Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients.

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

Evolution of interconsultal activity to endocrinology and nutrition in hospitalization floor in a third level hospital.

INTRODUCTION: Endocrinology and Nutrition (EyN) is an outpatient and hospital medical specialty. This study aims to understand the evolution of the activity of interdepartmental consultation (IC) carried out by EyN in hospitalization floor of a third level hospital, comparing its evolution with other medical specialties, and comparing endocrine IC with nutritional IC. MATERIAL AND METHODS: Longitudinal and retrospective study which analyzes IC notes of EyN and other medical specialties between 01-01-2013 and 31-12-2022. RESULTS: A total of 76093 IC notes (12623 patients) were performed by the EyN service (average age 65.4 years; 59% male) with an average of 4.8 notes per patient. Average annual growth was 7% in notes and 4% in patients (versus 6% and 3% of all other medical services, differences statistically significant). Of all patients hospitalized for 4 or more days, EyN went from attending 7.9% (2013) to 12.3% (2022). 66% of the IC performed by EyN was for nutritional cause and 34% for other pathologies. CONCLUSIONS: The EyN service is the one that most patients attend in hospital IC activity, with growth over the last few years greater than other medical specialties. Nutritional pathology is the main reason for IC.

First survey on the diagnosis and treatment of primary aldosteronism by Spanish Endocrinology and Nutrition specialists.

OBJECTIVE: To evaluate the indication and the resources for the screening/diagnosis of primary aldosteronism (PA) in Endocrinology units in Spain. MATERIAL AND METHODS: An anonymous 2-phase (2020/2021) online survey was conducted by the AdrenoSEEN group among SEEN members with data about screening, confirmation tests, availability of catheterisation and the treatment of PA. RESULTS: Eighty-eight (88) specialists completed the survey. Plasma aldosterone concentration and plasma renin activity were available at all centres; urinary aldosterone was available in 55% of them. The most frequent indications for determining the aldosterone/renin ratio (ARR) were adrenal incidentaloma (82.6%), hypertension with hypokalaemia (82.6%), hypertension in patients <40 years (79.1%) and a family history of PA (77.9%). 61% and 18% of the respondents used an ARR cut-off value of PA of ≥30 and 20ng/dl per ng/mL/, respectively. The intravenous saline loading test was the most commonly used confirmatory test (66.3%), followed by the captopril challenge test (24.4%), with the 25mg dose used more than the 50mg dose (65% versus 35%). 67.4% of the participants confirmed the availability of adrenal vein catheterization (AVC). 41% of this subgroup perform it with a continuous infusion versus 30.5% with an ACTH (1-24) bolus, whereas 70.3% employ sequential adrenal vein catheterization. 48% of the participants reported an AVC success <50%. Total laparoscopic adrenalectomy was the treatment of choice (90.6%), performed by specialists in General and Digestive Surgery specialising in endocrinological pathology. CONCLUSION: PA screening and diagnostic tests are extensively available to Spanish endocrinologists. However, there is a major variability in their use and in the cut-off points of the diagnostic methods. The AVS procedure remains poorly standardised and is far from delivering optimal performance. Greater standardisation in the study and diagnosis of PA is called for.

Improving management of severe hypoparathyroidism: a case series.

INTRODUCTION: Hypoparathyroidism is considered a rare endocrine disease. Despite being a deficiency of parathyroid hormone, the standard therapy is based on oral calcium and active vitamin D supplementation. This approach provides satisfactory management in most cases but may be inadequate for patients in the most complex spectrum of the disease. Other therapies are being explored, and among them, the use of recombinant human parathyroid hormone (PTH) has proved to decrease the requirements of calcium and active vitamin D to reach adequate therapeutic goals. OBJECTIVE: We aimed to provide information on the effectiveness of the current recombinant parathyroid hormone analogs in the clinical management of difficult to control cases of hypoparathyroidism. METHOD AND MATERIALS: We report our experience using teriparatide and PTH (1-84) through five complex cases of hypoparathyroidism of diverse etiologies. We describe each case and report the effectiveness of treatment in clinical practice. RESULTS: Four patients with postsurgical hypoparathyroidism and one patient with autoimmune hypoparathyroidism, all of them with suboptimal control under the standard treatment with calcium and calcitriol supplements or calcium gluconate infusion, are presented. They were all started on teriparatide or PTH (1-84), and all of them showed a diminishment of symptoms and were able to maintain normocalcemia without parenteral calcium despite a reduction of oral treatment. CONCLUSION: This article highlights the effectiveness and safety of hormonal replacement treatment in difficult to manage hypoparathyroidism and provides evidence which justifies its off-label prescription in the case of teriparatide. We consider that this treatment should be considered in cases in which standard treatment fails to reach adequate therapeutic goals.

