Reema L. Habiby

Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production.

Adrenal hypoplasia congenita (AHC) is an X-linked disorder that typically presents with adrenal insufficiency during infancy. Hypogonadotropic hypogonadism (HHG) has been identified as a component of this disorder in affected individuals who survive into childhood. Recently, AHC was shown to be caused by mutations in DAX-1, a protein that is structurally similar in its carboxyterminal region to orphan nuclear receptors. We studied two kindreds with clinical features of AHC and HHG. DAX-1 mutations were identified in both families. In the JW kindred, a single base deletion at nucleotide 1219 was accompanied by an additional base substitution that resulted in a frameshift mutation at codon 329 followed by premature termination. In the MH kindred, a GGAT duplication at codon 418 caused a frameshift that also resulted in truncation of DAX-1. Baseline luteinizing hormone (LIT), follicle-stimulating hormone (FSH), and free-alpha-subunit (FAS) levels were determined during 24 h of frequent (q10 min) venous sampling. In patient MH, baseline LH levels were low, but FAS levels were within the normal range. In contrast, in patient JW, the mean LH and FSH were within the normal range during baseline sampling, but LH secretion was erratic rather than showing typical pulses. FAS was apulsatile for much of the day, but a surge was seen over a 3-4-h period. Pulsatile gonadotropin releasing hormone (GnRH) (25 ng/kg) was administered every 2 h for 7 d to assess pituitary responsiveness to exogenous GnRH. MH did not exhibit a gonadotropin response to pulsatile GnRH. JW exhibited a normal response to the first pulse of GnRH, but there was no increase in FAS. In contrast to the priming effect of GnRH in GnRH-deficient patients with Kallmann syndrome, GnRH pulses caused minimal secretory responses of LH and no FAS responses in patient JW. The initial LH response in patient JW implies a deficiency in hypothalamic GnRH. On the other hand, the failure to respond to pulsatile GnRH is consistent with a pituitary defect in gonadotropin production. These two cases exemplify the phenotypic heterogeneity of AHC/HHG, and suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels.

Precocious puberty in children with neurofibromatosis type 1

We undertook a comprehensive study of children with neurofibromatosis type 1 (NF-1) cared for in a large multidisciplinary clinic to determine the prevalence of precocious puberty and its relationship to optic pathway tumors (OPTs). Precocious puberty was diagnosed in 7 of 219 children with NF-1 (5 boys and 2 girls) examined between Jan. 1, 1985, and April 20, 1993. All seven children had OPTs involving the optic chiasm; they represented 39% of children with NF-1 and chiasmal tumors (95% confidence interval, 17% to 64%). Eleven prepubertal children (aged 2 to 10 years) with NF-1 and OPTs, and age- and sex-matched NF-1 control subjects without OPTs, underwent luteinizing hormone-releasing hormone (LH-RH) stimulation tests. Two boys with OPTs had pubertal luteinizing hormone (LH) responses, and testosterone levels > 10 ng/dl. Basal LH levels were also elevated in these two boys when tested with a very sensitive immunochemiluminometric assay. None of the children without an OPT had either a pubertal response to LH-RH or an elevated basal LH level. We conclude that precocious puberty in children with NF-1 is found exclusively in those who have OPTs involving the optic chiasm; it is a common complication in those children. With the use of a highly sensitive LH assay, biochemical evidence of hypothalamic-pituitary-gonadal axis activation may be demonstrated, even without provocative testing.

Bone mineral density during treatment of central precocious puberty

Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.

Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon.

Background/Aims: Growth hormone (GH) excess in children with chiasmal optic pathway tumors (OPT), often associated with neurofibromatosis type 1 (NF1), is likely underrecognized. These children have elevated insulin-like growth factor 1 (IGF-1) levels, evidence of rapid growth despite treatment of precocious puberty, and failure to suppress GH levels following oral glucose challenge. The aim of this report is to describe the treatment course and natural history of this rare clinical condition in 7 patients. Methods: This is a descriptive case series of 5 children previously described and 2 additional children more recently diagnosed at our institution. All 7 children had clinical and biochemical evidence of GH excess and received treatment with the somatostatin analog octreotide. Results: Length of treatment varied among the patients. Five of the 7 patients have had resolution of GH excess and currently have normal IGF-1 levels without treatment. Conclusions: Unrestrained GH secretion occurs in a subset of children with OPT with potential adverse outcomes. Since GH excess appears to resolve over time, the benefit of treatment to alter outcomes or prevent tumor progression is unclear.

