Objectives: To examine the changes in diagnostic practices and clinical management of patients with 5α-reductase type 2 (SRD5A2) or 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency since molecular diagnoses became available. Methods: Clinical, laboratory, and therapeutic data were retrieved from the medical records of 52 patients with a molecular diagnosis of SRD5A2 (n = 31) or HSD17B3 (n = 21) deficiency. Temporal trends regarding age at assessment and initial sex assignment over 1994–2020 were qualitatively analyzed. Age at molecular diagnosis was compared between two subgroups of patients according to their year of birth. Results: Fifty-eight percent (n = 30) patients were diagnosed during the perinatal period, 33% (n = 17) during infancy, and 9% (n = 5) during adolescence or adulthood. Over the studied period, the patients’ age at initial assessment and diagnosis frankly decreased. The median (range) age at diagnostic confirmation was 10.5 (0–53.2) years for patients born before 2007 and 0.4 (0–9.3) years for those born in 2007 or later (P = 0.029). Genetic testing identified 27 different variants for the SRD5A2 gene (30% novel, n = 8) and 18 for the HSD17B3 gene (44% novel, n = 8). Before 2002, most patients were initially assigned as females (95%, n = 19), but this proportion dropped for those born later (44%, n = 14; P < 0.001). The influence of initial genital appearance on these decisions seemingly decreased in the most recent years. Therapeutic interventions differed according to the sex of rearing. Ten percent (n = 2) patients requested female-to-male reassignment during adulthood. Conclusion: This study showed, over the past two decades, a clear trend toward earlier diagnosis and assignment of affected newborns as males.

BackgroundCinacalcet is a calcimimetic approved in adults with primary hyperparathyroidism (PHPT). Few cases reports described its use in pediatric HPT, with challenges related to the risk of hypocalcemia, increased QT interval and drug interactions. In this study, we report the French experience in this setting.MethodsWe retrospectively analyzed data from 18 pediatric patients from 7 tertiary centers who received cinacalcet for PHPT. The results are presented as median (interquartile range).ResultsAt a median age of 10.8 (2.0–14.4) years, 18 patients received cinacalcet for primary HPT (N = 13 inactive CASR mutation, N = 1 CDC73 mutation, N = 1 multiple endocrine neoplasia type 1, N=3 unknown etiology). Cinacalcet was introduced at an estimated glomerular filtration rate (eGFR) of 120 (111–130) mL/min/1.73 m2, plasma calcium of 3.04 (2.96–3.14) mmol/L, plasma phosphate of 1.1 (1.0–1.3) mmol/L, age-standardized (z score) phosphate of −3.0 (−3.5;−1.9), total ALP of 212 (164–245) UI/L, 25-OHD of 37 (20–46) ng/L, age-standardized (z score) ALP of −2.4 (−3.7;−1.4), PTH of 75 (59–123) ng/L corresponding to 1.2 (1.0–2.3)-time the upper limit for normal (ULN). The starting daily dose of cinacalcet was 0.7 (0.6–1.0) mg/kg, with a maximum dose of 1.0 (0.9–1.4) mg/kg per day. With a follow-up of 2.2 (1.3–4.3) years on cinacalcet therapy, PTH and calcium significantly decreased to 37 (34–54) ng/L, corresponding to 0.8 (0.5–0.8) ULN (p = 0.01), and 2.66 (2.55–2.90) mmol/L (p = 0.002), respectively. In contrast, eGFR, 25-OHD, ALP and phosphate and urinary calcium levels remained stable. Nephrocalcinosis was not reported but one patient displayed nephrolithiasis. Cinacalcet was progressively withdrawn in three patients; no side effects were reported.ConclusionsCinacalcet in pediatric HPT can control hypercalcemia and PTH without significant side effects.

ObjectiveDisturbances in the activity of the hypothalamus-pituitary-adrenal axis could lead to functional alterations in the brain of diabetes patients. In a later perspective of investigating the link between the activity of the hypothalamus-pituitary-adrenal axis and the developing brain in children with diabetes, we assessed here nocturnal cortisol metabolism in prepubertal children with type 1 diabetes mellitus (T1DM).MethodsPrepubertal patients (aged 6–12 years) diagnosed with T1DM at least 1 year previously were recruited, along with matched controls. Nocturnal urine samples were collected, with saliva samples taken at awakening and 30 minutes after awakening. All samples were collected at home over 5 consecutive days with no detectable nocturnal hypoglycaemia. The State-Trait Anxiety Inventory (trait scale only) and Child Depression Inventory were also completed. Glucocorticoid metabolites in the urine, salivary cortisol (sF) and cortisone (sE) were measured by liquid chromatography–tandem mass spectrometry. Metabolic data were analysed by logistic regression, adjusting for sex, age, BMI and trait anxiety score.ResultsUrine glucocorticoid metabolites were significantly lower in T1DM patients compared to controls. 11β-hydroxysteroid dehydrogenase type 1 activity was significantly higher, while 11β-hydroxysteroid dehydrogenase type 2, 5(α+β)-reductase and 5α-reductase levels were all lower, in T1DM patients compared to controls. There was a significant group difference in delta sE level but not in delta sF level between the time of awakening and 30 minutes thereafter.ConclusionsOur findings suggest that altered nocturnal cortisol metabolism and morning HPA axis hyperactivity in children with T1DM leads to greater cortisol bioavailability and lower cortisol production as a compensatory effect. This altered nocturnal glucocorticoid metabolism when cortisol production is physiologically reduced and this HPA axis hyperactivity question their impact on brain functioning.

