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.

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.

Introdução: Há evidência que adolescentes com a mesma idade cronológica mas com estádios pubertários distintos têm comportamentos psicossociais diferentes. Desconhece-se, no entanto, se existe alguma relação entre o ritmo de maturação pubertária e o desenvolvimento do córtex pré-frontal e sistema límbico. Objetivo: Pretendeu-se com este trabalho avaliar através de ressonância magnética, o desenvolvimento cerebral de adolescentes do sexo feminino com a mesma idade cronológica mas com distintos ritmos de maturação pubertária. Material e Métodos: Avaliaram-se parâmetros hormonais e imagiológicos (idade óssea, ultrassonografia pélvica e ressonância magnética cerebral estrutural) a adolescentes de sexo feminino de 14 anos de idade. Resultados: Foram incluídas no estudo quatro adolescentes maturadoras precoces (grupo 1) e três maturadoras médias (grupo 2), A idade de início da puberdade foi a única variável biológica que distinguiu os 2 grupos (p=0,05). Apesar de não se encontrar significado estatístico, verificou-se que as maturadoras precoces, apresentavam volumes de todas as estruturas subcorticais estudadas superiores às maturadoras médias, com exceção do núcleo accumbens. Conclusões: Com base na pesquisa bibliográfica efetuada, este estudo foi o primeiro a tentar relacionar os ritmos de maturação pubertária e o desenvolvimento cerebral através da ressonância magnética. A tendência observada para o aumento do volume das estruturas subcorticais poderá estar relacionado com um possível atraso na maturação do núcleo accumbens nas maturadoras precoces e poderá explicar o aumento da vulnerabilidade deste grupo para comportamentos de risco. Consideramos que poderá constituir o ponto de partida para investigações futuras, de forma a compreender melhor o desenvolvimento adolescente e assim permitir encontrar formas mais eficazes de intervenção.

Aim: There is evidence that adolescents with distinct rhythms of pubertal maturation have different psychosocial behaviours. However, a relation between pubertal maturation and the development of the prefrontal cortex and limbic system was not yet established. The aim of this study was to apply brain magnetic resonance imaging to investigate brain development of teenagers with similar age but distinct timing of pubertal maturation. Methods: We compared the hormonal profiles and brain structure and volume using magnetic resonance imaging of two groups of 14 year-old girls, four with an early pubertal development (group 1) and three with an average pubertal development (group 2). Results: The age at onset of puberty was the only biological variable that distinguished the two groups (p = 0,05). There were no differences regarding global brain volume. However, early-maturers showed a tendency for an increased volume of all subcortical structures except for nucleus accumbens. Conclusion: To our knowledge, this is the first work to address the relation of pubertal maturation timing and central nervous system development using brain magnetic resonance imaging. The observed tendency for an increased volume of the subcortical structures may be related to a possible delayed development of the nucleus accumbens in early-maturers, and may explain the increased vulnerability of this group to risk behaviours.

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.

O Pseudohipoaldosteronismo tipo I é uma síndrome rara de resistência aos mineralocorticoides caracterizada clinicamente, no período neonatal, por vómitos, desidratação e má evolução estaturo-ponderal. Os doentes apresentam hiponatremia, hipercalemia e acidose metabólica associado a níveis elevados de aldosterona e renina no plasma. O Pseudohipoaldosteronismo tipo I surge devido a mutações que desativam os genes do canal de sódio epitelial, constituindo a forma autossómica recessiva (sistémica). As mutações inativadoras no gene do recetor mineralocorticoide estão presentes na variante autossómica dominante (renal) e em casos esporádicos da doença. Existe ainda outra forma de Pseudohipoaldosteronismo tipo I secundário normalmente devido a malformações e/ou infeções do trato urinário. Este trabalho expõe a vasta heterogeneidade genómica e clínico-fenotípica dos diversos tipos da doença. Devido à raridade da doença, é normalmente necessária uma análise da correlação genótipo-fenótipo para um correto diagnóstico. Esta doença requer uma melhor compreensão dos seus aspetos fisiológicos e genéticos, não só para um aperfeiçoamento do tratamento bem para melhor compreensão da regulação hidroeletrolítica.

The type I Pseudohypoaldosteronism is a rare syndrome of mineralocorticoid resistance which is characterized clinically by vomiting, dehydration and failure to thrive throughout the neonatal period. Patients present hyponatremia, hyperkalemia and metabolic acidosis associated with high levels of aldosterone and renin in the plasma. The type I Pseudohypoaldosteronism is due to mutations that inactivate the genes coding for the epithelial sodium channel in the autosomal recessive (systemic) form and for the mineralocorticoid receptor gene in the autosomal dominant (renal) form and sporadic cases of the disease. There is another form of secondary type I Pseudohypoaldosteronism usually caused by malformations and / or urinary tract infections. This article presents a wide genomic and phenotypic heterogeneity in the several forms of the disease. Owing to the rarity of the disease, an analysis of genotype-phenotype correlation is usually required for a correct diagnosis. This disease requires a better understanding of its physiological and genetic aspects not only for the improvement of the treatment but also for a better understanding of the hydroelectrolytic regulation.

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.

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.