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Brachytelephalangic chondrodysplasia punctata
Brachytelephalangic chondrodysplasia punctata (BCDP) is a form of non-rhizomelic chondrodysplasia punctata, a primary bone dysplasia, characterized by hypoplasia of the distal phalanges of the fingers, nasal hypoplasia, epiphyseal stippling appearing in the first year of life, as well as mild and non-rhizomelic shortness of the long bones.
ORPHA:79345Classification level: Disorder
The prevalence of BCDP is not available. A birth prevalence estimate of 1/500,000 newborns has been put forward. The genetic BCDP due to ARSE alterations is pan-ethnic and occurs almost exclusively in males. Another part of BCDP, phenocopies of the genetic ones due to environmental and maternal causes, are also described in both, males and females.
First signs of the disease are often found antenatally by ultrasound imaging, including nasal spine hypoplasia and epiphyseal abnormal calcifications. Stippled epiphyses are usually seen in the tarsus, knee, and distal phalanges, but may be more generalized, including epiphyses of the long bones, vertebrae, hips, hyoid and tracheal cartilage. At birth, the diagnosis is apparent with facial dysmorphism, quite similar to that of maxillonasal dysplasia (or Binder syndrome), i.e. severe nasomaxillary hypoplasia with flattened nasal base, reduced nasal tip protrusion but normal ala of the nose, and short columella. Usually this does not affect birth respiratory function. Typical radiological features of BCDP are hypoplastic pyramidal-shaped distal phalanges with the apices pointing proximally, slightly irregular metaphyses, relatively larger epiphyses, and punctuate calcifications (tracheal, vertebral and tarsal/carpal stippling seen in newborns disappearing in infancy and childhood). Anterior thoracolumbar vertebral body deformities, posterior scalloping and coronal cleft are also sometimes found. Affected individuals do not show asymmetry of the limbs or hypotonia. Relative micromelia without short stature usually develops postnatally and affected adults have a final normal stature. Delay in odontoid ossification may lead to cervical instability in the first months. Less common features include ichthyosis and delayed psychomotor development in cases associated with deletion of ARSE locus. In general, BCDP falls into the mildest end of chondrodysplasia punctata (CDP) spectrum with a good long-term prognosis.
The causative gene of BCDP is ARSE (Xp22) encoding the arylsulfatase E protein essential for the correct composition of cartilage and bone matrix during development. ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases.
Diagnosis can be challenging due to the extensive heterogeneity and variability of both phenotypical and genetic features. Radiographs taken shortly after birth may show only a few calcifications of tarsal and long bones epiphysis. Extensive epiphyseal calcifications (usually ankle and distal phalanges), vertebral stippling and distal phalangeal hypoplasia with proximal apices may also been reported. Calcifications can also occur in the larynx, trachea, and main stem bronchi. X-rays may also reveal vertebral abnormalities. Diagnosis can be confirmed in a male patient with identification of a hemizygous pathogenic variant in ARSE.
The differential diagnosis includes other types of chondrodysplasia punctata, warfarin embryopathy, pseudowarfarin embryopathy, vitamin K malabsorption embryopathy, lupus erythematosus embryopathy, hydantoin embryopathy, Keutel syndrome, and maxillonasal dysplasia.
Prenatal testing for at-risk pregnancies is possible if the ARSE pathogenic variant has been previously identified in the family.
The pattern of inheritance of BCDP is X-linked. Genetic counseling can inform parents that the risk of transmitting the pathogenic variant for a mother is 50% in each pregnancy. Affected males pass the pathogenic variant to all of their daughters and none of their sons.
Management and treatment
Treatment is supportive. All patients with CDP should be explored for clinical signs of spinal cord compression. In rare cases, respiratory difficulty can require in the first weeks monitoring, nasal stents, and feeding tube. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine should be screened within the first year, leading to positioning and manipulation prevention measures. Rarely, it may require a cervical collar or spinal fusion.
Prognosis is good, as most patients have been reported to have a benign course. However, in some cases cervical canal stenosis with cervical cord compression may lead to serious morbidity and early mortality.
Article for general public
- Clinical genetics review
- English (2020)