Vol 63, No 3 (2017)

Clinical endocrinology
Variable phenotype of pseudohypoparathyroidism in children
Makazan N.V., Orlova E.M., Tozliyan E.V., Melikyan M.A., Kareva M.A., Kalinchenko N.Y., Peterkova V.A.

Background. Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders associated with tissue insensitivity to parathyroid hormone. PHP is characterized by genetic heterogeneity and variable phenotype. In addition to the hypocalcemic syndrome and resistance to parathyroid hormone, PHP is also characterized by phenotypic features and resistance to other hormones (TSH, LH, FSH, and GHRH), which are known as Albright Hereditary Osteodystrophy (AHO). Until recently, no analysis of large cohorts of patients with PHP has been performed in Russian literature.

Objective — to examine a large cohort of patients with PHP and assess the clinical features of PHP.

Material and methods. A group consisting of 32 patients with different variants of course of the disease who had been examined at the Endocrinology Research Center in 2014—2016 was analyzed.

Results. Features of AHO phenotype in addition to hormonal resistance were identified in 16 (50%) patients; one of them had one feature (brachydactyly) and 15 patients had two and more features of AHO. Besides insensitivity to PTH, TSH resistance was found in 22 (68.75%) patients and one patient had resistance to PTH, TSH and LH/FSH. Hypothyroidism manifested before hypocalcaemia in 4 patients. Obesity was the first complaint in 8 patients; 5 of them had subclinical hypocalcaemia and the remaining 3 patients had an elevated PTH level with the normal level of calcium at the time of first examination. The most typical clinical signs of hypocalcaemia in 23 (72%) patients were seizures. Thirteen of them were misdiagnosed with epilepsy and had been followed by a neurologist for a period ranging between 2 months and 7 years before hypocalcaemia was revealed.

Conclusions. Pseudohypoparathyroidism is a rare genetic disorder associated with resistance to parathyroid hormone, which can have a lot of other clinical features in addition to the symptoms of PTH resistance. Obesity or hypothyroidism can be the earliest manifestation of PHP preceding hypocalcaemia. Evaluation of serum calcium level is important for all pediatric patients with seizures to timely diagnose hypocalcaemia and avoid misdiagnosing.

Problems of Endocrinology. 2017;63(3):148-161
Antiapoptotic effect of melatonin in nonalcoholic steatohepatitis developing in patients with type 2 diabetes mellitus
Popov S.S., Pashkov A.N., Esaulenko I.E., Popova T.N., Agarkov A.A., Kuptsova G.N.

Objective — to investigate the antiapoptotic effect of melaxen in nonalcoholic steatohepatitis associated with type 2 diabetes mellitus, as well as its effect on markers of cytolysis syndrome, parameters of lipid and carbohydrate metabolism.

Material and methods. Fifty-nine patients with nonalcoholic steatohepatitis associated with type 2 diabetes mellitus were included in the clinical study. Among them, 33 people were receiving background therapy; 26 patients received melaxen in addition to the background therapy. Biochemical values (aminotransferases, the lipid and carbohydrate profile) were measured using the conventional methods. Activities of caspase-1 and -3 in blood serum were determined spectrophotometrically. DNA fragmentation from white blood cells was detected by agarose gel electrophoresis followed by staining with ethidium bromide.

Results. It was shown that in this pathology, apoptotic processes are activated in addition to development of the cytolysis syndrome and disturbances of lipid and carbohydrate metabolism as evidenced by the increased caspase-1 and -3 activities. DNA fragmentation also took place. Activities of caspase-1 and 3 increased 1.7-fold (p<0.05) and 1.8-fold (p<0.05) compared with the normal values. The characteristic apoptotic «ladder» was also detected in the electrophoregram of DNA isolated from blood lymphocytes in patients with nonalcoholic steatohepatitis associated with type 2 diabetes mellitus. The combination therapy with melaxen changed the investigated parameters towards the normal values more significantly compared to the background treatment.

Conclusions. Hence, melatonin possesses antiapoptotic activity and can have a positive impact on treatment efficiency.

Problems of Endocrinology. 2017;63(3):162-168
Case Reports
A novel heterozygous mutation in POU1F1 is associated with combined pituitary hormone deficiency
Gavrilova A.E., Nagaeva E.V., Rebrova O.Y., Shiryaeva T.Y., Tiulpakov A.N., Peterkova V.A.

