Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

BACKGROUND: DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. METHODS: We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. RESULTS: Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). CONCLUSIONS: We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.

Whole-exome sequencing: opportunities in pediatric endocrinology.

Pediatric endocrinology services see a wide variety of patients with diverse clinical symptoms, including disorders of growth, metabolism, bone and sexual development. Molecular diagnosis plays an important role in this branch of medicine. Traditional PCR-based Sanger sequencing is a mainstay format for molecular testing in pediatric cases despite its relatively high cost, but the large number of gene defects associated with the various endocrine disorders renders gene-by-gene testing increasingly unattractive. Using new high-throughput sequencing technologies, whole genomes, whole exomes or candidate-gene panels (targeted gene sequencing) can now be cost-effectively sequenced for endocrine patients. Based on our own recent experiences with exome sequencing in a research context, we describe the general clinical ascertainment of relevant pediatric endocrine patients, compare different formats for next-generation sequencing and provide examples. Our view is that protocols involving next-generation sequencing should now be considered as an appropriate component of routine clinical diagnosis for relevant patients.

Re-emergence of papulonodular napkin dermatitis with use of reusable diapers: report of 5 cases.

The use of reusable diapers, often made of cotton and bamboo material, is becoming more widespread in France--with the "eco" fashion, as they are considered more natural, ecologic and economic. We report 5 cases of papulonodular lesions in convex skin areas associated with the use of these diapers in infants. One case was typical Sevestre and Jacquet erosive dermatitis. The 4 others presented skin-coloured umbilicated papules or nodules with slight or no erythema and could be considered early-stage Sevestre and Jacquet erosive dermatitis, granuloma gluteale (1 case) or pseudo-verrucous papules. These 3 diagnoses probably belong to the same disease spectrum, proposed as "irritant napkin papulonodules". Napkin lesions occurred subsequent to 1) in all cases, use of reusable diapers, which are probably less absorbent than disposable diapers; 2) in 2 cases, insufficient food, which was responsible for lack of weight gain and delayed healing; and 3) in 1 case, diarrhea, which worsened the moisture. We alert physicians to possible papulonodular napkin dermatitis in infants wearing reusable diapers.

Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study.

BACKGROUND/AIMS: Magnetic resonance imaging (MRI) is used to investigate the etiology of growth hormone deficiency (GHD). This study examined relationships between MRI findings and clinical/hormonal phenotypes in children with GHD in the observational Genetics and Neuroendocrinology of Short Stature International Study, GeNeSIS. METHODS: Clinical presentation, hormonal status and first-year GH response were compared between patients with pituitary imaging abnormalities (n = 1,071), patients with mutations in genes involved in pituitary development/GH secretion (n = 120) and patients with idiopathic GHD (n = 7,039). RESULTS: Patients with hypothalamic-pituitary abnormalities had more severe phenotypes than patients with idiopathic GHD. Additional hormonal deficiencies were found in 35% of patients with structural abnormalities (thyroid-stimulating hormone > adrenocorticotropic hormone > luteinizing hormone/follicle-stimulating hormone > antidiuretic hormone), most frequently in patients with septo-optic dysplasia (SOD). Patients with the triad [ectopic posterior pituitary (EPP), pituitary aplasia/hypoplasia and stalk defects] had a more severe phenotype and better response to GH treatment than patients with isolated abnormalities. The sex ratio was approximately equal for patients with SOD, but there was a significantly higher proportion of males (approximately 70%) in the EPP, pituitary hypoplasia, stalk defects, and triad categories. CONCLUSION: This large, international database demonstrates the value of classification of GH-deficient patients by the presence and type of hypothalamic-pituitary imaging abnormalities. This information may assist family counseling and patient management.

Bioinactive ACTH causing glucocorticoid deficiency.

CONTEXT: A 4-year-old girl and a 4-month-old boy presented with hypoglycemia, normal electrolytes, low cortisol, and high ACTH. A diagnosis of primary adrenal insufficiency was made and initial treatment was with glucocorticoids and mineralocorticoids. The genes known to cause ACTH resistance were normal. Whole exome sequencing revealed that the girl was compound heterozygous for POMC mutations: one previously described null allele and one novel p.R8C mutation in the sequence encoding ACTH and α-MSH. The boy was homozygous for the p.R8C mutation. HYPOTHESIS: The p.R8C ACTH mutant is immunoreactive, but the mutant peptides, ACTH-R8C and α-MSH-R8C, are bioinactive. METHODS: Methods included whole exome sequencing, Sanger sequencing, peptide synthesis, ACTH immunoradiometric assay, hormone binding, and activation assays in cells expressing melanocortin receptors. RESULTS: ACTH-R8C was immunoreactive but failed to bind and activate cAMP production in melanocortin-2 receptor (MC2R)-expressing cells, and α-MSH-R8C failed to bind and stimulate cAMP production in MC1R- and MC4R-expressing cells. CONCLUSION: These are the first documented cases of glucocorticoid deficiency due to the secretion of an ACTH molecule that lacks biological bioactivity but conserves immunoreactivity. POMC mutations should thus be considered in patients presenting with apparent ACTH resistance. Our findings also highlight a limitation to immunoassay-based diagnostics and demonstrate the value of genetic analysis. Establishing the molecular etiology of the disorder in our patients allowed cessation of the unnecessary mineralocorticoids. Finally, discovery of this mutation indicates that in humans, the amino acid sequence His(6)Phe(7)Arg(8)Trp(9) is important not only for cAMP activation but also for ACTH binding to MC2R.

