Disability in hereditary forms of connective tissue dysplasia: causes, manifestations, ways of rehabilitation

The term “connective tissue dysplasia” has become so ingrained in medical practice in the post-Soviet space that many specialists are reluctant to verify the monogenic syndromes often hidden behind the familiar appearance of a patient with connective tissue dysplasia (CTD). Patients diagnosed with Marfan syndrome and Ehlers-Danlos syndrome have virtually disappeared from clinical practice, while a large number of patients with undifferentiated CTD have emerged. The lack of commitment to clinical and genetic verification of hereditary connective tissue diseases, including analysis and interpretation of the facts, hinders the productive development of this area of scientific knowledge and sometimes leads to disabling and even fatal consequences in such patients. Objective: To evaluate the causes of disability in families with a phenotypic extension of connective tissue dysplasia manifestations and its association with gene mutations. Materials and Methods. A retrospective analysis of the records of 123 patients with syndromic and undifferentiated forms of CTD observed at the department (n = 123) was conducted to assess the causes of disability. A retrospective analysis of outpatient charts and medical records was conducted, along with a family history review of three families and examination of all available first-degree relatives. To establish syndromic forms of CTD, consensus criteria were applied, and genetic testing of the probands was conducted in the Genomed Molecular Pathology Laboratory. Results. Of the 123 patients, disability was noted in 44 cases during an observation period of 3 to 21 years; the average age was 41 ± 12.5 years. The causes of disability were divided into the following groups: osteoarticular and vertebrogenic (n = 9), cardiac and vascular (n = 7), bronchopulmonary (n = 6), neurological (n = 4), ophthalmological (n = 3), audiological (n = 2), nephrological (n = 1), and other (n = 12). Three families with CTD, initially observed with undifferentiated CTD or Ehlers-Danlos syndrome, are presented. The first family presented with hypermobility syndrome and decreased bone mineral density, accompanied by blue sclerae and multiple fractures. Osteogenesis imperfecta was diagnosed in the proband's daughter, and disability due to hearing loss was prevented. The second family presented with bilateral congenital hip dislocation in several generations, hypermobility syndrome, and disabling osteoarthritis. The proband (66 years old), disabled since childhood due to bilateral congenital hip dislocation, bilateral hip replacement, and axonal neuropathy, was found to have new mutations in the type I collagen A1 gene with unknown clinical pathogenicity significance, possibly associated with Ehlers-Danlos syndrome (type I or arthrocholasia type) or osteogenesis imperfecta. A third family with hypermobility syndrome and hyperelastic skin (Ehlers-Danlos syndrome, not confirmed genetically) is described. The proband (45 years old) has disabling kidney disease requiring renal replacement therapy and a kidney transplant, along with hearing loss. Whole-genome sequencing of the proband revealed no mutations in the pathogenic zone. In the proband's daughter, lifestyle modification and nephrological protection slowed the renal impairment (which could have led to disability, as in the proband). The practical significance of these clinical observations is the confirmation of a pronounced phenotypic prevalence of connective tissue dysplasia in families with disabilities arising from various causes associated with connective tissue defects. Conclusion. The presented clinical observations demonstrate the need for early diagnosis upon detection of signs of connective tissue dysplasia, including not only agreed-upon classification criteria for monogenic syndromes but also molecular genetic testing, which ensures the adequacy of treatment at earlier stages. Rehabilitation measures in the third clinical observation demonstrated that lifestyle can influence gene expression, reducing the severity of symptoms and the risk of disability. In our opinion, masking such patients with the term “undifferentiated connective tissue dysplasia,” especially in scientific papers, is unacceptable, especially in cases of disabling and, especially, early fatal events in families with CTD.

molecular genetic testing, Ehlers-Danlos syndrome, connective tissue dysplasia

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