Vol 63, No 2 (2017)

Original Studies
Clinical and genetic features of patients with multiple anterior pituitary hormone deficiency caused by mutations in the PROP1 gene; the efficacy of recombinant growth hormone therapy
Gavrilova A.E., Nagaeva E.V., Shiryaeva T.Y., Rebrova O.Y., Tiulpakov A.N., Peterkova V.A., Dedov I.I.

Rationale. One of the most common causes of multiple anterior pituitary hormone deficiency (MPHD) is genetic defects in the PROP1 gene. PROP1 deficiency leads to malfunction of somatotrophs, lactotrophs, thyrotrophs, corticotrophs, and gonadotrophs. Now, there is an opportunity to conduct large-scale population studies of patients with genetic MPHD, describe their clinical and genetic heterogeneity, and evaluate the efficacy of long-term therapy of these patients with a recombinant growth hormone (rGH).

Aim. The study aim was to assess the spectrum of PROP1 gene mutations in the Russian population of MPHD patients, rate and expected age of hypopituitarism components, and efficacy of rGH therapy.

Material and methods. We analyzed the data of 27 patients diagnosed with MPHD and genetically confirmed mutations in the PROP1 gene who were treated at the Institute of Pediatric Endocrinology of the Endocrinology Research Center (ERC) in 1978―2016. MPHD was diagnosed based on laboratory data and stimulatory tests characterizing the functional activity of the pituitary gland. The molecular genetic study was performed using high-performance parallel sequencing. We used a custom Ampliseq_HP primer panel developed at the Department of Hereditary Endocrinopathies of the ERC, which included coding regions of the following genes: ARNT2, GH1, GHRH, GHRHR, GHSR, GLI2, HESX1, LHX3, LHX4, OTX2, PAX6, POU1F1, PROP1, SHH, SOX2, and SOX3. All patients received rGH therapy at a growth-stimulating dose from the time of GH deficiency diagnosis until final height completion. We evaluated the efficacy of therapy by comparing the achieved final height with the genetically expected one.

Results. Non-familial cases prevailed (N=23) in the study cohort of patients with MPHD caused by mutations in the PROP1 gene; only two patients were monochorionic twin sisters; the other two patients were siblings. An analysis of the distribution of PROP1 gene mutations revealed a hot-point mutation c.301_302delAG in 24 patients (89%, 95% CI 71%; 98%). A mutation in the c.150delA locus occurred in 11 patients (41%, 95% CI 22%; 61%). Two patients had other mutations (c.629delC and c.43_49delGGGCGAG). Total GH deficiency was detected in all patients. The rate of secondary hypothyroidism (SHT) in patients of the study sample was 78% (95% CI 58%; 91%) at the time of diagnosis of GH deficiency and 100% (95% CI 81%; 100%) at the time of final height. The rate of secondary hypogonadism (SHG) at the time of final height was 100% (95% CI 81%; 100%), and the rate of secondary hypocorticism (SHC) was 41% (95% CI 22%; 61%). The normal level of prolactin was detected in 83% (95% CI 65%; 94%) of patients. At the time of growth plate closure, patients receiving rGH therapy at the growth-stimulating dose achieved the genetically expected final height.

Conclusion. According to our findings, the most common mutation in the PROP1 gene is a deletion of AG nucleotides in the 101 codon (c.301_302 delAG), which is found in 89% (95% CI 71%; 98) patients. Patients with MPHD caused by mutations in the PROP1 gene have total GH deficiency and are diagnosed with secondary hypothyroidism and secondary hypogonadism in 100% of cases. The possibility of delayed manifestation of hypopituitarism components requires regular screening of tropic hormone levels for the timely start of substitution therapy and prevention of life-threatening conditions. rGH therapy is highly effective for GH deficiency caused by PROP1 gene mutations and allows patients to achieve the genetically expected height in the case of early diagnosis of growth hormone deficiency.

Problems of Endocrinology. 2017;63(2):72-81
Economic and social aspects of pituitary dwarfism treatment with recombinant growth hormone
Vorontsova M.V., Nagaeva E.V., Naygovzina N.B.

Rationale. Pituitary dwarfism is an orphan disease requiring pathogenetic treatment. The domestic literature lacks studies devoted to the medical and economic effectiveness of treatment for growth hormone deficiency (GHD) using recombinant growth hormone (rGH) drugs.

Aim. To analyze the cost effectiveness of rGH therapy in GHD children in the Russian Federation under the Program «7 High-Cost Nosologies».

