Case report: An adolescent female with anosmic hypogonadotropic hypogonadism, intellectual disability, and papillary thyroid carcinoma: heterozygous deletion of TCF12.

Background: Isolated hypogonadotropic hypogonadism is a heterogeneous clinical entity. There is a growing list of molecular defects that are associated with hypogonadotropic hypogonadism (HH). TCF12, a recently identified molecular defect, causes craniosynostosis and is suggested to be used as a biomarker for prognosis in various cancer types. Recently, TCF12 variants were shown in a cohort with HH. Case presentation: A 15.3 years old female patient was referred to the endocrinology clinic for obesity. She had been gaining weight from mid-childhood. She had her first epileptic seizure at the age of 15.1 years and mildly elevated thyroid autoantibodies were detected during evaluation for etiology of seizures. She had not experienced menarche yet. She was operated for left strabismus at the age of 7 years. School performance was poor and she was receiving special education. Tanner stage of breast was 1 and pubic hair was 3. The endocrine workup revealed hypogonadotropic hypogonadism. Also, the Sniffin' Sticks test detected anosmia. Thyroid ultrasonography was performed due to the mildly elevated thyroid autoantibodies, and thyroid nodules with punctate calcifications were detected. Total thyroidectomy and central lymph node dissection were performed regarding the cytological findings of the nodules and multicentric papillary thyroid carcinoma with no lymph node metastasis was detected on pathology specimens. Regarding the phenotypic features of the patients, whole exome sequencing was performed and heterozygous deletion of exon 1 and exon 6-8 in TCF12 was detected. Conclusion: Haploinsufficiency of TCF12 causes anosmic HH. Probably due to the incomplete penetrance and variable expressivity of the disease, patients could display variable phenotypic features such as intellectual disability, developmental delay, and craniosynostosis. Further description of new cases with TCF12 variations could enhance our understanding of craniosynostosis and its potential link to Kallmann syndrome associated with this gene.

Dual-basal-insulin regimen for the management of dawn phenomenon in children with type 1 diabetes: a retrospective cohort study.

Background: Handling of the dawn phenomenon (DP) with multiple daily insulin injection (MDII) regimen is a real challenge. Objective: We aimed to demonstrate the effectiveness of a dual-basal-insulin (a long-acting glargine and an intermediate-acting neutral protamine Hagedorn (NPH)) regimen for the management of DP in children with type 1 diabetes mellitus (T1DM). The primary efficacy outcome was to overcome morning hyperglycemia without causing hypoglycemia during the non-DP period of the night. Design: Retrospective cohort study. Method: Charts of 28 children with T1DM (12 female; 42.8%, mean age 13.7 ± 2.1 years) treated with MDII were retrospectively reviewed. The median duration of diabetes was 4.5 years (range 2-13.5 years). DP was diagnosed using a threshold difference of 20 mg/dL (0.1 mmol/L) between fasting capillary blood glucose at 3 a.m. and prebreakfast. NPH was administered at midnight in addition to daily bedtime (08.00-09.00 p.m.) glargine (dual-basal-insulin regimen). Midnight, 03:00 a.m., prebreakfast and postprandial capillary blood glucose readings, insulin-carbohydrate ratios, and basal-bolus insulin doses were recorded the day before the dual-basal-insulin regimen was started and the day after the titration of the insulin doses was complete. Body mass index standard deviation scores (BMI SDS) at the onset-3rd-12th month of treatment were noted. Results: Before using dual basal insulin, prebreakfast capillary blood glucose levels were greater than those at midnight and at 03:00 a.m. (F = 64.985, p < 0.01). After titration of the dual-basal-insulin doses, there were significant improvements such that there were no statistically significant differences in the capillary blood glucose measurements at the three crucial time points (midnight, 03.00 a.m., and prebreakfast; F = 1.827, p = 0.172). No instances of hypoglycemia were reported, and the total daily insulin per kilogram of body weight did not change. The BMI SDS remained steady over the course of the 1-year follow-up. Conclusion: In this retrospective cohort study, the dual-basal-insulin regimen, using a long-acting glargine and an intermediate-acting NPH, was effective in overcoming early morning hyperglycemia due to insulin resistance in the DP. However, the effectiveness of the dual-basal-insulin regimen needs to be verified by prospective controlled studies using continuous glucose monitoring metrics or frequent blood glucose monitoring.

Long Term Growth Hormone Therapy in a Patient with IGF1R Deletion Accompanied by Delayed Puberty and Central Hypothyroidism.

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through insulin-like growth factor 1 receptor (IGF1R). Patients with IGF1R defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mild mental retardation. Genetic analysis for IGF1R revealed heterozygous deletion of the complete IGF1R. At the age of 12.3 years, daily subcutaneous rhGH was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he could not develop full puberty suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels sustained after cessation of rhGH therapy thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with IGF1R defects. However, long-term treatment with an early onset may have more beneficial effects. In addition, patients with IGF1R defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.

Comparison of high flow oxygen therapy versus noninvasive mechanical ventilation for successful weaning from invasive ventilation in children: An observational study.

