Knowledge on rare diseases and orphan drugs

Although epidemiological data is limited, prevalence at birth has been suggested at approximately 1/40,000-80,000.

The clinical features include a relatively large head, Pierre Robin sequence with cleft palate, flat face, laryngotracheomalacia, respiratory distress, 11 pairs of ribs, ambiguous genitalia or normal female external genitalia in an individual with a 46,XY karyotype. It also includes dislocated hips, short bowed femura and tibiae (lower limbs more frequently than upper limbs), pretibial skin dimples (bowing of the lower leg is often associated with a skin dimple over the apex of curve) and clubfeet. A few cases of a variant syndrome, referred to as ``acampomelic campomelic dysplasia'' have been described. This variant can be distinguished by the lack of long bone curvature. Many infants die in the neonatal period; additional problems identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive kyphoscoliosis, and hearing impairment. In some cases developmental delay is described.

The disorder is autosomal dominant; however, most cases are due to heterozygous de novo mutations in the SOX9 gene (localized to 17q24). In rare individuals the disorder is caused by chromosomal recombination (deletion or translocation) involving the region 17q24.

Diagnosis in based on peculiar facial anomalies (flat face, long philtrum, micrognathia), short stature and specific radiological findings (bowed femura and tibiae, dislocated hip, hypoplastic scapulae, hypoplastic and nonmineralized thoracic vertebral pedicles).

In the prenatal period, differential diagnoses include osteogenesis imperfecta type 2 and 3, hypophosphatasia and thanatophoric dysplasia and Stuve-Wiedemann syndrome; after birth, spondyloepiphyseal dysplasia congenita (SEDC), diastrophic dysplasia and Larsen syndrome may be considered.

Diagnosis is generally suspected prenatally during the second trimester ultrasound examination, based on the observation of delayed growth associated with bowed femura and tibiae. Prenatal genetic testing can be performed through chorionic villus sampling or amniocentesis when there is a suspicion of the diagnosis or in familial cases where an abnormality of the chromosomal region has already been identified.

Most cases arise sporadically and in these cases the recurrence risk in siblings of a proband is at estimated 2% (due to germline mosaicism). Approximately 5% of cases are a result of chromosomal recombination involving the region 17q24 and, in rare cases, there may be familial transmission. For this reason, genetic counseling is recommended for couples potentially at risk.

Treatment is symptomatic and follows standard protocols for cleft palate, clubfeet, hip subluxations, cervical instability and kyphoscoliosis. In individuals with a 46,XY karyotype and undermasculinization of the genitalia, the gonads should be removed due to the increased risk for gonadoblastoma. Hearing aids for those with hearing impairment.

Newborns suffering from campomelic dysplasia often die soon after birth as a result of respiratory insufficiency, but about 10 % of individuals survive. Complications (such as kyphoscoliosis, recurrent respiratory infections, hearing loss, light to moderate learning difficulties, small size and hip dislocation) can arise as the patients age.

Last update: January 2021 - Expert reviewer(s): Dr Maria Francesca BEDESCHI | ITHACA*

* European Reference Network