Clinical polymorphism of Allgrove (triple-A) syndrome in children: Possibilities for early diagnosis and approaches to therapy

The paper gives the data available in the literature, which reflect the manifestations, diagnosis, and treatments of the rare inherited disease Allgrove syndrome in children. Emphasis is placed on major difficulties in the differential and true diagnosis of this severe disease. The authors describe their clinical cases. Particular emphasis is laid on the clinical symptoms of the disease and on its diagnostic methods, among which the DNA diagnosis is of most importance. The probands were found to have mutations in the AAAS gene: in one case there was a mutation (c.856 C> T, p.Arg286Term) in homozygous state, which is described in the International Human Mutation Database (CM 10151); in other case there was a change in nucleotide sequence (c.709 delC), which is undescribed in the mutation and polymorphism databases and which leads to premature termination of the protein. It is shown that awareness of Allgrove syndrome among clinicians is low and the interdisciplinary approach is of importance

Polymorphism of the clinical manifestations of progressive mitochondrial encephalomyopathy associated with POLG1 gene mutation

The common cause of mitochondrial diseases is mutations in the POLG1 gene encoding the catalytic subunit of DNA-polymerase gamma that is responsible for the replication and repair of mitochondrial DNA. Diseases associated with POLG1 gene defects are characterized by obvious clinical polymorphism and may resemble some mitochondrial syndromes and other hereditary and nonhereditary diseases, which gives rise to diagnostic difficulties. Another characteristic feature is that phenotypic manifestations are of diversity in various patients having the same mutation in the POLG1 gene. The paper describes mitochondrial encephalomyopathy, caused by homozygous mutation in the polymerase gamma (POLG1, p.L304R), with different clinical manifestations and a poor outcome in patients from two different families

Dysmetabolic nephropathy in children with hereditary connective tissue dysplasia

Nephropathy is a common associated pathology with hereditary connective tissue dysplasiaPurpose. To determine clinical and laboratory signs of renal pathology in the conditions of persisting hypoxic syndrome and anatomic abnormalities of the urinary system with hereditary connective tissue dysplasia syndromes in children Characteristics of children and research methods. We examined 36 children with Ehlers–Danlos syndrome and 10 children with Marfan syndrome to reveal signs of metabolic disorders in the blood and urine.Results. All children revealed abnormalities of the urinary system. In addition, children with Ehlers–Danlos syndrome demonstrated an increase in certain signs of dysmetabolic nephropathy when growing older: an increased content of parathyroid hormone in the blood, which inactivation and elimination is normally provided by the kidneys. Hypermicroproteinuria with a high content of microelements in proteins, increased excretion of medium molecules, lipid hydroperoxides, glycosaminoglycans, a decrease in antioxidant defense and crystal formation inhibitors are the characteristic signs of dysmetabolic nephropathy.Conclusion. Children with hereditary connective tissue dysplasia syndromes have a risk of developing nephropathy with signs characteristic of dysmetabolic nephropathy, requiring dynamic monitoring by a nephrologist

Hypoxic syndrome in hereditary diseases of connective tissue

Objective. To analyze the influence of clinical and biochemical markers on the diagnostic algorithm for hypoxic syndrome in children with genetic diseases of connective tissue.Characteristics of children and methods. There were examined 60 children were examined: 50 children with Ehlers–Danlossyndrome and 10 children with Marfan syndrome.Results. Constant fatigue, fast fatigue, low tolerance to physical exercises, pale skin, muscle hypotonia and headache are the most frequent symptoms of a hypoxic state in children with connective tissue dysfunction. At the biochemical level, hypoxic syndrome was characterized by signs of oxidative stress. The authors noted an decrease in pO2 , an increase in pCO2 in the circulating blood, an increase in the activity of anaerobic glycolysis with accumulation of lactate and pyruvate, a decrease in the synthesis of macroergs (ATP, ADP, AMP) and the activity of the mitochondrial respiratory enzymes, the emersion of mitochondrial insufficiency in the form of ripped red fibers (RRF) in myocytes , conglomerates of lipids, calcium, glycogen. There was an increased content of peroxidation products in the blood, urine and saliva.Conclusion. Periodic use of antihypoxants, drugs with detoxifying and immunomodulatory effect is justified for the treatment of children

Metabolic nephropathies in children: Causes, clinical and laboratory manifestations

In the regions polluted with industrial or agricultural toxicants, dysmetabolic nephropathy is detected in every 2 or 3 children and this rate increases with age. Exogenous intoxication is not the only cause of dysmetabolic nephropathy; of no less importance are endogenous toxicants, such as oxidative stress products, excess of usual metabolites or emergence of unusual products of abnormal metabolism. The toxicants are ascertained to be able to change the conformation of protein molecules to give rise to additional ligand loci ensuring the aggressive uptake of trace elements that fix changes in protein molecules, making them antigenically alien to the body. Low molecular weight proteins with their changed structure, which penetrate through the basement membrane, are unrecognized by the reabsorption systems of proximal tubules and excreted with urine, determining the appearance of the most steady and age-increasing sign of dysmetabolic nephropathy – microproteinuria or trace elementuria

Specific features of the clinical and laboratory diagnosis of Lesch—Nyhan syndrome and current therapy options

The rare hereditary diseases encountered in the practice of pediatricians, pediatric neurologists, and geneticists include Lesch—Nyhan syndrome associated with purine metabolic disorders caused by mutations in the HPRT1 gene encoding the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT deficiency gives rise to hyperuricemia, hyperuricemic nephropathy, and a CNS lesion reminiscent of dystonic or hyperkinetic infantile cerebral paralysis concurrent with a propensity to have autoaggressive behavior. The diagnosis is based on a range of history data, characteristic neurological symptoms, the detection of high blood and urine uric acid levels, and the identification of pathogenic mutagens in the HPRT1 gene. Early diagnosis contributes to timely therapy and assists in medical genetic counseling. The paper describes a clinical case of a boy with Lesch-Nyhan syndrome and elucidates the problems of diagnosis and treatment of this disease

Beals syndrome (congenital contractural arachnodactyly) in children: Clinical symptoms, diagnosis, treatment, and prevention

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

Biopterin-deficient hyperphenylalaninemia: Diagnosis and treatment

The term phenylketonuria encompasses some genetically heterogeneous diseases from a group of hereditary amino acid metabolic disorders, the key biochemical sign of which is a steady increase in blood phenylalanine levels – hyperphenylalaninemia. Phenylketonuria is a most common disease of the above group; its rate in the Russian Federation is 1:7140 neonates. The rare causes of hyperphenylalaninemia include the cofactor (biopterin-deficient) forms associated with tetrahydrobiopterin deficiency, leading to the blocked metabolic pathways for converting phenylalanine to tyrosine and for synthesizing catecholamine and serotonin precursors (L-dopa and 5-hydroxytryptophan). The distinguishing feature of all cofactor forms of hyperphenylalaninemia is the inefficiency of an isolated low-protein diet. Cofactor therapy with sapropterin in combination with correction of neuromediatory disorders is used in the combination treatment of these patients. The paper presents a case history of a child with severe biopterin-deficient hyperphenylalaninemia resulting from a defect in the PTS gene. The clinical example illustrates difficulties associated with the diagnosis of cofactor hyperphenylalaninemia and with long individual dosage adjustments for medications