Pathogenic nucleotide variants in the MORC2 gene have recently been linked to axonal peripheral neuropathy (Charcot–Marie–Tooth disease, axonal type 2Z) and the syndrome of developmental and growth disorders, facial dysmorphia, and axonal neuropathy (DIGFAN syndrome). DIGFAN syndrome is marked by early onset and multisystem symptoms, particularly affecting the visual and auditory organs. In approximately 30% of cases, mitochondrial encephalomyopathy is initially considered a possible diagnosis. In a girl with a heterozygous MORC2 gene mutation, the presence of DIGFAN syndrome was confirmed. Her clinical profile included motor, speech, and physical developmental delays, along with visual and auditory impairments, peripheral neuropathy, facial dysmorphia, Lee-like changes on MRI, and moderate lactic acidemia. Following metabolic therapy targeting intracellular energy exchange processes, alongside a rehabilitation program, some improvement in her condition and normalization of blood lactate levels were observed. The importance of early diagnosis is highlighted, as it supports the timely initiation of metabolic therapy and other therapeutic interventions under specialist supervision. Confirming the diagnosis is critical for anticipating disease progression and providing genetic counseling for the proband and their family.

Geroderma osteodysplasticum (OMIM #231070) is a rare autosomal recessive disorder characterized by congenital wrinkled skin on the dorsal surface of the limbs and abdomen; marked osteoporosis in childhood. Pathogenic variants of the nucleotide sequence in the GORAB gene, which encodes the GORAB protein located in the Golgi apparatus and plays a crucial role in vesicle transport in the Golgi complex, lead to the disease. This is the first report of 2 patients with this disease in Russia. A detailed description of the clinical-radiological and genetic characteristics of these patients with new nucleotide variants in the GORAB gene in a compound heterozygous state is presented: c.170C>G (p.Ser57Ter) and c.790G>C (p.Ala264Pro); c.295C>T (p.Gln99Ter) and heterozygous deletion on chromosome 1 (chr1:g.170531967–170539494del), affecting exons 1 and 2 of the gene. The main clinical manifestations of the syndrome were congenital wrinkled skin, sagging cheeks, hypoplasia of the cheekbones, prognathism, muscle hypotonia and joint hypermobility. Radiological signs included congenital bilateral dislocation of the hip, compression fractures of the vertebral bodies, and disruption of the continuity of the growth plate of the distal femur and proximal tibia, referred to as “insertion.” The rarity of the syndrome, as well as the similarity of clinical manifestations with a heterogeneous group of hereditary diseases accompanied by decreased skin elasticity, leads to a late correct diagnosis. This necessitates the description of the clinical-genetic characteristics of the disease, the study of the dynamics of the formation of its phenotypic manifestations, and the methods of molecular-genetic diagnostics.

For citation: S.V. Papizh, V.M. Kenis, A.N. Tsygin, E.K. Petrosyan, S.V. Bochenkov, A.E. Lavrova, T.M. Pervunina, E.V. Rakitskaya, K.S. Kulikova. Resolution by the Expert Council: “Modern approaches to the diagnosis and treatment of children with X-linked hypophosphatemic rickets,” dated Dec. 22, 2023. Moscow, Russia. Pediatria n.a. G.N. Speransky. 2024; 103 (2): 129-136. DOI: 10.24110/0031-403X-2024-103-2-129-136.

Mucolipidosis type IV is a rare autosomal recessive disease from the group of lysosomal accumulation diseases caused by a malfunction of the cation channel due to mutations in the MCOLN1 gene. The clinical symptom complex includes a combination of neurological symptoms (impaired speech and motor development, spasticity, rigidity), corneal opacity and achlorhydria with iron deficiency anemia. The literature data on this disease and the medical history of a 13-year-old girl who was observed in the Department of Clinical Genetics of the Veltischev Institute are presented. The child had a characteristic clinical picture, including damage to the nervous system: decreased intelligence, muscular dystonia and spasticity, salivation, strabismus, hypoplasia of the corpus callosum; damage to the organ of vision — corneal opacity, cataracts, myopia, photophobia in combination with persistent iron deficiency anemia (apparently due to achlorhydria). The diagnosis was confirmed by the results of DNA diagnostics — a known pathogenic mutation NM_02533.3 was detected in the MCOLN1 gene: c.304C>T (p.Arg102Term) in a homozygous state; in the girl’s mother — in a heterozygous state. A differential diagnosis was made with phenotypically similar diseases, primarily with cerebral palsy, mucopolysaccharidosis, and other types of mucolipidosis. Further medical supervision of the child should be carried out with the obligatory participation of a neurologist, an optometrist, a gastroenterologist, an orthopedist and a nephrologist. Knowledge of the clinical features of pathology ensures more successful medical care with the prevention of complications.

