Intrasellar xanthogranuloma mimicking macroadenoma.

Intracranial xanthogranulomas (XGs) have been found at various sites, but xanthogranuloma of the sellar region is extremely rare. We report about a case of sellar XG in a 34-year-old female. Magnetic resonance imaging showed a solid-cystic mass located at the sella turcica. The cystic component was hyperintense on the T1-weighted image (WI) and T2WI. The solid component was hyperintense on T1WI and hypointense on T2WI. There was peripheral enhancement after gadolinium administration. The diagnosis of cystic macroadenoma was considered before surgery. Final diagnosis of XG was confirmed by histopathological examination after surgical resection. Gross total resection of the lesion was achieved using the microscope through endoscopic endonasal transsphenoidal approach. The patient had a good outcome and no symptom of diabetes insipidus, hormonal evaluation did not show any alterations compatible with hypopituitarism and prolactin levels were normal XG should receive diagnostic consideration for the sellar mass lesions with cystic components hyperintense on T1WI and T2WI, solid components hyperintense on T1WI and hypointense on T2WI, and CT without evidence of calcifications. It is important to consider the possibility of XG when pertinent, as it facilitates a proper surgical approach strategy.

Childhood-Onset GH Deficiency versus Adult-Onset GH Deficiency: Relevant Differences Regarding Insulin Sensitivity.

The results of the studies on the pattern of insulin sensitivity (IS) are contradictory in patients with GH deficiency (GHD); however, the interference of the GHD onset stage, childhood or adulthood in the IS has not been assessed by euglycemic hyperinsulinemic clamp (EHC), a gold-standard method for the assessment of insulin sensitivity. In a prospective cross-sectional study, we assessed IS and body composition in 17 adults with hypopituitarism without GH replacement, ten with childhood-onset (COGHD) and seven with adulthood-onset (AOGHD) and compared them to paired control groups. COGHD presented higher IS (p = 0.0395) and a similar percentage of fat mass (PFM) to AOGHD. COGHD showed higher IS than the control group (0.0235), despite a higher PFM (0.0022). No differences were found between AODGH and the control group. In AOGHD and the control group, IS was negatively correlated with PFM (rs: −0.8214, p = 0.0234 and rs: −0.3639, p < 0.0344), while this correlation was not observed with COGHD (rs: −0.1152, p = 0.7514). Despite the higher PFM, patients with COGHD were more sensitive to insulin than paired healthy individuals, while patients with AOGHD showed similar IS compared to controls. The lack of GH early in life could modify the metabolic characteristics of tissues related to the glucose metabolism, inducing beneficial effects on IS that persist into adulthood. Thus, the glycometabolic findings in patients with COGHD seems to be not applicable to AOGHD.

Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism.

Hypopituitarism is a disorder characterized by insufficient secretion of one or more pituitary hormones. New etiologies of hypopituitarism have been recently described, including head trauma, cerebral hemorrhage, and drug-induced hypophysitis. The investigation of patients with these new disorders, in addition to advances in diagnosis and treatment of hypopituitarism, has increased the prevalence of this condition. Pituitary hormone deficiencies can induce significant clinical changes with consequent increased morbidity and mortality rates, while hormone replacement based on current guidelines protects these patients. In this review, we will first discuss the different etiologies of hypopituitarism and then address one by one the clinical aspects, diagnostic evaluation, and therapeutic options for deficiencies of TSH, ACTH, gonadotropin, and GH. Finally, we will detail the hormonal interactions that occur during replacement of pituitary hormones.

Insulin signaling in the whole spectrum of GH deficiency

ABSTRACT GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91

Insulin Sensitivity Is Not Decreased in Adult Patients With Hypopituitarism Without Growth Hormone Replacement.

