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1.
J Clin Endocrinol Metab ; 101(5): 2185-95, 2016 05.
Article in English | MEDLINE | ID: mdl-26963950

ABSTRACT

CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.


Subject(s)
Adaptor Protein Complex 2/genetics , Adaptor Protein Complex sigma Subunits/genetics , GTP-Binding Protein alpha Subunits/genetics , Hypercalcemia/congenital , Hyperparathyroidism, Primary/genetics , Receptors, Calcium-Sensing/genetics , Adult , Calcium/blood , Cross-Sectional Studies , DNA Mutational Analysis , Female , Genotype , Humans , Hypercalcemia/blood , Hypercalcemia/genetics , Hyperparathyroidism, Primary/blood , Male , Middle Aged , Mutation , Parathyroid Hormone/blood , Phenotype
2.
Eur J Endocrinol ; 169(3): 271-6, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23756355

ABSTRACT

OBJECTIVE: Due to a strong genotype-phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis. SUBJECTS AND METHODS: We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene. RESULTS: The average age at diagnosis was 35.6 years ± 20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4-82 years). The mean follow-up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x-Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5-78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2-24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months. CONCLUSIONS: This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism.


Subject(s)
Carcinoma/genetics , Multiple Endocrine Neoplasia Type 2a/genetics , Mutation , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma/metabolism , Carcinoma/pathology , Carcinoma/surgery , Carcinoma, Neuroendocrine , Child , Child, Preschool , Codon , Female , France , Genetic Association Studies , Humans , Longitudinal Studies , Male , Middle Aged , Multiple Endocrine Neoplasia Type 2a/metabolism , Multiple Endocrine Neoplasia Type 2a/pathology , Multiple Endocrine Neoplasia Type 2a/surgery , Neoplasm Staging , Proto-Oncogene Mas , Proto-Oncogene Proteins c-ret/metabolism , Retrospective Studies , Thyroid Gland/pathology , Thyroid Gland/surgery , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Thyroidectomy/adverse effects , Young Adult
3.
Diabetes Care ; 33(9): 1913-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20551017

ABSTRACT

OBJECTIVE: We investigated the relationship between carbohydrate intake and postprandial blood glucose (BG) levels to determine the most influential meal for type 2 diabetic subjects treated with basal insulin and needing prandial insulin. RESEARCH DESIGN AND METHODS: Three-day BG profiles for 37 type 2 diabetic subjects, with A1C levels of 7.7%, treated with sulfonylurea and metformin, and well titrated on insulin glargine, were analyzed using a continuous glucose monitoring system. Food intake from 680 meals was recorded and quantified during continuous glucose monitoring. RESULTS: The median BG excursion (DeltaBG) was higher at breakfast than at lunch or dinner (111 [81; 160] vs. 69.5 [41.5; 106] and 82.5 mg/dl [53; 119] mg/dl, P < 0.0001). There was a weak overall correlation between DeltaBG and carbohydrate intake. Correlation improved when mealtime was taken into account. Simple relationships were established: DeltaBG (mg/dl) = 65 x carbohydrate/body weight + 73 for breakfast (R(2) = 0.20, P < 0.0001); the slope was reduced by half at lunch and by one-third at dinner. Twelve relevant variables likely to affect DeltaBG were integrated into a polynomial equation. This model accounted for 49% of DeltaBG variability. Two groups of patients were identified: responders, in whom DeltaBG was well correlated with carbohydrate intake (R(2) >or= 0.30, n = 8), and nonresponders (R(2) < 0.30, n = 29). Responders exhibited a greater insulinopenic profile than nonresponders. CONCLUSIONS: The carbohydrate intake in responders clearly drives DeltaBG, whereas, in nonresponders, other factors predominate. This sort of characterization should be used to guide therapeutic choices toward more targeted care with improved type 2 diabetes management.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Aged , Diabetes Mellitus, Type 2/drug therapy , Dietary Carbohydrates/adverse effects , Female , Gas Chromatography-Mass Spectrometry , Humans , Hypoglycemic Agents/therapeutic use , Insulin/analogs & derivatives , Insulin/therapeutic use , Insulin Glargine , Insulin, Long-Acting , Male , Metformin/therapeutic use , Middle Aged , Postprandial Period , Sulfonylurea Compounds/therapeutic use
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