Т убулопатия с ведущим синдромом метаболического алкалоза-синдром Гительмана (Gitelman) имеет аутосомно-рецессивный тип наследования (OMIM 263800), характеризуется клинической манифестацией у детей в школьном возрасте, выраженной гипомагниемией, гипокалиемией, метаболическим алкалозом, судорогами конечностей, гипокальциурией, отсутствием нефрокальциноза, полиурией и никтурией, нормальной концентрационной функцией почек [1]. Распространенность синдрома Гительмана 1:40 000-50 000 [1-7]. В настоящее время выделяют классический синдром Гительмана с типичными клиническими проявлениями (см. таблицу) и атипичную форму с церебральными кальцификатами [1, 2, 4, 5, 7-9]. Ген SLCI2A3, кодирующий протеин NCCT, картирован на хромосоме 16q13 [1-4, 10]. Кроме того, Гительманподобные гипомагниемии ассоциированы с мутациями в генах CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1 [11]. В литературе описаны единичные случаи атипичной формы синдрома Гительмана с двусторонними церебральными кальцификатами [9, 12]. Клинически эта форма синдрома проявляется утомляемостью, общей слабостью, тремором, парестезией, учащенным сердцебиением, гипомагниемией, гипокалиемией, метаболическим алкалозом, гипопаратиреозом и, как следствие, гипокальциемией, спастическими судорогами, тетанией, изменением ЭКГ (удлиненный интервал Q-T), нарушением сердечного ритма при наличии гипокалиемии, снижением интеллекта и т.д. [9, 11, 12]. Метаболические нарушения, связанные с мутациями генов, прямо или косвенно участвующих в транспорте ионов магния (Mg 2+), разделяют на четыре группы: гипомагниемии с гиперкальциурией (гены CLDN16, CLDN19, CASR, CLCNKB); Гительман
Orphan Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) (OMIM: 241530; ORPHA: 157215) with an autosomal recessive mode of inheritance occurs with an estimated prevalence of 1: 250,000 in the child population. HHRH was first described by M. Tieder, et al. (1985). The syndrome is caused by heterozygous or homozygous mutations in the SLC34A3 gene mapped to chromosome 9q34.3, which encodes a type II sodium phosphate cotransporter (NaPiIIc). Mutations result in loss of NaPi-IIc function and impairment of phosphate reabsorption in the proximal renal nephron. HHRH is characterized by a decrease in phosphate reabsorption in the proximal nephron tubules, manifested by hyperphosphaturia, hypercalciuria, hypophosphatemia, an increase in the concentration of 1,25(OH) 2D3, a decrease in parathyroid hormone (PTH) circulating in the blood, osteomalacia, inhibition of growth, low corrosiveness, low corrosiveness. The article presents the characteristics of the phenotype and genotype of HHRH, diagnostic criteria and treatment strategy. A description of a clinical case of HHRH with hypercalciuria, nephrocalcinosis and urolithiasis due to mutation of the SLC34A3gene is presented.
The purpose of the study was to evaluate the course and outcome in chronic kidney disease of congenital anomalies of the kidneys and urinary tract (CAKUT) associated with rare hereditary syndromes in children and adolescents, and to compare the results with literature data. The results of a follow-up study of the course and outcome in chronic kidney disease with syndromal congenital anomalies of the kidneys and urinary tract in rare hereditary syndromes (Pierson, Fraser 1 type, Renal hypodysplasia/ aplasia 3 type, Schuurs– Hoeómakers, CHARGE, Lowe, Renal-Coloboma, VACTERL association) and chromosomal abnormalities (Shereshevsky—Terner monosomia 45) are presented. In 4 out of 9 children and adolescents with congenital anomalies of the kidneys and urinary tract with rare hereditary syndromes, the formation of chronic kidney disease was established.
