Introduction. Noonan syndrome is a clinically and genetically heterogeneous disease with multiple organ involvement associated with mutations in the genes of the RAS/MAPK signalling pathway. Most patients with Noonan syndrom (up to 50–80%) have disorders of the cardiovascular system, presented by a wide range of congenital heart defects and/or cardiomyopathy, predominantly hypertrophic phenotype. Thanks to the introduction of high-throughput sequencing, knowledge of the genetic causes of Noonan syndrome has expanded significantly, so since 2014, the LZTR1 gene (OMIM 601247) has been included in the list of genes responsible for the development of Noonan syndrome. The nucleotide variants of this gene are known to be inherited both in an autosomal dominant and autosomal recessive manner. However, the number of reports describing the clinical and genetic characteristics of patients with LZTR1 gene mutations is scarce in the world scientific literature. Objective. To describe the clinical features of Noonan syndrome with an autosomal recessive type of inheritance caused by biallelic variants c.1259A>G (p.Q420R) and c.2051T>C (p.I684T) in the LZTR1 gene. Materials and methods. A detailed analysis of the history data, the results of clinical, laboratory, and instrumental studies, a molecular genetic study using high-throughput sequencing technology and direct Sanger sequencing was carried out. After verifying the biallelic variants in the proband, a search was made for the identified nucleotide substitutions in the venous blood samples of the parents and sibs. Results. The article presents the data of a clinical observation of a rare case of Noonan syndrome caused by pathogenic variants in the LZTR1 gene with an autosomal recessive type of inheritance by the Department of Cardiology of the National Medical Research Center for Children’s Health of the Ministry of Health of Russia. Conclusion. The diversity of clinical manifestations makes it difficult to diagnose Noonan syndrome based on phenotype alone. The possibility of using high-throughput sequencing improves the quality of diagnostics, contributes to the replenishment of data on new pathogenic variants and the establishment of genotype-phenotypic correlations.

The few foreign papers of the last decade have shown the relationship of various pathogenic variants of the ELAC2 gene to heterogeneous phenotypic manifestations, for which the unfavorable prognosis is common, caused by severe cardiomyopathy in the first year of life. The article presents the first clinical observation of a rare variant of the hypertrophic phenotype cardiomyopathy with a fatal outcome in the first year of life, and variants c.887T>C, p.L296P and c.1979A>T, p.K660I of the ELAC2 gene in Russia. The purpose of the work is to present clinical observation of a child with an early manifestation of a hypertrophic phenotype of cardiomyopathy caused by pathogenic variants of the ELAC2 gene.

Гандаева Л.А., Каверина В.Г., Басаргина Е.Н., Пушков А.А., Савостьянов К.В. Гипертрофическая кардиомиопатия в структуре RAS-патий у детей. Детские болезни сердца и сосудов. 2022; 19 (4): 297–303. DOI: 10.24022/1810-0686-2022-19-4-297-303 HTML

Danon disease is a rare hereditary disease with predominant damage to the heart and skeletal muscles. Danon disease is referred to lysosomal storage disorders with severe, progressive course and it often leads to an early mortality. The main cause of Danon disease is the mutations in the LAMP2 gene in the Xq24–q25 chromosome region. Danon disease has X-linked dominant nature of inheritance; women have a milder phenotype with older heart damage. For the first time the disease was described in boys with cardiomyopathy, severe skeletal myopathy and intellectual deficiency. The article presents up-to-date review on Danon disease and case reports of the cardiology department of the National Medical Research Center for Children’s Health, where 5 male patients were observed from 2014 to 2020, and the average age at diagnosis – 13,2 years. During the lab examination three patients demonstrated a significant increase of the heart failure marker (NT-proBNP) – more than 5 thousand pg/ml, the intracellular enzymes was more than 2,5 norms in 4 patients. The Wolff–Parkinson–White phenomenon is recorded in all patients on the ECG. Echocardiography in one patient showed a rare combination of myocardial hypertrophy and non-compact left ventricular myocardium. 2 patients had a combination of hypertrophic and dilated phenotypes with a reduced ejection fraction on Echo and severe myocardial fibrosis on MRI of the heart, which clinically manifested with chronic heart failure refractory to drug therapy, which required heart transplantation.