INTRODUCTION:Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.METHODS:This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.RESULTS:The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.CONCLUSION:This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OBJECTIVE:Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.DESIGN AND PATIENTS:This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.RESULTS:Hypercalcaemia was diagnosed at a median age of 53 years [IQR: 38-61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63-2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1-7.1], and the median 24-hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9-4.0]. Osteoporosis (dual X-ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established.CONCLUSION:This large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function.

CONTEXT Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are rare diseases characterized by hyperphosphatemia and ectopic calcifications or recurrent episodes of diaphysitis. In the setting of metabolic or inflammatory diseases, recent data suggest that systemic administration of sodium thiosulfate (STS) could be effective in the treatment of ectopic calcifications but may also be poorly tolerated (digestive symptoms, metabolic acidosis). Our group developed a topical formulation of STS to treat ectopic calcifications locally, therefore limiting patient exposure to the drug and its adverse effects. OBJECTIVE We aimed at describing efficacy and tolerance for a topical formulation of STS in treated patients. DESIGN We performed a retrospective study wherein clinical, radiological, and biological data before and after the application of the topical STS treatment were collected and analyzed. PATIENTS OR OTHER PARTICIPANTS Three patients admitted to 3 different hospitals with an ectopic calcification secondary to HFTC or HHS were treated with topical STS. INTERVENTION The topical STS was applied daily by the patients. RESULTS A significant clinical and radiological decrease of ectopic calcifications was observed after at least 5 months of treatment. The STS treatment was well tolerated and no clinical or biological side effects were observed. CONCLUSION Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.

L’hypercalcémie hypocalciurie familiale de type 1 (HHF1) est secondaire à des mutations hétérozygotes inhibitrices du gène codant pour le récepteur sensible au calcium (CaSR). Peu d’études récentes se sont intéressées aux caractéristiques phénotypiques de ces patients. Étude rétrospective multicentrique observationnelle incluant des patients présentant une mutation hétérozygote inhibitrice du CaSR diagnostiquée à l’âge adulte entre 2001 et 2012. Soixante-seize patients âgés en moyenne de 48 ans (15–76), lors de la découverte de l’hypercalcémie, ont été inclus. L’hypercalcémie a été découverte sur un bilan de routine chez 21/58 patients (36 %), lors d’une enquête familiale chez 8/58 patients (14 %), devant une asthénie chez 7/58 (12 %), devant une ostéoporose chez 5/58 patients (9 %). Cliniquement les patients présentaient : une hypertension artérielle 31/56 (55 %), une asthénie 23/52 (44 %), des troubles digestifs 17/52 (33 %), des troubles psychiatriques 17/54 (31 %), un antécédent de chondrocalcinose 12/49 (24 %), de fractures 8/55 (15 %), de coliques néphrétiques 7/53 (13 %). La calcémie médiane était à 2,75 mmol/L (25e–75e percentile : 2,63–2,86), la parathormone médiane était à 47 pg/mL (28,5–68,5), et la calciurie médiane à 2,80 mmol/24 h (1,90–4,11), soit 2 mg/kg/24 h. L’ostéodensitométrie diagnostiquait une ostéoporose chez 6/35 patients (17 %), et une ostéopénie chez 15/35 (43 %). L’échographie rénale retrouvait des lithiases rénales chez 7/30 patients (23 %). Une chirurgie parathyroïdienne a été réalisée chez 17 patients (22 %). L’anatomopathologie des parathyroïdes révélait un adénome parathyroïdien chez 2 patients (14 %) et une hyperplasie parathyroïdienne chez 10 patients (64 %). Le diagnostic différentiel clinique de l’HHFB avec l’hyperparathyroïdie primaire est difficile. Ce piège diagnostique doit être bien connu du clinicien. En effet, la présence de signes cliniques d’hypercalcémie, des calcémies supérieures à 2,9 mmol/L, une calciurie élevée, une ostéoporose fracturaire, des lithiases rénales, ou la présence d’un adénome parathyroïdien ne permettent pas d’exclure le diagnostic.

