Lessons from prospective longitudinal follow-up of a French APECED cohort.

BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8-10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. OBJECTIVE: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. METHODS: This was a retrospective and prospective multicenter cohort study (2015-2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. RESULTS: We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (-44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. CONCLUSION: Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed.

Diagnosis and management of congenital hypopituitarism in children.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

The experience of diagnosis announcement in rare endocrine diseases: A survey of the French FIRENDO network.

CONTEXT: Diagnosis announcement of a chronic disease is a crucial moment for patients as well as for their families and an important step in the management of severe conditions such as rare endocrine diseases. Little is known of how diagnosis is communicated to patients and families. The FIRENDO network was created by the third French Plan for Rare Diseases, to promote autonomy, care and research on rare endocrine diseases. OBJECTIVES: The aim of this study was to characterize, for the first time, the experience and needs of patients and/or their parents around the announcement of diagnosis to ensure optimal quality of care. METHODS: A quantitative self-administered survey on diagnosis announcement procedures in rare endocrine diseases was launched in April 2017 by the ad hoc FIRENDO thematic working group in collaboration with its 11 partnering patient associations and support groups. The questionnaire was designed and revised by patient support group representatives, adult and pediatric endocrinologists, psychologists and biologists, all expert in rare endocrine diseases. It was made available on the FIRENDO network website and distributed mainly by email with electronic links on their respective websites to members of all affiliated patient support groups. RESULTS: Questionnaires were filled out by 391 patients and 223 parents (median age of patients: 39 years). The following conditions were associated with at least 30 answers: Addison's disease, classical forms of congenital adrenal hyperplasia (CAH), Russell-Silver syndrome, Cushing's syndrome, acromegaly and craniopharyngioma. Overall, some announcement modalities were judged favorably by patients: physician's empathy, availability and use of clear terms, and presence of family at the time of announcement. However, a lack of psychological care and information documents was reported, as well as some inadequate procedures such as postal mail announcements. CONCLUSION: This work suggests that better knowledge of the patient's experience is useful for improving the diagnosis announcement of rare endocrine disorders. The main recommendations derived from the survey were the need for several announcement visits, information on patient support groups and reference centers, imperatively avoiding impersonal announcement, and the usefulness of a written accompanying document.

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.

Position statement on the diagnosis and management of acromegaly: The French National Diagnosis and Treatment Protocol (NDTP).

Acromegaly is a rare disease with prevalence of approximately 60 cases per million, slight female predominance and peak onset in adults in the fourth decade. Clinical diagnosis is often delayed by several years due to the slowly progressive onset of symptoms. There are multiple clinical criteria that define acromegaly: dysmorphic syndrome of insidious onset, symptoms related to the pituitary tumor (headaches, visual disorders), general signs (sweating, carpal tunnel syndrome, joint pain, etc.), complications of the disease (musculoskeletal, cardiovascular, pneumological, dental, metabolic comorbidities, thyroid nodules, colonic polyps, etc.) or sometimes clinical signs of associated prolactin hypersecretion (erectile dysfunction in men or cycle disorder in women) or concomitant mass-induced hypopituitarism (fatigue and other symptoms related to pituitary hormone deficiencies). Biological confirmation is based initially on elevated IGF-I and lack of GH suppression on oral glucose tolerance test or an elevated mean GH on repeated measurements. In confirmed cases, imaging by pituitary MRI identifies the causal tumor, to best determine management. In a minority of cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context. The first-line treatment is most often surgical removal of the somatotroph pituitary tumor, either immediately or after transient medical treatment. Medical treatments are most often proposed in patients not controlled by surgical removal. Conformal or stereotactic radiotherapy may be discussed on a case-by-case basis, especially in case of drug inefficacy or poor tolerance. Acromegaly should be managed by a multidisciplinary team, preferably within an expert center such as a reference or skill center for rare pituitary diseases.

Motivational interviewing for the management of child and adolescent obesity: a systematic literature review.

