Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Genetic testing in prolactinomas: a cohort study.

BACKGROUND: Prolactinomas represent 46%-66% of pituitary adenomas, but the prevalence of germline mutations is largely unknown. We present here the first study focusing on hereditary predisposition to prolactinoma. OBJECTIVE: We studied the prevalence of germline mutations in a large cohort of patients with isolated prolactinomas. MATERIALS AND METHODS: A retrospective study was performed combining genetic and clinical data from patients referred for genetic testing of MEN1, AIP, and CDKN1B between 2003 and 2020. SF3B1 was Sanger sequenced in genetically negative patients. RESULTS: About 506 patients with a prolactinoma were included: 80 with microprolactinoma (15.9%), 378 with macroprolactinoma (74.7%), 48 unknown; 49/506 in a familial context (9.7%). Among these, 14 (2.8%) had a (likely) pathogenic variant (LPV) in MEN1 or AIP, and none in CDKN1B. All positive patients had developed a macroprolactinoma before age 30. The prevalence of germline mutations in patients with isolated macroprolactinoma under 30 was 4% (11/258) in a sporadic context and 15% (3/20) in a familial context. Prevalence in sporadic cases younger than 18 was 15% in men (5/33) and 7% in women (4/57). No R625H SF3B1 germline mutation was identified in 264 patients with macroprolactinomas. CONCLUSIONS: We did not identify any LPVs in patients over 30 years of age, either in a familial or in a sporadic context, and in a sporadic context in our series or the literature. Special attention should be paid to young patients and to familial context.

Dengue clinical features and harbingers of severity in the diabetic patient: A retrospective cohort study on Reunion island, 2019.

AIM: Diabetes mellitus is associated with both the risks of severe dengue and dengue-related deaths, however the factors characterizing dengue in the diabetic patient are ill-recognized. The objective of this hospital-based cohort study was to identify the factors characterizing dengue and those able to early identify dengue severity in the diabetic patient. METHODS: We retrospectively analysed demographic, clinical and biological parameters at admission in the cohort of patients who consulted at the university hospital between January and June 2019 with confirmed dengue. Bivariate and multivariate analyses were conducted. RESULTS: Of 936 patients, 184 patients (20%) were diabetic. One hundred and eighty-eight patients (20%) developed severe dengue according to the WHO 2009 definition. Diabetic patients were older and had more comorbidities than non-diabetics. In an age-adjusted logistic regression model, loss of appetite, altered mental status, high neutrophil to platelet ratios (>14.7), low haematocrit (≤ 38%), upper-range serum creatinine (>100 µmol/l) and high urea to creatinine ratio (>50) were indicative of dengue in the diabetic patient. A modified Poisson regression model identified four key independent harbingers of severe dengue in the diabetic patient: presence of diabetes complications, non-severe bleeding, altered mental status and cough. Among diabetes complications, diabetic retinopathy and neuropathy, but not diabetic nephropathy nor diabetic foot, were associated with severe dengue. CONCLUSION: At hospital first presentation, dengue in the diabetic patient is characterized by deteriorations in appetite, mental and renal functioning, while severe dengue can be early identified by presence of diabetes complications, dengue-related non-severe haemorrhages, cough, and dengue-related encephalopathy.

Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes.

AIM: Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant. METHODS: A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed. RESULTS: In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers. CONCLUSIONS: OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.

A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies.

AIMS: LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. METHODS: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n = 65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. RESULTS: Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. CONCLUSIONS: The level of expression of the LMNA 'Reunionese' variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

Invasive Group B Streptococcal Disease in Non-pregnant Adults, Réunion Island, 2011.

OBJECTIVES: While the prevalence of Group B streptococcus (GBS) colonization is important, little is known about invasive GBS (iGBS) disease in tropical areas. Our objective was to assess the burden of iGBS disease among non-pregnant adults. METHODS: A prospective hospital-based study of all non-pregnant adult patients with iGBS disease was conducted between January and December 2011 in Saint Pierre, Réunion Island, to assess its cumulative incidence rate (CIR). Capsular serotyping and multilocus sequence typing were performed to characterize GBS isolates. Case-control study was done to identify risk factors. RESULTS: The overall CIR of iGBS disease was 10.1 per 100,000. The CIR in elderly patients (≥ 65 yrs) was estimated at 40.6 per 100.000, and that of adults (15-64 years) at 6.7 per 100.000. Aboriginal origin in the Indian Ocean and overweight were both associated with iGBS disease. The most prominent clinical forms were osteo-articular and skin/soft tissue infections, as a consequence of diabetic foot. The serotypes were classic, type-Ia being the most prevalent. The hyper virulent ST-17 (CC17) was associated with type-III. CONCLUSIONS: The incidence of iGBS disease found in Réunion island is twofold that usually reported. This burden is linked to overweight in aboriginal people from the Indian Ocean.

