Eduardo Pimentel Dias

Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with germline HRPT2 mutations

Background Familial forms of hyperparathyroidism are responsible for approximately 10% of the cases of primary hyperparathyroidism, and their management is different from the sporadic forms. Our objective was to study the gene sequence and expression of HRPT2 and clinical outcome regarding recurrence or persistence rates in three Brazilian kindreds with familial hyperparathyroidism after up to 30 years of follow-up. Methods Clinical and biochemical data, direct sequencing of germline DNA of the HRPT2 gene, and analysis of parafibromin expression (HRPT2 gene product) using RT-PCR and immunohistochemistry of resected parathyroid neoplasms were performed. Results Affected members of kindred A were found to carry a novel, germline, nonsense mutation in exon 1 (c.96G>A; W32X) of HRPT2. Six of seven patients who have undergone less than total parathyroidectomy recurred after up to 30 years of follow-up. An unrelated affected patient from kindred B had a germline mutation in exon 7 (c.686delGAGT), and the disease recurred with several pulmonary metastases after 5 years follow-up. The affected member of kindred C also had a previously described mutation in exon 7 (c.679delAG) and the disease recurred after 10 years of follow-up. All parathyroid neoplasms from these families had diffuse loss of expression by immunohistochemistry. Conclusions An unacceptable recurrence/persistence rate (80%) associated with increasingly difficult re-operations and risk of parathyroid carcinoma in the setting of germline mutations of HRPT2 gene with familial hyperparathyroidism suggest that a more aggressive operative approach should be undertaken in these patients. Parafibromin immunohistochemistry may serve as a cost-effective screen for HRPT2-related aggressive parathyroid disease.

Prevalência de deficiência e insuficiência de vitamina D e sua correlação com PTH, marcadores de remodelação óssea e densidade mineral óssea, em pacientes ambulatoriais

Consequences of VD deficiency include rickets and osteomalacia. However, marginal concentrations of 25-hydroxyvitamin D (25(OH)VD) are associated with secondary hyperparathyroidism and osteoporosis. In this context, levels of 25(OH)VD capable to elevate parathyroid hormone (PTH) could be considered as insufficient. The VD insufficiency, although widely prevalent, is still under-recognized and under-treated. The authors have studied 180 patients followed in a endocrinology clinic in Belo Horizonte, who had 25(OH)VD measured, correlating it with PTH, biochemical bone turnover markers and bone mineral density. To determine the sufficiency of VD, 25(OH)VD was correlated with PTH and the cutoff found was of 32ng/ml. CTX-1 and PTH were significantly negative correlated to 25(OH)VD and the prevalence of VD insufficiency was 42%. One concludes that the VD insufficiency is widely prevalent among patients who frequently come to our offices, alerting us for the importance to assess VD status more often and to practice politics for prevention of VD insufficiency.

Duplication of the hypophysis associated with precocious puberty: presentation of two cases and review of pituitary embryogenesis

Pituitary duplication is a rare malformation commonly associated with other major neural/craniofacial anomalies, easily shown by magnetic resonance imaging. The authors describe two girls with duplication of the pituitary gland and thickening of the hypothalamus, facial dysmorphism and precocious pubertal development. The pathogenesis of pituitary duplication and its relationship with precocious pubertal development are discussed.

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafibromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafibromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75%), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotype-genotype correlation in larger series, to best define their treatment.

Serum and salivary cortisol in the diagnosis of adrenal insufficiency and as a predictor of the outcome in patients with severe sepsis

OBJECTIVES To compare salivary with serum total cortisol in patients with severe sepsis, postoperative patients and healthy controls. MATERIALS AND METHODS Serum total cortisol was determined by chemiluminescence immunoassay; salivary cortisol was determined by enzyme immunoassay. RESULTS In patients with severe sepsis, median concentration of salivary cortisol was 14.0 and 2.6 higher than that of postoperative patients and healthy subjects. In postoperative patients, salivary cortisol was 5.4 times higher than in control patients. Serum total cortisol was also higher in patients with severe sepsis than in controls and postoperative patients. This increment, however, was much lower (2.33 and 1.64, respectively). Patients with a salivary cortisol greater than 7.2 µg/dL had a mortality rate of 80%, a statistically significant result when compared with the group with lower cortisol levels (Z = 2.38 and p < 0.05). CONCLUSIONS Salivary cortisol in critically ill patients may be a better laboratory indicator of cortisol levels than serum total cortisol.

Alterações da haste hipofisária e suas implicações clínicas

Magnetic resonance imaging (MRI) of the pituitary stalk has revealed certain abnormalities with significant clinical relevance. In order to correctly appreciate them, one must be aware of the embryology and anatomy of the pituitary-hypothalamic axis and the criteria that define a normal MRI. Pituitary stalk thickening is frequently related to Diabetes Insipidus and this finding requires further evaluation, especially in children and adolescents. A truncated, thin or absent stalk can be associated with growth hormone deficiency and contribute to the prediction of the severity and the pattern of the hypopituitarism. At last, mutations of different transcription factors controlling pituitary development may be associated with characteristic pituitary-hypothalamic MRI abnormalities, underscoring its utility in the assessment of congenital hypopituitarism.

Doença de cushing subclínica: relato de três casos e revisão da literatura

Unlike subclinical Cushings disease, adrenal subclinical Cushings syndrome is widely recognized. It is defined as an autonomous cortisol hyperproduction of mild intensity not causing specific clinical signs, but detectable biochemically as derangements of the hypothalamic-pituitary-adrenal axis function. Although Cushings disease accounts for the majority of hypercortisolism states, subclinical Cushings disease has been rarely reported. Three cases of subclinical Cushings disease due to pituitary corticotrophic macroadenomas, confirmed by immunohistochemistry, are presented in order to underscore its recognition by clinical endocrinologists and to emphasize a diagnostic evaluation of hypercortisolism in all cases of pituitary adenomas.

Whole-exome identifies RXRG and TH germline variants in familial isolated prolactinoma

Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored.