linked recessive (CDPX1) is a genetic disorder present from birth that affects bone and cartilage development.

Epidemiology

The prevalence of X-linked chondrodysplasia punctata 1 is unknown. Several dozen affected males have been reported in the scientific literature.

Cause

X-linked chondrodysplasia punctata 1 is caused by genetic changes involving the ARSL gene. This gene provides instructions for making an enzyme called arylsulfatase E. The function of this enzyme is unknown, although it appears to be important for normal skeletal development and is thought to participate in a chemical pathway involving vitamin K. Evidence suggests that vitamin K normally plays a role in bone growth and maintenance of bone density.

• Between 60 and 75 percent of males with the characteristic features of X-linked chondrodysplasia punctata 1 have a mutation in the ARSL gene. These mutations reduce or eliminate the function of arylsulfatase E.
• Another 25 percent of affected males have a small deletion of genetic material from the region of the X chromosome that contains the ARSL gene. These individuals are missing the entire gene, so their cells produce no functional arylsulfatase E. Researchers are working to determine how a shortage of arylsulfatase E disrupts the development of bones and cartilage and leads to the characteristic features of X-linked chondrodysplasia punctata 1.
• Some people with the features of X-linked chondrodysplasia punctata 1 do not have an identified mutation in the ARSE gene or a deletion involving the gene. Other, as-yet-unidentified genetic and environmental factors may also be involved in causing this disorder.

Inheritance

X-linked recessive inheritance

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the ARSL gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Signs and symptoms

Chondrodysplasia punctata is an abnormality that appears on x-rays as spots (stippling) near the ends of bones and in cartilage. In most infants with X-linked chondrodysplasia punctata 1, this stippling is seen in bones of the ankles, toes, and fingers; however, it can also appear in other bones. The stippling generally disappears in early childhood.

Other characteristic features of X-linked chondrodysplasia punctata 1 include short stature and unusually short fingertips and ends of the toes. This condition is also associated with distinctive facial features, particularly a flattened-appearing nose with crescent-shaped nostrils and a flat nasal bridge.

People with X-linked chondrodysplasia punctata 1 typically have normal intelligence and a normal life expectancy. However, some affected individuals have had serious or life-threatening complications including abnormal thickening (stenosis) of the cartilage that makes up the airways, which restricts breathing. Also, abnormalities of spinal bones in the neck can lead to pinching (compression) of the spinal cord, which can cause pain, numbness, and weakness. Other, less common features of X-linked chondrodysplasia punctata 1 include delayed development, hearing loss, vision abnormalities, and heart defects.

Diagnosis

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.

Treatment

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.

Prognosis

Most individuals with CDPX1 have a normal life span; however, some people have significant medical problems that can lead to early death. These life-threatening complications include abnormalities of the respiratory tract that result in a narrow airway and abnormalities of the spinal bones in the neck that narrow the spinal cord canal.

NIH genetic and rare disease info

• NIH info on Chondrodysplasia punctata 1, X-linked recessive

Chondrodysplasia punctata 1, X-linked recessive is a rare disease.

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