Decreased insulin sensitivity in patients with hypopituitarism without GH replacement (pHP-WGHR) remains conflicting in literature. It is known that these patients present a decrease in free fat mass and an increase in fat mass. Typically, these kinds of alterations in body composition are associated with a decrease in insulin sensitivity; however, there is no consensus if this association is found in pHP-WGHR. Thus, we investigated pHP-WGHR regarding insulin sensitivity by euglycemic hyperinsulinemic clamp, the gold standard method, and body composition. In a cross-sectional study, we evaluated 15 pHP-WGHR followed up in a Service of Neuroendocrinology and 15 individuals with normal pituitary function as a control group with similar age, gender and body mass index. Insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp and homeostatic model assessment insulin resistance (HOMA-IR). Kappa coefficient evaluated the agreement between these two methods. Percentage of fat mass, percentage of free fat mass, fat mass weight and free fat mass weight were assessed by electrical bioimpedance. The pHP-WGHR presented similar insulin sensitivity to control group by euglycemic hyperinsulinemic clamp, both by the M-value, (p = 0.0913) and by the area under the glucose infusion rate curve, (p = 0.0628). These patients showed lower levels of fasting glycemia (p = 0.0128), insulin (p = 0.0007), HOMA-IR (p = 0.009). HOMA-IR shows poor concordance with euglycemic hyperinsulinemic clamp (Kappa = 0.16) in pHP-WGHR, while in the control group the agreement was good (Kappa = 0.53). The pHP-WGHR presented higher values of percentage of fat mass (p = 0.0381) and lower values of percentage of free fat mass (p = 0.0464) and free fat mass weight (0.0421) than the control group. This study demonstrated that the insulin sensitivity evaluated by euglycemic hyperinsulinemic clamp in pHP-WGHR was similar to individuals with normal pituitary function, despite the pHP-WGHR presenting higher fat mass percentage. HOMA-IR was not a good method for assessing insulin sensitivity in pHP-WGHR.

Insulin signaling in the whole spectrum of GH deficiency.

GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91.

Panhypopituitarism Without GH Replacement: About Insulin Sensitivity, CRP Levels, and Metabolic Syndrome.

A complete deficiency of anterior pituitary hormones from several etiologies characterizes Panhypopituitarism (PH). Despite advances in treatment, patients with PH maintain high rates of morbidity and mortality, a reason to investigate some insulin sensitivity, metabolic and inflammatory parameters that could be related to the increase of these indicators. This was a cross-sectional study comprising 41 PH patients under hormonal replacement, except for growth hormone, and 37 individuals in a control group (CG) with similar age, gender and body mass index (BMI). We assessed clinical data as age, sex, BMI, waist circumference, waist/hip ratio (WHR), history of hypertension, diabetes mellitus and dyslipidemia as well as fasting glycaemia, insulin, HOMA-IR, HbA1c, high-sensitivity CRP (hs-CRP), and lipid profile. PH patients presents lower values of glycaemia, insulin, HOMA-IR (0.88 vs 2.1) and WHR, but higher levels of hs-CRP (0.38 vs 0.16mg/dl) when compared with the CG. Although the occurrence of dyslipidemia was higher in patients with PH, the frequency of metabolic syndrome was similar between the groups. In multivariate linear regression analysis, the PH group independently predicted lower HOMA-IR and WHR values. In conclusion, this study demonstrated that patients with PH without GH replacement have lower HOMA-IR and WHR values and higher levels of hs-CRP than a CG paired by age, gender and BMI. The diagnosis of dyslipidemia was more frequent in patients with PH, but the occurrence of MS was similar to CG. Further studies are needed to confirm our findings and to better understand the metabolic characteristics of patients with PH.

Three new Brazilian cases of 17α-hydroxylase deficiency: clinical, molecular, hormonal, and treatment features.

BACKGROUND: Deficiency of 17α-hydroxylase (17OHD) is a rare form of adrenal hyperplasia. Diagnosis is generally delayed, impairing appropriate treatment. CASE PRESENTATION: Here, we report the clinical, molecular, hormonal, and treatment data of three unrelated 17OHD patients, aged 14-16 years with hypergonadotrophic hypogonadism; uncontrolled hypertension; primary adrenal insufficiency; and high progesterone, low to normal potassium, and low dehydroepiandrosterone, androstenedione, and testosterone levels. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) at baseline and after an adrenocorticotropic hormone test showed low cortisol and cortisone and high deoxycorticosterone (DOC) and corticosterone levels; both DOC/21-deoxycortisol and costicosterone/cortisol ratios were very high. Patient 2 had 46,XX karyotype and patients 1 and 3, had 46,XY. A molecular analysis showed that two of the patients were homozygous for p.W406R mutation and the other patient was compound heterozygous for p.W406R and p.P428L. Hypertension was controlled only after the administration of both prednisone and mineralocorticoid antagonist. CONCLUSIONS: Hypertension in young women must lead to diagnostic suspicion, even in the pre-pubertal period. The basal level of progesterone is an indicator of 17OHD. Mineral and glucocorticoid ratios obtained from LC-MS/MS can reinforce the diagnosis. Hypertension can be controlled using glucocorticoid replacement therapy and mineralocorticoid antagonist.

Pituitary carcinoma: A case report and discussion of potential value of combined use of Ga-68 DOTATATE and F-18 FDG PET/CT scan to better choose therapy.

