Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants.

BACKGROUND: Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. OBJECTIVE: Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. DESIGN: The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). METHODS: NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. RESULTS: NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. CONCLUSIONS: The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.

Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

SPIOMET4HEALTH-efficacy, tolerability and safety of lifestyle intervention plus a fixed dose combination of spironolactone, pioglitazone and metformin (SPIOMET) for adolescent girls and young women with polycystic ovary syndrome: study protocol for a multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO. DISCUSSION: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention. TRIAL REGISTRATION: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 .

Comparison of humoral immune response in heterologous and homologous COVID-19 booster vaccine groups using CoronaVac and mRNA-based BNT162b2 vaccines.

BACKGROUND: Heterologous COVID-19 booster vaccination is an alternative strategy to homologous vaccination, especially in developing countries, due to shortages, delays, or unequal distribution of COVID-19 vaccines. We compared cohorts vaccinated with different vaccine combinations to investigate whether a heterologous booster dose of mRNA-based BNT162b2 vaccine boosts the immune response in individuals primed with the CoronaVac vaccine. METHODS: Anti-RBD IgG is generally measured 4 weeks after primary immunization and 4 weeks after booster vaccination. Data on anti-receptor-binding domain (anti-RBD) IgG antibody titers and clinical characteristics were provided by infection control units. RESULTS: The highest median anti-RBD IgG antibody titers (14589 AU/mL) after primary immunization was observed in the group vaccinated with two doses of BNT162b2 vaccine. Antibody titers were lower 4 months or more after the second CoronaVac vaccine dose in CoronaVac recipients with or without previous COVID-19. In the homologous COVID-19 booster vaccine group (primed with two doses of CoronaVac 4 weeks apart and a single booster dose of CoronaVac) the median anti-RBD titers decreased from 1025 to 242 AU/mL before the booster dose. In the heterologous group (primed with two doses of CoronaVac 4 weeks apart and a single booster dose of BNT162b2), the median anti-RBD titer increased to 31624 AU/mL, a 132-fold increase, 16 days after the booster dose. CONCLUSIONS: After the second dose of CoronaVac, protective neutralizing antibody levels decrease over time, and a booster dose is required. Heterologous COVID-19 booster vaccination with BNT162b2 is effective at boosting neutralizing antibody levels.

Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey

Objective: A significant rise in the number of trans adolescents seeking medical interventions has been reported in recent years. The aim of this study was to report the clinical features, treatment, and follow-up of adolescents with gender dysphoria (GD) with our increased experience. Methods: Twenty-six male-to-female (MTF) and twenty-seven female-to-male (FTM) adolescents who were referred to the GD-outpatient clinic between 2016 and 2022 were reviewed. The clinical and laboratory findings of thirty transgender adolescents (15 FTM /15 MTF) who received medical intervention were evaluated retrospectively. Results: Most individuals (60.4%) were admitted between 2020 and 2022, and the remaining (39.6%) were admitted between 2016 and 2019. At the time of referral, median age was 16.3 years [interquartile range (IQR) 1.53; range 13.2-19.4] in 26 MTF, and 16.4 years (IQR 1.74; range 11.7-21.6) in 27 FTM adolescents. The median age at pubertal blockage with gonadotropin-releasing hormone analog and androgen receptor blocker was 16.4 years (IQR 1.4; range 11.7-17.8) in 22 adolescents (9 MTF, 13 FTM), and 17.4 years (IQR 1.4; range 15.5-19.4) in 6 MTF individuals, respectively. Cross-sex hormone therapy was commenced in 21 adolescents (12 MTF, 9 FTM) at the median age of 17.7 years (IQR 0.61; range 16-19.5). Fifteen individuals (8 MTF, 7 FTM) have been transferred to the adult endocrinology department in transition clinics. Conclusion: All treatments were generally well tolerated and effective, including bicalutamide, and no significant side effects were observed. Transition clinics played an important role in the better management of gender reassignment processes.

A Rare Cause of Hypergonadotropic Hypogonadism: Transaldolase Deficiency in Two Siblings.

