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Objectives We aimed to identify the origin of atypical diabetes in a family with four generations of diabetes from South Asia. The family members showed different clinical phenotypes. Members of generation one to three were presumed to have type 2 diabetes and generation four to have type 1 diabetes. Case presentation We performed a genetic analysis of the family using targeted high throughput sequencing. Conclusions We identified a novel nonsense variant in the neurogenic differentiation 1 (NEUROD1) gene, co-segregating with diabetes. The variant was located in the DNA-binding domain, altering a protein residue that was very well conserved among different species.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

BACKGROUND: The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. METHODS: Whole exome sequencing was performed on a large cohort of probands with congenital hypogonadotropic hypogonadism to identify ultra-rare variants in NOS1. The activity of NOS1 mutants identified was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. FINDINGS: We identified 5 heterozygous NOS1 loss-of-function mutations in 6 probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss and intellectual disability. In addition, NOS1 was found to be transiently expressed by newly born GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects not only in sexual maturation but also olfaction, hearing and cognition. The pharmacological inhibition of NO production in infantile mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. INTERPRETATION: The lack of timely NOS1 activity causes GnRH deficiency and lifelong sensory and intellectual comorbidities in humans and mice. NO treatment during a critical window, by reversing deficits in sexual maturation, olfaction and cognition in Nos1-deficient mice, thus holds therapeutic potential for humans.

Context Patients with classic congenital adrenal hyperplasia (CAH) often do not achieve their full growth potential. Adrenarche may accelerate bone maturation and thereby result in decreased growth in CAH. Objective The study aimed to analyze the impact of growth during adrenarche on final height of adequately treated classic CAH patients. Methods This retrospective, multicenter study (4 academic pediatric endocrinology centers) included 41 patients with classical CAH, born 1990-2012. We assessed skeletal maturation (bone age), growth velocity, and (projected) adult height outcomes, and analyzed potential influencing factors, such as sex, genotype, and glucocorticoid therapy. Results Patients with classic CAH were shorter than peers (−0.4 SDS ± 0.8 SD) and their parents (corrected final height −0.6 SDS ± 1.0 SD). Analysis of growth during adrenarche revealed 2 different growth patterns: patients with accelerating bone age (49%), and patients with nonaccelerating bone age relative to chronological age (BA-CA). Patients with accelerating BA-CA were taller than the normal population during adrenarche years (P = 0.001) and were predicted to achieve lower adult height SDS (−0.9 SDS [95% CI, −1.3; −0.5]) than nonaccelerating patients when assessed during adrenarche (0.2 SDS [95% CI, −0.3; 0.8]). Final adult height was similarly reduced in both accelerating and nonaccelerating BA-CA groups (−0.4 SDS [95% CI, −0.9; 0.1] vs −0.3 SDS [95% CI, [−0.8; 0.1]). Conclusion Patients with and without significant bone age advancement, and thus differing height prediction during adrenarche, showed similar (predicted) final height when reassessed during pubertal years. Bone age alone should not be used during adrenarche as clinical marker for metabolic control in CAH treatment.

ContextEstrogen resistance due to mutations in the estrogen receptor α gene (ESR1) has been described in men and women and is characterized by osteoporosis, delayed bone age and continuous growth in adulthood, and delayed puberty and multiple ovarian cysts in women. Although mutations in the estrogen receptor β gene ESR2 were found in 46, XY patients with differences of sex development, no genetic variants of ESR2 were linked to gonadal defects in women.Settings and PatientHere we describe a 16-year-old female patient who came to our tertiary care hospital with complete lack of estrogen action, as demonstrated by absent breast development, primary amenorrhea, and osteoporosis, resembling patients with ESR1 mutation. However, her gonads were clearly abnormal (streak), a finding not observed in ESR1-deficient patients.DesignTo gain insights into the molecular consequences of the ESR2 defect, whole exome sequencing and extensive functional transactivation studies in ovarian, bone, and breast cells were conducted, with or without the natural activator of estrogen receptors, 17β-estradiol.ResultsWe identified a loss-of-function heterozygous mutation of a highly conserved residue in ESR2 that disrupts estradiol-dependent signaling and has a dominant negative effect, most likely due to failure to interact with its coactivator, nuclear coactivator 1.ConclusionsThis is a report of a loss-of-function mutation in the estrogen receptor β in a young woman with complete ovarian failure, suggesting that ESR2 is necessary for human ovarian determination and/or maintenance and that ESR1 is not sufficient to sustain ovarian function in humans.

