[A promising approach for therapy control in congenital adrenal hyperplasia. Problems of Endocrinology].

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders requiring lifelong glucocorticoid replacement (GC) therapy. Lack of GC therapy leads to precocious puberty in boys, heterosexual development in girls, accelerated bone maturation and short final height in both sexes. In adolescence, the lack of GC therapy is the cause of menstrual disorders in girls and the development of TART in boys, as a result reducing the reproductive potential in both sexes. On the other hand, an overdose of GC leads to drug-induced Itsenko-Cushing's syndrome. In order to select adequate doses of GC in childhood and adolescence, multiple determinations of 17-hydroxyprogesterone, androstenedione, and testosterone in blood plasma, and thus multiple venous blood sampling are required. The blood sampling requires specially trained medical staff and can effect on the results due to stress reaction especially in young patients. Hence, the development and implementation of a non-invasive method for determining the steroid profile is extremely important in monitoring GC therapy in children. In addition, the currently used immunofluorescence assay cannot determine other adrenal steroids, has a high variation due to the «cross-reaction¼ of steroids that are similar in structure, which inflates the results. Unlike immunofluorescence assay, liquid chromatography and tandem mass spectrometry is more preferable method, since it is more specific and accurate. In this literature review, saliva presented as an alternative substrate and the non-invasive method for determining the steroid profile. This method can solve the above disadvantages, simplify and make more accurate the selection of GC therapy in patients with CAH, which is especially important in childhood.

[Intestinal ganglioneuromatosis as an early extra-endocrine manifestation of type 2B multiple endocrine neoplasia].

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare variant of hereditary tumor syndromes caused by germinal mutations in the proto-oncogene RET. One of the components of the syndrome is multiple neurinomas, the early detection of  which is not always given due attention. We present a description of the case of MEN 2B, manifested in the first months of life by intestinal ganglioneuromatosis. The disease presented with chronic constipation, including episodes of intestinal obstruction that required repeated surgical interventions. MEN 2B was suspected at the age of 15. At the time of diagnosis, an increase in serum calcitonin levels was noted (1041 pg/ml, norm <9.5 pg/ml), and a node in the thyroid gland was also determined (1,3*1,0*1,2 see, TIRADS 5), subsequently verified as a neoplasm of C-cells. By DNA analysis, a pathogenic variant p.Met918Thr, typical for MEN2 B, was detected in the RET gene. No signs of pheochromocytoma were found at the time of investigation. The patient underwent a thyroidectomy with lymphadenectomy. The difficulties of early diagnosis of sporadic cases of MEN 2B due to the nonspecificity of gastrointestinal manifestations of the disease are discussed.

[A deep intronic mutation in AR gene causing androgen insensitivity syndrome: difficulties of diagnostics].

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450-42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

[Clinical and molecular genetic features of cases of isolated hypogonadotropic hypogonadism, associated with defects in GNRHR genes].

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Clinically, there are variants of CHH with hypo-/anosmia (Kalman syndrome) and normosmic hypogonadotropic hypogonadism. Given a  growing list of gene mutations accounting for CHH, the application of next generation sequencing (NGS) comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. Biallelic mutations in GNRHR gene lead to the development of hypogonadotropic hypogonadism with normosmia. In this paper, we describe 16 patients with proven GnRH resistance and estimate the frequency of pathogenic variants in the GNRHR gene in the Russian population.

[Clinical Findings in Two patients with DSD 46XY caused by new variant of the Desert Hedgehog Gene and review of the literature of the role of DHH signaling pathway in sex development].

Mutations in the gene DHH are an extremely rare cause of disorders of sex development 46,XY (DSD,46XY). The article describes the clinical cases of two unrelated patients with gonadal dysgenesis 46,XY with female phenotype. By using a next generation sequencing method, in both cases the same biallelic variant substitution c. 419T>G in the DHH gene was revealed. Taking into account the data on the role of DHH in the formation of the nervous system, the diagnosis of minifascicular polyneuropathy at the preclinical stage was confirmed in both cases. These cases demonstrate the value of using NGS, which allows simultaneous analysis of a wide range of candidate genes in DSD and the diagnosis of comorbidities before the development of the clinical picture. These are the first descriptions of patients with mutations in the DHH gene in the Russian population.

[Gonadal dysgenesis 46,XY DSD associated with variants in the MAP3K1 gene].

Disorders of sex development (DSDs) are congenital conditions in which phenotype does not correspond to chromosomal and gonadal sex. To date, the etiology of DSD is established only in half of the cases. With the development of modern methods of molecular genetic diagnostics in the last decade, a number of new regulators of gonad differentiation have been discovered, whose expression disorders can lead to DSD. Among these factors, Mitogen-activated triple protein kinase 1 (MAP3K1). A distinctive feature of studying the detected variants in the MAP3K1 gene that they lead to activation of MAP3K1. It does not allow using generally accepted pathogenicity assessment algorithms. However, the frequency of detection of changes in MAP3K1 is up to 18% of all cases of DSD, according to literature, which emphasizes the importance of studying each identified case, establishing the relationship of the disease with the identified genetic disorders. In this article, we present a clinical, hormonal, and molecular genetic description of 7 cases of DSD associated with variants in MAP3K1, an analysis of the significance of our own data, and a short analysis of the current scientific literature on this issue.

[Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome].

Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

[Molecular genetic verification of isolated mineralocorticoid deficiency due to aldosterone synthase deficiency].

Isolated mineralocorticoid deficiency is a rare hereditary autosomal recessive disorder that is characterized by salt wasting and that has the severest manifestations in infants. This paper is the first in the Russian literature to describe cases of isolated aldosterone deficiency. In both cases, the patients were monitored and treated for misdiagnosed congenital adrenal hyperplasia; however, the permanently low level of 17-hydroxyprogesterone could put in doubt the diagnosis and suspect isolated mineralocorticoid deficiency, by keeping in mind a history of salt wasting. By using the presented cases as an example, the authors give an algorithm for the examination and differential diagnosis of this condition and other diseases that have the similar clinical picture. Aldosterone synthase deficiency in patients was verified by molecular genetic studies - there were mutations in the CYP112 gene.