Georgios Papadakis

Menopausal Hormone Therapy Is Associated With Reduced Total and Visceral Adiposity: The OsteoLaus Cohort

Context After menopause, fat mass (FM) and visceral adipose tissue (VAT) increase and nonbone lean body mass (LBM) decreases. Whether menopausal hormone therapy (MHT) reverses these changes remains controversial. Objective To assess the effect of MHT on FM, VAT, and LBM before and after its withdrawal and evaluate potential confounders. Design Cross-sectional study. Setting General community. Patients or Other Participants Women of the OsteoLaus cohort (50 to 80 years old) who underwent dual-energy X-ray absorptiometry (DXA) with body composition assessment. After we excluded women with estrogen-modifying medications, the 1053 participants were categorized into current users (CUs), past users (PUs), and never users (NUs) of MHT. Intervention None. Main Outcome Measures VAT measured by DXA was the primary outcome. We assessed subtotal and android FM, LBM, muscle strength (hand grip), and confounding factors (caloric intake, physical activity, biomarkers). Results The groups significantly differed in age, NU < CU < PU. Age-adjusted VAT was lower in CUs than NUs (P = 0.03). CUs exhibited lower age-adjusted body mass index (BMI) (-0.9 kg/m2) and a trend for lower FM (-1.3 kg). The 10-year gain of VAT (P < 0.01) and subtotal and android FM (P < 0.05) was prevented in CUs. No difference in LBM or hand grip was detected. No residual effect was detected for PUs, including for early MHT discontinuers. The confounding factors did not significantly differ between groups except for higher caloric intake in PUs compared with NUs. Conclusions MHT is associated with significantly decreased VAT, BMI, and android FM. No benefit is detected for LBM. The benefits are not preserved in PUs, suggesting caution when MHT is discontinued.

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures

Objective Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Conclusions Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Uptake of 99mTc-MIBI by Sclerosing Pneumocytoma Raising a False Suspicion of Metastasis From Medullary Thyroid Carcinoma

Abstract Technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI; sestamibi) single-photon emission computed tomography (SPECT)/computed tomography (CT) performed for preoperative localization of parathyroid adenomas or for other indications can reveal incidentalomas. Interpretation of such findings can be challenging, particularly when thyroid or other endocrine tumors are also present. Preoperative staging of a 59-year-old female patient with medullary thyroid carcinoma (MTC) showing moderate hypermetabolism on 18F-fluorodeoxyglucose positron emission tomography/CT also detected a slightly hypermetabolic pulmonary nodule (standardized uptake value normalized by body weight max = 2.0 g/mL). A sestamibi SPECT/CT performed because of concomitant primary hyperparathyroidism showed increased uptake by both the MTC and the pulmonary nodule, raising suspicion of MTC metastasis. Lung wedge resection biopsy revealed a sclerosing pneumocytoma (SPC), a rare benign pulmonary tumor not previously known to retain sestamibi. In contrast to classical knowledge that sestamibi uptake by tumors is associated with its retention by mitochondria, immunohistochemical analyses showed that the mitochondrial content of the patient’s SPC was low. This case illustrates the behavior of SPC in sestamibi scintigraphy and indicates that SPC is a potential cancer mimicker in this setting.

DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.

Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants.

PurposeCongenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined.MethodsRare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype–phenotype correlations were evaluated.ResultsOf the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01).ConclusionPathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.