Material and methods. We analyzed data of 50 GHD children living in 4 regions of the Russian Federation and receiving rGH therapy under the Program «7 High-Cost Nosologies». We evaluated the amount of drug consumption and the economic component: the cost of treatment and monitoring for ≥ 6 years. The incremental cost was calculated as the difference between a program providing a GHD child with rGH treatment and monitoring and an alternative program providing a GHD child with financial and social assistance and medical examination.

Results. The median cost of treatment of a single child with rGH at a dose of 0.033 mg/kg/day was 437.5 thousand rubles or 8.12 thousand US dollars for the entire analyzed period (mean, 6.95 years). The median cost of treatment per child per year was 63.6 thousand rubles/year or 1.09 thousand USD/year. Given the cost of treatment and monitoring, the integrated management of one patient cost 68.4 thousand rubles per year (470.7 thousand rubles for 6.95 years), on average, with monitoring accounting for 7.05%. The total cost of all benefits and examinations for one disabled child was 178.97 thousand rubles per year or 1,243.86 thousand rubles for 6.95 years (medical examinations accounted for 1.2%). Upon calculating the cost difference between the program providing a GHD child with treatment and monitoring and the alternative program when a GHD child was not provided with treatment, but received appropriate disability payments and medical examination, the incremental cost amounted to 110.6 thousand rubles per child per year (773.18 thousand rubles for 6.95 years).

Conclusion. The study demonstrates that treatment of GHD children under Program «7 High-Cost Nosologies» is cost-effective for both the patient and society and the state in general. For example, the incremental cost between the two programs is 110.6 thousand rubles for a year or 773.18 thousand rubles for 6.95 years. The study results indicate the importance of thorough analysis of the effects and costs in assessing the effectiveness of medical programs, especially in the case of orphan diseases.

Problems of Endocrinology. 2017;63(2):82-91
Case Reports
Cushing’s syndrome in an infant
Kareva M.A., Makazan N.V., Orlova E.M., Poddubnyi I.V., Peterkova V.A.

Endogenous hypercorticism in infants occurs extremely rare. The causes of Cushing’s syndrome in early childhood include space-occupying lesions and bilateral hyperplasia of the adrenal glands. ACTH-independent hypercorticism due to bilateral nodular hyperplasia of the adrenal glands in children in the first months of life is most often associated with McCune-Albright-Braitsev syndrome. This syndrome is a rare disease caused by hyperfunction of the stimulatory G-protein alpha-subunit due to somatic mutations in the GNAS gene. The McCune-Albright-Braitsev syndrome is a multicomponent disease, the clinical manifestations of which include café-au-lait spots, fibrous dysplasia, and different types of endocrine hyperfunction, among which hypercorticism is one of the rare cases. The clinical picture of Cushing’s syndrome manifested in early childhood is characterized by some peculiarities that can delay the correct diagnosis: the first manifestations include low weight and height at birth, physical retarfation in the absence of a redistribution of subcutaneous fat typical of Cushing’s syndrome, psychomotor retardation, and complications caused by immunodeficiency and hypertension. We present a case of ACTH-independent hypercorticism in an infant.

Problems of Endocrinology. 2017;63(2):92-97
Mutations in the ghrelin receptor gene GHSR in congenital hypopituitarism
Bashnina E.B., Berseneva O.S., Glotov A.S., Glotov O.S., Turkunova M.E., Serebryakova E.A., Baranov V.S.

The results of molecular genetic studies indicate the potential involvement of ghrelin in the pathogenesis of some dwarfism forms. However, in the case of isolated somatotropin insufficiency, mutations in the ghrelin receptor gene are a rare cause of the disease. The article describes a case of identification, based on new generation sequencing (NGS) using the AmpliSeq technology, of a functionally significant marker ― the c.837C>A substitution in the ghrelin receptor gene GHSR (OMIM: 615925) in the heterozygous state in two sisters with isolated growth hormone deficiency and the clinical picture of malabsorption syndrome. We have supposed that mutations in the GHSR gene may be an etiological factor of isolated somatotropin insufficiency in a combination with malabsorption syndrome and eating disorders. Mutations in the GHSR gene enable predicting the development of somatotropin insufficiency not associated with abnormality of other pituitary hormones.

Problems of Endocrinology. 2017;63(2):98-102
Growth and sexual retardation in a boy with celiac disease
Brzhezinski L.B., Latyshev O.Y., Samsonova L.N., Okminyan G.F., Kiseleva E.V., Kasatkina E.P., Pykov M.I.

