Research Centre for Medical Genetics
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RCMG Experts Identified Patients with a Rare Disease that Suffered Henri de Toulouse-Lautrec for the First Time in Russia

Pycnodysostosis, an ultra-rare disease, was diagnosed in the Research Centre for Medical Genetics for the first time in Russia. 
The prevalence of this disease is one person per million in the population. 

The uniqueness of the situation is that RCMG experts identified three patients from unrelated families from different regions of Russia with this disease. New mutations in the CTSK gene have been identified in all three: two have a nucleotide replacement of c.746T>A (p. Ile249Asn) in a homozygous state, the third having a nucleotide replacement of c.746T> C (p. Ile249Thr). The article appeared in «Molecular Genetics & Genomic Medicine» (T. Markova, V. Kenis, E. Melchenko, D. Guseva, D. Osipova, N. Galeeva, T. Nagornova, E. Dadali).

Pycnodysostosis is a rare skeletal dysplasia from the group of lysosomal accumulation diseases with an autosomal recessive type of inheritance. The cause of the disease are the mutations in the cathepsin gene K - CTSK, localised on the chromosome 1q21. Typical signs of the disease are: low growth of patients, hypoplasia of the middle part of the face, slow closure of the fontanels at an early age. Also patients have broad phalanges of the fingers and toes, nail dysplasia, characteristic beak-shaped nose. Patients are predisposed to spontaneous fractures, after which bone recovery is extremely slow. The typical clinical manifestations of the disease and the small size of the CTSK gene make direct Sanger sequencing the optimal diagnostic method of pycnodysostosis. A similar method can not only determine the carrying of pathogenic variants in the CTSK gene, but also carry out prenatal diagnostics of this disease. 

Pycnodysostosis is suspected from the eminent French postimpressionist Henri de Toulouse-Lautrec (1864-1901), as well as the ancient Greek writer Aesop (620-564 BC). At the age of thirteen, Toulouse-Lautrec got out of his chair and broke the hip neck of his right leg. A year later he fell and suffered a fracture of the hip neck of his left leg. After that, the legs stopped growing. The diagnosis of pycnodysostosis was established on clinical grounds first in RCMG, then the patients were referred for DNA diagnostics. 

The polymorphism of the clinical manifestations of pycnodysostosis and its low prevalence make accurate diagnostics difficult. In some cases, patients are mistakenly diagnosed with imperfect osteogenesis. Bisphosphonates are prescribed in such a disease - medications that strengthen bone tissue. However, these medications are contraindicated for patients with pycnodysostosis, because their bone tissue has an excessive density. Such therapy can aggravate the situation, lead to even more frequent fractures and even longer recovery from them. 

Etiotropic treatment for patients with pycnodysostosis is not currently available. However, accurate diagnostics, detection of molecular-genetic causes of the disease will allow to avoid the prescription of ineffective therapy, and will allow the family to plan childbirth in the future and prevent the rebirth of children diagnosed with pycnodysostosis. 

New mutations in the CTSK gene leading to pycnodisostosis, which were identified in RCMG, are recorded in the database «ClinVar». This will allow to diagnose other patients in short time not only in Russia but also in other countries.