Clinical differences between patients with MODY-3, MODY-2 and type 2 diabetes mellitus with I27L polymorphism in the HNF1alpha gene.

OBJECTIVE: The aim of our study was to describe and evaluate the clinical and metabolic characteristics of patients with MODY-3, MODY-2 or type 2 diabetes who presented I27L polymorphism in the HNF1alpha gene. METHODS: The study included 31 previously diagnosed subjects under follow-up for MODY-3 (10 subjects from 5 families), MODY-2 (15 subjects from 9 families), or type 2 diabetes (6 subjects) with I27L polymorphism in the HNF1alpha gene. The demographic, clinical, metabolic, and genetic characteristics of all patients were analyzed. RESULTS: No differences were observed in distribution according to sex, age of onset, or form of diagnosis. All patients with MODY-2 or MODY-3 had a family history of diabetes. In contrast, 33.3% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene had no family history of diabetes (p < 0.05). No differences were observed in body mass index, prevalence of hypertension, or microvascular or macrovascular complications. Drug therapy was required by 100% of MODY-3 patients, but not required by 100% of MODY-2 patients or 16.7% of patients with type 2 diabetes mellitus and I27L polymorphism in the HNF1alpha gene (p < 0.05). CONCLUSIONS: Occasional difficulties may be encountered when classifying patients with MODY-2, MODY-3 or type 2 diabetes of atypical characteristics, in this case patients who present I27L polymorphism in the HNF1alpha gene.

Practical guide on the initial evaluation, follow-up, and treatment of adrenal incidentalomas Adrenal Diseases Group of the Spanish Society of Endocrinology and Nutrition. / Guía práctica sobre la evaluación inicial, seguimiento y tratamiento de los incidentalomas adrenales. Grupo de patología adrenal de la Sociedad Española de Endocrinología y Nutrición.

Initial evaluation of adrenal incidentalomas should be aimed at ruling out malignancy and functionality. For this, a detailed clinical history should be taken, and an adequate radiographic assessment and a complete blood chemistry and hormone study should be performed. The most controversial condition, because of the lack of consensus in its definition, is autonomous cortisol secretion. Our recommendation is that, except when cortisol levels <1.8µg/dL in the dexamethasone suppression test rule out diagnosis and levels ≥5µg/dL establish the presence of autonomous cortisol secretion, diagnosis should be based on a combined definition of dexamethasone suppression test ≥3µg/dL and at least one of the following: elevated urinary free cortisol, ACTH level <10 pg/mL, or elevated nocturnal cortisol (in serum and/or saliva). During follow-up, dexamethasone suppression test should be repeated, usually every year, on an individual basis depending on the results of prior tests and the presence of comorbidities potentially related to hypercortisolism. The initial radiographic test of choice for characterization of adrenal incidentalomas is a computed tomography scan without contrast, but there is no unanimous agreement on subsequent monitoring. Our general recommendation is a repeat imaging test 6-12 months after diagnosis (based on the radiographic characteristics of the lesion). If the lesion remains stable and there are no indeterminate characteristics, no additional radiographic studies would be needed. We think that patients with autonomous cortisol secretion with comorbidities potentially related to hypercortisolism, particularly if they are young and there is a poor control, may benefit from unilateral adrenalectomy. The indication for unilateral adrenalectomy is clear in patients with overt hormonal syndromes or suspected malignancy. In conclusion, adrenal incidentalomas require a comprehensive evaluation that takes into account the possible clinical signs and comorbidities related to hormonal syndromes or malignancy; a complete hormone profile (taking into account the conditions that may lead to falsely positive and negative results); and an adequate radiographic study. Monitoring and/or treatment will be decided based on the results of the initial evaluation.

