 | This articleneeds additional citations forverification. Please helpimprove this article byadding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Campomelic dysplasia" – news ·newspapers ·books ·scholar ·JSTOR(August 2021) (Learn how and when to remove this message) |
| Campomelic dysplasia | |
|---|---|
 | |
| This condition is usually inherited in an autosomal dominant manner | |
| Specialty | Medical genetics |
Campomelic dysplasia (CMD) is agenetic disorder characterized by bowing of the long bones and many other skeletal and extraskeletal features.[1]It can be lethal in theneonatal period due torespiratory insufficiency, but the severity of the disease is variable, and a significant proportion of patients survive into adulthood.The name is derived from the Greek rootscampo (orcampto), meaning bent, andmelia, meaning limb. An unusual aspect of the disease is that up to two-thirds of affected 46,XYgenotypic males display a range ofdisorders of sexual development (DSD) and genital ambiguities or may even develop as normalphenotypic females as in complete 46 XYsex reversal. An atypical form of the disease with absence of bowed limbs is called, prosaically, acampomelic campomelic dysplasia (ACD) and is found in about 10% of patients, particularly those surviving theneonatal period.[citation needed]
While the definitive presentation of the disease is a patient having bowed lower limbs andsex reversal in 46,XY males, there are other clinical criteria that can be used, absent these characteristics, to make the diagnosis. Patients may present with shortened and angulated lower limbs, a vertically oriented and narrow pelvis, an enlarged head, an undersized jaw, cleft palate, flat nasal bridge, low set ears, club feet. On radiographs, underdeveloped shoulder blades, dislocated hips, hypoplastic vertebral pedicles in the thoracic region, 11 pairs of ribs instead of 12, or kyphosis of the cervical spine are useful diagnostic clues. Respiratory distress can be caused by an underdeveloped trachea which collapses on inhalation or by insufficient rib cage development.[citation needed]
CMD is commonly caused by chromosomal abnormalities in or around the geneSOX9 on the long arm ofchromosome 17, specifically at position 17q24, generally spontaneously arising orde novomutations. Also, numerous single nucleotide variants been identified involving theSOX9 gene that cause some form of CMD.TheSOX9 gene codes for aproteintranscription factor which, when expressed at theembryonic stage, plays an important role in determining sexual characteristics and greatly influences skeletal development.When theSRY gene of theY chromosome is expressed in human embryos, a cascade of gene interactions controlled bySOX9 begins and ultimately leads to male gender.[citation needed]. Any mutation within thecoding region ofSOX9 can cause campomelic dysplasia and 75% of the reported mutations lead to sex reversal.
Four major classes ofheterozygousSOX9mutations can cause CMD:amino acid substitutions in theHMG-box, truncations or frameshifts that alter the C-terminal end,mutations at the splice junction, and chromosomaltranslocations.Additionally, mutations upstream fromSOX9 can also cause CMD. Several researchers have reportedcis-acting control elements upstream ofSOX9.Translocation breakpoints scattered over 1Mb proximal to SOX9 indicate the presence of an extended control region.[citation needed]
The lack of correlation between specific geneticmutations and observedphenotype, particularly with regard to sex reversal, give clear evidence of thevariable expressivity of the disease.
Milder forms of the disease, seen in those who live beyond the neonatal period and those with ACD, may perhaps be attributable to somaticmosaicism—particularly for those with mutations within theSOX9coding region.[2]Chromosomal aberrations in the upstream control regions or residual activity of the mutantSOX9protein could also be responsible for the milder forms of the disease.[2]Long-term survivors of CMD are significantly more likely to have translocation and inversion mutations upstream of SOX9 rather than mutations in the SOX9coding region itself.[citation needed]
In utero sonographic diagnosis is possible when characteristic features such as bilateral bowed femurs and tibia, clubbed feet, prominent curvature of the neck, a bell-shaped chest, pelvic dilation, and/or an undersized jaw are apparent.[3]Radiographic techniques are generally used only postnatally and also rely on prototypical physical characteristics.[4] However, bent bones are an unspecific sign and most fetuses with bent bones will have conditions other than campomelic dysplasia[5]
Genetic screening can be done bycomparative genomic hybridization (CGH) studies usingDNA microarrays, and byPCR and sequencing of the entireSOX9 gene. Many differenttranslocation breakpoints and related chromosomal aberrations in patients with CMD have been identified.
In more than half of the cases, death occurs in theneonatal period due torespiratory distress, generally related to small chest size or insufficient development of the trachea and other upper airway structures.[2]
Among survivors of CMD, the skeletal malformations change over time to include worseningscoliosis orkyphosis resulting in decreased trunk size relative to the limb length. Neurological damage is also often seen including spinal cord compression anddeafness. Even among survivors of the prenatal period, CMD patients have shortened life spans due to lifelong respiratory issues. Those patients withambiguous genitalia or sex reversal at birth, of course, maintain that state, and are either sterile or have reduced fertility.[citation needed]
Campomelic dysplasia has a reported incidence of 0.05-0.09 per 10000 live births.[citation needed]