Thyroid dyshormonogenesis (TDH) is characterized by the defective synthesis of thyroid hormones. We present a patient with congenital hypothyroidism (CH) who presented in newborn screening with elevated serum thyroid-stimulating hormone (TSH), decreased free thyroxine (fT4) and increased thyroglobulin (Tg) concentrations. Ultrasound scan revealed a properly structured thyroid gland. Treatment with L-thyroxine was initiated. At the age of 2 years, thyroxine replacement was stopped. The patient remained untreated until 6 years of age when TSH levels progressively increased and L-thyroxine treatment was restarted at a dose of 12.5 μg/day. Genetic analysis revealed a double heterozygosity for likely pathogenic variants of dual oxidase 2 (DUOX2) and thyroid stimulating hormone receptor (TSHR). Both genes were earlier shown to be associated with CH. In a literature review, our patient was compared to previously published patients with similar clinical characteristics, and a good genotype-phenotype correlation was identified.

Much is known about estrogen action in experimental animal models and in human physiology. This article reviews the mechanisms of estrogen activity in animals and humans and the role of its two receptors α and β in terms of structure and mechanisms of action in various tissues in health and in relationship with human pathologies (e.g., osteoporosis). Recently, the spectrum of clinical pictures of estrogen resistance caused by estrogen receptors gene variants has been widened by our description of a woman with β-receptor defect, which could be added to the already known descriptions of α-receptor defect in women and men and β-receptor defect in men. The essential role of the β-receptor in the development of the gonad stands out. We summarize the clinical pictures due to estrogen resistance in men and women and focus on long-term follow-up of two women, one with α- and the other with β-receptor resistance. Some open questions remain on the complex interactions between the two receptors on bone metabolism and hypothalamus-pituitary-gonadal axis, which need further deepening and research.

When diabetes is associated with congenital malformations, without autoimmune antibodies, a genetic cause is suspected. Here, we aimed to identify a defective gene that led to diabetes. We performed an exome analysis of an index case and his healthy parents. The child presented with childhood-onset diabetes, congenital hypopituitarism, cardiac malformation, and anal atresia. A DNA analysis revealed a heterozygous de novo pathogenic variant in the developmental transcription factor, forkhead box A2 (FOXA2). The mutation resided in the DNA-binding domain, which is highly conserved among species. Tridimensional molecular dynamics simulation modeling predicted an altered interaction between the mutated protein and DNA. A defect in the FOXA2 DNA-binding domain was associated with childhood-onset diabetes and multiple congenital anomalies, which reflected the pleiotropic nature of the gene. This report extends the recently described phenotype of neonatal hypoglycemia to later-onset diabetes. We suggest to include FOXA2 analysis for neonatal hypoglycemia and to implement a long-term follow-up, particularly for the risk of diabetes.

GATA6gene variants come along with possible features such as pancreas agenesis/hypoplasia, neonatal diabetes and congenital heart defect. Congenital hypothyroidism, and hepatobiliary and gut abnormalities are also detectable. Children with congenital heart defects and neonatal diabetes were already described in 1970. GATA6 variants can be due tode novovariants or due to inherited variants. To date, 11 cases due to an inherited variant have been described. Herein we present a novel heterozygous GATA6 variant (c.1291C > T p.[Gln431*]) in a boy with transient neonatal diabetes, diaphragmatic hernia, congenital heart defect and early-onset scoliosis. The same variant was also present in the mother. At the age of 3 years, a random evaluation revealed a hemoglobin A1c(HbA1c) level of 7.8% (62 mmol/mol) without any diabetes-related symptoms. He was started on insulin therapy and HbA1cnormalized. A short review of the literature of hereditary cases of the GATA6 variant revealed the variable phenotypic spectrum and showed that patients with a mild phenotype are likely to have children with a more severe phenotype.

