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.

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Using Digital Droplet Polymerase Chain Reaction to Detect the Mosaic GNAS Mutations in Whole Blood DNA or Circulating Cell-Free DNA in Fibrous Dysplasia and McCune-Albright Syndrome.

The GNAS postzygotic mosaic activating mutations involved in fibrous dysplasia and McCune-Albright syndrome (MAS) are not detectable in leukocytes by Sanger sequencing. Digital droplet polymerase chain reaction detects GNAS mutations in 7 of 12 patients (58.3%) suspected to have fibrous dysplasia/MAS from whole blood DNA, and in 4 of 5 patients (80%) from circulating cell-free DNA.

Fertility preservation in Turner syndrome: Karyotype does not predict ovarian response to stimulation.

OBJECTIVE: Turner syndrome (TS) is responsible for gonadal dysgenesis with high risk of premature ovarian insufficiency. Little is known about fertility preservation (FP) strategies is this population. DESIGN: Data from women with TS consulting with a fertility specialist in our FP centre from 2014 to 2018 were retrospectively collected. MEASUREMENT: Total number of mature oocytes cryopreserved using vitrification. PATIENTS: Nine women with TS were referred. Three women with different karyotypes underwent controlled ovarian stimulation (COS) for oocyte vitrification. Mean age at TS diagnosis was 13.7 years [9-20]. Mean referral delay between TS diagnosis and fertility consultation was 9.7 years [7-14]. First counselling for FP was provided at 23.7 years [18-28]. Mean AMH serum level prior to COS was 53.8 pmol/L [3.6-95]. RESULTS: All three women succeeded in obtaining cryopreserved oocytes with a mean number of 15.3 per woman [9-20] and 9.2 per COS cycle [2-20]. Ovarian response to COS was unexpectedly remarkable for the woman with a complete 45,X monosomy. Procedure was well tolerated for all women. None of them have used oocytes for in vitro fertilization yet. CONCLUSIONS: Independently of karyotype, antral follicular count, AMH and FSH levels seemed to be reliable predictive markers of oocyte cryopreservation success. In a monosomic TS woman, cryptic ovarian mosaicism could explain a successful ovarian response to stimulation with a high number of retrieved oocytes. In case of spontaneous menarche, TS adolescents should be referred during transition to adulthood for FP counselling to avoid referral delay and limit time-related diminished ovarian reserve.

Family History is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families.

PURPOSE: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes. MATERIALS AND METHODS: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1. RESULTS: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048). CONCLUSIONS: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.

Successful IVF pregnancy despite inadequate ovarian steroidogenesis due to congenital lipoid adrenal hyperplasia (CLAH): a case report.

Steroidogenic acute regulatory protein (StAR) mutations are the most frequent aetiologies of congenital lipoid adrenal hyperplasia (CLAH). Phenotypes may vary, and puberty may be absent in affected individuals. To date, only two pregnancies have been described in 46,XX CLAH patients with StAR mutations; these patients exhibited ovarian steroidogenesis along with spontaneous puberty and menarche and normal menses. The patient described here presented with CLAH caused by the homozygous (unreported, 1 bp) deletion c.719del in the StAR gene, which was diagnosed after acute adrenal insufficiency when the patient was 10 days old. The patient did not undergo spontaneous puberty, so puberty was induced by HRT when the patient was 13 years old. At the age of 25 years, the patient was referred to our reproductive unit because she desired to conceive. An initial cycle of clomiphene, stimulation produced follicular growth with two mature follicles measuring 18 and 15 mm, respectively, but the plasma oestradiol levels remained low (18 pg/ml) and the endometrium was thin (3 mm). Pregnancy was finally achieved after ovarian stimulation, IVF and transfer of frozen-thawed embryos after endometrial preparation with HRT. A normal female child was delivered following a 40 weeks' uneventful pregnancy. We therefore report the first IVF pregnancy achieved in a 46,XX CLAH patient homozygous for a StAR mutation, with inadequate ovarian steroidogenesis and no spontaneous puberty.

[Cross-cultural adaptation and psychometric tests of a self-efficacy scale and an adherence scale for French adolescents with Type 1 diabetes] / Adaptation transculturelle et tests psychométriques d'outils de mesure de l'efficacité personnelle et de l'adhésion thérapeutique pour une population d'adolescents diabétiques de type 1 français.

Introduction : many structured educational programs, using the concept of self-efficacy, have been studied in English-speaking countries. Background : tools were developed in English to assess this concept along with treatment adherence. However, there seems to be no French version of these tools in scientific literature. Aim : to adapt the tools to the French language and to test the psychometric properties of the Self-Efficacy for Diabetes Self-Management (SEDM) and the Diabetes Self-Management Profile (DSMP). Methods : a cross-cultural adaptation of the SEDM and DSMP in French was performed. The psychometric properties were tested in a pilot study that took place between January 1st and December 31st, 2015. Results : Cronbach's alpha coefficient of SEDM in French was 0.84, test-retest reliability 0.80 and sensitivity to change was moderate. The Cronbach's alpha and sensitivity to change of the French DSMP were low, and the test-retest was 0.71. Discussion and conclusions : the first results of the psychometric properties of French SEDM were rather encouraging. The use of the French version of DSMP seems compromised in terms of psychometric properties and the opinion of the participants.

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.

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.

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.

Position statement on the diagnosis and management of congenital pituitary deficiency in adults: The French National Diagnosis and Treatment Protocol (NDTP).

Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.

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.

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.

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.

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.

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.

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.

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.