José Manuel Cabezas-Agrícola

High variability in CYP21A2 mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effect

Objective To detect common as well as rare and novel CYP21A mutations in 21‐hydroxylase deficiency patients. To estimate the distribution of mutations and compare them with other European studies. To construct haplotypes linked to a recurrent novel mutation.

Progression of Nephropathy in Type 2 Diabetes: The Glycation Gap Is a Significant Predictor After Adjustment for Glycohemoglobin (Hb A1c)

BACKGROUND The glycation gap has been proposed as an index of nonglycemic determinants of glycated hemoglobin (Hb A(1c)). We investigated whether it predicts progression of nephropathy in type 2 diabetic patients. METHODS We recorded albumin excretion rate, Hb A(1c), and serum fructosamine in 2314 patients over an average of 6.5 years. Hb A(1c) was regressed on fructosamine by using a repeated-measures longitudinal regression model and data for all visits of all patients; the raw glycation gap gg was calculated at each visit, as measured by Hb A(1c) minus the value predicted by the regression; and the mean glycation gap (GG) was defined for each patient as the mean of the values for the raw glycation gap (gg) calculated at each visit. The study group was divided into high-, medium- and low-GG groups of equal sizes, which were compared for progression of nephropathy by Cox regression analyses controlling for age, sex, duration of diabetes, initial nephropathy status, therapy, baseline Hb A(1c), mean Hb A(1c), and mean fructosamine. The design of the study was a retrospective cohort study with follow-up for 6.5 (SD 4.2) years. RESULTS The gg exhibited considerable stability over time. In the high- and medium-GG groups, the risk of progression of nephropathy was respectively 2.5 and 1.6 times that of the low-GG group (P < 0.0001 and P = 0.001, respectively) after adjustment as described above. CONCLUSIONS GG predicts the progression of nephropathy in type 2 diabetic patients independently of fructosamine and even after adjustment for Hb A(1c). The joint use of the glycation gap and fructosamine as measures of nonglycemic and glycemic determinants of glycation, respectively, may improve evaluation of the risk of nephropathy and of the glycemic control desirable for the individual patient.

Pituitary Stalk Dysgenesis-Induced Hypopituitarism in Adult Patients: Prevalence, Evolution of Hormone Dysfunction and Genetic Analysis

Objectives: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. Design: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. Results: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. Conclusion: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.

CARDIAC AUTONOMIC NEUROPATHY, ESTIMATED CARDIOVASCULAR RISK, AND CIRCADIAN BLOOD PRESSURE PATTERN IN DIABETES MELLITUS

This study was designed to investigate potential factors involved in the disruption of the circadian blood pressure (BP) pattern in diabetes mellitus, as well as the relation between BP, cardiac autonomic neuropathy, and estimated cardiovascular risk. We studied 101 diabetic patients (58% with type 2 diabetes; 59% men), age 21–65 yrs, evaluated by 48 h BP monitoring. We performed three autonomic tests in a single session: deep breathing, Valsalva maneuver, and standing up from a seated position. Patients were classified according to the number of abnormal tests and their 10 yr risk of coronary heart disease or stroke. The prevalence of non-dipping 24 h patterning ranged from 47.6% in type 1 to 42.4% in type 2 diabetes. The awake/asleep ratio of systolic BP (SBP) was comparable between patients with or without abnormal autonomic tests. Pulse pressure (PP) was significantly higher in patients with ≥1 abnormal autonomic test (p < 0.001). Ambulatory SBP was significantly elevated in the group with higher risk of coronary heart disease (p < 0.001). Patients with higher stroke-risk had higher SBP but lower diastolic BP, and thus an elevated ambulatory PP by 9 mmHg, compared to those with lower risk (p < 0.001). Cardiac autonomic neuropathy is not the main causal-factor for the non-dipper BP pattern in diabetes mellitus. The most significant finding from this study is the high ambulatory PP found in patients with either cardiac autonomic dysfunction or high risk for coronary heart disease or stroke. After correcting for age, this elevated PP level emerged as the main cardiovascular risk factor in diabetes mellitus.

Thyroid Pathology Findings in Cowden Syndrome: A Clue for the Diagnosis of the PTEN Hamartoma Tumor Syndrome.

OBJECTIVES PTEN hamartoma tumor syndrome (PHTS) is a hereditary disorder caused by germline inactivating mutations of the PTEN gene. PHTS includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. We describe how the peculiar pathologic and immunohistochemical thyroid features lead pathologists to suggest PHTS. METHODS A 28-year-old white Spanish woman had a multinodular goiter. Total thyroidectomy was performed after fine-needle aspiration biopsy. Microscopic, immunohistochemical, and molecular analyses of the thyroid lesions were realized. RESULTS The thyroid was multinodular, showing one papillary microcarcinoma, five follicular adenomas, three adenolipomas, 46 tiny adenomatous nodules (microadenomas), scattered foci of adipose tissue, and lymphocytic thyroiditis. Tumors were positive for thyroglobulin, thyroperoxidase, pendrin, cyclin D1, and p27 but negative for calcitonin and PTEN. A germline heterozygous deletion of one adenine at nucleotide 827 in exon 8 of the PTEN gene was confirmed. No BRAF, NRAS, or KRAS somatic mutations were detected in the papillary microcarcinoma, follicular adenoma, adenolipomas, or microadenomas. Negativity for PTEN was also found in the colonic tubulovillous adenoma and the storiform collagenoma. CONCLUSIONS Pathologists play a crucial role in recognizing pathologic thyroid findings associated with PHTS for selecting patients for genetic testing.