BACKGROUND: Among children or adolescents with obesity, 40-70.5% will remain obese as adults according to their paediatric body mass index (BMI). The recommended management involves changes in their nutritional habits (diet, physical activity, and sedentary lifestyle). Motivational interviewing (MI), a patient-centred consultation, has proven its worth in many fields where acting on behaviours is essential. AIM: To investigate the use and outcomes of MI in the management of children and adolescents who are overweight and obese. DESIGN & SETTING: A systematic review evaluated MI in the management of children and adolescents who are overweight and obese. METHOD: PubMed, Web of Science, Cochrane Library, and CISMeF were searched between January 2022 and March 2022 for following terms: 'motivational interviewing', 'overweight or obesity', 'children or adolescent' to identify randomised controlled trials (RCTs). Inclusion criteria were interventions involving MI in children or adolescents who were commonly (polygenically) overweight or obese. Exclusion criteria were: studies before 1991; and articles not written in English or French. The first stage of the selection process was carried out by reading the titles and abstracts. A second stage was carried out by reading the complete studies. A secondary inclusion of articles was carried out following the reading of bibliographic references, mainly from systematic reviews and meta-analyses. The data were summarised in synthetic tables based on the Population, Intervention, Comparison, Outcomes, and Study (PICOS) tool. RESULTS: From 444 articles the review identified 26 RCTs. Statistically significant results were found for all criteria (anthropometric and behavourial) in both children and adolescents. Quality of life and depression scores were also improved. Parental presence in the interview appeared to be essential for children, whereas for adolescents, the supportive involvement of parents outside of the interviews seemed more appropriate. The frequency and duration of the interventions played a major role in obtaining results, as did the number of people involved, and the diversity of the places where they are taken care of. CONCLUSION: MI seems promising for children and adolescents with overweight or obesity, within the framework of a comprehensive, multiprofessional, family management, carried out over a long period with regular consultations.

Assessment of a new home-based care pathway for children newly diagnosed with type 1 diabetes.

AIM: To compare the outcomes of home-based and conventional hospital-based care for children newly diagnosed with type 1 diabetes mellitus. METHODS: A descriptive study was conducted of all children newly diagnosed with diabetes mellitus at the Timone Hospital in Marseille, France, between November 2017 and July 2019. The patients received either home-based or in-patient hospital care. The primary outcome was the length of initial hospital stay. The secondary outcome measures were glycemic control in the first year of treatment, families' diabetes knowledge, the effect of diabetes on quality of life, and overall quality of care. RESULTS: A total of 85 patients were included, 37 in the home-based care group and 48 in the in-patient care group. The initial length of hospital stay was 6 days in the home-based care group versus 9 days in the in-patient care group. Levels of glycemic control, diabetes knowledge and quality of care were comparable in the two groups despite a higher rate of socioeconomic deprivation in the home-based care group. CONCLUSION: Home-based care for children with diabetes is safe and effective. This new healthcare pathway provides good overall social care, especially for socioeconomically deprived families.

Deficient anterior pituitary with common variable immune deficiency (DAVID syndrome): a new case and literature reports.

Deficient anterior pituitary with common variable immune deficiency (DAVID) syndrome is a rare condition characterized by adrenocorticotropic hormone (ACTH) deficiency and primary hypogammaglobulinemia. It is due to heterozygous mutations of the nuclear factor kappa-B subunit 2 (NFKB2) gene. Only a few isolated cases have been reported since its first description by our team. Through the international multicenter GENHYPOPIT network, we identified a new case of DAVID syndrome. We then conducted an extensive review of the DAVID syndrome cases published from 2012 to 2022. A 7-year-old boy was diagnosed with symptomatic hypoglycemia revealing ACTH deficiency. Laboratory tests showed asymptomatic hypogammaglobulinemia. He harbored a heterozygous point mutation in NFKB2 gene (c.2600C > T, p.Ala867Val). His management included hydrocortisone replacement treatment, and he also received subcutaneous immunoglobulins during the Covid-19 pandemic. We analyzed 28 cases of DAVID syndrome with ACTH deficiency. ACTH deficiency was the only hormone deficiency in 79% of patients, but some patients harbored growth hormone (GH) and thyroid stimulating hormone (TSH) deficiencies. The first presenting symptoms were sinus/pulmonary infections (82%, mean age of 3 years) and alopecia (mean age of 4.7 years). ACTH deficiency was the third presenting condition (mean age at diagnosis of 8.6 years). All patients had hypogammaglobulinemia (decreased IgA and IgM levels), and 57% of patients had at least one autoimmune manifestation. Heterozygous mutations at the 3'end of the NFKB2 gene, coding for the C-terminal domain of the protein, were identified in all cases. Better knowledge of DAVID syndrome will help clinicians make an early diagnosis to avoid life-threatening complications.