Transaldolase deficiency is a rare inborn autosomal recessive disorder caused by biallelic mutations in the TALDO1 gene. It is characterized by intrauterine growth restriction, dysmorphism, abnormal skin, cytopenia, hepatosplenomegaly, liver cirrhosis, endocrine problems, renal and cardiac abnormalities. We present two siblings of Turkish origin with early-onset form of transaldolase deficiency and hypergonadotropic hypogonadism in both sexes. The girl (index) was followed-up with cryptogenic cirrhosis, leukopenia and thrombocytopenia, skin abnormalities, congenital heart defects, hypercalciuria, nephrolithiasis, proteinuria, chronic kidney disease throughout childhood. She developed hypergonadotropic hypogonadism in adolescence period. Whole exome sequencing due to the multisystemic involvement revealed a previously described homozygous inframe deletion in TALDO1 gene. Her brother was born as a small for gestational age baby and was also followed-up with cryptogenic cirrhosis since his infancy, together with cytopenia, congenital heart defects, bilateral cryptorchidism, short stature, hypercalciuria, proteinuria and chronic kidney disease in childhood. He presented with testicular microlithiasis and hypergonadotropic hypogonadism in adolescence. Sanger sequencing of TALDO1 gene confirmed the presence of the same homozygous deletion with his sister. The mother was found to be a heterozygous carrier for this deletion. We describe two patients with multisystemic involvement since neonatal period who presented with an additional hypergonadotropic hypogonadism in adolescence. The diagnosis of transaldolase deficiency should be kept in mind for these patients, and they must be evaluated for gonadal functions especially during puberty.

A novel homozygous nonsense NDNF variant in Kallmann syndrome.

Kallmann syndrome (KS) is a rare genetic disease characterized by pubertal failure and olfactory defects. Although many genes associated with KS have been reported, most are rare. Recently, heterozygous inactivating mutations in the neuron-derived neurotrophic factor gene (NDNF) were reported to cause KS. Here, we present a 14-year-old Kurdish boy with KS who has a novel homozygous nonsense c.1251C>A (p.Tyr417Ter) variant in NDNF. The variant was not observed in reference population databases and was predicted to be deleterious. Segregation analysis performed with Sanger sequencing indicated the autosomal recessive inheritance of the clinical phenotype. His heterozygous parents have experienced timely pubertal development and normal reproductive features. This study reported the first homozygous truncating NDNF variant, enabling the direct observation of the clinical consequences of predictively absent NDNF function. These results support the contention that the inactivating mutations in NDNF cause KS, and provide additional evidence for the complex inheritance of KS.

Indoor environmental quality in naturally ventilated schools of a dusty region: Excess health risks and effect of heating and desert dust transport.

Indoor air quality (IAQ) is impacted by polluted outdoor air in naturally ventilated schools, especially in places where both anthropogenic and natural sources of ambient air pollution exist. CO2 , PM2.5 , PM10 , temperature, relative humidity (RH), and noise were measured in five naturally ventilated primary schools in City of Sanliurfa, in a dusty region of Turkey, Southeast Anatolia. Excess risk levels were estimated for particulate matter. Investigation was conducted through an educational year including two seasons in terms of anthropogenic effect, that is, heating/non-heating, and natural effect, that is, desert dust transport/non-dust transport. The median CO2 concentration was measured to be >1000 ppm in all seasons/schools. Temperature and RH fell out of the comfort zone in October-December, during which pollutant concentrations were considerably increased, specifically in November, that heating and dust transport periods coincide. The overall mean indoor PM10 and PM2.5 levels were 58 and 31.8 µg/m3 , respectively. Risk assessment indicate that both short (incidence of asthma symptoms in asthmatic children) and long-term (prevalence of bronchitis) effects are considerable with 10.9 (2.4-19.6)% and 19.5 (2.2-38.8)%, respectively. The findings suggest that mechanical ventilation retrofitting with particle filtration is needed to mitigate potential negative health consequences on children.

Ovarian and paraovarian adrenal rest tumors are not uncommon in gonadectomy materials of historical congenital adrenal hyperplasia cases in childhood.

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients. Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male. Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient. Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Steroid Hormone Profiles and Molecular Diagnostic Tools in Pediatric Patients With non-CAH Primary Adrenal Insufficiency.

CONTEXT: There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. OBJECTIVE: This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. METHODS: Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology. RESULTS: A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P < .0001, area under the receiver operating characteristic curve: .96, .88, and .87, respectively). Plasma cortisol of less than 4 ng/mL, cortisone of less than 11 ng/mL, and corticosterone of less than 0.11 ng/mL had a greater than 95% specificity to ensure the diagnosis of non-CAH PAI of unknown etiology. CONCLUSION: Steroid hormone profiles are highly sensitive for the diagnosis of non-CAH PAI of unknown etiology, but they are unlikely to point to a specific molecular diagnosis. TPS is an optimal approach in the molecular diagnosis of these patients with high efficacy, whereas little additional benefit is expected from WES.

Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

Long-term Follow-up of a Toddler with Papillary Thyroid Carcinoma: A Case Report with a Literature Review of Patients Under 5 Years of Age

Papillary thyroid cancer (PTC) is extremely rare in children. Herein, we present a case diagnosed with PTC at 15 months of age. We conducted a literature review of the published cases with PTC under five years of age. A 1.25-year-old male patient had initially presented with a complaint of progressively enlarging cervical mass that appeared four months earlier. On physical examination, a mass located in the anterior cervical region with the largest measurements of around 3x3 cm was detected. Cervical and thyroid ultrasonography showed a 50x27 mm solid mass in the right lateral neck. Excisional biopsy revealed a follicular variant of PTC with capsular invasion. Subsequently, he underwent a complementary total thyroidectomy. He was diagnosed with intermediate-risk (T3N0M0) PTC. He developed permanent hypoparathyroidism. In the first year of the operation, he was treated with radioiodine ablation (RAI) since basal and stimulated thyroglobulin (Tg) levels tended to increase. Whole-body scintigraphy was normal in the first year of RAI ablation. On levothyroxine sodium (LT4) treatment, levels of thyroid stimulating hormone (TSH) and Tg were adequately suppressed. He is now 8.5-years-old and disease-free on LT4 replacement therapy for seven years and three months. Pediatric PTC has different biological behavior and an excellent prognosis compared to adults. The optimal treatment strategy for pediatric TC is total thyroidectomy, followed by RAI ablation. Post-operative management should include regular follow-up, TSH suppression by adequate LT4 therapy, serial Tg evaluation, and radioiodine scanning when indicated.

Clinical and Hormonal Profiles Correlate With Molecular Characteristics in Patients With 11ß-Hydroxylase Deficiency.

BACKGROUND: Given the rarity of 11ß-hydroxylase deficiency (11ßOHD), there is a paucity of data about the differences in clinical and biochemical characteristics of classic (C-11ßOHD) and nonclassic 11ßOHD (NC-11ßOHD). OBJECTIVE: To characterize a multicenter pediatric cohort with 11ßOHD. METHOD: The clinical and biochemical characteristics were retrospectively retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. RESULTS: 102 patients (C-11ßOHD, n = 92; NC-11ßOHD, n = 10) from 76 families (46,XX; n = 53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female adult height was 152 cm [-1.85 SD score (SDS)] and male 160.4 cm (-2.56 SDS).None of the NC-11ßOHD girls had ambiguous genitalia (C-11ßOHD 100%), and none of the NC-11ßOHD patients were hypertensive (C-11ßOHD 50%). Compared to NC-11ßOHD, C-11ßOHD patients were diagnosed earlier (1.33 vs 6.9 years; P < 0.0001), had higher bone age-to-chronological age (P = 0.04) and lower adult height (-2.46 vs -1.32 SDS; P = 0.05). The concentrations of 11-oxygenated androgens and 21-deoxycortisol were low in all patients. The baseline ACTH and stimulated cortisol were normal in NC-11ßOHD. Baseline cortisol; cortisone; 11-deoxycortisol; 11-deoxycorticosterone and corticosterone concentrations; and 11-deoxycortisol/cortisol, 11-deoxycorticosterone/cortisol, and androstenedione/cortisol ratios were higher in C-11ßOHD than NC-11ßOHD patients (P < 0.05). The 11-deoxycortisol/cortisol ratio >2.2, <1.5, and <0.1 had 100% specificity to segregate C-11ßOHD, NC-11ßOHD, and control groups. CONCLUSION: NC-11ßOHD can escape from clinical attention due to relatively mild clinical presentation. However, steroid profiles enable the diagnosis, differential diagnosis, and subtyping of 11ßOHD.

Growth and relationship of phenotypic characteristics with gonadal pathology and tumour risk in patients with 45, X/46, XY mosaicism.

OBJECTIVE: To evaluate the growth data, gonadal functions and tumour risk in children with 45, X/46, XY mosaicism. DESIGN: We reviewed retrospectively the records of 45 patients with 45, X/46, XY mosaicism or variants presented to our Unit from 1989 to 2019. RESULTS: The age at diagnosis ranged from 0.03 to 17.5 years. Twenty-eight patients had genital anomaly, 14 patients had female external genitalia and 3 patients had normal male genitalia. Patients showed normal height under 2 years of age. Mean height standard deviation score (HSDS) of 19 patients diagnosed before 2 years of age was -0.9 ± 0.6 and that of 26 patients diagnosed after 2 years of age was -2.6 ± 1.5. Ten patients diagnosed before 2 years of age showed growth deceleration after 2 years of age (HSDS decreasing from -0.6 ± 0.7 to -1.4 ± 0.9). Twenty-one patients reached adult height (AH). Growth hormone (GH) treatment was initiated in 10 patients. Although AHSDS of GH-treated patients was significantly greater than their mean HSDS before GH therapy (p =.013), it was not significantly different from AHSDS of the untreated group. Seventeen (37.8%) patients exhibited phenotypical features of Turner syndrome (TS) other than short stature. Two patients with genital anomaly had gonadoblastoma and germ cell neoplasia in situ, and one patient with female external genitalia had gonadoblastoma. CONCLUSIONS: GH therapy seems to improve AH of patients. Both patients with genital anomaly and female external genitalia have increased risk of germ cell tumours.