Mutations in the POU1F1 gene (OMIM#613038) are a rare case of combined pituitary hormone deficiency (CPHD), which is characterized by deficiency of growth hormone, TSH, and prolactin. Brain mri reveals hypoplasia of the anterior lobe of the pituitary gland. The prevalence of this disease has not been fully studied, but it is reported that the incidence of mutations in the POU1F1 gene in patients with CPHD from nonrelated marriages is 3—7%, reaching 25—52% among familial cases. Both the autosomal dominant and the autosomal recessive inheritance patterns are possible. More than 30 mutations in POU1F1 have been described in patients with CPHD. One child in the family had a pronounced delay in physical and psychomotor development, characteristic signs of dysmorphogenesis, an extremely low IGF-1 level, low levels of ft4 and prolactin, and a normal cortisol level. Molecular genetic testing revealed a heterozygous mutation c.500a> g: p.q167r in the POU1F1 gene. This mutation has never been previously described. The patient showed a good response to the recombinant GH (rhGH) therapy.

Problems of Endocrinology. 2017;63(3):169-173
Hypopituitarism due to mutation in the PROP1 gene in association with the 47,XYY karyotype and autosomal dominant atrioventricular septal defect: two case reports
Gubaeva D.N., Orlova E.M., Pankratova M.S., Vorontsov A.V., Kareva M.А.

Application of genetic analysis in clinical practice enables identifying a combination of two rare diseases in one patient. We report two cases of patients with hypopituitarism due to PROP1 gene mutations in combination with the 47,XYY karyotype (case 1) and autosomal dominant partial atrioventricular septal defect (case 2). These clinical cases clearly demonstrate that several rare diseases can be present in one patient. The morphology of the pituitary gland has specific features in patients with a PROP1 gene mutation: signal inversion on T1- and T2-weighted images, as well as changes in size of the pituitary gland over time. In case of short stature, the hormonal evidence of secondary hypopituitarism, low IGF-1 levels, and specific morphological features observed in MRI images, we recommended carrying out molecular genetic analysis of the PROP1 gene without conducting growth hormone stimulation test.

Problems of Endocrinology. 2017;63(3):174-178
The case of Crohn's disease in a child with congenital growth hormone deficiency.
Bashnina E.B., Berseneva O.S., Korytko T.E., Turkunova M.E.

A female patient with congenital hypopituitarism is followed up at the Children’s Endocrinology Centre (St. Petersburg, Russia). Growth hormone deficiency was confirmed by the diagnostic stimulation test; the maximum peak value of growth hormone was 8.3 ng/ml. At the moment of diagnosis, the growth deficit was –3.9 SDS. MRI showed the «empty Turkish saddle», the heterogeneous structure of the pituitary gland. No dysfunction of the other endocrine glands was identified. Bone age lagged behind the chronological age and was 9 years. The somatogenic causes of growth delay and chromosomal abnormalities were ruled out. Molecular genetic testing of the genes associated with hypopituitarism revealed no mutations. Growth hormone therapy was started in a daily dose of 0.033 mg/kg body weight. Two months after the growth hormone therapy had been started, the patient was admitted to the Surgical Department with the symptoms of «acute abdomen». The growth hormone therapy was suspended. The patient was diagnosed with Crohn’s disease upon further examination. After surgical treatment and prescription of specific therapy with Remicade, treatment with growth hormone was resumed after the 6-month break. Now the patient is receiving replacement therapy with growth hormone and permanent therapy of the concomitant Crohn’s disease.

Problems of Endocrinology. 2017;63(3):179-181
Hypoglycemia as a manifestation of congenital multiple pituitary hormone deficiency in patients without growth retardation: a clinical series
Kareva M.A., Orlova E.M., Melikyan M.A., Vorontsov A.V., Vladimirova V.P., Peterkova V.A.

Congenital hypopituitarism is usually diagnosed in children with growth retardation. Severe life-threatening hypoglycemia and cholestasis can be early manifestations of hypopituitarism in neonates. The pituitary stalk interruption syndrome revealed by MRI confirms the diagnosis of congenital hypopituitarism.

We report six cases of children admitted with recurrent ketotic hypoglycemia since early age. The median age of the first clinical presentation of hypoglycemia was 16 months. The median age at primary endocrinological examination was 45 months. At the first examination none of the patients had growth failure. Neonatal jaundice was noticed in four patients. Free T4 levels were decreased in all the patients (median level, 8.6 pmol/l; the lower limit of normal being 10 pmol/l), while the TSH level was normal or moderately increased, suggesting secondary hypothyroidism. Cortisol levels were low (median 92 nmol/L; range, 37—130 nmol/l). IGF-1 level was below the limit of detection (<25 ng/ml) in all patients and reached the normal values in none of patients. All children had elevated prolactin levels: 540—1778 mU/l (normal level, 90—540 mU/l). MRI of the brain revealed similar abnormalities in the chiasmal sellar region in all the patients: anterior pituitary hypoplasia, thin or interrupted pituitary stalk, ectopic neurohypophysis into the chiasm and the hypothalamic structures.