Primary hyperparathyroidism is common, with epidemiological studies suggesting it may effect up to 1% of the population, and up to 3% of post-menopausal females. Many cases are diagnosed incidentally on routine blood sampling, with the majority of patients being seemingly asymptomatic at diagnosis, and often having mild hypercalcaemia of <2.85 mmol/L. Individuals with this so-called mild or asymptomatic primary hyperparathyroidism may however have undiagnosed complications, along with subtle neuropsychological symptoms, and possibly increased cardiovascular risk. Revised international guidelines suggest a more proactive approach to screening for vertebral fractures and renal stones, although the thresholds for recommending definitive surgical management with parathyroidectomy remain similar. The natural history of mild primary hyperparathyroidism will be reviewed, with particular reference to the Parathyroid Epidemiology and Audit Research Study (PEARS), which has used population level data from Tayside, Scotland (UK), along with recent data describing an association with cardiovascular disease. Results of intervention studies, including randomised controlled trials, will also be discussed.L’hyperparathyroïdie primaire est une situation commune, et les études épidémiologiques suggèrent qu’elle peut affecter jusqu’à 1 % de la population et jusqu’à 3 % des femmes au-delà de la ménopause. De nombreux cas sont fortuitement repérés à l’occasion de prélèvements sanguins de routine et la majorité des patients sont alors en apparence asymptomatiques au moment du diagnostic, avec souvent une hypercalcémie discrète de < 2.85 mmol/L. Les individus atteints de cette hyperparathyroïdie primaire, qualifiée de fruste ou asymptomatique, peuvent toutefois être atteints de complications non diagnostiquées, aussi de subtils symptômes neuropsychologiques et possiblement d’une majoration du risque cardiovasculaire. Les recommandations internationales réactualisées suggèrent une approche plus incisive du dépistage des fractures vertébrales et des calculs rénaux, bien que demeurent similaires les seuils interventionnels pour la prise en charge chirurgicale radicale par parathyroïdectomie. Sera revisitée l’histoire naturelle de l’hyperparathyroïdie primaire fruste, particulièrement en référence à la Parathyroid Epidemiology and Audit Research Study (PEARS) qui a exploité les données recueillies au niveau de la population de Tayside en Écosse au Royaume-Uni, avec des informations récentes faisant état d’une association avec les maladies cardiovasculaires. Les résultats des études interventionnelles, incluant les essais cliniques contrôlés randomisés, seront également discutés.

BACKGROUNDExcept after neck surgery, hypoparathyroidism is a rare disease caused by defects in genes involved in parathyroid gland development (TBX1/22q11.2 del, GCMB, GATA3, TBCE) or function [calcium sensing receptor (CASR), GNA11, PTH], or the autoimmune polyglandular syndrome type 1 (AIRE). Approximately 90% of sporadic cases and 30% of familial cases of isolated hypoparathyroidism remain unexplained. Recurrent missense mutations in AP2S1, a calcium-sensing receptor regulator, have been recently identified in familial hyperparathyroidism.AIMThe aim of the study was to investigate AP2S1 as a putative hypoparathyroidism-causing gene.METHODSSequencing analysis and quantitative genomic PCR of the AP2S1 gene in a large cohort of 10 index cases (from nine families) and 50 sporadic cases affected with isolated hypoparathyroidism were investigated.RESULTS AND CONCLUSIONSNone of the 60 patients presented with nucleotidic changes or copy number variation in the AP2S1 gene, thereby excluding AP2S1 defects as a frequent cause of isolated hypoparathyroidism.

CONTEXT:Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population.OBJECTIVE:We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions.DESIGN:The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions.PATIENTS AND SETTINGS:One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study.RESULTS:Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients.CONCLUSION:Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Background Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. Objective To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. Design and methods In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. Results A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. Conclusion Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.

Context: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes.Objective: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient.Design: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA.Patients or Other Participants: A5-year-old French boy with HHS and his family members participated.Results: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC.Conclusion: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.

Background: Endocrine modifications at puberty, in particular the rise of Growth Hormone (GH) and Insulin Growth Factor 1(IGF-1) , influence the pharmacokinetics of corticosteroids.This changes induce a decrease of the activity of beta-HSD, the enzyme which catalyzes the interconversion of cortisone to cortisol and that of prednisone to prednisolone.Objective: To determine the possible influence of these changes at puberty on exogenous corticosteroids.Methods: We studied the pharmacokinetics of prednisone (PO) and prednisolone (POH) in two groups of children after a single prednisone administration (0.5 mg/kg/weight p.o); a group of six prepubertal (age 4.4-6.6 yrs) and pubertal children (0.5-2 yrs) without immunological pathologies (controls),and a group of ten prepubertal children(4.4-6.6 yrs) and six pubertal children (11.5-14.3yrs) with autoimmune pathologies.A third group of seven children (three prepubertal and four pubertal) where on chronic treatment.All underwent blood sampling over eight hours period after their morning dose.PO, POH and cortisol levels were determinated by HPLC analysis.Results: Control pubertal children had higher Cmax and AUC of PO as well as higher PO/POH ratio compared to prepubertal children indicating a reduced activity of 11 beta-HSD1.This is confirmed by the significant positive correlation of IGF-1 levels and the AUC ratio (p<0.03).In children with autoimmune pathologies prepubertal patients had higher PO/POH ratio compared to controls and not significantly different from pubertal patients either after single or chronic dosing.Conclusions: These data indicate that the pharmacokinetics of glucocorticoids undergoing hydroxylation such as prednisone is markedly influenced by hormonal canges at puberty and children can not be regarded as an unique population.