Misconceptions and beliefs around hormone replacement therapy after childhood hematopoietic stem cell transplantation: A qualitative study among women leukemia survivors.

PURPOSE: After childhood leukemia and hematopoietic stem cell transplantation, hormone replacement therapy is often required to induce puberty because of premature ovarian insufficiency. Observance of this kind of treatment in adolescents and young women seems quite poor, and literature about its acceptance remains scarce; in order to learn about their experience and to better understand their attitude towards hormone replacement therapy, we used qualitative methods. DESIGN AND PATIENTS: 13 young women childhood cancer survivors completed an individual interview. RESULTS: We report that the negative experience of leukemia may cause rejection of the treatment, closely related to infertility unacceptance. Misconceptions and lack of adequate information of hormonal treatment effects are also major barriers to a good compliance. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: Observance of hormone replacement therapy for young women childhood cancer survivors can be improved with a confidential patient-physician relationship, patient education, choice of galenic formulation according to personal preference, and psychological support during the long-time follow up.

The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency.

Design: Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function. Objective: Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network. Methods: Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA). Results: A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHß and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHß, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported. Conclusion: Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future.

Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.

BACKGROUND: Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yielding infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology. METHODS: 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. FINDINGS: A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromosomal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link. INTERPRETATION: We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogenesis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility. FUNDING: Université Paris Saclay, Agence Nationale de Biomédecine.

Congenital Central Hypothyroidism Caused by a Novel IGSF1 Variant Identified in a French Family.

INTRODUCTION: Congenital central hypothyroidism (CCH) is a rare disorder that can be caused by X-linked mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. Here, we describe four familial cases with a variable presentation due to a novel IGSF1 pathogenic variant. CASE PRESENTATION: In the index case, an investigation at birth of a suspected brain-lung-thyroid syndrome surprisingly revealed a central hypothyroidism. Next-generation sequencing uncovered a novel IGSF1 pathogenic variant: a hemizygous single base duplication (G) resulting in a premature stop codon (NM_001555.4: c.2485dup, p.Ala829Glyfs*15). Further family investigations revealed missed neonatal CCH for the older brother who presented with prolonged jaundice (thyroid stimulating hormone 3.06 mUI/L, FT4 9.4 pmol/L, FT3 4.2 pmol/L). It also led to the diagnosis of CCH at 11 months of age for the younger brother, whose thyroid function was considered normal at birth. Neuropsychological evaluations showed no cognitive impairment for the eldest two brothers, but a slightly reduced processing-speed index compared with the other parameters for the oldest. Furthermore, a maternal uncle was diagnosed with biochemical CCH at 34 years of age, despite having few symptoms, and a complete workup revealed prolactin deficiency and macroorchidism. DISCUSSION: This report of a rare case of neonatal CCH caused by IGSF1 deficiency highlights the importance of recognizing the neonatal signs of hypothyroidism to diagnose CCH as early as possible. Our results also show the importance of performing family genetic screening if a pathogenic variant is identified, to properly monitor carriers as CCH may develop over time. We suggest that these families should be followed up in the long term to better understand the natural history of this syndrome and evaluate the need for hormone substitution.

Teriparatide administration by the Omnipod pump: preliminary experience from two cases with refractory hypoparathyroidism.

