The novel p.Cys65Tyr mutation in NR5A1gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency

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. We report a Brazilian family with a novel NR5A1 mutation causing ambiguous genitalia in 46,XY affected individuals without Müllerian derivatives and apparently normal Leydig function after birth and at puberty, respectively. Their mother, who is also heterozygous for the mutation, presents evidence of primary ovarian insufficiency. Three siblings with 46,XY DSD, ambiguous genitalia and normal testosterone production were included in the study. Molecular analyses for AR, SRD5A2 genes did not reveal any mutation. However, NR5A2 sequence analysis indicated that all three siblings were heterozygous for the p.Cys65Tyr mutation which was inherited from their mother. In silico analysis was carried out to elucidate the role of the amino acid change on the protein function. After the mutation was identified, all sibs and the mother had been reevaluated. Basal hormone concentrations were normal except that ACTH levels were slightly elevated. After 1 mcg ACTH stimulation test, only the older sib showed subnormal cortisol response. The p.Cys65Tyr mutation located within the second zinc finger of DNA binding domain was considered deleterious upon analysis with predictive algorithms. The identification of heterozygous individuals with this novel mutation may bring additional knowledge on structural modifications that may influence NR5A1 DNA-binding ability, and may also contribute to genotype-phenotype correlations in DSD. The slightly elevated ACTH basal levels in all three patients with 46,XY DSD and the subnormal cortisol response after 1 mcg ACTH stimulation in the older sib indicate that a long-term follow-up for adrenal function is important for these patients. Our data reinforce that NR5A1 analysis must also be performed in 46,XY DSD patients with normal testosterone levels without AR mutations.15

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. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.54754-6

Mutations At The Sf-1 Ligand-binding Domain Can Lead To Different Effects On Dna Binding: Report Of Two Novel Mutations

86126326

Papel multifuncional do fator esteroidogênico 1 e as doenças do desenvolvimento sexual

Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1. Arq Bras Endocrinol Metab. 2011;55(8):607-12Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Estadual Campinas, CBMEG, BR-13083875 Campinas, SP, BrazilUniv Estadual Campinas, Fac Ciencias Med, Dept Med Genet, Campinas, SP, BrazilUniv Estadual Campinas, Fac Ciencias Med, Dept Pediat, Campinas, SP, BrazilWeb of Scienc

Multifunctional Role Of Steroidogenic Factor 1 And Disorders Of Sex Development.

Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1.55607-1

Mutations at the SF-1 ligand-binding domain can lead to different effects on DNA binding: report of two novel mutations

sem informação86126326455th Annual Meeting of the European Society for Paediatric Endocrinolog

Perfusion patterns in migraine with aura

Background/Aims. Studies on 46,XY partial gonadal dysgenesis (PGD) have focused on molecular, gonadal, genital, and hormone features; little is known about follow-up. Our aim was to analyze long-term outcomes of PGD. Methods. Retrospective longitudinal study conducted at a reference service in Brazil. Ten patients were first evaluated in the 1990s and followed up until the 2010s; follow-up ranged from 13.5 to 19.7 years. All were reared as males and had at least one scrotal testis; two bore NR5A1 mutations. Main outcomes were: associated conditions, pubertal development, and growth. Results. All patients had normal motor development but three presented cognitive impairment; five had various associated conditions. At the end of the prepubertal period, FSH was high or high-normal in 3/6 patients; LH was normal in all. At the last evaluation, FSH was high or high-normal in 8/10; LH was high or high-normal in 5/10; testosterone was decreased in one. Final height in nine cases ranged from −1.57 to 0.80 SDS. All had spontaneous puberty; only one needed androgen therapy. Conclusions. There is good prognosis for growth and spontaneous pubertal development but not for fertility. Though additional studies are required, screening for learning disabilities is advisable

Partial and mixed gonadal dysgenesis cannot be distinguished by histological picture: clinical evaluation, histological differences and long-term follow up of 61 Brazilian patients

Differential diagnosis between XY partial (PGD) and mixed gonadal dysgenesis (MGD) was initially established by histological evaluation; however, when there is a 45,X lineage there are differences not only in clinical aspects but also in prognosis. Objective and hypotheses: The aim of this work was to analyze clinical picture of patients with genital ambiguity due to testicular dysgenesis, with and without a 45,X lineage, and compare these conditions in terms of phenotype and prognosis. Method: All patients with a diagnosis of testicular dysgenesis who were seen in our service between 1989 and 2013 were selected. Patients were divided in two groups (with and without a 45,X cell line), which were compared in regard to gonadal histology, anatomy of external and internal genitalia, gonadal hormone function; growth, puberty and fertility prognosis. Our sample included 61 patients, 25 with mosaicism (MGD) and 36 with an homogenous 46,XY karyotype (PGD). Results: There were no differences between the groups in terms of age at the first visit, gestational and family history, degree of external virilization, position and histology of gonads, gonadal hormone function, spontaneous pubertal development and need for hormonal replacement, presence of associated conditions and fertility prognosis. There were significant difference regarding sex of rearing (more often female in MGD); presence of uterus (more common in MGD); higher maternal age (in PGD); lower birth weight and length (in MGD) and short stature (more frequent in MGD). Conclusion: PGD and MGD were indistinguishable in terms of gonadal histology and function and genital features, except for the higher frequency of uterus in MGD. They did differ in terms of pre and post-natal growth; in this regard, patients with MGD require specific therapeutic measures. Therefore, the old classification based on histological findings should be abandoned in favor of that based on chromosome constitution, and screening for a 45,X lineage should be thorough in all patients with 46,XY testicular dysgenesis86126626

46,xy partial gonadal dysgenesis caused by an Xp21.2 interstitial duplication that does not encompass the NR0B1 gene

sem informação86125625655th Annual meeting of the European Society for Paediatric Endocrinolog