Ketotic hypoglycemia can be the first manifestation of congenital hypopituitarism before the growth failure. Hormonal results showing secondary hypothyroidism, secondary adrenal failure, low IGF-1 and pituitary stalk interruption syndrome detected by MRI are sufficient for making the diagnosis of congenital combined pituitary deficiency in children with hypoglycemia; GH-stimulation tests could be avoided in these cases.

Problems of Endocrinology. 2017;63(3):182-188
Insulin autoimmune syndrome: a rare cause of hypoglycemia. The case report of the syndrome in pediatric practice
Kuznetsova E.S., Pilipenko O.V., Melikyan M.А.

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia accompanied by an increased insulin level and presence of insulin autoantibodies while no exogenous insulin was used. This disorder is the third leading cause of hypoglycemia in Southeastern Asia. The disorder develops in individuals with a genetic predisposition, mostly after they had administered drugs containing a sulfhydryl moiety, such as methimazole, penicillin g, etc. The syndrome is typical of adults and extremely rare among children. We report the case of developing IAS in a 3.5-year-old Caucasian girl, possibly induced by pyritinol therapy.

Problems of Endocrinology. 2017;63(3):189-194
Familial case of congenital hyperinsulinism associated with mutation in the GLUD1 gene
Melikyan M.A., Tiulpakov A.N., Kareva M.A.

Congenital hyperinsulinism (CHI) is a rare hereditary disease characterized by hypoglycemia in children during the first year of life. Late diagnosis and inadequate therapy may result in severe neurological complications. Mutations in the GLUD1 gene that encodes glutamate dehydrogenase are one of the causes of CHI. This form of CHI is characterized by protein-induced hyperinsulinemic hypoglycemia and hyperammonemia in patients. Diagnosing can be challenging because hyperinsulinemic hypoglycemia cannot be detected using the conventional fasting glucose test. Extensive examination including the protein load test is needed to refine diagnosis. We report a familial case where the mother and two daughters were diagnosed with CHI and had a mutation in the catalytic domain of the GLUD1 gene. The clinical presentation, the laboratory data, the outcome of therapy, and the dynamic follow up data for the patients are presented.

Problems of Endocrinology. 2017;63(3):195-200
Ovotesticular disorder of sexual development in a patient with 46,XY karyotype
Raygorodskaya N.Y., Bolotova N.V., Jarkov D.A., Palatova T.V., Dorovskaya N.S.

A 46,XY ovotesticular disorder of sexual development is a rare variant of pathological gonadal differentiation. A 15-month-old patient had ambiguous external genitalia, no palpable gonads, and the 46,XY karyotype. The uterus was detected by imaging of the lesser pelvis. Gonads resided on the fallopian tubes and macroscopically resembled ovotestes: each gonad consisted of two compartments separated by a connective tissue interlayer. Histological examination showed that one gonadal portion consisted for ovarian tissue, was differentiated into the cortical and medullary matter, and contained primordial follicles with pronounced dystrophic changes. The remaining portions consisted of immature tubular epithelium with proliferative cellular changes. The decision about bringing up as a female with possible adaptation during puberty was justified in this case. The surgical approach was selected on the basis of histological examination and a decision on performing gonadectomy was made.

Problems of Endocrinology. 2017;63(3):201-203
Molecular genetic aspects of gestational diabetes
Pakin V.S.

The incidence of gestational diabetes mellitus (GDM) is currently dramatically increasing throughout the world. The relevant studies of origin and pathogenesis of GDM are of great clinical and scientific value taking into account the intimate association of GDM with serious perinatal complications, including preeclampsia, preterm labor, fetal macrosomia, as well as long-term effects such as the high risk of metabolic syndrome and type 2 diabetes mellitus (T2DM). The pathogenic mechanisms of GDM are rather similar to those of other diabetes, especially T2DM, thus suggesting that GDM is a common multifactorial disorder involving numerous genetic and provocative exogenous factors. The data in favor of inherited predisposition to GDM are briefly discussed and a short overview of the known GDM candidate genes is given. According to present knowledge, the gene network of GDM includes dozens of genes and is rather similar to that in GDM. The features of gene network associated with GDM and the ones known for other types of DM are outlined. Special attention is given to the known GDM biomarkers, which are especially important for understanding of the molecular genetic and epigenetic mechanisms of GDM development, its early predictive diagnosis, efficient prevention and personalized treatment.

Problems of Endocrinology. 2017;63(3):204-207

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