This review presents the latest data on the classification, pathogenesis, clinical and genetic features, and therapy of primary hyperoxaluria types I, II, and III in children with autosomal recessive inheritance. ORPHA portal of orphan diseases presents genes responsible for primary hyperoxaluria type I AGXT (93598); type II and type II GRHPR (93599), type III HOGA1 (93600). Worldwide genetic studies have established the pathogenesis, clinical phenotype and genotype features of primary hyperoxaluria. The pathogenesis of primary hyperoxaluria in children is based on impaired hepatic glyoxylate metabolism. The enzyme AGT catalyzes the conversion of L-alanine and glyoxylate to pyruvate and glycine, with vitamin B6 (pyridoxine) serving as a coenzyme for this reaction. Increased production of endogenous oxalate leads to increased blood oxalate concentrations and urinary oxalate excretion with the formation of renal calcium oxalate crystals and radiopaque concrements (calcium oxalate monohydrate – vevelite, calcium oxalate dihydrate – vedellite). High risk of progression to chronic kidney disease in primary hyperoxaluria in children of types I and II. Systemic oxalosis develops with increasing serum oxalate levels and the formation of calcium oxalate crystals with deposition in many organs and tissues. Therapy for primary hyperoxaluria in children includes: hydration (3l/m2/day) and citrates 100–150 mg/kg/day (potassium citrate 0.3–0.5 mmol/kg/day), pyridoxine at a dose of 5 to 20 mg/kg/day for vitamin B6 sensitive type I primary hyperoxaluria. Administration of oxalobacter formigenes and diet is effective. Combined liver and then kidney transplantation or simultaneous liver and kidney transplantation in patients with type I PH in B6-insensitive and isolated liver transplantation in B6-sensitive variants are performed. Timely molecular genetic testing in children with nephrocalcinosis makes it possible to establish a clinical and genetic diagnosis of type I, II, III PH, to carry out a personalised approach to treatment and to predict future health status.
Hypophosphatasia (HPP) ORPHA 436 is a rare disease with an autosomal recessive/autosomal dominant mode of inheritance due to mutations in the ALPL gene mapped on chromosome 1p36.12, encoding a nonspecific tissue isoenzyme alkaline phosphate (TNSALP). Currently, there are more than 400 known mutations in the ALPL gene. HPF is characterized by variability of manifestations from a mild course with minor damage to bones and teeth to severe forms with damage to the nervous system, lungs, and kidneys. In different countries, data on the prevalence of HPP differ, the average prevalence of severe forms is ~ 3.3 cases per 1 million newborns. In Europe, the prevalence of severe forms is 1: 300000 and moderately severe 1: 63701. The prevalence of mild HPP is thought to be much higher. The expected prevalence of severe forms in the Russian Federation is 1: 100000. GPP is diagnosed in patients of any age (with manifestation in utero, in childhood, or in adulthood).HPP is an orphan disease, occurring in patients with damage to many organs and systems: bone (osteoporosis, rickets, fractures, growth retardation), lungs (hypoplasia of the lungs, respiratory failure), central nervous system (vitamin B-dependent convulsions), kidney (calciuria, nephrocalcinosis, chronic kidney disease). In the absence of timely enzyme replacement therapy for severe forms of HPP, characterized by a progressive course, the prognosis for life is unfavorable. The only effective treatment for patients is enzyme replacement therapy in combination with symptomatic therapy. The article presents the features of the phenotype and genotype, clinical forms of HPP (perinatal severe, lethal, perinatal benign, infant, pediatric, adult, and odontohypophosphatasia), methods of early diagnosis, the strategy of pathogenetic enzyme replacement therapy of severe and moderate forms in pediatric and adult patients. In the absence of a timely diagnosis, pathogenetic treatment of GFF, there is a high risk of progression with disability and death.
The review presents literature data on tubulopathies with hypokalemic alkalosis: Bartter and HELIX syndromes. Orphan Bartter syndrome with autosomal recessive (types I, II, III, IV, V) or X-linked recessive types of inheritance (type V) due to mutations in the SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA/CLCNKB, MAGED2 genes, causing impaired reabsorption ions K+, Na+, Cl-, Ca2+, Mg2+ in the thick ascending loop of Henle and in the distal convoluted tubule, characterized by hypokalemia, metabolic alkalosis, hyperreninemia and secondary hyperaldosteronism, high PgE2 levels against normal or low blood pressure, hyperplasia of the juxtaglomerular apparatus, nephrocalcinosis with I, II, V types. A new tubulopathy HELIX syndrome is described in detail, the name is formed by the first letters of symptoms (Hypohidrosis, Electrolyte imbalance, Lacrimal gl and dysfunction, Ichthyosis, Xerostomia), due to mutations in the CLDN10 gene encoding Claudin-10b necessary for paracellular reabsorption of Na+ in the thick ascending part of the loop of Henle and exocrine glands. HELIX syndrome is manifested by extrarenal symptoms (dysfunction of the salivary, sweat, lacrimal glands with impaired secretion of water into saliva, sweat — hypohidrosis and tears — alacrima) and renal (hypokalemia, hypermagnesemia, less often hypercalcemia, metabolic alkalosis, hypocalciuria).