Axonal neuropathy, long limbs and bumpy tongue: think of MEN2B.

Introduction: Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. Methods: A 14‐year‐old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot‐Marie‐Tooth syndrome). Results: Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. Conclusions: Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis. Muscle Nerve, 2012

Severe localized lipoatrophy related to therapy with insulin analogs in type 1a diabetes mellitus

Insulin analog-related lipoatrophy is a rare complication of this type of treatment. We report a case of severe localized lipoatrophy in different locations in a patient with type 1a diabetes mellitus associated with other autoimmune disease.

Long-term outcome of multimodal therapy for giant prolactinomas

Giant prolactinomas are rare tumors characterized by their large size, compressive symptoms, and extremely high prolactin secretion. The aim of this study is to describe our experience with a series of 16 giant prolactinomas cases in terms of clinical presentation, therapeutic decisions, and final outcomes. Retrospective analysis of adult patients diagnosed with giant prolactinomas at the endocrine departments of three university tertiary hospitals. We included 16 patients (43.7 % women); mean age at diagnosis: 42.1 ± 21 years. The most frequent presentation was compressive symptoms. The delay in diagnosis was higher in women (median of 150 months vs. 12 in men; p = 0.09). The mean maximum tumor diameter at diagnosis was 56.9 ± 15.5 mm, and mean prolactin levels were 10,995.9 ± 12,157.8 ng/mL. Dopamine agonists were the first-line treatment in 11 patients (mean maximum dose: 3.9 ± 3.2 mg/week). Surgery was the initial treatment in five patients and the second-line treatment in six. Radiotherapy was used in four cases. All patients but one, are still with dopamine agonists. After a mean follow-up of 9 years, prolactin normalized in 7/16 patients (43.7 %) and 13 patients (81 %) reached prolactin levels lower than twice the upper limit of normal. Mean prolactin level at last visit: 79.5 ± 143 ng/mL. Tumor volume was decreased by 93.8 ± 11.3 %, and final maximum tumor diameter was 18.4 ± 18.8 mm. Three patients are actually tumor free. Giant prolactinomas are characterized by a large tumor volume and extreme prolactin hypersecretion. Multimodal treatment is frequently required to obtain biochemical and tumor control.

Severe hypertension and hypokalemia as first clinical manifestations in ectopic Cushing's syndrome

Ectopic ACTH production occurs in about 10% of all cases of Cushings syndrome, and about 25% of cases of ACTH-dependent Cushings syndrome. Diverse tumor types are able to produce ACTH ectopically, including small cell lung carcinoma. Ectopic ACTH secretion by malignant neoplasm has been reported to have earlier and more aggressive metabolic effects. We report a 59-year-old male patient with severe hypertension, metabolic alkalosis and hypokalemia as the first clinical manifestations of an ACTH-secreting small cell lung carcinoma, although the typical phenotypic features of Cushings syndrome were not present. Ectopic Cushings syndrome should always be ruled out in patients with severe hypertension and hypokalemia.

Betahidroxibutirato capilar en la monitorización de la cetoacidosis diabética

BACKGROUND AND OBJECTIVE Diabetic ketoacidosis (DKA) is the most severe acute metabolic complication of type 1 diabetes mellitus. Insulin treatment is commonly guided by plasma glucose levels and changes in venous blood gases, while β-hydroxibutyrate (BHB) levels are rarely measured. The study objective was to evaluate the value of capillary BHB monitoring in the course and resolution of DKA. PATIENTS AND METHODS Thirty patients with type 1 diabetes admitted for DKA were enrolled. A standard protocol including monitoring of blood glucose, venous blood gases, semiquantitative ketonuria, and capillary BHB was used. Patients were divided into three groups by time to DKA resolution (group 1:<24 h, group 2: 24-48 h, group 3: >48 h), and BHB results were compared to all other biochemical measurements. RESULTS Mean laboratory results upon admission were: blood glucose 415 (standard deviation [SD] 106) mg/dL; bicarbonate 9.6 (SD 1.5) mmol/L; pH 7.13 (SD 0.04); BHB 4.33 (SD 0.48) mmol/L, and ketonuria 3+ in 22 patients and 4+ in 6. BHB correlated well with bicarbonate (r=-0.24139; P=0.0161) and pH (r=-0.56419; P<0.0001). BHB normalized earlier than ketonuria in all cases (group 1: 15.5 vs 18.8 hours P<0.05; group 2: 18.2 vs 23.5 hours P<0.01; group 3: 37.3 vs 41.7 hours P<0.01). Ten percent of patients still had ketonuria when blood ketone levels were already normal (<0.5 mmol/L). CONCLUSION BHB measurement is an easy, practical, and reliable monitoring method in DKA and may be used as a parameter to adjust insulin treatment.