Detecção de calcificação de aorta abdominal por densitometria / Detection of abdominal aortic calcification by densitometry

OBJETIVO: Analisar a acurácia da detecção de calcificação da aorta abdominal por meio de densitometria em comparação com a radiografia lateral de coluna. MATERIAIS E MÉTODOS: Casuística de 80 indivíduos, sendo 50 com diagnóstico de calcificação de aorta abdominal e 30 sem calcificação. Densitometria realizada uma única vez em cada participante, com o paciente em decúbito lateral direito. RESULTADOS: Em relação à idade e ao índice de massa corporal tivemos grupos semelhantes, com idade média de 74,56 ± 10,55 anos e 68,40 ± 10,80 anos e índice de massa corporal de 28,94 ± 6,06 kg/m2 e 26,84 ± 4,11 kg/m2 nos grupos com calcificação de aorta abdominal e sem calcificação de aorta abdominal, respectivamente. A comparação estatística da densitometria com a radiografia mostra que são semelhantes na detecção da calcificação de aorta abdominal, com valores de 100% na especificidade e valor preditivo positivo; sensibilidade de 94%, valor preditivo negativo de 90,9% e acurácia de 96,3%. Equivalência qualitativa no diagnóstico foi demonstrada pelo índice de correlação de kappa de 0,922. CONCLUSÃO: Os resultados da radiografia e da densitometria são estatisticamente equivalentes, o que permite sugerir a investigação de calcificação de aorta abdominal pela densitometria para a detecção de calcificação da aorta abdominal.

OBJECTIVE: To evaluate the accuracy in the detection of abdominal aortic calcification by densitometry as compared with lateral spine radiography. MATERIALS AND METHODS: Study comprising 80 individuals, 50 of them with abdominal aortic calcification and 30 without calcification. Densitometry was performed once for each participant, with the patient in right lateral decubitus position. RESULTS: Both groups were similar in terms of age range and body mass index - mean age of 74.56 ± 10.55 years and 68.40 ± 10.80 years and mean body mass index of 28.94 ± 6.06 kg/m2, and 26.84 ± 4.11 kg/m2, respectively for the individuals with abdominal aortic calcification and for the individuals without calcification. A statistical comparison between densitometry and radiography demonstrates similar performances of the two methods in the detection of abdominal aortic calcification, with 100% specificity and positive predictive value, 94% sensitivity, 90.9% negative predictive value, and 96.3% accuracy. Qualitative equivalence in diagnosis was demonstrated by kappa correlation index of 0.922. CONCLUSION: The results obtained by radiography and densitometry were statistically equivalent, which endorses the indication of densitometry for investigating abdominal aortic calcification.

Densidade mineral óssea em nutrizes / Bone mineral density in nursing mothers

Objetivo. Avaliar a possível correlação entre o aleitamento e a densidade mineral óssea em nutrizes. Método. Estudo transversal, no qual se avaliou a densidade mineral óssea de nutrizes com aleitamento materno exclusivo na data da realização do exame, que ocorreu do 12.º ao 70.º dias de aleitamento. Foram colhidas informações sobre a história gestacional atual e pregressa, os dados do consumo alimentar e dos fatores de risco de osteoporose. Foram realizadas avaliações antropométricas, da composição corporal, além da densidade mineral. Para correlacionar a densidade mineral óssea com prováveis fatores de risco de diminuição de massa óssea foi utilizada a correlação de Pearson. Resultados. Participaram do estudo 107 nutrizes, com a média de 27,6 ± 5,1 anos de idade. Os resultados da densidade mineral óssea revelaram 58 nutrizes (54,2%) com densitometria normal e 49 (45,8%) com sua diminuição, sendo 43 casos (40,2%) de osteopenia e seis casos (5,6%) de osteoporose. Conclusão. A diminuição da massa óssea foi elevada no início do aleitamento, provavelmente por se tratar de período pós-gestacional e pela mobilização das reservas de cálcio em decorrência da amamentação.

Objective. To evaluate the possible association between breastfeeding and bone mineral density in nursing mothers. Method. It is a transversal study evaluating the bone mineral density in lactating women with exclusive breastfeeding at the time of the examination, conducted between 12th and 70th days of lactation. The following data were collected: current and previous pregnancy history, food consumption data and risk factors for osteoporosis. Anthropometry, body composition and bone mineral density profile were measured. To correlate bone mineral density with probable risk factorsfor osteoporosis, Pearson correlation was performed. Results. The study included 107 mothers, mean age of 27.6 ± 5.1 years. The results of bone mineral density revealed 58 mothers (54.2%) had normal densitometry, 49 (45.8%) had reduced bone mass being 43 cases with osteopenia(40.2%) and six cases with osteoporosis (5.6%). Conclusion. The decrease of bone mass was high in early lactation, probably because it is a post-pregnancy period and by great mobilization of calcium as a result of breastfeeding.