Campomelic dysplasia is a lethal genetic disease from the group of osteochondrodysplasia characterized by severe skeletal abnormalities and other disorders that often lead to fetal death or death of a newborn in the first weeks of life. Symptoms of this condition are severe curvature of the tubular bones of the extremities, the presence of 11 pairs of ribs and bell-shaped deformity of the chest. In some cases, gender inversion occurs. Diagnosis of campomelic dysplasia is most often performed on the basis of data from prenatal ultrasound, karyotyping and molecular genetic studies, after the birth of a child, radiography data can be used for confirmation. There is no cure for this genetic disease.
Campomelic dysplasia (campomelic dwarfism) is a genetic disease accompanied by numerous skeletal abnormalities and a violation of sexual differentiation. The pathology was first described by the famous French pediatrician Pierre Maroto in 1971, but for a long time the etiology and pathogenesis of this condition remained unknown. Only in recent years, the methods of modern genetics have been able to identify the gene whose defects lead to the development of campomelic dysplasia, and to determine the sequence of pathological processes in this condition. The incidence of pathology is approximately 1 in 150-200 thousand newborns, but some researchers dispute these figures, pointing to an increased risk of prenatal death, which is not taken into account by statistics. It has been established that campomelic dysplasia is an autosomal dominant condition, but almost always occurs due to spontaneous mutations in the embryo or in the germ cells of the parents. There are reports of several patients with this pathology who survived to adolescence.
At the dawn of the study of campomelic dysplasia, many geneticists were baffled by an unusual combination of disorders – skeletal abnormalities of the limbs, shoulder blades, ribs and pathology of the skull (cleft of the hard palate, microcephaly) with hermaphroditism and sexual inversion. The reason for such an unusual combination lay in the gene whose mutations cause the disease – the SOX-9 gene located on the 17th chromosome. The gene encodes a protein of the same name, which is one of the most important transcription factors in the human body. For example, it controls the work of the Col2A1 gene, which is localized on the 12th chromosome and encodes the sequence of the main type 2 collagen variety involved in the processes of skeletal formation and ossification. Defects in the structure of the SOX-9 protein lead to a sharp decrease in Col2A1 gene expression, collagen deficiency and, as a consequence, to campomelic dysplasia.
Another important function of SOX-9 is the activation of the AMH gene located on chromosome 19. Basically, this gene is expressed in Sertoli cells in men during embryonic development. AMH encodes the so-called Muller inhibitory factor, which leads to the destruction of the Muller duct, which plays an important role in fetal sexual differentiation. With mutations of the SOX-9 gene, this function is disrupted, as a result, approximately 75% of patients with campomelic dysplasia with karyotype XY have phenotypically female sexual characteristics. In the past, due to the discrepancy between the genotype and phenotype, it was believed that this disease affects girls much more often than boys. Many researchers assume the active participation of the SOX-9 protein in the control of other genes, which is indirectly indicated by the presence of many other developmental abnormalities in campomelic dysplasia.
With campomelic dysplasia, pre- or intranatal death often occurs due to severe respiratory failure in an infant. In cases where the patient is born alive, pronounced deformation of the long tubular bones of the arms and legs, elongation of the cerebral part of the skull with a significant decrease in the facial region, micrognathia and reduced body size are detected. In patients with campomelic dysplasia, a flat face is revealed, a cleft of the hard palate and a congenital dislocation of the hip are often observed. The examination also determines hypoplasia of the shoulder blades, deformities of the feet, hydronephrosis and various congenital heart defects. Campomelic dysplasia leads to the death of the patient during the first days or weeks of life. As a rule, death occurs due to severe respiratory distress syndrome, malformations of the skull, urinary and cardiovascular systems contribute.
Diagnosis and treatment
The main role in determining campomelic dysplasia is played by prenatal diagnostic techniques: ultrasound, karyotyping and molecular genetic analyses. By ultrasound methods, this disease can be detected already from the 2nd trimester of carrying a child, the leading manifestations will be the curvature of the bones of the limbs, the presence of 11 pairs of ribs and the bell-shaped shape of the chest. Malformations of the skull, face, heart and kidneys, hypoplasia of the shoulder blades and vertebral bodies, an increase in the size of the pelvic opening can also be determined. Based on the listed data of prenatal ultrasound examination, it is reasonable to assume the presence of campomelic dysplasia and raise the question of termination of pregnancy for medical reasons.
Karyotyping is performed in order to exclude aneuploidy or chromosomal abnormalities that can cause similar manifestations and malformations of the fetus. At the same time, in the case of campomelic dysplasia, the definition of the karyotype may indicate the male sex of the fetus, whereas the results of ultrasound examinations will determine the girl. This serves as an additional confirmation of this disease, since it is characterized by hermaphroditism and sexual inversions. For the most accurate diagnosis, molecular genetic analyses can be used by sequencing the sequence of the SOX-9 gene. The detection of mutations in this gene is the final confirmation of the presence of campomelic dysplasia.
In some cases, the diagnosis of campomelic dysplasia is performed in a live newborn. To do this, in addition to the above techniques, X-ray examination of the skeleton is used. Numerous deformations of the tubular bones and other signs that were detected on ultrasound are determined on radiographs. Neonatologists can also identify a heart defect, kidney abnormalities and respiratory disorders in a newborn with campomelic dysplasia. Often, the final confirmation of the diagnosis is made on the basis of the data of the pathoanatomic examination. Any practical therapeutic measures, even of a palliative nature, are ineffective in this disease and are unable to prolong the patient’s life.
Prognosis and prevention
Since campomelic dysplasia is a lethal form of osteochondrodysplasia with concomitant disorders, the prognosis of this disease is exceptionally unfavorable. If a child manages to survive in the intranatal period, death occurs in the first weeks of life from respiratory and other disorders. Individual reports on the survival rate of patients with campomelic dysplasia up to adolescence are skeptically perceived in the scientific community. Prevention of this condition, given the spontaneous nature of SOX9 gene mutations, is possible only within the framework of prenatal examination. If campomelic dysplasia is detected in the fetus and this diagnosis is confirmed, the question of termination of pregnancy for medical reasons is raised.