A Common Variant in the CDK8 Gene Is Associated with Sporadic Pituitary Adenomas in the Portuguese Population: A Case-Control Study.

The majority of pituitary adenomas occur in a sporadic context, and in the absence of known genetic predisposition. Three common variants at the NEBL (rs2359536), PCDH15 (rs10763170) and CDK8 (rs17083838) loci were previously associated with sporadic pituitary adenomas in the Han Chinese population, but these findings have not yet been replicated in any other population. The aim of this case-control study was to assess if these variants are associated with susceptibility to sporadic pituitary adenomas in the Portuguese population. Genotype and allele frequencies were determined in 570 cases and in 546 controls. The CDK8 rs17083838 minor allele (A allele) was significantly associated with sporadic pituitary adenomas, under an additive (odds ratio (OR) 1.73, 95% confidence interval (CI) 1.19-2.50, p = 0.004) and dominant (OR 1.82, 95% CI 1.24-2.68, p = 0.002) inheritance model. The NEBL rs2359536 and PCDH15 rs10763170 variants were not associated with the overall risk for the disease, although a borderline significant association was observed between the PCDH15 rs10763170 minor allele (T allele) and somatotrophinomas (dominant model, OR 1.55, 95% CI 1.02-2.35, p = 0.035). These findings suggest that the CDK8 rs17083838 variant, and possibly the PCDH15 rs10763170 variant, may increase susceptibility to sporadic pituitary adenomas in the Portuguese population.

Maturity-Onset Diabetes of the Young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 Mutations.

Maturity-onset diabetes of the young (MODY) is a frequently misdiagnosed type of diabetes, which is characterized by early onset, autosomal dominant inheritance, and absence of insulin dependence. The most frequent subtypes are due to mutations of the GCK (MODY 2), HNF1A (MODY 3), and HNF4A (MODY 1) genes. We undertook the first multicenter genetic study of MODY in the Portuguese population. The GCK, HNF1A, and HNF4A genes were sequenced in 46 unrelated patients that had at least two of the three classical clinical criteria for MODY (age at diagnosis, family history, and clinical presentation). The functional consequences of the mutations were predicted by bioinformatics analysis. Mutations were identified in 23 (50%) families. Twelve families had mutations in the GCK gene, eight in the HNF1A gene, and three in the HNF4A gene. These included seven novel mutations (GCK c.494T>C, GCK c.563C>G, HNF1A c.1623G>A, HNF1A c.1729C>G, HNF4A c.68delG, HNF4A c.422G>C, HNF4A c.602A>C). Mutation-positive patients were younger at the time of diagnosis when compared to mutation-negative patients (14.3 vs. 23.0 years, p = 0.011). This study further expands the spectrum of known mutations associated with MODY, and may contribute to a better understanding of this type of diabetes and a more personalized clinical management of affected individuals.

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform.

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms.

Malignant paraganglioma presenting with hemorrhagic stroke in a child.

Sympathetic paragangliomas are rare catecholamine-secreting tumors of extra-adrenal origin, and their diagnosis in children is even more infrequent. They usually manifest as hypertension, palpitations, headache, sweating, and pallor. Malignant paragangliomas are identified by the presence of metastasis. Hemorrhagic stroke in the pediatric population is a life-threatening condition with several etiologies. We report here the case of a 12-year-old boy with malignant sympathetic paraganglioma presenting with hemorrhagic stroke. Severe hypertension was found and the patient evolved into a coma. Brain computed tomography scan showed right thalamus hemorrhage with intraventricular extension. After clinical improvement, further investigation revealed elevated catecholamine and metanephrine levels, and 2 abdominal tumors were identified by computed tomography. Resection of both lesions was performed, and histologic findings were consistent with paraganglioma. Multiple metastatic involvement of bones and soft tissues appeared several years later. Genetic testing identified a mutation in succinate dehydrogenase subunit B gene, with paternal transmission. 131I-metaiodobenzylguanidine therapy was performed 3 times with no tumoral response. Our patient is alive, with adequate quality of life, 25 years after initial diagnosis. To our knowledge, this is the first pediatric case of paraganglioma presenting with hemorrhagic stroke. Intracerebral hemorrhage was probably caused by severe hypertension due to paraganglioma. Therefore, we expand the recognized clinical spectrum of the disease. Physicians evaluating children with hemorrhagic stroke, particularly if hypertension is a main symptom, should consider the possibility of catecholamine-secreting tumors. Metastatic disease is associated with succinate dehydrogenase subunit B mutations and, although some patients have poor prognosis, progression can be indolent.

Thyroid tuberculosis with abnormal thyroid function--case report and review of the literature.

OBJECTIVE: To report an extremely rare case of thyroid tuberculosis (TT) with abnormal thyroid function and to review the related literature. METHODS: We present the patient's history, clinical findings, laboratory test results, imaging examinations, cytological data, management, and follow-up. In addition, we perform a review of the previously published cases of TT and give special attention to those with hypothyroidism. RESULTS: A 45-year-old Indian man presented to the outpatient clinic with neck swelling and respiratory and constitutional symptoms. Cervical ultrasound revealed a thyroid nodule and a necrotic right cervical adenopathy. Fine-needle aspiration cytology (FNAC) was performed and purulent material was removed from thyroid and lymph node. In both specimens, the culture was positive for Mycobacterium tuberculosis complex, and a cytological examination revealed epithelioid cell granulomas and necrosis. Mycobacterium tuberculosis complex was also identified by sputum culture. Antibiotic testing revealed sensitivity to all first-line drugs. A diagnosis of disseminated tuberculosis with thyroid and cervical lymph node involvement was made. Thyroid function was consistent with subclinical hyperthyroidism that subsequently evolved to hypothyroidism, requiring thyroid hormone replacement, and reflected tuberculous thyroiditis. Anti-tuberculosis drugs were started with good therapeutic response. CONCLUSION: TT is a rare condition and its association with thyroid function abnormalities is even rarer. To our knowledge this is the third report of hypothyroidism related to TT and the first to identify a period of hyperthyroidism preceding hypothyroidism. Despite its rarity, TT should be considered in the differential diagnosis of neck mass. FNAC is a useful procedure and thyroid function should be monitored.