Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Neonatal presentation of growth hormone deficiency in CHARGE syndrome: the benefit of early treatment on long-term growth

SUMMARY CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene. Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency. GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained. We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life. Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up. This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.

Permanent neonatal diabetes by a new mutation in KCNJ11: unsuccessful switch to sulfonylurea

Permanent neonatal diabetes (PNDM) can result from activating heterozygous mutations in KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channels (KATP). Sulfonylureas promote KATP closure and stimulate insulin secretion, being an alternative therapy in PNDM, instead of insulin. Male, 20 years old, diagnosed with diabetes at 3 months of age. The genetic study identified a novel heterozygous mutation in exon 1 of the KCNJ11 gene – KCNJ11:c1001G>7 (p.Gly334Val) – and confirmed the diagnosis of PNDM. Therefore it was attempted to switch from insulin therapy to sulfonylurea. During glibenclamide institution C-peptide levels increased, however the suboptimal glycemic control lead us to restart an intensive insulin scheme. This new variant of KCNJ11 mutation had a phenotypic lack of response to sulfonylurea therapy. Age, prior poor metabolic control and functional change of KATP channel induced by this specific mutation may explain the observed unsuccessful switch to sulfonylurea. Interestingly, C-peptide levels raise during glibenclamide administration support some degree of improvement in insulin secretory capacity induced by the treatment. Understanding the response to sulfonylurea is crucial as successful treatment may be life-changing in these patients.

Clinicopathological features of 45, X/46, Xidic(Y) mosaicism and therapeutic implications: case report / Características clínicopatológicas dos mosaicos 45, X/46, Xidic(Y) e implicações terapêuticas: caso clínico

CONTEXT: 45,X/46,Xidic(Y) mosaicism demands careful and thorough study because of both its variable clinical features and its potential complications. CASE REPORT: The present case relates to a three-year-old girl with the mosaic karyotype 46,X,idic(Y)(q11.2)[23]/45,X[6]. She had no signs of virilization or Turner's syndrome phenotype, but she was referred to our hospital because she presented reduced growth rate, abnormal facies and a melanotic nevus. After examination, she underwent prophylactic gonadectomy because of the risk of gonadoblastoma. Cytogenetic analysis on the streak gonads and blood showed significant differences in the 45,X cell line between these two tissues. The presence of the sex-determining region Y (SRY) gene did not determine male differentiation, which meant in the present case that the predominance of the X cell line in the gonadal tissue was probably due to the determining factor for female sexual differentiation.

CONTEXTO: O mosaicismo 45,X/46,Xidic(Y) é uma anomalia genética que exige um estudo minucioso pelas suas variadas formas clínicas e suas potenciais complicações. RELATO DE CASO: O presente caso clínico refere-se a uma menina de três anos de idade com cariótipo de linfócitos 46,Xidic(Y)(q11.2)[23]/45,X[6], sem sinais de virilização ou estigmas Turner à excepção de má evolução estaturo-ponderal, fácies peculiar e nevo melânico. Estudada, foi submetida a gonadectomia profiláctica por risco de gonadoblastoma. As bandas gonádicas e sangue periférico foram analisados com evidência de uma diferença acentuada no predomínio de linhagem 45,X nos dois tecidos. A presença do gene SRY não se mostrou determinante no sentido da diferenciação masculina pelo que, neste caso, o predomínio da linhagem X no tecido gonadal parece ter sido o fator determinante no sentido da diferenciação sexual feminina.