CONTEXT: Hypoparathyroidism (hypoPTH) in adults is mainly due to total thyroidectomy. Conventional therapies (calcium, active vitamin D) can fail to normalize calcemia, expose the patient to hypercalciuria and impact quality-of-life. Human parathormone (PTH) replacement therapy is a suitable option in these cases, although few clinical reports have been published so far. METHODS: We describe two cases of patients with refractory postsurgical hypoPTH, in whom subcutaneous infusion of recombinant PTH (teriparatide) through the Omnipod® pump was initiated after failure of all other therapeutic options. Besides, we performed a review of literature of hypoPTH cases treated by continuous infusion of teriparatide. RESULTS: Two women aged 46 and 61 years old failed to normalize calcemia either with conventional treatments (calcium 8 g/day + calcitriol 9 mcg/day and calcium 5 g/day + calcitriol 12 mcg/day) or with thrice daily subcutaneous injections of teriparatide. As a last resort, teriparatide infusion via Omnipod® device normalized their calcemia and allowed calcium/vitamin D withdrawal, with average teriparatide dose of 23 and 32 mcg/day, respectively. The flow of teriparatide was adapted according to a protocol based on measured calcemia, under medical supervision. In the literature, 15 adult cases (13 women, mean age 44.5 ± 5.2 years old) are reported. HypoPTH was consecutive to surgery in all of them. Mean dose of teriparatide administered was 25 ± 6 mcg/day with improvement of calcemia level and quality-of-life in all patients. CONCLUSIONS: Continuous administration of teriparatide through Omnipod® appears as an efficient therapeutic option in refractory hypoPTH, whose administration to the patient can be assisted by medically-supervised protocol.

A novel TBX19 gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin.

Isolated ACTH deficiency (IAD) is a life-threatening condition, particularly in the neonatal period, while a main consequence of undiagnosed isolated ACTH deficiency in survivors is cognitive impairment. TBX19 is involved in the differentiation and proliferation of corticotropic cells and TBX19 mutations are responsible for more than 60% of neonatal cases of IAD. We describe a new variant of the main TBX19 transcript (NM 005149.3, c.840del (p.(Glu280Asp fs*27)), classified as pathogenic, whose pathogenicity is assumed to be due to nonsense mediated decay leading to non-expression of T-box transcription factor TBX19. Moreover we summarize the TBX19 mutations published as individual cases since our last large cohort. Interestingly, this pathogenic variant was identified in four patients from three apparently unrelated families. Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect. Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients.

Copeptin assays in children for the differential diagnosis of polyuria-polydipsia syndrome and reference levels in hospitalized children.

OBJECTIVES: Polyuria-polydipsia syndrome (PPS) is a common presentation in children but the differential diagnosis rests on burdensome water deprivation tests. The aims of this study were to determine a copeptin threshold to distinguish patients with central diabetes insipidus from those with primary polydipsia and to estimate the normal range of copeptin concentrations in children. DESIGN: Single-centre retrospective descriptive study. PATIENTS: Two hundred and seventy-eight children aged 2 months to 18 years who consulted for PPS (N = 40) or other reasons (control group, N = 238) at La Timone University Hospital in Marseille, France, between April 2015 and September 2019 and had a copeptin assay. MEASUREMENTS: Ultrasensitive copeptin assays on blood samples. RESULTS: Among the children with PPS, the mean copeptin concentrations were 1.72, 55.2 and 15.7 pmol/l in those with central diabetes insipidus (N = 21), nephrogenic diabetes insipidus (N = 3), and primary polydipsia (N = 16), respectively. Copeptin levels lower than 3.53 pmol/l were diagnostic of central diabetes insipidus with 100% sensitivity and 87.4% specificity (p < .001). The 5th-95th copeptin percentile range in the control group was 2.53-21.03 pmol/L. Copeptin levels were significantly higher in boys than in girls but there was no association with age, pubertal stage, body mass index, or the reason for consulting. CONCLUSIONS: Our results indicate copeptin assays may be valuable in the differential diagnosis of PPS in children. Larger prospective studies are required to establish their accuracy in everyday clinical practice.

Position statement on the diagnosis and management of premature/primary ovarian insufficiency (except Turner Syndrome).

Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed.