Local recurrence and metastatic disease in pheochromocytomas and sympathetic paragangliomas.

Purpose: To evaluate the rate of recurrence among patients with pheochromocytomas and sympathetic paragangliomas (PGLs; together PPGLs) and to identify predictors of recurrence (local recurrence and/or metastatic disease). Methods: This retrospective multicenter study included information of 303 patients with PPGLs in follow-up in 19 Spanish tertiary hospitals. Recurrent disease was defined by the development of local recurrence and/or metastatic disease after initial complete surgical resection. Results: A total of 303 patients with PPGLs that underwent 311 resections were included (288 pheochromocytomas and 15 sympathetic PGLs). After a median follow-up of 4.8 years (range 1-19), 24 patients (7.9%) had recurrent disease (3 local recurrence, 17 metastatic disease and 4 local recurrence followed by metastatic disease). The median time from the diagnosis of the PPGL to the recurrence was of 11.2 months (range 0.5-174) and recurrent disease cases distributed uniformly during the follow-up period. The presence of a pathogenic variant in SDHB gene (hazard ratio [HR] 13.3, 95% CI 4.20-41.92), higher urinary normetanephrine levels (HR 1.02 per each increase in standard deviation, 95% CI 1.01-1.03) and a larger tumor size (HR 1.01 per each increase in mm, 95% CI 1.00-1.02) were independently associated with disease recurrence. Conclusion: The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.

Genetic Study in Pheochromocytoma: Is It Possible to Stratify the Risk of Hereditary Pheochromocytoma?

INTRODUCTION: It is estimated that 30-40% of patients with apparently sporadic pheochromocytomas (PHEOs) have an inherited predisposition syndrome. The aim of our study was to develop a predictive model of hereditary PHEO based on the clinical, hormonal, and radiological features present at the diagnosis of patients with PHEOs. METHODS: A retrospective multicenter cohort study of patients with PHEOs with available genetic study from 18 tertiary hospitals. Clinical, biochemical, and radiological features were used to build a multivariate logistic regression model. The estimation of all possible equations was used to select the model with the best diagnostic accuracy (lower Akaike index). RESULTS: A total of 245 patients were included: 169 (69.0%) patients with sporadic PHEOs and 76 (31%) with hereditary PHEOs. The parsimonious predictive model with the highest diagnostic accuracy for the prediction of hereditary PHEO combined the variables age, non-cardiovascular disease, urinary norepinephrine levels, and tumor size. The area under the ROC curve of this model was 0.800 (0.705-0.887). Based on the predictive model, the probability of hereditary PHEO in patients older than 60 years with cardiovascular disease, high levels of urinary norepinephrine and unilateral PHEOs >60 mm was <2%. And if the age was above 80 years, lower than 1%. The probability of sporadic PHEO linearly increased with age (MH Test for linear Trend: χ2 (1) = 30.05; p < 0.001). CONCLUSION: In certain populations such as old patients with cardiovascular disease, with high levels of urinary norepinephrine and large tumors in which the probability of hereditary PHEO is very low, genetic testing could be avoided in the absence of specific suspicion.

Nonfunctioning adrenal incidentalomas with cortisol post-dexamethasone suppression test >0.9 µg/dL have a higher prevalence of cardiovascular disease than those with values ≤0.9 µg/dL.

PURPOSE: To analyze the differences in the cardiometabolic profile in patients with nonfunctioning adrenal incidentalomas (NFAI) with post-dexamethasone suppression test (DST) cortisol ≤1.4 µg/dL (NFAI ≤ 1.4) and those with post-DST cortisol >1.4 µg/dL (NFAI > 1.4) and between NFAI with post-DST cortisol ≤0.9 µg/dL (NFAI ≤ 0.9) and those with levels >0.9 µg/dL (NFAI > 0.9). METHODS: Multicenter retrospective observational study of patients with NFAIs. NFAI was defined as an adrenal incidentaloma with negative hormonal study (including metanephrines, post-DST cortisol ≤1.8 µg/dL and aldosterone/renin ratio when screening was indicated). Autonomous cortisol secretion (ACS) development was defined as an NFAIs in which post-DST serum cortisol >1.8 µg/dL were evidenced during hormonal follow-up evaluation. RESULTS: A total of 593 NFAI were included. Based on the 1.4 µg/dL threshold in the DST, most of the NFAI were classified as NFAI ≤ 1.4 (74.5%). Patients in the NFAI > 1.4 group were older than those in the NFAI ≤ 1.4 group, but there was no difference in the cardiometabolic profile after adjusting for age. A total of 69.5% of the patients had DST > 0.9 µg/dl. They were older and had a higher prevalence of cardiovascular disease than NFAI ≤ 0.9, even after adjusting by age (adjusted OR = 2.23 [1.10-4.53]). Patients in the NFAI > 1.4 group developed ACS more commonly than the NFAI ≤ 1.4 group (23.5% vs. 7.44%, P < 0.001). However, when the threshold of 0.9 µg/dL was considered, no difference was found between NFAI ≤ 0.9 and NFAI > 0.9 (P = 0.126). CONCLUSION: The threshold of 1.4 µg/dL in the DST is useful to predict which patients with NFAI had a higher risk of ACS development during follow-up; and the threshold of 0.9 µg/dL to identify those patients with NFAI with a higher cardiovascular risk.