The term «homocystinuria» combines a number of genetically determined nosological forms caused by defects of the metabolism of sulfur-containing amino acids (methionine, homocysteine), cobalamin and folate. The group of these diseases includes «classical» homocystinuria caused by insufficiency of cystathionine beta-synthase and forms associated with defects in methionine remethylation processes. More information is given about one of these forms — homocystinuria and megaloblastic anemia, type cblG, caused by MTR gene mutations. The results of observation of a child with this disease are presented. The clinical status includes: intellectual disability, autistic behavioral traits, stereotypes, nystagmus, visual impairment, macrocytic anemia, epilepsy in remission. Effective treatment requires the use of medications not registered in the Russian Federation — betaine and hydroxocobalamin.

Angelman syndrome is a rare neurogenetic disease caused by the loss of the function of the maternal allele of the UBE3A gene on chromosome 15 (site 15q11.2–q13) and is characterized by severe mental retardation, lack of speech, epilepsy, microcephaly and a characteristic facial phenotype with a unique behavior in the form of frequent laughter. The combination of microcephaly, epilepsy, speechlessness and mental retardation poses a problem for differential diagnosis with many genetic diseases presenting with similar symptoms. Epileptic encephalopathy due to CDKL5 gene mutation and Rett syndrome have the greatest similarity. The hallmark of Angelman syndrome are laughter attacks and specific EEG changes. The authors have presented a table of the differential diagnosis of Angelman syndrome with some phenotypically similar genetic syndromes, indicating the most significant distinguishing features, which should facilitate for the pediatrician and neurologist the diagnostic path of establishing the correct diagnosis.

Наследственные синдромы дисплазии соединительной ткани составляют большую группу патологий, в которую входят около 50 заболеваний и их типов. Синдромы, как правило, имеют мультисистемные проявления, и пациенты требуют наблюдения команды специалистов. Такие заболевания, как несовершенное костеобразование и буллезный эпидермолиз, отличаются характерным фенотипом, но при других нозологических формах моногенных болезней соединительной ткани отмечается много общих проявлений, что обусловливает диагностические трудности. Цель лекции – подчеркнуть сходство клинической картины и выделить различия фенотипа отдельных синдромов дисплазии соединительной ткани. В отделении врожденных и наследственных заболеваний Института Ю.Е. Вельтищева в 2022 г. были обследованы 202 ребенка с моногенными дисплазиями соединительной ткани, среди них с несовершенным костеобразованием – 78, синдромом Элерса – Данло – 59, синдромом Марфана – 53, синдромами Стиклера и Лоеца – Дитца – по 4, синдромом Билса – 3 и cutis laxa – 1. При установлении диагноза оценивали клинический фенотип, принимали во внимание наличие/отсутствие кардинальных признаков того или иного синдрома, учитывали генетические данные. Обращено внимание на фенотипическое сходство синдромов Элерса – Данло, Марфана, Стиклера, Лоеца – Дитца, Билса, cutis laxa. Диагностические трудности также были связаны с манифестацией неполного симптомокомплекса в детском возрасте и с сочетанием двух синдромов дисплазии соединительной ткани у одного пациента. Подчеркнуто, что точная идентификация нозологической формы болезни достигается при проведении генетического тестирования. Hereditary syndromes of connective tissue dysplasia constitute a large group of pathologies, which includes about 50 diseases and their types. Syndromes, as a rule, have multisystem manifestations, and patients require the supervision of a team of specialists. Diseases such as osteogenesis imperfecta and epidermolysis bullosa are characterized by a characteristic phenotype, but in other nosological forms of monogenic connective tissue diseases, there are many common manifestations, which causes diagnostic difficulties. Purpose of the lecture – to emphasize the similarity of the clinical picture and highlight the differences in the phenotype of individual syndromes of connective tissue dysplasia. In the Department of Congenital and Hereditary Diseases of the Yu.E. Veltischev Institute 202 children with monogenic connective tissue dysplasia were examined in 2022, among them with osteogenesis imperfect – 78, Ehlers – Danlos syndrome – 59, Marfan syndrome – 53, Stickler and Loetz – Dietz syndromes – 4, Beals syndrome – 3 and cutis laxa – 1. When diagnosing, the clinical phenotype was evaluated, the presence/absence of cardinal signs of a particular syndrome and genetic data were taken into account. Attention is drawn to the phenotypic similarity of Ehlers – Danlo, Marfan, Stickler, Loetz – Dietz, Beals, cutis laxa syndromes. Diagnostic difficulties were also associated with the manifestation of an incomplete symptom complex in childhood and with a combination of two syndromes of connective tissue dysplasia in one patient. It is emphasized that the сorrect identification of the nosological form of the disease is achieved through genetic testing.