BACKGROUND: Pituitary carcinoma is extremely rare and carries a very poor prognosis. In most cases, apparently indolent tumors become malignant; however, there are no satisfactory biomarkers for predicting tumor behavior. Thus, scientific advances in the search for new biological markers, diagnostic methods, and therapies are needed to improve the prognosis of these patients. CASE DESCRIPTION: We report the case of a woman with initial diagnosis of nonfunctioning pituitary adenoma which evolved to carcinoma after 4 years. Diagnosis was confirmed after biopsy of metastatic pulmonary nodules, in which neoplastic cells were immunohistochemically positive for chromogranin, synaptotophysin, prolactin, and growth hormone. Investigation with conventional somatostatin receptor scintigraphy, positron emission tomography-computed tomography (PET-CT) with Ga-68 DOTATATE and F-18 fluorodeoxyglucose (FDG) are showed. During temozolomide therapy, our patient had severe pancytopenia resulting in death from generalized infection despite 10 days of intensive care. CONCLUSION: The present case of an aggressive pituitary carcinoma rising from a typical adenoma illustrates the importance of developing new prognostic biomarkers in these cases. In addition to demonstrating a serious side effect with the use of temozolomide, our case report suggests that the combined use of Ga-68 DOTATATE and F-18 FDG PET-CT scan may scale somatostatin receptors vs. tumor aggressiveness, therefore, helping to better choose the therapy for aggressive pituitary tumors.

Polycystic ovary syndrome and chronic autoimmune thyroiditis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) has been associated with an autoimmune origin, either per se or favoring the onset of autoimmune diseases, from a stimulatory action on the inflammatory response. Thus, autoimmune thyroiditis (AIT) could be more prevalent among women with PCOS. OBJECTIVE: To evaluate the prevalence of AIT in women with PCOS. STUDY DESIGN: It was a cross-sectional study, in a tertiary center, including 65 women with PCOS and 65 women without this condition. Clinical and laboratory parameters were evaluated and a thyroid ultrasound scan was performed. Levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase (anti-TPO) antibodies, anti-thyroglobulin (anti-TG) antibodies, and thyroid ultrasound findings were evaluated. RESULTS: The prevalence of subclinical hypothyroidism (SCH) in women with PCOS was 16.9% and 6.2% in the non-PCOS group. AIT was more common in the PCOS group compared with the non-PCOS group (43.1% versus 26.2%). But, when it was adjusted by weight and insulin resistance, the difference in the thyroiditis risk was not observed (OR 0.78, CI 0.28-2.16). CONCLUSION: AIT risk was similar in the PCOS and the non-PCOS group. SCH are more common in women with PCOS, highlighting a need for periodic monitoring of thyroid function.

Pituitary macroadenoma presenting as a nasal tumor: case report / Macroadenoma hipofisário, apresentando-se como um tumor nasal: relato de caso

CONTEXT: Pituitary macroadenomas are rare intracranial tumors. In a few cases, they may present aggressive behavior and invade the sphenoid sinus and nasal cavity, causing unusual symptoms. In this paper, we report an atypical case of pituitary adenoma presenting as a nasal mass. CASE REPORT: The patient was a 44-year-old woman who had had amenorrhea and galactorrhea for ten months, with associated nasal obstruction, macroglossia and acromegaly. Both growth hormone and prolactin levels were increased. Magnetic resonance imaging showed a large mass originating from the lower surface of the pituitary gland, associated with sella turcica erosion and tumor extension through the sphenoid sinus and nasal cavity. Histopathological analysis demonstrated a chromophobe pituitary adenoma with densely packed rounded epithelial cells, with some atypias and rare mitotic figures. There was no evidence of metastases. CONCLUSION: Macroadenoma invading the nasal cavity is a rare condition and few similar cases have been reported in the literature. This study contributes towards showing that tumor extension to the sphenoid sinus and nasopharynx needs to be considered and investigated in order to make an early diagnosis when atypical symptoms like nasal obstruction are present. .

CONTEXTO: Macroadenomas hipofisários são tumores intracraniais raros. Em alguns casos, podem apresentar comportamento agressivo e invadir o seio esfenoidal e a cavidade nasal, causando sintomas não usuais. Neste relato de caso, descrevemos um caso atípico de adenoma hipofisário manifestando-se como uma massa nasal. RELATO DE CASO: A paciente de 44 anos, do sexo feminino, apresentava amenorreia e galactorreia por 10 meses associando-se a obstrução nasal, macroglossia e acromegalia. Os níveis do hormônio de crescimento e de prolactina apresentaram-se aumentados. Ressonância magnética mostrou uma grande massa originada da superfície inferior da glândula hipofisária associada com erosão da sela túrcica e extensão do tumor através do seio esfenoidal e cavidade nasal. Análise histopatológica demonstrou adenoma hipofisário cromófobo com células epiteliais arrendondadas densamente agrupadas com algumas atipias e escassas figuras de mitose. Não houve evidências de metástase. CONCLUSÃO: O macroadenoma invasivo para a cavidade nasal é uma condição rara e há poucos relatos similares descritos na literatura. Este trabalho contribui para mostrar que, na presença de sintomas atípicos como a obstrução nasal, a extensão para o seio esfenoidal e para a nasofaringe deve ser considerada e investigada para um diagnóstico precoce. .