Growth and sexual retardation in boys can be caused by both endocrine and somatogenic causes. One of the somatogenic causes of growth and puberty retardation is celiac disease that is a genetic disorder of the small intestine, which is associated with deficiency of enzymes breaking down the gluten peptide. The clinical picture of celiac disease may be dominated by gastrointestinal manifestations (diarrhea, recurrent abdominal pain, nausea, constipation, appetite disorders) and nonspecific symptoms (irritability, apathy, physical and sexual retardation, impaired reproductive function, anemia, etc.). We present a case of late diagnosis of celiac disease in a 15-year-old boy with physical (height SDS, −4.1; bone age SDS, −8.2) and sexual (Tanner 1) retardation. The negative results of gonadoliberin (max LH, 2 mIU/mL) and chorionic gonadotropin (Δ-testosterone, 2,3 nmol/L) tests indicated the lack of activation of the hypothalamo-pituitary-gonadal system. However, inhibin B (29.9 pg/mL) and anti-Mullerian hormone (43.8 ng/mL) levels indicated preservation of the reserve capabilities of this system. During follow-up, after treatment with a gluten-free diet for 10 months, the patient demonstrated an improved growth rate (2.7 SDS), progression of the sexual development stage (Tanner 2), and positive results of diagnostic diphereline (max LH, 16.8 IU/mL) and chorionic gonadotropin (Δ-testosterone, 11.8 nmol/L) tests. This case demonstrates the need to exclude celiac disease in patients with growth and sexual retardation, especially when these pathologies are combined with protein-energy deficiency, gastrointestinal symptoms, and anemia, as well as the need to use additional indicators of the reproductive system condition in boys, e.g. inhibin B and anti-Mullerian hormone.

Problems of Endocrinology. 2017;63(2):103-105
A case of nephrogenic syndrome of inappropriate antidiuresis caused by a mutation of the vasopressin type 2 receptor
Makazan N.V., Zubkova N.A., Tiulpakov A.N.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X-linked disorder of water balance, which was first described in two unrelated male infants with severe symptomatic hyponatremia. NSIAD is caused by activating mutations of the arginine vasopressin receptor 2 (AVPR2) gene, resulting in impaired reabsorption of free water, which leads to increased osmolarity of urine, plasma hypo-osmolarity, and persistent hyponatremia. We report, for the first time in the domestic literature, a case of isolated euvolemic hyposmolality hyponatremia in a child with oligodipsia. Because hypocorticism and renal pathology were excluded, and there was no antidiuretic hormone hypersecretion, NSIAD was suggested. A molecular genetic study revealed a new mutation L312S, not described earlier, in the seventh transmembrane domain of the AVPR2 gene. Pathogenicity of the mutation was proved by a functional study. We provide the clinical and laboratory characteristics of SIAD and the main principles of treatment. This disease should be considered in the differential diagnosis of hyponatremia syndrome.

Problems of Endocrinology. 2017;63(2):106-109
A case of congenital hypothyroidism combined with sensorineural hearing loss (Pendred syndrome) caused by a TPO gene defect
Makretskaya N.A., Bezlepkina O.B., Chikulaeva O.A., Vasilyev E.V., Petrov V.M., Dedov I.I., Tiulpakov A.N.

Congenital hypothyroidism is a genetically heterogeneous group of diseases caused by two mechanisms: gland dysgenesis and dyshormonogenesis. The disease pattern includes a number of syndromic forms, one of which is a combination of congenital hypothyroidism and sensorineural hearing loss (Pendred syndrome) initially associated with SLC26A4 gene defects. The article describes a patient with clinical manifestations of Pendred syndrome who was diagnosed with a TPO gene defect during a molecular genetic analysis using next generation sequencing (NGS). Therefore, a combination of congenital hypothyroidism and sensorineural hearing loss can have a different molecular basis. Our findings illustrate the value of NGS for genetic verification of the diagnosis.

Problems of Endocrinology. 2017;63(2):110-113
Papillary thyroid cancer in an adolescent with a toxic single nodular goiter
Rogova O.S., Okminyan G.F., Samsonova L.N., Kiseleva E.V., Latyshev O.Y., Egarmina N.N., Kasatkina E.P.