Цель. Представить редкий клинический случай сочетания 2 генетических заболеваний – Х-сцепленного доминантного гипофосфатемического рахита и синдрома Нунан I типа у четырехлетнего мальчика. Материалы и методы. Генеалогический анализ, клиническое обследование с включением биохимических и рентгенорадиологических методов, а также молекулярно-генетическая диагностика с использованием полноэкзомного секвенирования ДНК. Результаты. Рассмотрен клинический случай пациента, у которого выявлено сочетание Х-сцепленного доминантного гипофосфатемического рахита и синдрома Нунан I типа. Молекулярно-генетическое исследование выявило патогенные варианты в генах PHEX и PTPN11, подтверждающие наличие обоих заболеваний. Представлены актуальные сведения литературы об этиологии, патогенезе, клинических особенностях и современных подходах к лечению гипофосфатемического рахита и синдрома Нунан I типа. Заключение. Описанный клинический случай подчеркивает важность использования современных молекулярно-генетических методов исследования для выявления редких сочетаний наследственных заболеваний. Это необходимо для прогнозирования возможных осложнений, определения мультидисциплинарного подхода к диагностике, ведению пациента и назначению патогенетической терапии. Purpose. To present a rare clinical case of a combination of two genetic diseases – X-linked dominant hypophosphatemic rickets and Noonan syndrome type I in a four-year-old boy. Materials and methods. Genealogical analysis, clinical examination including biochemical and X-ray radiological methods, as well as molecular genetic diagnostics using whole exome DNA sequencing. Results. The clinical case of a patient with a combination of X-linked dominant hypophosphatemic rickets and Noonan syndrome type I is considered. Molecular genetic testing revealed pathogenic variants in the PHEX and PTPN11 genes, confirming the presence of both diseases. The current literature data on the etiology, pathogenesis, clinical features and modern approaches to the treatment of hypophosphatemic rickets and Noonan syndrome type I are presented. Conclusion. The described clinical case emphasizes the importance of using modern molecular genetic research methods to identify rare combinations of hereditary diseases. This is necessary to predict possible complications, determine a multidisciplinary approach to diagnostics, patient management and prescribing pathogenetic therapy.

Article is devoted to one of the rare forms of monogenic connective tissue disease, Cutis Laxa with an autosomal recessive type of inheritance (ARCL1C), the Urban-Rifkin-Davis syndrome. The bibliographical data on this disease and the medical records of a 6-year-old male pediatric patient who was observed at the Clinical Genetics Department of the Research and Clinical Institute of Pediatrics named after Academician Yuri Veltischev with the Pirogov Russian National Research Medical University (Moscow, Russia) are presented. In addition to skin lesions, the child had disorders of the cardiovascular, respiratory and urinary systems. The diagnosis was confirmed by the DNA diagnostics results: the two mutations in the compound heterozygous state were found in the LTBP4 gene: the variant rs397515430 p.1342C>T previously described in the scientific sources in exon 11 leading to a stop codon and premature termination of translation - p.Arg475Ter; the second variant, not previously described in the literature, was found in intron 4 - c.452-22A>C. A differential diagnosis with other phenotypically similar diseases was carried out. Further medical supervision of the patient should be carried out with the mandatory involvement of the pulmonologist, the cardiologist and the nephrologist.

