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Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex., Objectives: Gain insight into the inheritance mode of CHTD., Design: Prospective multicenter nationwide translational study in France., Patients: We prospectively included 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes., Methods: Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation and in vitro functional studies focusing on cell migration have been performed., Results: We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7%(14/182) and 3.9%(7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in one of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model., Conclusion: This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up., Clinicaltrials.gov Registration: NCT01916018., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective, Design, and Methods: Although 17-hydroxyprogesterone (17OHP) has historically been the steroid assayed in the diagnosis of congenital adrenal 21-hydroxylase deficiency (CAH-21D), its C11-hydroxylated metabolite, 21-deoxycortisol (21DF), which is strictly of adrenal origin, is assayed in parallel in this pathology. This steroid (21DF) is oxidized by 11beta-hydroxysteroid dehydrogenase type 2 into 21-deoxycortisone (21DE). In the context of CAH-21D confirmation testing, confounding factors (such as intensive care unit admission, stress, prematurity, early sampling, and variations of sex development) can interfere with the interpretation of the gold-standard biomarkers (17OHP and 21DF). Since its tissue concentrations are especially high in the placenta, we hypothesized that 21DE quantification in the neonatal periods could be an interesting biomarker in addition to 17OHP and 21DF. To verify this hypothesis, we developed a new mass spectrometry-based assay for 21DE in serum and applied it to newborns screened for CAH-21D., Results: In newborns with CAH-21D, the mean serum levels of 21DE reached 17.56 ng/mL (ranging from 8.58 ng/mL to 23.20 ng/mL), and the mean 21DE:21DF ratio was 4.99. In contrast, in newborns without CAH-21D, the 21DE serum levels were low and not statistically different from the analytical 21DE limit of quantification (0.01 ng/mL)., Conclusion: Basal serum 21DE appears to be a novel sensitive and specific biomarker of CAH-21D in newborns., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Question: Can a combination of metabolomic signature and machine learning (ML) models distinguish nonclassic 21-hydroxylase deficiency (NC21OHD) from polycystic ovary syndrome (PCOS) without adrenocorticotrophic hormone (ACTH) testing?, Summary Answer: A single sampling methodology may be an alternative to the dynamic ACTH test in order to exclude the diagnosis of NC21OHD in the presence of a clinical hyperandrogenic presentation at any time of the menstrual cycle., What Is Known Already: The clinical presentation of patients with NC21OHD is similar with that for other disorders of androgen excess. Currently, cosyntropin stimulation remains the gold standard diagnosis of NC21OHD., Study Design, Size, Duration: The study was designed using a bicentric recruitment: an internal training set included 19 women with NC21OHD and 19 controls used for developing the model; a test set included 17 NC21OHD, 72 controls and 266 PCOS patients used to evaluate the performance of the diagnostic strategy thanks to an ML approach., Participants/materials, Setting, Methods: Fifteen steroid species were measured in serum by liquid chromatography-mass spectrometry (LC-MS/MS). This set of 15 steroids (defined as 'steroidome') used to map the steroid biosynthesis pathway was the input for our models., Main Results and the Role of Chance: From a single sample, modeling involving metabolic pathway mapping by profiling 15 circulating steroids allowed us to identify perfectly NC21OHD from a confounding PCOS population. The constructed model using baseline LC-MS/MS-acquired steroid fingerprinting successfully excluded all 17 NC21OHDs (sensitivity and specificity of 100%) from 266 PCOS from an external testing cohort of originally 549 women, without the use of ACTH testing. Blood sampling timing during the menstrual cycle phase did not impact the efficiency of our model., Limitations, Reasons for Caution: The main limitations were the use of a restricted and fully prospective cohort as well as an analytical issue, as not all laboratories are equipped with mass spectrometers able to routinely measure this panel of 15 steroids. Moreover, the robustness of our model needs to be established with a larger prospective study for definitive validation in clinical practice., Wider Implications of the Findings: This tool makes it possible to propose a new semiology for the management of hyperandrogenism. The model presents better diagnostic performances compared to the current reference strategy. The management of patients may be facilitated by limiting the use of ACTH tests. Finally, the modeling process allows a classification of steroid contributions to rationalize the biomarker approach and highlight some underlying pathophysiological mechanisms., Study Funding/competing Interest(s): This study was supported by 'Agence Française de Lutte contre le dopage' and DIM Région Ile de France. This study was supported by the French institutional PHRC 2010-AOR10032 funding source and APHP. All authors declare no competing financial interests., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context and Objective: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations., Design: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients., Results: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01)., Conclusions: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis., (© 2016 European Society of Endocrinology.)

Context: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions., Objective: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test)., Design and Setting: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice., Patients: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included., Intervention: DEX was offered after informed consent to pregnant women., Main Outcome Measure: The sensitivity of an early SRY test was evaluated after data collection., Results: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero., Conclusions: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.

Context: Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause., Objective: We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease., Design: Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed., Results: We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects., Conclusion: TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.

