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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-reaction» 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.

Background:  Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) with upper-normal or elevated blood calcium levels due to primary thyroid gland pathology. PHPT is a rare pathology in children, with a prevalence of 2-5:100,000 children according to the literature. Due to the non-specificity of clinical manifestations at onset (nausea, vomiting, abdominal pain, emotional lability), the disease may remain undiagnosed for a long time., Aim:  To study the features of the course and molecular genetic basis of primary hyperparathyroidism in children., Materials and Methods:  Retrospective observational study of 49 patients diagnosed with primary hyperparathyroidism. All patients underwent a comprehensive laboratory-instrumental and molecular genetic study at the Institute of Pediatric Endocrinology, Endocrinology Research Center of Russia in the period 2014-2022., Results:  The first clinical symptoms of PHPT were noted at the age of 13.8 years [10.6; 1 5.2], among which fatigue, headaches, dyspepsia, lower limb pain, and fractures were the most common. The age of diagnosis was 15.81 years [13.1; 16.8], all children were found to have high levels of PTH, total and ionized calcium, with hypophosphatemia in 93.9% of patients (n=46) and hypercalciuria in 43% (n=21). Five out of 49 patients (10.2%) were found to have ectopy of the thyroid: 3 showed an intrathyroidal location, 2 in the mediastinal region. Molecular genetic study revealed mutations in 32.7% of patients (n=16, CI (21; 47)), mutations in MEN1 being the most frequent (n=11). Pathogenic variants in CDC73 were detected in 3 patients, RET - in 2. Among the operated 39 patients, adenoma of the thyroid was detected in 84.6% of cases (n=33), hyperplasia in 7.7% (n=3), atypical adenoma in 5.1% (n=2), carcinoma in 5.1% of cases (n=2)., Conclusion:  The paper presents the peculiarities of the course and the results of molecular genetic study of pediatric PHPT. This sample is the largest among those published in the Russian Federation.

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.

n the article some corrections were needed. Abstract: "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described". has been corrected to read "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described". Results: "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described", has been corrected to read "Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described". Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1  synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame - p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors.

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.

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.

CHARGE syndrome is a rare autosomal dominant disease caused by CHD7 gene mutations. Individuals with CHARGE display a wide spectrum of clinical features. It might be presented only as a delay puberty, which does not require any hormone replacement therapy to severe CHARGE phenotype, requiring a multidisciplinary therapeutic approach. Wild spectrum of clinical presentation can be seen even among the patients with identical mutation. Diagnosis might be suspected by a combination of major and minor clinical criteria of this disorder, but molecular genetic analysis is mandatory for final verification. Accurate diagnosis is essential to informing patients about all possible clinical features, reproductive status and choosing the correct treatment approach. The most common endocrine abnormality in patients with CHARGE syndrome is the disturbance in gonadotropins function ranged from delay puberty to persistent hypogonadotropic hypogonadism with different olfactory phenotypes, resulted by specific role of CHD7 in GnRH neuronal embryogenesis.We describe a familial case of CHARGE syndrome with significant intrafamilial clinical heterogeneity due to CHD7 gene mutation.

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.

The article reviews scientific papers devoted to the problem of reproductive health in men with Klinefelter syndrome (KS). Pathogenesis from a very early age (in utero), the possibility of ensuring biological paternity upon reaching sexual maturity and the risk of chromosomal abnormalities in offspring are discussed. Despite the fact that KS is one of the most common causes of male infertility associated with chromosomal abnormalities, due to the variability of clinical manifestations the proportion of patients identified before puberty did not exceed 10% before the widespread introduction of non-invasive prenatal testing. According to the research results presented in the article, the reproductive potential of males with KS is often already reduced in early childhood. These circumstances should be considered when choosing further patient management tactics.There are few reports on the onset of spontaneous pregnancy in the case of KS, so ensuring biological paternity in this group of patients is often possible only using surgical methods of sperm extraction and assisted reproductive technologies. This article discusses methods like testicular sperm extraction (TESE) and microdissection testicular sperm extraction (mTESE) in terms of their effectiveness and safety for the patient, and the factors influencing the outcome of the operation. The optimal period of these manipulations seems to be the patient's age from 18 to 30 years, although the feasibility of adolescent boys undergoing the aforementioned procedures is highly controversial.The research papers presented in the article suggest that the risk of transmitting chromosomal abnormalities to offspring is rather low, which does not exclude the need for medical and genetic counseling to explain all possible risks to the patient. Preimplantation or intrauterine diagnostics are also deemed necessary.

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.

One of the variants of congenital dysfunction of the adrenal cortex is a deficiency of the enzyme P450scc, which catalyzes the first stage of steroidogenesis. This is a rare autosomal recessive disease, the classic manifestation of which is primary adrenal insufficiency with a deficiency of gluco-and mineralocorticoids and a violation of the synthesis of sex steroids, which usually leads to a complete lack of masculinization in patients with karyotype 46, XY and hypergonadotropic hypogonadism in both sexes. Previously, it was suggested That p450scc deficiency is incompatible with the normal course of pregnancy, since the enzyme is expressed in the placenta, where it is necessary for the synthesis of progesterone, the main pregnancy hormone, and, consequently, the birth of a child with A p450scc deficiency is impossible. However, the literature describes clinical cases of p450scc deficiency with partially preserved enzyme function, which explains the normal course of pregnancy. Whereas cases of confirmed p450scc deficiency with zero enzyme activity are unique, not being explained until now. We present a description of severe p450scc deficiency in a child born from a dizygotic twin pregnancy in which the second Sib was healthy. It is possible that the preserved hormonal function of the second placenta and (or) treatment with progesterone analogs during gestation contributed to gestation in this rare form of steroidogenesis disorder.

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.

Aromatase excess syndrome (SIA) is a rare autosomal dominant disease caused by increased extraglandular conversion of androgens to estrogens. SIA is characterizedby early gonadotropin-independent hyperestrogenemia, causing pre-pubertal gynecomastia in boys and premature isosexual development in girls. Adults patients have short stature, due to the early closure of epiphyses because of hyperestrogenemia. Women usually have macromastia, endometrial hyperplastic processes and the late onset of menopause. In men, there is a moderate decrease of gonadotropins, leading to secondary hypogonadism. SIA in children can be suspected on a combination of the clinical picture of an excess of estrogens, increased levels of estrogens with low levels of gonadotropins after the exclusion of an estrogen-producing tumor. The frequency of occurrence of SIA is unknown, due to the rarity of the disease and the complexity of its molecular and genetic verification. In this article, we describe a clinical case of a 10-year-old patient with a late diagnosis of aromatase overactivity syndrome caused by a 15q21.2 microduplication of the CYP19A1 gene, and conduct a brief review of the literature.

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.

The presented clinical case of a girl with a salt-wasting form of congenital adrenal hyperplasia in combination with chronic recurrent infection and lower urinary tract dysfunction demonstrates the need to change conventional two-staged approach to surgical feminization in favor of a one-stage intervention in order to prevent a progression of genitourinary complications. After controlling for the underlying condition, the one-stage feminization was performed, including modified tightening introitoplasty using a Passerini-Glazel flap and a correction of hypertrophic clitoris and labia minora. Good short- and long-term results were achieved.

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.