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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.

Mutations in the NNT gene (nicotinamide nucleotide transhydrogenase), which is involved in NADPH generation in mitochondria, have recently been described in familial glucocorticoid deficiency. We report two patients, one with isolated glucocorticoid deficiency and the other with a combined glucocorticoid and mineralocorticoid deficiency. Through whole exome sequencing, both cases were found to carry two different NNT mutations, confirming previous results for these patients. Each patient also carries multiple heterozygous protein-altering mutations in other genes involved in steroid hormone biogenesis and regulation. The patient with a combined glucocorticoid and mineralocorticoid deficiency is a compound heterozygote for common missense variants in the ME3 gene (mitochondrial malic enzyme 3), the product of which also generates NADPH in mitochondria. Mutations in NNT are the likely proximal cause of the glucocorticoid deficiency in both patients, but genetic background effects may be important in modulating the specific phenotype of adrenal insufficiency.

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.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0139-9) contains supplementary material, which is available to authorized users.

International audience; 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.

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.The p.R8C ACTH mutant is immunoreactive, but the mutant peptides, ACTH-R8C and α-MSH-R8C, are bioinactive.Methods included whole exome sequencing, Sanger sequencing, peptide synthesis, ACTH immunoradiometric assay, hormone binding, and activation assays in cells expressing melanocortin receptors.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.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.

To describe the features of Frey syndrome (auriculotemporal nerve dysfunction with gustatory flushing) in childhood.A multicenter, retrospective, descriptive observational national case series study was conducted with the help of French academic societies. Diagnostic criteria were based on clinical history, and sometimes also on photographs or provocation tests.Forty-eight cases were identified, with 2 subtypes: 35 unilateral and 13 bilateral. Associated sweating was reported in only 10% of cases. Diagnosis was made in only 20% of children at the first consultation and inappropriate dietary restriction was prescribed for 21%. Instrumented vaginal delivery was significantly associated with unilateral forms (OR [unilateral vs bilateral] = 29; 95% CI 3.99-311.58; P .001). The outcome was favorable overall with 57% regression, 20% recovery, and only 23% persistence of initial symptoms. Regression was more frequent in unilateral forms (OR = 6.60; 95% CI 1.23-44.04; P = .016), observed in 69% of unilateral forms at a median age of 27 (24-48) months. Recovery predominated in bilateral forms (OR = 0.05; 95% CI 0-0.38; P = .001), observed in 58% of bilateral cases at a median age of 8 (7-9) months.Frey syndrome in childhood is a rare but benign condition with mild symptoms and a favorable outcome in most cases. Unilateral forms are mostly associated with instrumented delivery. Pediatricians should be familiar with this disorder in order to avoid misdiagnosis, mainly as food allergy, and unnecessary referrals and tests.