Campomelic Dysplasia

Campomelic dysplasia (CMD) is a genetic disorder marked by the bowing of long bones and various other skeletal and extraskeletal features. It can be fatal during the neonatal period due to respiratory insufficiency, but the severity of the condition varies, and a notable number of patients live into adulthood. The name comes from the Greek roots campo (or campto), meaning bent, and melia, meaning limb. A unique aspect of the disorder is that up to two-thirds of affected 46,XY genotypic males exhibit a range of disorders of sexual development (DSD) and genital ambiguities or may even develop as normal phenotypic females, as seen in complete 46 XY sex reversal. An atypical form of the disease, lacking bowed limbs, is simply called acampomelic campomelic dysplasia (ACD) and occurs in about 10% of patients, especially those who survive the neonatal period.

Signs and symptoms

While the definitive presentation of the disease is a patient having bowed lower limbs and sex reversal in 46,XY males, other clinical criteria can be used for diagnosis in the absence of these traits. Patients may exhibit shortened and angulated lower limbs, a vertically oriented and narrow pelvis, an enlarged head, a small jaw, cleft palate, flat nasal bridge, low set ears, and club feet. Radiographs may reveal underdeveloped shoulder blades, dislocated hips, hypoplastic vertebral pedicles in the thoracic region, 11 pairs of ribs instead of 12, or cervical spine kyphosis, which are helpful diagnostic indicators. Respiratory distress may be due to an underdeveloped trachea that collapses on inhalation or insufficient rib cage development.

Genetics

CMD is often caused by chromosomal abnormalities in or around the SOX9 gene on the long arm of chromosome 17, specifically at position 17q24, usually arising spontaneously or de novo mutations. Numerous single nucleotide variants in the SOX9 gene have been identified that cause some form of CMD. The SOX9 gene encodes a protein transcription factor that, when expressed during the embryonic stage, plays a crucial role in determining sexual characteristics and significantly influences skeletal development. When the SRY gene of the Y chromosome is expressed in human embryos, a cascade of gene interactions controlled by SOX9 begins, ultimately leading to male gender. Any mutation within the coding region of SOX9 can result in campomelic dysplasia, and 75% of reported mutations lead to sex reversal.

Four major classes of heterozygous SOX9 mutations can cause CMD: amino acid substitutions in the HMG-box, truncations or frameshifts altering the C-terminal end, mutations at the splice junction, and chromosomal translocations. Additionally, mutations upstream of SOX9 can also cause CMD. Several researchers have identified cis-acting control elements upstream of SOX9. Translocation breakpoints scattered over 1Mb proximal to SOX9 suggest an extended control region.

The lack of correlation between specific genetic mutations and observed phenotype, particularly concerning sex reversal, clearly demonstrates the variable expressivity of the disease.

Milder forms of the disease, seen in those who survive beyond the neonatal period and those with ACD, may be attributed to somatic mosaicism—especially for those with mutations within the SOX9 coding region. Chromosomal aberrations in the upstream control regions or residual activity of the mutant SOX9 protein might also contribute to the milder forms of the disease. Long-term survivors of CMD are significantly more likely to have translocation and inversion mutations upstream of SOX9 rather than mutations in the SOX9 coding region itself.

Diagnosis

In utero sonographic diagnosis is feasible when characteristic features such as bilateral bowed femurs and tibia, clubbed feet, prominent neck curvature, a bell-shaped chest, pelvic dilation, and/or a small jaw are evident. Radiographic techniques are typically employed postnatally and also rely on typical physical characteristics. However, bent bones are a nonspecific sign, and most fetuses with bent bones will have conditions other than campomelic dysplasia.

Screening

Genetic screening can be performed using comparative genomic hybridization (CGH) studies with DNA microarrays, and by PCR and sequencing of the entire SOX9 gene. Many different translocation breakpoints and related chromosomal aberrations have been identified in patients with CMD.

Prognosis

In over half of the cases, death occurs during the neonatal period due to respiratory distress, generally linked to a small chest size or inadequate development of the trachea and other upper airway structures.

Among CMD survivors, skeletal malformations evolve over time, often resulting in worsening scoliosis or kyphosis, leading to a decreased trunk size relative to limb length. Neurological damage is also common, including spinal cord compression and deafness. Even among those who survive the prenatal period, CMD patients have shortened life spans due to lifelong respiratory issues. Patients with ambiguous genitalia or sex reversal at birth continue to experience these conditions and are either sterile or have reduced fertility.

Epidemiology

Campomelic dysplasia has an incidence rate of 0.05-0.09 per 10,000 live births.