Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adultonset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling.

Loss-of-function mutations in PROK2 and PROKR2 underlie both KS and nIHH.

Objective: To examine the expression of selected transcription factors involved in adipogenesis and genes related to lipid metabolism in abdominal subcutaneous and omental fat tissue. Research design and methods: We obtained subcutaneous and omental adipose tissue samples from 40 women undergoing abdominal hysterectomies (age: 4775 years; BMI 27.975.3 kg/m 2 ). We measured isolated adipocyte size and metabolism, and detailed measures of body fat accumulation and body fat distribution were obtained (dual-energy X-ray absorptiometry and computed tomography, respectively). Results: Adipocyte size of both subcutaneous and omental fat were increased with higher body fat mass values, with similar regression slopes in each compartment. In contrast, with higher body fat mass values, fat accumulation was progressively higher in the subcutaneous than in the visceral fat compartment, suggesting hyperplasia in the subcutaneous fat compartment. Messenger RNA levels of CEBPa, PPARg2, SREBP1c and genes related to lipid metabolism (LPL, FABP4, DGAT1, DGAT2, PLIN and HSL) were significantly higher in subcutaneous than in omental fat tissue (Pp0.001 for all). Only subcutaneous expression of these genes tracked with obesity levels as reflected by significant positive associations between subcutaneous fat CEBPa, SREBP1c and DGAT2 expression and total body fat mass (r ¼ 0.37, r ¼ 0.41, r ¼ 0.57, respectively, Pp0,05), fat percentage (r ¼ 0.40, r ¼ 0.39, r ¼ 058, respectively, Pp0,05) and subcutaneous adipose tissue area (r ¼ 0.36, r ¼ 0.38, r ¼ 0.58, respectively, Pp0,05). Omental adipose tissue expression levels of these genes were not significantly related to adiposity measures. Conclusions: These results show that in obese women, hyperplasia is predominant in the subcutaneous fat depot, whereas fat cell hypertrophy is observed both in the omental and subcutaneous compartments.

Primary adrenal insufficiency (PAI) in the pediatric population (0 -18 yr) is most commonly attributed to congenital adrenal hyperplasia (CAH), which occurs in about 1 in 15,000 births, followed by Addison's disease, with an assumed autoimmune etiology. However, molecular advances have increased the number of possible diagnoses. The objective of this study was to determine the incidence and etiologies of PAI in our pediatric population. All patients with a diagnosis of PAI followed by the Endocrinology Service at our institution between September 1981 and September 2001 were studied. One hundred three patients (48 boys) were identified, primarily by the Endocrinology Clinic case registry. CAH was the most frequent etiology (71.8%). However, non-CAH etiologies accounted for 28.2%, of which 55% were nonautoimmune in etiology. Importantly, the CAH sex ratio was 1:1, despite the absence of biochemical screening for this condition in Quebec newborns. Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) developed adrenal insufficiency 4 yr earlier than those with non-autoimmune disease. Finally, we review the rare etiologies of PAI and propose an algorithm to aid in targeted genetic testing.