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.

Neonatal diabetes is caused by single gene mutations reducing pancreatic ß cell number or impairing ß cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in ß cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human ß cell models (YIPF5 silencing in EndoC-ßH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects ß cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and ß cell failure. Partial YIPF5 silencing in EndoC-ßH1 cells and a patient mutation in stem cells increased the ß cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in ß cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

CONTEXT: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. OBJECTIVE: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. SETTING: Twelve tertiary pediatric endocrine referral centers. PATIENTS: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. MAIN OUTCOME MEASURES: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. RESULTS: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. CONCLUSION: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Comparison of the effectiveness of simple carbohydrates on hypoglycemic episodes in children and adolescents with type 1 diabetes mellitus: A randomized study in a diabetes camp.

BACKGROUND: Hypoglycemia is the most common and severe complication of insulin treatment during the management of type 1 diabetes mellitus (T1DM). Despite its importance, there is a lack of data about the efficacy and superiority of the carbohydrate sources used in hypoglycemia management in children and adolescents. OBJECTIVE: We aimed to compare the effectiveness of honey, fruit juice, and sugar cubes as simple carbohydrates used in the primary treatment of hypoglycemia in children and adolescents with T1DM, who attended a diabetes summer camp. METHODS: A prospective randomized study was performed in a 5-days-long diabetes summer camp. Three different types of simple carbohydrates; sugar cubes, honey, or fruit juice were randomly given for the treatment of hypoglycemia and the recovery results in the three groups were compared. RESULTS: About 32 patients (53.1% male, mean age 12.9 ± 1.9 years) were included and 158 mild hypoglycemic episodes were observed. Sugar cubes, honey, and fruit juice were given in 46 (29.1%), 60 (37.9%), and 52 (33%) events, respectively. We found that honey and fruit juice had similar efficiency in recovering hypoglycemia in 15 minutes with a rate of 95% and 98%, respectively. However, sugar cubes had a significantly lower impact on treatment of hypoglycemia than the others, with a recovery rate of 84.7% at 15 minutes. CONCLUSIONS: This study showed, for the first time, that honey and fruit juice were more effective in treating hypoglycemia than sugar cubes, and can be preferred in treating hypoglycemic events in children and adolescents with T1DM.

An Investigation of Hearing (250-20,000 Hz) in Children with Endocrine Diseases and Evaluation of Tinnitus and Vertigo Symptoms.

Introduction Despite much advancement in medicine, endocrine and metabolic diseases remain an important cause of morbidity and even mortality in children. Objective The present study was planned to investigate the evaluation of hearing that also includes high frequencies, and the presence and degree of vertigo and tinnitus symptoms in pediatric patients diagnosed with endocrine diseases such as type 1 diabetes mellitus (DM), growth hormone deficiency (GHD), obesity, idiopathic short stature, and precocious puberty Methods The present study included a patient group of 207 children patients diagnosed with endocrine disease (95 males, 112 females; mean age 9.71 years old [range 6-16 years old]) and a control group including 55 healthy children who do not have any kind of chronic disease (26 males, 29 females; mean age 9.33 years old [range 6-16 years old]). The subjects underwent a hearing test with frequencies between 250 and 20,000 Hz. The vestibular and tinnitus symptoms were evaluated with the Pediatric Vestibular Symptom Questionnaire. Results Out of 207 patients in the patient group, 5 (2.4%) had hearing loss in pure tones, 10 (4.8%) had it in high frequencies, 40 (19.3%) had tinnitus symptoms, and 18 (8.7%) had vertigo symptoms. A total of 4 out of 207 patients in the study group (1.9%), 2 out of 59 with type 1 DM patients (3.4%), 1 out of 46 with GHD (2.2%), and 1 out of 43 obesity patients (2.3%) had hearing loss, vertigo, and tinnitus symptoms. Conclusions Our results suggest that some childhood endocrine diseases can cause some changes in the inner ear, although the exact cause is unknown. Perhaps, a detailed hearing and balance examination should be a routine in a child diagnosed with an endocrine disease. We think it is necessary to work on more comprehensive patient groups and tests in the future.

Revisiting Classical 3ß-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases.

CONTEXT: The clinical effects of classical 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency are insufficiently defined due to a limited number of published cases. OBJECTIVE: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3ßHSD2 deficiency. DESIGN: Multicenter, cross-sectional study. SETTING: Nine tertiary pediatric endocrinology clinics across Turkey. PATIENTS: Children with clinical diagnosis of 3ßHSD2 deficiency. MAIN OUTCOME MEASURES: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3ßHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. RESULTS: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ±â€…5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3ßHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. CONCLUSIONS: Genetically-documented 3ßHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3ßHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3ßHSD2 deficiency.