The rate of nodular goiter in children ranges from 0.05 to 5.1%; in this case, the risk of thyroid cancer in childhood amounts to 3―70% of all cases of thyroid pathology. Therefore, the main issue is the differential diagnosis of a nosological variant of a thyroid nodule, which defines the optimal therapeutic tactics for a particular patient. The risk of malignancy is traditionally believed to be low in the case of decompensated functional autonomy of a thyroid nodule; therefore, the need for fine needle aspiration biopsy (FNAB) followed by cytomorphological analysis of the aspirate is avoided in most cases. The presented clinical case demonstrates papillary cancer in an adolescent with a toxic single nodular goiter. A thyroid ultrasound examination revealed a nodular lesion in the boy. An increase in the thyroid size and thyrotoxicosis manifestation occurred 3 years later. A cytomorphological study identified follicular neoplasia; scintigraphy revealed a hot nodule. Surgical treatment was planned. Antithyroid therapy was prescribed to prepare for surgery. After compensation of thyrotoxicosis, hemithyroidectomy was performed. A histological examination diagnosed papillary thyroid cancer, which required repeated thyroidectomy followed by radioiodine I131 ablation. The postoperative period was uneventful; the patient well tolerated suppressive levothyroxine therapy. Therefore, the presence of a toxic single nodular goiter does not exclude thyroid cancer, which defines the need to discuss the indications for FNAB of thyroid nodules in children.

Problems of Endocrinology. 2017;63(2):114-116
Masks of severe acquired hypothyroidism in preschool children
Alimova I.L., Labyzova Y.V.

We describe two cases of severe acquired hypothyroidism associated with autoimmune thyroiditis in preschool children. Hypothyroidism was masked by pericarditis in the first case and by polyarthritis in the second case. Both patients presented with the full-blown clinical picture of hypothyroidism in the form of increased fatigue and drowsiness, a pale and pasty skin, overweight, constipation, marked hypercholesterolemia, anemia, and an increased and indurated thyroid. In both cases, diagnosis of hypothyroidism was performed after consultation of the endocrinologist for overweight/obesity. Finally, the relationship between cardiac and joint changes and hypothyroidism was confirmed by positive changes in clinical and laboratory-instrumental data in the course of levothyroxine therapy and by follow-up results of patients. The presented cases indicate the need for timely diagnosis of hypothyroidism that may be a potential cause of pericarditis and polyarthritis in children.

Problems of Endocrinology. 2017;63(2):117-120
Pseudohypertrophic myopathy in a child with hypothyroidism (Kocher—Debre—Semelaigne syndrome)
Bogova E.A., Shiryaeva T.Y.

The Kocher-Debre-Semelaigne syndrome (KDSS) is a rare disease that clinically manifests as hypothyroidism and muscle pseudohypertrophy of the trunk and extremities. KDSS occurs mainly in countries where there is no screening for congenital hypothyroidism; however, this syndrome can develop when there is acquired hypothyroidism. In this syndrome, muscle hypertrophy is false (pseudohypertrophy); it is not accompanied by an increase in muscle strength but, on the contrary, leads to a decrease in muscle strength and the development of muscle hypotension. Increased levels of creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH) are the characteristic laboratory sign of myopathy in this syndrome. The signs of hypothyroidism and muscle pseudohypertrophy are reduced by levothyroxine therapy. Indicators of the final height in the case of delayed treatment may remain poor. The clinical signs characteristic of the disease, especially in the presence of a nonspecific clinical picture of hypothyroidism, enable an early diagnosis and timely treatment, which emphasizes the importance of doctors’ awareness of this syndrome.

Problems of Endocrinology. 2017;63(2):121-123
De la Chapelle syndrome: clinical and laboratory characteristics of 4 patients
Sannikova E.S., Latyshev O.Y., Samsonova L.N., Kiseleva E.V., Okminyan G.F., Kasatkina E.P.

We describe 4 cases of 46,XX testicular disorder of sex development. Depending on the presence of the SRY gene, two variants of this disease are distinguished: SRY-positive and SRY-negative ones. The SRY (sex-determining region Y) gene is involved in differentiation of Sertoli cells and development of the testes. The pathogenesis of the disease in SRY-positive patients is related to translocation of the SRY gene from the Y chromosome to the X chromosome. The pathogenesis of the disease in SRY-negative patients is associated with overexpression of genes (SOX9, SOX3, etc.) responsible for the development of male genitalia or inadequate gene expression (WNT4, RSPO1, etc.) responsible for the development of female genitalia. The patients had a hermaphroditic genital structure with a masculinization score (EMS) of 6 and 11 and were SRY-negative in 50% of cases; 50% of the patients were SRY-positive with full masculinization, microorchidism, and gynecomastia. All children underwent a hormonal examination in the neutral and pubertal periods. Patients who reached pubertal age developed partial and total hypergonadotropic hypogonadism. The patients have had no need in substitution therapy with testosterone. One of the patients underwent a semiological analysis that revealed necrozoospermia and oligoasthenoteratozoospermia. A SRY-negative patient with cryptorchidism underwent biopsy of the cryptorchid gonad; no Leydig cells were found.