ESPE Position Statement for Paediatric Endocrinology Subspecialty

Paediatric Endocrinology, under the leaderships of Lawson Wilkins in the US and of Andrea Prader in Europe, started to take shape as a subspecialty in the 1960s. Since that time, paediatric endocrinology has developed at a tremendous speed, especially during the last 30 years, in line with increasing knowledge in the field of genetics and other basic sciences, as well as improved medications and technical facilities. Endocrine conditions encountered in childhood are diverse and show a wide spectrum that is in many aspects substantially different from endocrine diseases in adults and the elderly. Children are simply not little adults. Handling of paediatric endocrine disorders requires the special attention of medical specialists with significant background training in paediatrics, to understand all aspects of human growth and development, along with specialised training in paediatric endocrinology. Developmental issues, including sex differentiation, body growth, skeletal development, pubertal maturation, and neuropsychological development from the intrauterine period to adolescence and young adulthood, are specific paediatric issues that cannot be fully understood and managed without paediatric training as the basic medical background. Recognising, classifying, diagnosing, and managing disorders of growth and development are specific tasks for fully trained paediatric endocrinologists. At the European Academy of Paediatrics (EAP), a subsection of the European Union of Medical Specialists (UEMS; formerly CESP), each paediatric subspecialty is represented by a liaison officer within the Tertiary Care Working Group (TCWG). The EAP has its own legislation/constitution (Belgian/ EU law) representing the central unifying platform for paediatric training in Europe. One of the major goals of the liaison officers is to update the current syllabus and accreditation procedures for their subspecialty, aiming at harmonisation of paediatric training throughout Europe. ESPE has recently, in 2014, revised its training program and this was approved by the General AsPublished online: July 6, 2016 HORMONE RESEARCH IN PÆDIATRICS

Central and Gonadal Hypogonadism in X-Linked Lissencephaly

OBJECTIVE To directly test gonadal function in a patient with X-linked lissencephaly with ambiguous genitalia (XLAG) in light of lack of previous functional data. STUDY DESIGN AND RESULTS We studied an infant who failed to increase testosterone levels in response to hCG stimulation. CONCLUSION In XLAG, the gonads are not only structurally dysgenetic but also functionally abnormal.

Extensive miRNA expression analysis in craniopharyngiomas

PurposeCraniopharyngiomas are benign tumors of the sellar or parasellar regions. They arise from the remnants of Rathke’s pouch and are considered a “developmental disease.” microRNAs are short non-coding RNAs that play a key regulatory role in the control of expression of entire gene networks. We performed an extensive analysis of miRNAs in craniopharyngiomas aiming to identify a miRNA expression signature that might aid in the prognosis of disease progression and outcome.MethodsThirty-seven craniopharyngioma samples from twenty-three patients, ten age-matched controls from autopsy, and ten infant controls from the developing pituitary from autopsy were evaluated for the expression of 754 miRNAs using TaqMan® Low Density Arrays (TLDAs) v2.0 (Applied Biosystems, Foster City, CA).ResultsAmong the most differentially expressed miRNAs, downregulation of miR-132 appears to be a marker of aggressiveness and also plays a role in epithelial–mesenchymal transition.ConclusionsThis is the first time that an extensive study of miRNA expression has been performed in craniopharyngiomas. Further research needs to be performed to investigate the potential role of miR-132 in the development and progression of craniopharyngiomas, and its value as a prognostic marker of aggressiveness.

Refractory hypoglycemia in a pediatric patient with desmoplastic small round cell tumor

Abstract Background Tumor-induced hypoglycemia is a rare and serious complication that is usually a consequence of either excessive insulin secretion (insulinoma) or because of non-islet cell tumor hypoglycemia (NICTH). NICTH is a rare phenomenon seen most often in adult patients. It is associated with different tumor types. Here, we report the first case to the best of our knowledge in the literature of a pediatric patient with NICTH associated with desmoplastic small round cell tumor (DSRT). Case presentation This is a 15-year-old girl who presented with symptomatic hypoglycemia and abdominal mass. She required an intravenous glucose infusion rate as high as 9 mg/kg/min in addition to glucose containing oral supplements in order to maintain her blood glucose above 60 mg/dL. Computed tomography (CT) scan of the chest, abdomen and pelvis showed multiple hepatic lesions with an intraperitoneal soft tissue mass which subsequently was diagnosed as DSRT. When the blood glucose was 45 mg/dL, the insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were suppressed with an appropriate elevation of cortisol. Subsequently, an insulin-like growth factor-2 (IGF-2) level was sent and the IGF-2:IGF-1 ratio was found to be elevated >10 consistent with NICTH. After the first dose of chemotherapy, hypoglycemia improved, and she was weaned off glucose containing fluids. Conclusions NICTH should be considered in all cancer patients regardless of their age with refractory hypoglycemia.