Increased plasma ß-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia.

OBJECTIVE: The objective of the present study was to determine whether a plasma ß-hydroxybutyrate (BOHB) level >2700 µmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH). RESEARCH DESIGN AND METHODS: We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-H fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels 2700 MOL/L (group 1), EHH PATIENTS with BOHB levels 2700 MOL/L (group 2) and 59 controls (median glycaemia: 3.2  mmol/l and median BOHB: 6095 µmol/l). RESULTS: During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700  µmol/l (median 6140 and range 2957-7824) and 30 patients (group 2) had BOHB levels <2700 µmol/l (median 542 and range 0-2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation. CONCLUSION: During a fasting test, a BOHB level >2700 µmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

Virilizing sclerosing-stromal tumor of the ovary in a young woman with McCune Albright syndrome: clinical, pathological, and immunohistochemical studies.

CONTEXT: McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, café-au-lait skin pigmentations, and gonadotropin-independent sexual precocious puberty, resulting from a somatic postzygotic activating mutation of the GNAS1 gene. SETTING: We report a virilizing sclerosing-stromal tumor of the ovary in a young female with MAS. PATIENT: She presented polyostotic fibrous dysplasia of the left upper and lower limbs and a café-au-lait skin spot in the posterior area of the neck. She had a history of precocious puberty, diagnosed at the age of 6 years and treated with cyproterone acetate until the age of 10 years; then she developed central puberty with severe oligomenorrhea. At the age of 23 years, she was hospitalized for a virilization syndrome including hirsutism, acne, deepening of the voice, amenorrhea, and clitoromegaly. Serum levels of T were dramatically increased (1293 ng/dl; normal range, 10-80). The abdominal computed tomography scan revealed a solid mass located on the left ovary. INTERVENTION: An ovariectomy was performed, and histological examination revealed a sclerosing-stromal tumor with pseudolobular pattern. RESULTS: Immunohistochemical studies revealed that the tumor cells expressed all steroidogenic enzymes involved in androgen synthesis. Molecular analysis revealed that ovarian tumor cells harbored the Arg 201 activating mutation in the GNAS1 gene. After surgery, T levels returned to normal, the patient retrieved a normal gonadal function, and she was able to become pregnant. CONCLUSION: This observation extends the clinical spectrum of ovarian pathology of women with MAS. However, the mechanisms causing this ovarian tumor remain unclear, even if the gsp oncogene has been implicated in the pathogenesis of some gonadal tumors.

Tamoxifen enhances the control of acromegaly treated with somatostatin analog lanreotide.

We present the case of a 51-year old female patient with acromegaly that was resistant to somatostatin analogs and dopamine agonists. The patient was diagnosed with breast cancer requiring treatment with the anti-estrogen tamoxifen. Prior to initiating the treatment with tamoxifen, the IGF-I level was very high at 415% of the upper limit of normal for the patient's age and sex. During the tamoxifen treatment, the level of IGF-I dropped spectacularly down to normal levels. This observation highlights the effect of an anti-estrogen treatment in certain female patients with acromegaly.

Glucose status in patients with acromegaly receiving primary treatment with the somatostatin analog lanreotide.