Pituitary macroadenoma presenting as a nasal tumor: case report.

CONTEXT: Pituitary macroadenomas are rare intracranial tumors. In a few cases, they may present aggressive behavior and invade the sphenoid sinus and nasal cavity, causing unusual symptoms. In this paper, we report an atypical case of pituitary adenoma presenting as a nasal mass. CASE REPORT: The patient was a 44-year-old woman who had had amenorrhea and galactorrhea for ten months, with associated nasal obstruction, macroglossia and acromegaly. Both growth hormone and prolactin levels were increased. Magnetic resonance imaging showed a large mass originating from the lower surface of the pituitary gland, associated with sella turcica erosion and tumor extension through the sphenoid sinus and nasal cavity. Histopathological analysis demonstrated a chromophobe pituitary adenoma with densely packed rounded epithelial cells, with some atypias and rare mitotic figures. There was no evidence of metastases. CONCLUSION: Macroadenoma invading the nasal cavity is a rare condition and few similar cases have been reported in the literature. This study contributes towards showing that tumor extension to the sphenoid sinus and nasopharynx needs to be considered and investigated in order to make an early diagnosis when atypical symptoms like nasal obstruction are present.

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.

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 patient's 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.

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil / Seis novos casos confirmam o perfil clínico molecular de deficiência combinada de 17 alfa-hidroxilase/17,20-liase no Brasil

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50 percent and 32 percent of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

Em 2004, segundo Costa-Santos e cols., p.W406R e p.R362C correspondiam a 50 por cento e 32 por cento dos alelos mutantes do gene CYP17A1, respectivamente, em 24 pacientes de 19 famílias brasileiras com deficiência da 17α-hidroxilase. Apresentamos os dados clνnicos e moleculares de seis pacientes de três famílias consanguíneas brasileiras com deficiência da 17α-hidroxilase. Todas as pacientes apresentavam hipogonadismo, amenorreia e hipertensão ao diagnóstico. Duas irmãs tinham cariótipo 46,XY, ambas com gônadas palpáveis na região inguinal. Todas tinham hipogonadismo hipergonadotrófico, com nível aumentado de ACTH (> 104 ng/mL), atividade de renina plasmática suprimida, baixos níveis de potássio (< 2,8 mEq/L) e progesterona aumentada (> 4,4 ng/mL). Três delas, incluindo duas irmãs, apresentaram homozigose para a mutação p.W406R e as outras três (duas irmãs e uma prima) foram homozigotas para a mutação p.R362C. A recorrência das mutações p.W406R e p.R362C no gene CYP17A1 aqui relatada em famílias adicionais confirma que essas são as mais frequentes causadoras do fenótipo completo da deficiência combinada de 17α-hidroxilase/17,20-liase em pacientes brasileiros.

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 / Seguimento de longo prazo em um menino de 8 anos de idade com insulinoma como primeira manifestação de neoplasia endócrina múltipla tipo 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.

A neoplasia endócrina múltipla tipo 1 (NEM1) é uma doença hereditária autossômica dominante, caracterizada principalmente por tumores de paratireoide, enteropancreáticos e adeno-hipofisários. Apresentamos o caso de um menino com 8 anos encaminhado por crises de hipoglicemia. Seu diagnóstico foi insulinoma pancreático. Sua avó paterna faleceu por úlceras gastroduodenais de repetição e a tia paterna tinha as mesmas manifestações. Na primeira avaliação, o pai apresentou apenas úlcera gástrica, porém com a evolução desenvolveu hiperparatireoidismo e tumor carcinoide pulmonar. Durante cerca de 15 anos de seguimento, os três irmãos e o caso índice desenvolveram hiperparatireoidismo e hiperprolactinemia. O estudo molecular mostrou a substituição G por A no intron 4, a nove nucleotídeos do sítio aceptor de splicing, criando um novo sítio de splicing. Todos os membros da família afetados e estudados tinham a mesma mutação. A NEM1 é uma condição rara que requer assistência médica permanente. As identificações clínicas e genéticas precoces são essenciais para o tratamento e aconselhamento genético.

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.