Лекция содержит анализ результатов использования бисфосфонатов (БФ) в лечении нарушений обмена кальция в костях и мягких тканях у детей и взрослых. БФ – целый класс (более 10) синтетических аналогов естественных регуляторов обмена кальция в организме – неорганических пирофосфатов. За 40 лет клинического использования БФ определены показания к их применению (резорбция кости, риск переломов, наследственные остеопатии у детей и взрослых). Установлены основные механизмы действия БФ (ингибиторы ферментов, повышающих активность остеокластов). Определены фармакологические свойства БФ, различия в степени активности отдельных препаратов (от 1 до 10 000 единиц), выявлены их противовоспалительные свойства. Определены дозы, способы введения БФ и схемы лечения, а также условия, при которых повышается риск побочных эффектов. Продолжается поиск новых видов БФ для лечения некостных заболеваний. The lecture contains an analysis of outcomes of bisphosphonates (BP) use in treatment of calcium metabolism disorders in bones and soft tissues in children and adults. BP is a whole class (more than 10) of synthetic analogues of natural regulators of calcium metabolism in the body - inorganic pyrophosphates. Over 40 years of clinical use of BP, indications for their use (bone resorption, fractures risk, hereditary osteopathies in children and adults) were determined. The main mechanisms of BP action were established (inhibitors of enzymes that increase the activity of osteoclasts). Pharmacological properties of BP, differences in the activity of individual drugs (from 1 to 10,000 units) were defined, and their anti-inflammatory properties were revealed. Doses, methods of BP administration and treatment regimens were determined, as well as conditions increasing adverse effects risk. Further investigations of new types of BP for non-bone diseases treatment are underway.

Angelman syndrome is a genetic disorder characterized by mental retardation and severe speech delay, movement disorders and ataxia, dysmorphic features, and behavioral disorders. Angelman syndrome is caused by the loss of the 15q11.2-q13 region of chromosome 15 received from the mother, which leads to a violation of the expression of the UBE3A gene. Purpose. To analyze clinical manifestations in children with Angelman syndrome to identify early-onset and characteristic clinical signs. Characteristics of children and research methods. The study included 60 children. In all cases, Angelman syndrome was diagnosed on the basis of international clinical criteria and the results of genetic testing. The researchers used clinical, functional and molecular genetic research methods. Results. 80-100% of children demonstrated delayed mental and motor development, lack of speech, affective behavior, ataxia, hand stereotypes, apraxia of hand movements, strabismus, sialorrhea. 72% of children had epileptic seizures; all patients (regardless of the presence / absence of epilepsy) had a pattern characteristic of Angelman syndrome on the electroencephalogram. Differential diagnosis was based on the gene / chromosomal syndromes characterized by similar clinical signs. Conclusion. The combination of such most frequent, early clinical symptoms as difficulties in feeding, strabismus, impaired muscle tone, delayed motor and psycho-speech development, affective behavior with frequent laughter, and sleep disorders may indicate Angelman syndrome in a child.

Проведен анализ эффективности оказания медицинской помощи детям с редкими наследственными заболеваниями в специализированной генетической клинике. Установлено, что около половины госпитализированных больных (и их родственники) нуждалась в осуществлении генетических исследований для установления или подтверждения диагноза, уточнения формы заболевания, медико-генетического консультирования. При этом 20% обследованных детей нуждались в проведении дополнительного генетического тестирования или повторной биоинформатической интерпретации полученных данных. The effectiveness of medical care for children with rare hereditary diseases in a specialized genetic clinic was analyzed. About half of the hospitalized patients (and their relatives) needed genetic research to establish or confirm the diagnosis, clarify the form of the disease, and provide medical and genetic counseling. About 20% of the examined children required additional genetic testing or repeated bioinformatic interpretation of the data.

Purpose: to analyze the structure of hereditary pathology and the results of genetic studies in children in a specialized clinic.Results.1045 children from 79 regions of the Russian Federation were examined and treated in the pediatric department of congenital and hereditary diseases in 2018. There were 25% of patients from Moscow and Moscow region and 75% from other territories. After examination all patients were divided into 2 large cohorts: patients with hereditary diseases diagnosed by clinical and laboratory data (737 children; 70%) and patients with undifferentiated pathological conditions with unclear genesis at the time of discharge from the hospital (308 children; 30%). In the cohort of hereditary diseases there were the most numerous (about 100 children in each) groups of patients with Ehlers–Danlos syndrome, imperfect osteogenesis and rare heterogeneous genetic syndromes. The groups of rickets- like diseases, chromosomal syndromes and Rett syndrome included 50-70 patients. Other groups were smaller. Half of the hospitalized patients required genetic analysis. The highest percentage of molecular genetically / cytogenetically confirmed diagnoses was found in the groups of chromosomal diseases, rare genetic syndromes of lysosomal and mitochondrial diseases, Rett syndrome, and aminoacidopathy. It is worth mentioning that a primary diagnosis was not established during a genetic study in 57 children (18%) children from the general cohort of patients with hereditary diseases, so the researchers used other methods of analysis or bioinformatic revision of the results.Conclusion: The authors found a large variety of genetic diseases in children requiring examination and treatment in a specialized hospital. 1/5 of the examined children require additional genetic testing or repeated bioinformatic interpretation of the data.