Insulin doses requirements in patients with type 1 diabetes using glargine U300 or degludec in routine clinical practice.

There are not many real-world studies evaluating daily insulin doses requirements (DIDR) in patients with type 1 diabetes (T1D) using second-generation basal insulin analogs, and such comparison is necessary. The aim of this study was to compare DIDR in individuals with T1D using glargine 300 UI/mL (IGlar-300) or degludec (IDeg) in real clinical practice. An observational, retrospective study was designed in 412 patients with T1D (males: 52%; median age 37.0±13.4 years, diabetes duration: 18.7±12.3 years) using IDeg and IGla-300 ≥6 months to compare DIDR between groups. Patients using IGla-300 (n=187) were more frequently males (59% vs 45.8%; p=0.004) and had lower glycosylated hemoglobin (HbA1c) (7.6±1.2 vs 8.1%±1.5%; p<0.001) than patients using IDeg (n=225). Total (0.77±0.36 unit/kg/day), basal (0.43±0.20 unit/kg/day) and prandial (0.33±0.23 unit/kg/day) DIDR were similar in IGla-300 and IDeg groups. Patients with HbA1c ≤7% (n=113) used significantly lower basal (p=0.045) and total (p=0.024) DIDR, but not prandial insulin (p=0.241), than patients with HbA1c between 7.1% and 8% and >8%. Patients using IGla-300 and IDeg used similar basal, prandial and total DIDR regardless of metabolic control subgroup. No difference in basal, prandial and total DIDR was observed between patients with T1D using IGla-300 or IDeg during at least 6 months in routine clinical practice.

Tumor carcinoide sobre teratoma ovárico quístico / Carcinoid tumor on cystic ovarian teratoma

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Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.

Utilidad del estudio genético en la hipercalcemia hipocalciúrica familiar en familias con presentaciones clínicas atípicas / Usefulness of genetic tests in familial hypocalciuric hypercalcemia with atypical clinical presentation

Tradicionalmente se ha pensado que las pruebas bioquímicas del metabolismo fosfocálcico permiten diferenciar el hiperparatiroidismo primario (HPT1) y la hipercalcemia hipocalciúrica familiar (HHF) pero hay casos de difícil diagnóstico incluso para clínicos experimentados. Nos planteamos como objetivo evaluar la validez de las pruebas diagnósticas de la HHF así como la correcta indicación del estudio genético. Pacientes y métodos Hemos realizado un estudio descriptivo de 2 familias con hipercalcemia y sospecha de HHF de características atípicas. En orina de 24h hemos valorado los índices de excreción urinaria de calcio (eliminación de calcio [CE], cociente calcio/creatinina [CR] y cociente aclaramiento de calcio/aclaramiento de creatinina [CCCR]), junto con las concentraciones séricas de PTH y 25 hidroxivitamina D. A los casos índices se les realizó el estudio genético. Resultados Una paciente presentó hipercalciuria franca y persistente con valores más concordantes con HPT1 que de HHF si consideramos, como proponen las guías, un CCCR inferior a 0,01 como indicativo de HHF y superior a 0,02 como HPT1. Al caso índice de la segunda familia se le extirpó un adenoma de paratiroides. En ambos casos índice, encontramos la misma mutación c. 164C>T (p.Pro55Leu) en el exón 2 en heterocigosis descrita como responsable de HHF. Conclusiones El diagnóstico definitivo de HHF en las guías clínicas actuales requiere confirmación genética, lo cual ha permitido en nuestro caso la detección de 2 familias con HHF y características clínicas atípicas. En nuestra opinión el uso racional de estas pruebas ante la sospecha de HFF puede evitar intervenciones quirúrgicas innecesarias y gastos excesivos en su monitorización (AU)

Objectives: Biochemical tests related to calcium and phosphorus metabolism have traditionally been considered as a reliable tool to differentiate familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism (PHPT). However, diagnosis may sometimes be difficult even for experienced clinicians. Our objective was to assess the accuracy of diagnostic tests in FHH and the circumstances in which genetic studies are required. Patients and methods: A descriptive study was conducted of two families with hypercalcemia and suspected atypical FHH. Urinary calcium excretion was measured in 24-hour urine using different tests (calcium excretion (CE), urinary calcium/creatinine clearance ratio (UCCR)),and serum PTH and 25-hydroxyvitamin D levels were tested. Index cases underwent genetic study. Results: One patient from the first family showed overt, persistent hypercalciuria with values more consistent with PHPT than with FHH if we consider, as proposed by guidelines, a UCCR lower than 0.01 as diagnostic of FHH and a value higher than 0.02 as diagnostic of PHPT. The index case of the second family underwent surgery for a parathyroid adenoma. Both cases had a mutation c. 164C>T (Pro55Leu) in exon 2 in heterozygosis. Conclusions: According to current clinical guidelines, definitive diagnosis of FHH requires genetic confirmation, which allowed in our case for detection of two families with FHH and atypicalclinical presentations. We think that rational use of genetic tests may avoid unnecessary surgery and excess monitoring costs (AU)