Fraser syndrome (OMIM # 219000; ORPHA: 2052; ICD-10: Q87.0) is a rare, disease with an autosomal recessive type of inheritance is characterized by abnormalities in the development of the eyes, kidneys, larynx, ears, and bone systems (cryptophthalmos, syndactyly, abnormalities of the kidneys, urogenital tract, and respiratory system). The article presents current literature data on the phenotypic and genotypic features of Fraser syndrome, the management of patients with new opportunities for genetic diagnosis and treatment. The syndrome, described by D. Fraser in 1962, is caused by mutations in the FRAS1, FREM2, GRIP genes. The diagnosis of the Fraser syndrome phenotype is established in the presence of the main criteria (cryptophthalmos, syndactyly, abnormalities of the urinary and respiratory system, genitals, family history indicating a closely related marriage) and secondary (congenital malformations of the nose and ears, skull ossification defects, anorectal abnormalities, umbilical hernia, etc.). Molecular genetic testing proves a rare disease, requires genetic counseling. The management of patients is carried out jointly by an ophthalmologist, an otolaryngologist, an audiologist, a nephrologist, a urologist, a maxillofacial surgeon and other specialists.
Цель. Оценить почечный прогноз при пузырно-мочеточниковом рефлюксе в структуре врожденных аномалий почек и мочевыводящих путей (ВАПМП/CAKUT). Материалы и методы. Обследовано 113 детей с врожденными аномалиями почек и мочевыводящих путей, не имеющих редких наследственных синдромов, у 60 (53,1%) из которых выявлен пузырно-мочеточниковый рефлюкс (ПМР) I–V степени. Степень ПМР определена согласно международной радиологической классификации R.L. Lebowitz et al. (1985). Оценка типа рефлюкс-нефропатии (РН) проведена по классификации I. Goldraich (1983), стадии хронической болезни почек (ХБП) – по NKF-K/DOQI (2002), National Kidney Foundation’s Kidney Disease и R. Hogg и соавт. (2003). Результаты. Установлена частота встречаемости одностороннего и двустороннего ПМР, РН и ХБП у пациентов с ВАПМП. Из 60 (53,1%) детей с ВАПМП и ПМР у 31 (51,7%) выявлен односторонний, а у 29 (48,3%) – двусторонний рефлюкс. ПМР чаще диагностировался у детей на первом году жизни (у 63,3% пациентов) с одинаковой частотой у мальчиков и девочек. Из 60 детей у 45 (75%) установлена III–V степень ПМР. Формирование РН 1–4-го типа выявлено у 25 (41,7%) детей с ПМР. Из 60 детей с ПМР и ВАПМП у 43 (71,7%) старше 2 лет проведена градация по стадиям ХБП и у 11 (25,6%) пациентов с РН 3–4-го типа к возрасту 12–16 лет имела место ХБП С4–5. Заключение. Фенотип ПМР и аномалий почек установлен у 93,3% детей, РН 1–4-го типа – в 41,7% случаев. Наличие ПМР и РН являются неблагоприятными факторами прогрессирования ХБП. Purpose. To evaluate the renal prognosis for vesicoureteral reflux in the structure of congenital anomalies of the kidneys and urinary tract. Materials and methods. 113 children with congenital anomalies of the kidneys and urinary tract, without rare hereditary syndromes, were examined, 60 (53.1%) of whom were diagnosed with vesicoureteral reflux (VUR) grades I–V. The degree of VUR was determined according to the international radiological classification R.L. Lebowitz et al. (1985). Assessment of the type of reflux nephropathy (RN) was carried out according to the classification I. Goldraich (1983), NKF-K/DOQI stages of chronic kidney disease (CKD) (2002), National Kidney Foundation’s Kidney Disease (2003) and R. Hogg et al. (2003). Results. The frequency of occurrence of unilateral and bilateral VUR, RN and CKD in patients with CAKUT was established. Of the 60 (53.1%) children with CAKUT and VUR, 31 (51.7%) had unilateral, and 29 (48.3%) had bilateral reflux. VUR was more often diagnosed in children in the first year of life (in 63.3% of patients) with the same frequency in boys and girls. Of the 60 children, 45 (75%) were diagnosed with grade III–V VUR. The formation of RN types 1–4 was detected in 25 (41.7%) children with VUR. Of 60 children with VUR and CAKUT, 43 (71.7%) older than 2 years were graded according to the stages of CKD and 11 (25.6%) patients with RN types 3–4 had CKD C4–5 by the age of 12–16 years. Conclusion. The phenotype of VUR and kidney anomalies was detected in children in 93.3%, RN type 1–4 in 41.7%. The presence of VUR and RN are unfavorable factors in the progression of CKD.
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