Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.

Purpose: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT).

Methods: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven.

Results: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel.

So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity.

Background: The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene.

Investigation of polymorphisms in pre-eclampsia related genes VEGF and IL1A.

Introduction: Pre-eclampsia (PE) is a pregnancy-specific multisystemic syndrome characterized by high blood pressure and presence of protein in the urine. The pathogenesis of pre-eclampsia is poorly understood and many factors such as environment, genetic, and immunology may be involved in PE pathophysiology. Among the genetic factors, there is an association between pre-eclampsia and polymorphisms in some genes of different population samples, as vascular endothelial growth factor and interleukin 1 alpha.

The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency.

Background: Disorders of sex development (DSD) is the term used for congenital conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical. Nuclear receptor subfamily 5, group A, member 1 gene (NR5A1) encodes steroidogenic factor 1 (SF1), a transcription factor that is involved in gonadal development and regulates adrenal steroidogenesis. Mutations in the NR5A1 gene may lead to different 46,XX or 46,XY DSD phenotypes with or without adrenal failure.

New mutation in the myocilin gene segregates with juvenile-onset open-angle glaucoma in a Brazilian family.

Mutations in the myocilin gene (MYOC) account for most cases of autosomal dominant juvenile-onset open-angle glaucoma (JOAG), an earlier and more severe form of POAG. We accessed seven members of a Brazilian JOAG family by clinical and molecular investigation. Four out of seven family members were diagnosed with JOAG.

Frasier syndrome: four new cases with unusual presentations.

Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma.

Molecular diagnosis of 5α-reductase type II deficiency in Brazilian siblings with 46,XY disorder of sex development.

The steroid 5α-reductase type II enzyme catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT), and its deficiency leads to undervirilization in 46,XY individuals, due to an impairment of this conversion in genital tissues. Molecular analysis in the steroid 5α-reductase type II gene (SRD5A2) was performed in two 46,XY female siblings. SRD5A2 gene sequencing revealed that the patients were homozygous for p.

Structural aspects of the p.P222Q homozygous mutation of HSD3B2 gene in a patient with congenital adrenal hyperplasia.

Type II 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4)-isomerase (3β-HSD2), encoded by the HSD3B2 gene, is a key enzyme involved in the biosynthesis of all the classes of steroid hormones. Deleterious mutations in the HSD3B2 gene cause the classical deficiency of 3β-HSD2, which is a rare autosomal recessive disease that leads to congenital adrenal hyperplasia (CAH). CAH is the most frequent cause of ambiguous genitalia and adrenal insufficiency in newborn infants with variable degrees of salt losing.

Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma.

Phenotypic variability in a family with x-linked adrenoleukodystrophy caused by the p.Trp132Ter mutation.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease with clinical heterogeneity varying from presymptomatic individuals to rapidly progressive cerebral ALD forms. This disease is characterized by increased concentration of very long chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues. Affected individuals can be classified in different clinical settings, according to phenotypic expression and age at onset of initial symptoms.

The novel WT1 gene mutation p.H377N associated to Denys-Drash syndrome.

Denys-Drash syndrome (DDS, Online Mendelian Inheritance in Man number 194080) is a rare human developmental disease generally occurring in 46,XY individuals characterized by the combination of disorder of sex development, early onset nephropathy, and Wilms' tumor (WT). DDS is mainly caused by mutations in the WT1 gene. This report describes a novel WT1 gene mutation in a DDS patient.

Heterozygosis for CYP21A2 mutation considered as 21-hydroxylase deficiency in neonatal screening.

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90% of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.

Mutations in the vitamin D receptor gene in four patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Mutations in the vitamin D receptor (VDR) are associated to the hereditary 1,25-dihydroxivitamin D-resistant rickets. The objectives of this work are: search for mutations in the VDR and analyze their functional consequences in four Brazilian children presented with rickets and alopecia. The coding region of the VDR was amplified by PCR e direct sequenced.

Clinical and genetic findings of five patients with WT1-related disorders.

Aim: To present phenotypic variability of WT1-related disorders.

Methods: Description of clinical and genetic features of five 46,XY patients with WT1 anomalies.

Results: Patient 1: newborn with genital ambiguity; he developed Wilms tumor (WT) and chronic renal disease and died at the age of 10 months; the heterozygous 1186G>A mutation compatible with Denys-Drash syndrome was detected in this child.

Absence of mutations in Pax6 gene in three cases of morning glory syndrome associated with isolated growth hormone deficiency.

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system.