To describe glucose status changes in patients with acromegaly receiving somatostatin analog lanreotide as primary treatment. This retrospective, single-center study conducted during 1996-2008, included acromegalic patients receiving primary lanreotide treatment. Baseline and last follow-up visit assessments included glucose status (according to American Diabetes Association criteria), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) levels. Glucose control was considered improved when fasting plasma glucose or antidiabetic treatments were reduced, and deteriorated if fasting glucose was the same/higher but with increased antidiabetic treatments. 42 patients (median age 50 years; range 29-75 years) were included. At baseline, 26 (62%) were normoglycemic, eight (19%) had impaired glucose tolerance/fasting glycemia, and eight (19%) had diabetes mellitus; family history of diabetes mellitus was significantly associated with abnormal glucose status. At final visit, the mean (SE) lanreotide dose was 108 (21) mg/month. Median treatment duration was 23 months, range 3-138 months, and 74% of patients received the 120-mg dose. Median GH levels decreased significantly (baseline, 12 [5-20] µg/l; final visit, 2.1 [1.0-4.7] µg/l; P < 0.0001); IGF-1 levels were age- and sex-normalized in 33% of patients. Glucose control deteriorated in seven patients (17%) and improved from abnormal levels in 10 (24%). Deterioration was associated with smaller GH decreases (median change, -3.4 µg/l vs. -10.7 µg/l, P = 0.014) and improvement with trend to lower BMI and younger age. During primary lanreotide treated acromegalic patients 60% had no change, 24% had an improvement and 17% had a worsening of glucose status. Deterioration was significantly associated with smaller GH decreases during primary lanreotide treatment.

Clinical and metabolic characteristics of acromegalic patients with high IGF1/normal GH levels during somatostatin analog treatment.

CONTEXT: Divergence between GH and IGF1 values are often reported in treated acromegalic patients, but the mechanisms of this discrepancy have not been completely explored. OBJECTIVE: To evaluate the frequency of divergence between GH and IGF1 values and identify the role of clinical and metabolic factors in treated patients with acromegaly, according to the latest criteria of Cure published in July 2010. DESIGN: Retrospective study of patients' records between October 2002 and March 2008. Patients were grouped according to their mean GH and IGF1 values as 'controlled' (normal GH and IGF1), 'divergent' (high IGF1 and normal GH) and 'uncontrolled' (high GH and IGF1), and compared with respect to their clinical characteristics and metabolic markers. RESULTS: Patients (n=104) were grouped as 'controlled' (n=20), 'divergent' (n=43) and 'uncontrolled' (n=41). More patients in the divergent group (93%) and uncontrolled group (98%) were treated with somatostatin analogs than in the controlled group (65%; P=0.001 for the comparison of the three groups). Patients in the divergent group had higher fasting blood glucose (0.94 g/l (interquartile range: 0.83-1.17)) and systolic blood pressure (130 mmHg (120-140) compared with the controlled group (0.84 g/l (0.80-0.92); P=0.017) and 120 mmHg (interquartile range: 110-130; P=0.029). In patients with divergent IGF1/GH levels, fasting glucose and GH were both strongly associated with IGF1. CONCLUSION: Totally 41% of treated acromegalic patients had a high IGF1 and normal GH level. In these divergent patients treated with somatostatin analogs, these clinical and metabolic parameters might either play a causal role or be a marker for disease activity.

Nontruncated amino-terminal parathyroid hormone overproduction in two patients with parathyroid carcinoma: a possible link to HRPT2 gene inactivation.

OBJECTIVE: Some patients with parathyroid carcinoma present with an over-production of nontruncated amino-terminal (NT-N) parathyroid hormone (PTH), a post-transcriptionally modified form of PTH(1-84). This is usually picked up on an elevated whole (W) PTH (third-generation)/total (T) (second-generation) PTH assay ratio (N > 0·8). PATIENTS AND DESIGN: Two parathyroid cancer patients with several episodes of hypercalcaemia and multiple surgeries are described. In both patients, W-PTH, T-PTH and circulating PTH molecular forms separated by high-pressure liquid chromatography (HPLC) were measured with the same assays. qPCR was used to study HRPT2 gene mutation. RESULTS: The first patient had total calcium of 3·8 and 3·22 mmol/l before the fourth and fifth surgeries, and third/second-generation PTH ratios of 2·95 and 3·6, respectively. After the fourth surgery, the ratio remained normal for 1 year and increased progressively to 3·6 over 15 months. This preceded hypercalcaemia by 6 months. The ratio became normal after the fifth surgery. HPLC analysis disclosed an over-expression of NT-N PTH to 82·2% (N < 10%) relative to hPTH(1-84) before the fifth surgery. A deletion of all the tested exons of the HRPT2 gene was identified. In the second patient, W-PTH/T-PTH ratio was 0·89 when serum calcium was 3·3 mmol/l. NT-N PTH was also over-expressed at 51·9%. An inactivating mutation of the HRPT2 gene was also identified. CONCLUSIONS: This may suggest that a progressive rise in third/second-generation ratio may have possible clinical utility to monitor parathyroid cancer recurrence. A possible association between NT-N PTH overproduction and HRPT2 gene inactivation is also suggested.