[Clinical, hormonal and molecular genetic characteristics of patients with 46,XY disorders of sex development associated with variants in the gene].

Background: Deficiency of 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is a rare variant of 46,XY disorders of sex development (DSD).

Aim: To give clinical, hormonal and molecular genetic characteristics of cases of 46,XY DSD associated with variants in the HSD17B3 gene.

Materials And Methods: The study included 310 patients with 46,XY DSD for the period from 2015 to 2019.

Out-of-frame translation rescues a loss-of-function variant in a novel TBCE phenotype.

Context: Pathogenic variants in the TBCE gene, encoding tubulin-specific chaperone E crucial for tubulin folding, are linked to three severe neurodevelopmental disorders: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, Kenny-Caffey syndrome type 1, and progressive encephalopathy with amyotrophy and optic atrophy.

Objective: We identified patients with a novel, milder TBCE-associated phenotype and aimed to characterize it at the clinical and molecular levels.

Materials And Methods: We conducted splicing analysis using deep NGS sequencing of RT-PCR products and detected TBCE through Western blotting.

Combination approach for -related parathyroid carcinoma in an adolescent female patient: a case report and literature review.

Parathyroid carcinoma (PC) is extremely rare in children and adolescent. PC is more often sporadic, but also it could be associated with germline mutations. The clinical features of primary hyperparathyroidism (PHPT) are nonspecific in children and adolescent, which delays the diagnosis for years.

[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.

[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.

High carrier frequency of a nonsense p.Trp230* variant in gene in Ossetians.

Background: Congenital adrenal hyperplasia (CAH) caused by 3β-HSD deficiency is a rare form of congenital adrenal deficiency with an autosomal recessive type of inheritance. Previously we have demonstrated that a single nucleotide variant (SNV) p.Trp230* in the homozygous state is a frequent cause of CAH among the indigenous population of North Ossetia-Alania represented by Ossetians.

A Founder Mutation in the POMC 5'-UTR Causes Proopiomelanocortin Deficiency Through Splicing-Mediated Decrease of mRNA.

Context: The syndrome of adrenal insufficiency, obesity, and red hair is a rare autosomal recessive disorder. The majority of disease-causing variants associated with the syndrome are located in the coding region of the POMC gene.

Objective: This work describes 7 unrelated patients who shared a novel homozygous mutation in the 5'-untranslated region (UTR) of the POMC gene and functionally characterize this novel variant.

[Erratum: clinical and molecular characteristics of patients with 46,xy dsd due to nr5a1 gene mutations (Probl Endokrinol (Mosk). 2020 Sep 16;66(3):62-69. Russian. doi: 10.14341/probl12445)].

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".

[Clinical guidelines «Precocious puberty»].

The precocious puberty is an urgent problem of pediatric endocrinology characterized by clinical and pathogenetic heterogeneity. The appearance of secondary sex characteristics before the age of 8 years in girls and 9 years in boys requires timely diagnosis and the appointment of pathogenetically justified treatment in order to achieve the target indicators of final growth and prevent social deprivation. The developed clinical guidelines are the main working tool of the practitioner.

[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.

[Clinical Findings in Two patients with DSD 46XY caused by new variant of the 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.

[Familial case of hypogonadotropic hypogonadism as the CHARGE syndrome manifestation].

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.

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

[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.

[Klinefelter syndrome: literature review on using modern methods of assisted reproductive technologies].

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.

[Dizygotic pregnancy as a possible mechanism of fetal gestation with a biallel mutation in the CYP11A1 gene: clinical case description].

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.

[A clinical case of aromatase excess syndrome associated with 15Q21.2 duplication].

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.

[Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations].

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.

[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.

[Early correction of hypospadias in girl with a disorder of sex development. clinical case].

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.

A Novel Mutation in the Critical P-Box Residue of Steroidogenic Factor-1 Presenting with XY Sex Reversal and Transient Adrenal Failure.

Background: Although the importance of steroidogenic factor-1 (SF1, NR5A1) for adrenal development is supported by numerous in vitro and in vivo studies, cases of SF1 deficiency associated with adrenal failure are exceptionally rare. The first human NR5A1 mutation was a heterozygous de novo p.G35E variant identified in a patient with disorder of sex development (DSD) 46,XY and primary adrenal insufficiency.

Partial deficiency of 17α-hydroxylase/17,20-lyase caused by a novel missense mutation in the canonical cytochrome heme-interacting motif.

Background: Deficiency of 17α-hydroxylase/17,20-lyase is a rare cause of 46,XY disordered sex development.

Objective: We characterize in vitro and in vivo effects of two novel CYP17A1 gene mutations identified in a patient with a mild phenotype of CYP17A1 deficiency.

Subjects And Methods: A 46,XY patient presented with ambiguous genitalia.

[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.