Problems of Endocrinology. 2017;63(2):124-126
HCG-secreting hepatoblastoma
Koroleva D.N., Olina T.S., Kovalenko T.V.

We describe a case of precocious sexual development in a 4-year-old boy, which was caused by HCG-secreting hepatoblastoma. The precocious sexual development manifested two months after starting polychemotherapy for hepatoblastoma, which presented as the emergence and rapid progression of pubic hair, low voice, and acceleration of the growth rate and bone age. The size of the testicles remained at the prepubertal level. We, together with oncologists, developed a therapeutic tactics: surgical removal of the tumor after the fourth course of polychemotherapy. Antiandrogenic drugs were not used because of their hepatotoxicity and inefficacy in this clinical situation.

Problems of Endocrinology. 2017;63(2):127-129
Combination of lipoatrophic diabetes mellitus with systemic scleroderma and phenylketonuria
Svetlova G.N., Kuraeva T.L., Alekseev D.L., Peterkova V.A.

We present the first report of a rare form of lipoatrophic diabetes mellitus in a child with partial autoimmune lipodystrophy combined with systemic scleroderma and phenylketonuria. We describe the features of clinical manifestations, diagnosis, and therapy. To exclude the monogenic form of lipodystrophy, we performed a molecular genetic analysis of genes ZMPSTE24, LMNA, BSCL2, PLIN1, PTRF, LMNB2, POLD1, AKT2, CIDEC, PIK3CA, PPARG, PSMB8, CAV1, PPP1R3A, and AGPAT2 that are responsible for the development of lipodystrophy and insulin resistance. No mutations were found. The presence of systemic scleroderma of autoimmune genesis enabled the diagnosis of autoimmune lipodystrophy. Treatment of insulin-resistant diabetes mellitus in lipodystrophy is a challenge: biguanide therapy is dangerous due to impairment of liver functions, and insulin therapy is not effective enough; administration of high doses is required. The presence of phenylketonuria further complicates compliance with the dietary regimen. The combination of three rare diseases ― lipoatrophic diabetes, phenylketonuria, and systemic scleroderma ― in one patient has not been found in the available literature.

Problems of Endocrinology. 2017;63(2):130-133
Long-term follow-up of a child with Rabson—Mendenhall syndrome
Atanesyan R.A., Klimov L.Y., Vdovina T.M., Uglova T.A., Stoyan M.V., Kuryaninova V.A., Alaverdyan L.S., Krasilnikova E.E., Arakelyan R.I.

A case of Rabson—Mendenhall syndrome in a boy is described. Rabson—Mendenhall syndrome is an extremely rare form of insulin resistance and is characterized by a severe course. To date, less than 50 cases of the syndrome have been reported around the world. Its prevalence is unknown because cases ending in death at early age often remain undiagnosed. The most pathognomonic features include acanthosis nigricans and hyperkeratosis of the skin in the area of natural folds, which reflect insulin resistance. Diabetes mellitus in children with Rabson—Mendenhall syndrome develops in childhood and has a labile course, which is manifested by frequent ketoacidosis episodes. Severe insulin resistance in patients with Rabson—Mendenhall syndrome prevents compensation of diabetes mellitus. Chronic glucosotoxicity in these children leads to progression of diabetic complications and to early disability. The literature reports single cases of long-term follow-up of patients with Rabson—Mendenhall syndrome.

Problems of Endocrinology. 2017;63(2):134-138
Glycogenosis type IX in a 9-year-old child
Bolotova N.V., Averyanov A.P., Filina N.Y., Zaharova E.Y., Melikyan M.A., Velikotskaya O.A., Strokova T.V., Paltseva Y.V.

Since the age of 1 year, a child presented with hypoglycemic conditions accompanied by ketosis as well as periodic hyperglycemia, for which reason he was hospitalized to the Pediatric Endocrinology Department of the Mirotvortsev Saratov Clinical Hospital. At the hospital, the child underwent a comprehensive examination that excluded diseases such as hyperinsulinism and diabetes mellitus. In the Laboratory of Hereditary Diseases of Metabolism of the Medical Genetics Research Center, a hemizygotic mutation in the PHKA2 gene (glycogenosis type IX) was detected. The mother was also detected with the heterozygous mutation c.226G>A (p.E76K in the PHKA2 gene). Based on the results of the genetic examination of the child and mother, the patient was finally diagnosed with glycogenosis type IX. The patient was put on an individualized protein diet avoiding edible sugar and fatty foods; corn starch (30 g every 6 h and overnight) was recommended. Strict adherence to the diet resulted in less frequent seizures and decreased severity of episodes.

Problems of Endocrinology. 2017;63(2):139-142

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