Post-extubation respiratory failure is associated with a poor prognosis due to increased ventilator-associated pneumonia, and longer length of stay in the ICU and hospital. In this study, we aimed to evaluate the efficacy of high-flow nasal cannula (HFNC) and noninvasive mechanical ventilation (NIMV) on extubation success in children. A total of 48 patients, aged between 1 month and 18 years, who were weaned to either NIMV or HFNC were included. Patients who had tracheostomy or were not weaned and underwent unplanned extubation were excluded. Age, gender, anthropometric parameters, Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction scores, oxygenation index, mechanical ventilation length of stay (LOS), HFNC/NIMV LOS, Modified Downes-Silverman score (MDS), and venous blood gas parameters, pediatric intensive care unit (PICU) LOS were recorded. 24 patients were extubated to NIMV, and 24 patients to HFNC. HFNC LOS and NIMV LOS were similar (P = .621). The failure rates at the 48th hour of HFNC and NIMV were 33% (n = 8), and 33% respectively (n = 8) (P = 1.0). PICU LOS and mortality rate was also similar (P = .06, P = .312 respectively). MDS decreased significantly in both groups (P < .001, P = .02 respectively). Changes in blood gas parameters and MDS within the first 48-hour of device application were similar between the 2 groups. HFNC is not inferior to NIMV in patients with extubation difficulty or those expected to have such difficulty in terms of treatment success, PICU LOS, and mortality. Therefore, HFNC appears to be a weaning technique alternative to NIMV after extubation.

Psychosocial Impact of the COVID-19 Pandemic on Children with Congenital Adrenal Hyperplasia and Their Families.

OBJECTIVE: This study aimed to investigate the psychosocial impact of the pandemic in pediatric patients with congenital adrenal hyperplasia and their families and whether congenital adrenal hyperplasia imposes an additional burden compared to other endocrine disorders. MATERIALS AND METHODS: Patients with congenital adrenal hyperplasia (n = 38) and congenital hypothyroidism (n = 41) and their families were enrolled in the prospective longitudinal survey study. Questionnaires that were completed remotely in June 2020 and in July 2021 included Depression Anxiety Stress Scale short form, The State-Trait Anxiety Inventory for Children, and purpose-built daily routine, parent, and child COVID information scores, factors affecting drug usage, and parents' thoughts about the pandemic. At the end of 1 year, Depression Anxiety Stress Scale short form and State-Trait Anxiety Inventory for Children were repeated in the congenital adrenal hyperplasia group and they were questioned about the incidence and severity of coronavirus infection. RESULTS: Median Depression Anxiety Stress Scale short form and State-Trait Anxiety Inventory for Children scores were similar between the congenital adrenal hyperplasia and congenital hypothyroidism groups. In the congenital adrenal hyperplasia group, median purpose-built daily routine was higher in those who had a State-Trait Anxiety Inventory for Children-State score above the threshold (P = .048), also Depression Anxiety Stress Scale short form-Depression, Depression Anxiety Stress Scale short form-Anxiety, Depression Anxiety Stress Scale short form-Stress, Parent COVID Information Score were higher among parents who followed news/data because of chronic diseases/medications of the child (P = .010, P = .034, P = .044, P = .045, respectively), and State-Trait Anxiety Inventory for Children-State was higher among parents who believed "having chronic diseases" and "using medications" increase the risk of COVID-19 infection (P = .011, P = .016, respectively). In the second survey, State-Trait Anxiety Inventory for Children-State, Depression Anxiety Stress Scale short form-Anxiety, and Depression Anxiety Stress Scale short form-Stress decreased significantly (P < .01, P = .009, P = .008, respectively). Three patients with congenital adrenal hyperplasia who reported positive nasopharyngeal swab tests revealed mild symptoms. CONCLUSION: The pandemic has negative consequences on the mental well-being of individuals with chronic diseases, albeit from different causes.

Stress Induced Hyperglycemia in Early Childhood as a Clue for the Diagnosis of NEUROD1-MODY

Maturity-onset diabetes of young 'MODY' Type 6 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and BMI at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting blood glucose (BG) (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m2). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m2 and a normal oral glucose tolerance test (OGTT). Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals.

Management of prolactinomas in children and adolescents; which factors define the response to treatment?

PURPOSE: Prevalence, presentation and clinical outcome of prolactinomas vary in children and adults. In this study, we evaluated the clinical features and outcome of children and adolescents with prolactinoma to identify the differences from that of adults, and thus to establish the management strategies for this age group. METHODS: Patients with prolactinoma diagnosed before 18 years of age from a single center in the last 20-years were included. Clinical and laboratory data, radiological findings and treatment outcome were evaluated retrospectively. RESULTS: Twenty-eight patients (23 female; 82.1%) with prolactinoma were included. Median age at diagnosis was 15.2 years (12.6-17.7 years) in girls, 12.9 years (12.0-16.7 years) in boys. First line treatment was cabergoline in 82% of patients and normal prolactin level was achieved with maximum dose of 2 mg/week in 78%. Surgery was required in 28% of patients. Adenomas < 13.5 mm responded conventional doses of CAB. Adenomas > 30 mm were drug resistant or required surgery. Adenomas between 13.5 mm and 30 mm with invasion/extension were more likely to have drug resistance. CAB had to be continued following surgery in all patients. One macroprolactinoma had an increase in size which was accompanied with increasing prolactin level. CONCLUSIONS: All microprolactinomas responded well to DA treatment. However, all adenomas larger than 30 mm was resistant to CAB or required surgery. Probability of drug resistance and requirement of second line therapy were higher in adenomas between 13.5 mm and 30 mm with invasion/extension. Doses over 2 mg/week of CAB in drug-resistant patients may not provide additional benefit. The frequency of follow-up MRI could be determined based on prolactin levels and emergence of new neurological symptoms.

Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?

OBJECTIVES: Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel SERPINF1 mutations, who show great variation in their treatment response to bisphosphonates. CASE PRESENTATION: The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead. CONCLUSION: SERPINF1 transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.

Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.

BACKGROUND: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. OBJECTIVE: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. METHODS: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. RESULTS: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. CONCLUSION: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.