Objective Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. Design We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. Methods Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). Results Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10−11) or controls (18%, P = 5.5 × 10−12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10−7). Conclusions Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Aims/hypothesis: Loss of pancreatic beta cells is the crucial event in the development of type 1 diabetes. It is the result of an imbalance between autoimmune destruction and insufficient regeneration of islet cells. To study the role of islet cell regeneration in the pathogenesis of type 1 diabetes, we focused on PAX4, a paired homeodomain transcriptional repressor that is involved in islet cell growth. Methods: The study included 379 diabetic children and 1,070 controls from two distinct populations, and a cohort of children who had not developed type 1 diabetes, despite the presence of islet cell antibodies. Genomic DNA analysis of PAX4 was carried out via direct sequencing of PCR-amplified fragments and allelic discrimination. We compared the transrepression potential of the PAX4 variants in βTC3 cells and analysed their influence on beta cell growth. Results: The type 1 diabetic subjects are different from the normal individuals in terms of the genotype distribution of the A1168C single nucleotide polymorphism in PAX4. The C/C genotype is frequent among type 1 diabetic children (73%) and rare among the control population (32%). Conversely, the A/C genotype is prevalent among control subjects (62%) and antibody-positive children without type 1 diabetes (73.6%), but uncommon among subjects with type 1 diabetes (17.5%). The combination of PAX4A and PAX4C is functionally more active than PAX4C alone (the ‘diabetic' variant). Beta cells expressing PAX4A and PAX4C efficiently proliferate when stimulated with glucose, whereas cells expressing the PAX4C variant alone do not. Conclusions/interpretation: We have identified a link between beta cell regenerative capacity and susceptibility to type 1 diabetes. This finding could explain the fact that not all of the individuals who develop autoimmunity against beta cells actually contract the disease. The C/C genotype of the A1168C polymorphism in PAX4 can be viewed as a predisposition marker that can help to detect individuals prone to develop type 1 diabetes

Congenital adrenal hyperplasia (CAH) is one of the most frequent autosomal recessive diseases in Europe. Treatment is a challenge for pediatric endocrinologists. Important parameters to judge the outcome are adult height and menstrual cycle. We report the follow-up from birth to adulthood of two Caucasian sisters with salt-wasting (SW) CAH due to the same mutation, homozygosity c.290-13A>G (I2 splice), in the 21-hydroxylase gene. Their adherence to treatment was excellent. Our objective was to distinguish the effects of treatment with hydrocortisone (HC) and fludrocortisone (FC) on final height (FH) from constitutional factors. The older girl (Patient 1), who showed virilised genitalia Prader scale III-IV at birth, reached FH within familial target height at 18 years (yr) of age. Menarche occurred at the age of 15. Her menstrual cycles were always irregular. Total pubertal growth was normal (29 cm). She showed a growth pattern consistent with constitutional delay. The younger sister (Patient 2) was born without masculinization of the genitalia after her mother was treated with dexamethasone starting in the fourth week of pregnancy. She reached FH at 16 yr of age. Her adult height is slightly below familial target height. Menarche occurred at the age of 12.5, followed by regular menses. Total pubertal growth was normal (21 cm). The average dose of HC from birth to FH was 16.7 mg/m2 in patient 1 and 16.8 mg/m2 in patient 2. They received FC once a day in doses from 0.05 to 0.1 mg. Under such therapy, growth velocity was normal starting from the age of 2.5 yr with an overall average of +0.2 SD in patient 1 and - 0.1 SD in patient 2, androstenedione levels were always within normal age range. Similarly, BMI and blood pressure were always normal; no acne and no hirsutism ever appeared. Conclusion: Two siblings with the same genetic form of 21-hydroxylase deficiency and excellent adherence to medication showed different growth and menstrual cycle patterns, rather related to constitutional factors than to underlying congenital adrenal hyperplasia. In addition, the second patient represents an example of successful in utero glucocorticoid treatment to prevent virilisation of the external genitalia.

Background/Aims: Primary hypoaldosteronism is a rare inborn disorder with life-threatening symptoms in newborns and infants due to an aldosterone synthase defect. Diagnosis is often difficult as the plasma aldosterone concentration (PAC) can remain within the normal range and thus lead to misinterpretation and delayed initiation of life-saving therapy. We aimed to test the eligibility of the PAC/plasma renin concentration (PRC) ratio as a tool for the diagnosis of primary hypoaldosteronism in newborns and infants. Methods: Data of 9 patients aged 15 days to 12 months at the time of diagnosis were collected. The diagnosis of primary hypoaldosteronism was based on clinical and laboratory findings over a period of 12 years in 3 different centers in Switzerland. To enable a valid comparison, the values of PAC and PRC were correlated to reference methods. Results: In 6 patients, the PAC/PRC ratio could be determined and showed constantly decreased values Conclusion: A PAC/PRC ratio

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both