We recently read with interest the article by Ricketts and colleagues [2010] based on a genotype-phenotype association study performed in a very large number of germline SDHB or SDHD mutation carriers. Genetic variants in three of the four succinate dehydrogenase genes (SDHB, SDHC, and SDHD) are known to cause hereditary susceptibility to three closely related paraganglioma syndromes: PGL4 (MIM 115310), PGL3 (MIM 605373), and PGL1 (MIM 168000), respectively. Although the development of extraadrenal paragangliomas is the main clinical feature common to these three syndromes, the presence of extra-paraganglial manifestations and metastases in PGL4 highlights the need for improved understanding of SDHB-mutation-associated characteristics. In this regard, it should be noted that SDHB-related paragangliomas usually appear as isolated masses in elderly patients with no familial antecedents [Cascon et al., 2009a], which strongly indicates that mutations in this gene have a low penetrance (age-specific cumulative risk of cancer). Ricketts and colleagues [2010] estimated an average penetrance of 50% by age 50 years using 295 affected and unaffected SDHB mutation carriers from 125 families. This estimate was lower than that previously reported by Neumann and colleagues [2004] (75% by 50 years), but was more consistent with that found by Benn and colleagues [2006] ($55% by 50 years). These three studies estimated the penetrance using standard Kaplan-Meier methods applied to tested mutation carriers. These methods overestimate the average penetrance because no correction is made for the ascertainment of mutation carriers. All mutation carriers are identified via index cases that have both the mutation and the disease, and this should be taken into consideration in the analysis.To estimate the penetrance of mutations in SDHB, we carried out a similar family-based study of 446 people from 33 mutationcarrier families from Italy and Spain. Families were identified via a consecutive series of paraganglioma patients who were tested for mutations regardless of family history (Fig. 1). Information was collected for index patients and their relatives on relationship, sex, current age or age at death, paraganglioma diagnosis, and age at diagnosis. We estimated the age-specific average cumulative risk of paraganglioma via a maximum likelihood method using modified segregation analysis implemented in the pedigree analysis software, MENDEL. This method has been previously described in detail [Antoniou et al., 2003;Lange et al., 1988]. For each family, we maximized the conditional likelihood of observing all genotypes and disease phenotypes in the family, given the phenotype of the first individual to test positive. The incidence rates for mutation carriers were assumed to follow a Cox proportional hazards model, under which the incidence in mutation carriers is a constant multiple of the age-specific incidence in the general population. Individuals were followed from birth, and were censored at the first of paraganglioma diagnosis, ...
Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD-PHP-Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP-Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP-Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP-Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single-nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP-Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP-Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. ß
Our study suggests that female gender and high levels of A1C and systolic blood pressure throughout the course of the disease are the main factors associated with an increased risk for development of nephropathy in patients with type 1 diabetes mellitus.
Background: Recent guidelines for the treatment of hypoparathyroidism emphasize the need for long-term disease control, avoiding symptoms and hypocalcaemia. Our aim has been to analyze the prevalence of poor disease control in a national cohort of patients with hypoparathyroidism, as well as to evaluate predictive variables of inadequate disease control.Methods: From a nation-wide observational study including a cohort of 1792 patients undergoing total thyroidectomy, we selected 260 subjects [207 women and 53 men, aged (mean ± SD) 47.2±14.8 years] diagnosed with permanent hypoparathyroidism. In every patient demographic data and details on surgical procedure, histopathology, calcium (Ca) metabolism, and therapy with Ca and calcitriol were retrospectively collected. A patient was considered not adequately controlled (NAC) if presented symptoms of hypocalcemia or biochemical data showing low serum Ca levels or high urinary Ca excretion.Results: Two hundred and twenty-one (85.0%) patients were adequately controlled (AC) and 39 (15.0%) were NAC. Comparison between AC and NAC patients did not show any significant difference in demographic, surgical, and pathological features. Rate of hospitalization during follow-up was significantly higher among NAC patients in comparison with AC patients (35.9% vs. 10.9%, P<0.001). Dose of oral Ca and calcitriol were also significantly higher in NAC subjects. In a subgroup of 129 patients with serum parathyroid hormone (PTH) levels available, we found that NAC patients exhibited significantly lower postoperative PTH concentrations than AC patients [median (interquartile range) 3 (1.9-7.8) vs. 6.9 (3.0-11) pg/mL; P=0.009].Conclusions: In a nation-wide cohort of 260 subjects with definitive hypoparathyroidism, 15% of them had poor disease control. These patients required higher doses of oral Ca and calcitriol, had higher rate of hospitalization during follow-up and showed lower PTH concentrations in the postoperative period.
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