Context: IGF-I is essential for fetal and postnatal development. Only three IGF1 defects leading to dramatic loss of binding to its type 1 receptor, IGF-1R, have been reported., Patient: We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene., Result: We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient's IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay., Conclusion: This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use.

Context: Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, and frequent body asymmetry, spares cranial growth. Maternal uniparental disomy for chromosome 7 (mUPD7) is found in 5-10% of cases. We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS., Objective: The aim was to screen for 11p15 epimutation and mUPD7 in RSS and non-RSS small-for-gestational-age (SGA) patients and identify epigenetic-phenotypic correlations. STUDIED POPULATION AND METHODS: A total of 127 SGA patients were analyzed. Clinical diagnosis of RSS was established when the criterion of being SGA was associated with at least three of five criteria: postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties. Serum IGF-II was evaluated for 82 patients., Results: Of the 127 SGA patients, 58 were diagnosed with RSS; 37 of these (63.8%) displayed partial LOM of the 11p15 ICR1 domain, and three (5.2%) had mUPD7. No molecular abnormalities were found in the non-RSS SGA group (n = 69). Birth weight, birth length, and postnatal body mass index (BMI) were lower in the abnormal 11p15 RSS group (ab-ICR1-RSS) than in the normal 11p15 RSS group [-3.4 vs.-2.6 SD score (SDS), -4.4 vs.-3.4 SDS, and -2.5 vs.-1.6 SDS, respectively; P < 0.05]. Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM. All ab-ICR1-RSS patients had at least four of five criteria of the scoring system. Postnatal IGF-II levels were within normal values., Conclusion: The 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure to thrive. We propose a clinical scoring system (including a BMI < -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the gene AIRE (autoimmune regulator). APECED affects mainly endocrine organs resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, hypogonadism, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. APECED's first manifestation generally is mucocutaneous candidiasis presumably related to T cell dysfunction., Patient: A 5-yr-old Iranian girl presented first with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. She had renal dysfunction due to chronic interstitial nephritis (CIN), which progressed to end-stage renal failure. She was transplanted 1 yr later. Common causes of CIN were excluded. APECED was suspected first because she developed progressively hypoparathyroidism, adrenocortical failure, glucose intolerance, and hypothyroidism., Results: Genetic analysis revealed a large homozygous deletion (g.424&#95;2157del1734), spanning exons 2-4, in the AIRE gene. The predicted protein, if it is produced, has only 44 amino acids (exon 1) in common with the wild-type protein. Immunosuppression after the first renal transplant included prednisone, azathioprine, and cyclosporine A. Multiple acute rejection episodes occurred. Chronic rejection resulted in lost graft and she was retransplanted 2 yr later. Surprisingly, all APECED-related symptoms including candidiasis and autoantibody levels decreased, presumably due to the reinforced immunosuppression (tacrolimus, mycophenolate mofetil, prednisone)., Conclusions: This is the first report of an APECED patient with CIN resulting in end-stage renal failure. Clinical and biological improvement was observed under posttransplant multidrug immunosuppression including tacrolimus and mycophenolate mofetil.

The IGFs, IGF-I and IGF-II, regulate fetal growth by activating IGF type 1 receptors (IGF-IR). We aimed to quantify the binding of IGF-I to its cognate receptors in intrauterine growth-retarded children (IUGR). We measured the affinity of the erythrocyte IGF-IR and the number of IGF-IR receptors in 17 children with retarded growth (mean height, -2.7 SD), normal levels of GH, and a history of idiopathic intrauterine growth retardation (height at birth, -10 to -2 SD; mean, -3.1 SD). These children had reduced receptor affinity (Kd = 0.47 nM; P < 0.01) and more receptors per cell [binding capacity (Bmax) = 11.7 binding sites/cell; P < 0.05)] compared with control children (Kd = 0.32 nM; Bmax = 7.8 binding sites/cell). Moreover, the distributions of Kd and Bmax suggested that there were two groups of IUGR children. Group 1 included subjects with normal receptor binding function (Kd = 0.36 nM; Bmax = 8.2 sites/cell) and normal levels of circulating IGF-I. Group 2 comprised children with low receptor affinity (Kd = 0.56 nM) and increased receptor number (Bmax = 14.7 sites/cell). This group showed significantly decreased IGF-I levels (-2.1 SD; P < 0.01). We investigated these IGF-IR binding parameters in two additional groups of growth-retarded children (Turner syndrome and patients with chronic renal failure), in whom the IGF-I axis was not believed to be the primary cause, and found that Kd and Bmax were normal or nearly normal. We also measured IGF-IR binding parameters in 4 Seckel syndrome patients with IUGR and severely retarded growth (mean height, -7.9 SD). Their receptor affinity was reduced, but not statistically different, from that in controls, and their receptor number was normal, whereas IGF-I levels were elevated. Our results suggest heterogeneous alterations in IGF-IR binding function in IUGR patients.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324-->Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546-->Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.