The article is devoted to the rare disease of the lysosomal storage disease group – Fabry’s disease. The disease is associated with the sphingolipids dysmetabolism, is caused by the accumulation of the globotriosylceramide (Gb3 ) and othersphingolipidsin the organism tissues and cells; it is characterized by the progression and severity of the course. The diagnostic results of 6 patient children aged from 5 to 17 years are analyzed; 2 boys and 4 girls from 3 families. The hereditary burden with a large number of the disease cases, 16 patients in 3 families including 6 children, comes under notice. All 6 children were diagnosed with Fabry’s disease based on the genealogical analysis as well as biochemical and molecular genetic examination. The activity of α-galactosidase A enzyme in the blood leukocytes was significantly decreased in two boys, insignificantly decreased in two sisters, and was normal in two girls. When performing the molecular genetic analysis, 3 mutations in exon 5 of GLA gene were identified. It has been established that the damages of cardiovascularsystem and nervoussystem, kidneys and visual organ, depression of the perspiratory gland function shall be considered as the first clinical signs of the disease in the children; it seems likely that the angiokeratoma appearance is characteristic only for boys. The presence of the non-specific symptoms and signs of the connective tissue dysplasia is noteworthy. The emphasis is made towards the importance of the early Fabry’s disease diagnosis, as it is essential for the timely (prior to appearance of the clinical symptoms and signs) beginning of the pathogenic treatment with the enzyme replacement drug.

The paper deals with a rare monogenic connective tissue disease from a group of fibrillinopathies with autosomal dominant inheritance — Beals syndrome caused by a mutation in the FBN2 gene. Attention is drawn to the high phenotypic similarity of this disease and Marfan syndrome (FBN1 gene mutation), which is associated with the almost complete identity of two proteins: fibrillin 1 and fibrillin 2. The paper describes a clinical case of a child with Beals syndrome and the typical manifestations of the disease: asthenic constitution, arachnodactyly of the hands and feet, congenital contractures of the large and small joints, chest deformity, kyphoscoliosis, talpes, and crushed ears. The investigators made a differential diagnosis with other connective tissue diseases, such as Marfan syndrome, Stickler syndrome, Ehlers–Danlos syndrome, homocystenuria, and arthrogryposis. DNA diagnosis verified the Beals syndrome in the proband. Exon 28 in the FBN2 gene showed the previously undescribed missense mutation of c.3719G>A, resulting in the amino acid substitution of cysteine for tyrosine (p.Cys1240Tyr) in the structure of the protein fibrillin 2. A de novo mutation occurred. There is evidence for its pathogenicity in the development of the clinical symptoms of the disease. The problems of effective medical genetic counseling in this family are discussed.

The paper deals with a rare monogenic connective tissue disease from a group of fibrillinopathies with autosomal dominant inheritance — Beals syndrome caused by a mutation in the FBN2 gene. Attention is drawn to the high phenotypic similarity of this disease and Marfan syndrome (FBN1 gene mutation), which is associated with the almost complete identity of two proteins: fibrillin 1 and fibrillin 2.The paper describes a clinical case of a child with Beals syndrome and the typical manifestations of the disease: asthenic constitution, arachnodactyly of the hands and feet, congenital contractures of the large and small joints, chest deformity, kyphoscoliosis, talpes, and crushed ears. The investigators made a differential diagnosis with other connective tissue diseases, such as Marfan syndrome, Stickler syndrome, Ehlers–Danlos syndrome, homocystenuria, and arthrogryposis. DNA diagnosis verified the Beals syndrome in the proband. Exon 28 in the FBN2 gene showed the previously undescribed missense mutation of c.3719G>A, resulting in the amino acid substitution of cysteine for tyrosine (p.Cys1240Tyr) in the structure of the protein fibrillin 2. A de novo mutation occurred. There is evidence for its pathogenicity in the development of the clinical symptoms of the disease. The problems of effective medical genetic counseling in this family are discussed.