[Treatment of Cushing's disease. Transsphenoidal surgery and pituitary radiotherapy]. / Tratamiento de la enfermedad de Cushing. Cirugía transesfenoidal y radioterapia hipofisaria.

Transsphenoidal surgery is currently considered the treatment of choice for Cushing's disease. Initial remission is achieved in approximately 70-85%, but 10-15% of patients with remission will suffer a recurrence months or years later. Pituitary irradiation has been used as a therapeutic tool for many years. Nowadays, this option is considered a second-line treatment, to be used when there is postsurgical persistence or recurrence of the disease. The present article reviews the surgical approaches, remission rates reported by different groups, prognostic factors, and the most frequent complications after transsphenoidal surgery. We also review the different techniques that can be used for pituitary irradiation, as well as the efficacy and morbidity reported for each of these techniques in patients with Cushing's disease.

[Thyroid orbitopathy, an overview with special attention to the role of radiotherapy]. / Orbitopatía tiroidea, una visión global con atención especial al papel de la radioterapia.

Thyroid orbitopathy is the most prevalent non-thyroid symptom in Graves' syndrome. It has a high incidence and particularly affects young women. Smoking is clearly involved in its development and progress, and in its response to different treatments. This autoimmune condition usually has a benign course, independent from hyperthyroidism, but its severe, progressive forms represent a major therapeutic challenge. Clinical evaluation poses great difficulties, as there is no truly objective rating scale representing disease activity. New molecular or inflammation markers may prove to be useful in this regard. This review reports new findings about its pathophysiology and the different techniques used for treatment over time. Discussion particularly focuses on the immunomodulatory role of radiotherapy, as well as on its role together with corticosteroids.

Metabolic consequences of craniopharyingioma and their management.

Most patients diagnosed with craniopharyngioma survive long-term, but suffer many consequences of the disease and its treatment. Among the metabolic consequences, there is a high prevalence of panhypopituitarism and diabetes insipidus, mainly due to the surgical treatment. Obesity is also more prevalent in these patients than in the general population, and gets worse with time. It is a consequence of a diminished basal metabolic rate and a lower physical activity compared to that of matched controls, with a similar or lower caloric intake. Many different hormonal alterations that could be responsible for those changes in the energy balance have been found. Patients whose tumor involved the hypothalamus are more prone to develop obesity and its consequences. Cardiovascular risk factors are also more prevalent in these patients, leading to a high cardiovascular morbidity and mortality. Sleep disturbances, dysfunction in thermoregulation and thirst and a lower bone mineral density can also be found. Although randomized clinical trials comparing different treatments are lacking, it looks like therapeutic strategies have a minor influence on the risk of long-term sequelae.

Importance of clinical variables in the diagnosis of MODY2 and MODY3.

AIMS: MODY (maturity onset diabetes of the young) is a group of well-defined diseases clinically characterised by onset before age 25 years that does not require insulin treatment (at least initially) to prevent the formation of ketone bodies and autosomal dominant inheritance. Despite the importance of accurate classification, it is not always simple to catalogue the diagnosis of a young patient with diabetes, and genetic studies are often improperly used. METHODS: We describe the clinical features of patients negative for MODY2 and MODY3 and compared them to patients positive for these subtypes. RESULTS: All patients with MODY3 had been diagnosed before age 25 years and required drug therapy for blood glucose control. MODY2 patients were diagnosed at the first laboratory workup either incidentally or as part of gestational diabetes screening. The clinical description of the 19 patients negative for MODY2 and MODY3 showed that only two patients presented a clinical picture consistent with MODY3 and one patient with MODY2. CONCLUSIONS: Clinical features can be used for early exclusion of a MODY2 or MODY3 diagnosis and may reduce the need for genetic testing.