Heraldo Mendes Garmes

Loss-of-Function Mutations in the Genes Encoding Prokineticin-2 or Prokineticin Receptor-2 Cause Autosomal Recessive Kallmann Syndrome

CONTEXT Physiological activation of the prokineticin pathway has a critical role in olfactory bulb morphogenesis and GnRH secretion in mice. OBJECTIVE To investigate PROK2 and PROKR2 mutations in patients with hypogonadotropic hypogonadism (HH) associated or not with olfactory abnormalities. DESIGN We studied 107 Brazilian patients with HH (63 with Kallmann syndrome and 44 with normosmic HH) and 100 control individuals. The coding regions of PROK2 and PROKR2 were amplified by PCR followed by direct automatic sequencing. RESULTS In PROK2, two known frameshift mutations were identified. Two brothers with Kallmann syndrome harbored the homozygous p.G100fsX121 mutation, whereas one male with normosmic HH harbored the heterozygous p.I55fsX56 mutation. In PROKR2, four distinct mutations (p.R80C, p.Y140X, p.L173R, and p.R268C) were identified in five patients with Kallmann syndrome and in one patient with normosmic HH. These mutations were not found in the control group. The p.R80C, p.L173R, and p.R268C missense mutations were identified in the heterozygous state in the HH patients and in their asymptomatic first-degree relatives. In addition, no mutations of FGFR1, KAL1, GnRHR, KiSS-1, or GPR54 were identified in these patients. Notably, the new nonsense mutation (p.Y140X) was identified in the homozygous state in an anosmic boy with micropenis, bilateral cryptorchidism, and high-arched palate. His asymptomatic parents were heterozygous for this severe defect. CONCLUSION We expanded the repertoire of PROK2 and PROKR2 mutations in patients with HH. In addition, we show that PROKR2 haploinsufficiency is not sufficient to cause Kallmann syndrome or normosmic HH, whereas homozygous loss-of-function mutations either in PROKR2 or PROK2 are sufficient to cause disease phenotype, in accordance with the Prokr2 and Prok2 knockout mouse models.

Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency.

CONTEXT FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency. OBJECTIVE Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations. METHODS AND PATIENTS The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. RESULTS Two unique heterozygous nonsense mutations in FGF8 (p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. CONCLUSIONS We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency.

Endocrine-metabolic effects of the treatment with pioglitazone in obese patients with polycystic ovary syndrome.

The hyperandrogenism found in polycystic ovary syndrome (PCOS) can be a consequence of hyperinsulinemia as a result of peripheral insulin resistance. Metformin and insulin sensitizers have become a potential therapeutic tool for treating these patients; however, there are few studies with pioglitazone in PCOS. Elevated luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratios and LH hyper-responsivity to stimulation with gonadotropin-releasing hormone (GnRH) are common findings in PCOS. The reason why hyperinsulinemia produces hyperandrogenism and whether insulin action on the pituitary alters gonadotropin liberation remain unknown. In the present study, we evaluated the effect of pioglitazone (30 mg/day for 2 months) on insulin response to an oral glucose tolerance test (OGTT), serum levels of androgens and sex hormone-binding globulin (SHBG), and pituitary gonadotropin response to GnRH stimulation in 15 obese PCOS women. We found a significant decrease in insulin response to the OGTT and also in total and free testosterone levels, an increase in SHBG and a reduction in the LH response to GnRH stimulation after pioglitazone treatment. In conclusion, this short-term treatment with pioglitazone decreased hyperinsulinemia and hyperandrogenemia in obese PCOS patients, and there was a significant reduction in LH response to GnRH stimulation. Further research should be carried out to establish the risks and benefits of pioglitazone, which would assist in the physiopathologic comprehension of PCOS.

Subclinical hypothyroidism in young women with polycystic ovary syndrome: an analysis of clinical, hormonal, and metabolic parameters

OBJECTIVE To analyze the relationship between selected clinical and metabolic parameters in young women with polycystic ovary syndrome (PCOS) and normal thyroid function or subclinical hypothyroidism (SCH). DESIGN A cross-sectional cohort study. SETTING Tertiary care clinic. PATIENT(S) Women diagnosed with PCOS according to the Rotterdam criteria (n = 168). INTERVENTION(S) Clinical, hormonal, and metabolic parameters were evaluated. SCH was defined as TSH levels of 4.5-10 mIU/L. MAIN OUTCOME MEASURE(S) Separately, PCOS and SCH exert adverse effects on metabolic parameters; however, in conjunction their effect is unclear. This study evaluated whether SCH in women with PCOS affects clinical, hormonal, and metabolic parameters. RESULT(S) The mean age of the 168 women was 24 ± 5.8 years. Mean body mass index was 33.4 ± 8.2 kg/m(2). Thyroid function was normal in 149 women, and 19 had SCH. Only serum low-density lipoprotein cholesterol and PRL levels were significantly higher in the women with SCH (122.6 ± 25.6 mg/dL and 17.7 ± 7.7 ng/mL, respectively) compared with those with normal thyroid function (105.6 ± 33 mg/dL and 14 ± 10.3 ng/mL, respectively). CONCLUSION(S) In young women with PCOS, SCH is associated with higher low-density lipoprotein cholesterol levels, albeit with no changes in other lipid profile parameters, insulin resistance, or phenotypic manifestations. This study adds to current evidence supporting an association between PCOS and SCH.

Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1

Objective  Congenital hypogonadotropic hypogonadism with anosmia (Kallmann syndrome) or with normal sense of smell is a heterogeneous genetic disorder caused by defects in the synthesis, secretion and action of gonadotrophin‐releasing hormone (GnRH). Mutations involving autosomal genes have been identified in approximately 30% of all cases of hypogonadotropic hypogonadism. However, most studies that screened patients with hypogonadotropic hypogonadism for gene mutations did not include gene dosage methodologies. Therefore, it remains to be determined whether patients without detected point mutation carried a heterozygous deletion of one or more exons.

Severe rhabdomyolysis due to adipsic hypernatremia after craniopharyngioma surgery

UNLABELLED The association of diabetes insipidus and adipsia after craniopharyngioma surgery has high morbidity. Hypernatremia can be caused by adipsia and be aggravated by diabetes insipidus. Rhabdomyolysis rarely occurs. CASE REPORT This is the first report of a diabetic patient with craniopharyngioma who developed diabetes insipidus and adipsia after surgery, evolving with severe hypernatremia that caused considerable rhabdomyolysis. CONCLUSION The importance of the evaluation of muscle integrity when under hypernatremic states is pointed out. Although adipsia may have a simple solution through volunteer water ingestion, serious consequences such as repeated severe hypernatremia episodes and intense rhabdomyolysis with high morbidity could occur, if adipsia is not diagnosed.

Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

Leptin and adiponectin blood levels in women with premature ovarian failure and age- and weight-matched women with normal menstrual cycles

Objective: The aim of this study was to evaluate leptin and adiponectin blood levels in women with premature ovarian failure (POF) and women with a normal menstrual cycle. Methods: This was a cross-sectional study involving 60 women divided into two groups: the study group (G1) comprising 30 women with POF not receiving hormone therapy for at least 3 months and the control group (G2) comprising 30 women with a normal menstrual cycle. Both groups were age and body mass index (BMI) matched. Results: Study participants had a mean (±SD) age of 34.4 (±5.3) and 34.2 (±5.6) years and mean BMI (±SD) of 24.7 (±6.3) and 24.5 (±4.6) kg/m2 in G1 and G2, respectively. Serum leptin levels were significantly lower in G1 compared with G2 (8.8 ± 12.2 and 12.2 ± 9.7 ng/mL; P < 0.05). Serum adiponectin levels were similar in both groups. Leptin levels were positively correlated to weight (r = 0.38; P = 0.03) but were not correlated to BMI and age in women with POF (G1); in G2, they were positively correlated to BMI (r = 0.59; P = 0.0006), weight (r = 0.63; P = 0.0006), and age (r = 0.40; P = 0.02). Adiponectin levels did not correlate to weight, BMI, or age in both groups. Conclusions: These results suggest that gonadal function loss may decrease leptin circulating levels, independently from age and BMI. Adiponectin seems not to correlate to hormonal status.

17-Hydroxyprogesterone deficiency as a cause of sexual infantilism and arterial hypertension: Laboratory and molecular diagnosis – a case report

The differential diagnosis of hypertension associated with hypokalemia in infancy and adolescence should necessarily include deficiency of the 17α-hydroxylase enzyme, a rare form of congenital adrenal hyperplasia (CAH). In addition to hypertension, the classic syndrome caused by this deficiency is characterized by suppressed production of sex hormones and consequently sexual infantilism. Although rare (1% of all forms of CAH), there appears to be a higher incidence of this syndrome in some population groups. This is a case report on two sisters followed up at the Department of Obstetrics and Gynecology, School of Medicine, Universidade Estadual de Campinas (UNICAMP), who were both found to have the 46,XY genotype with homozygosis for W406R, exon 7 of the CYP17 gene (OMIM 202110). The condition was diagnosed only at puberty when hypergonadotropic hypogonadism resulted in sexual infantilism; however, arterial hypertension had been present since infancy and late diagnosis and lack of timely adequate treatment resulted in complications.

A pituitary adenoma secreting follicle-stimulating hormone with ovarian hyperstimulation: treatment using a gonadotropin-releasing hormone antagonist

OBJECTIVE To describe the management of a patient with a pituitary adenoma secreting follicle-stimulating hormone (FSH) associated with ovarian hyperstimulation who was treated with a gonadotropin-releasing hormone (GnRH) antagonist. DESIGN Case report. SETTING University teaching hospital. PATIENT(S) A woman of reproductive age with secondary amenorrhea and ovarian hyperstimulation due to a pituitary adenoma secreting FSH, which persisted after transsphenoidal surgery. INTERVENTION(S) Clinical treatment with a GnRH antagonist. MAIN OUTCOME MEASURE(S) A decrease in serum estradiol levels. RESULT(S) During the treatment period, ovarian hyperstimulation decreased as shown by a reduction in estradiol levels and an improvement in the patients clinical condition and in the ultrasonography parameters. CONCLUSION(S) The GnRH antagonist was found to be effective for the short-term treatment of ovarian hyperstimulation secondary to a pituitary adenoma secreting FSH, thus representing a therapeutic option that should be taken into consideration in such cases.