Alterations in insulin-like growth factor system in spinal muscular atrophy.

INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. METHODS: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. RESULTS: A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p = .02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p = .03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. DISCUSSION: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

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.

Which parameters predict the beneficial effect of GnRHa treatment on height in girls with central precocious puberty?

OBJECTIVE: Data about GnRHa on adult height in girls with central precocious puberty (CPP) have shown variable results, ranging from improvement of growth prognosis to lack of any benefit. This study was designed to delineate the criteria to decide which girls with idiopathic CPP (iCPP) will have a height benefit from GnRHa treatment. DESIGN: Retrospective PATIENTS: 102 girls with iCPP who had reached final height (FH) were included. MEASUREMENTS: Auxological, hormonal and radiological findings at treatment onset, and FHs were extracted from records. RESULTS: Most important factor affecting height gain was chronological age (CA) at treatment onset. All the girls treated ≤6.4 years of age achieved a height gain of ≥1SDS, while none of the girls treated ≥8.3 years of age made the target. 75.6% of patients who started GnRHa between the ages of 6.4 and 8.3 years had a height gain of ≥1SDS. Most important factors affecting height gain in those treated 6.4-8.3 years were advanced bone age (BA), basal estradiol (E2 ) and pubertal stage (r2 : 0.906; P < .001). All individuals with BA advancement of ≥2.6 years or E2 of ≥32.6 pg/ml or pubertal stage of ≥3 had significant height gain, and none of the cases with BA advancement of <2 years or E2 of <21.5 pg/ml or pubertal stage of <2 had a height gain of ≥1SDS. CONCLUSIONS: Treatment with GnRHa is unquestionably beneficial to improve FH in girls with iCPP when initiated ≤6.4 years of age. GnRHa treatment after 8.3 years of age may not improve FH. Girls between the ages of 6.4 and 8.3 years at presentation can have a better height gain if BA (≥2.6 years over CA) and pubertal findings (pubertal stage ≥3 or E2 ≥32.6 pg/ml) are well-advanced.

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.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11ß-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11ß-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11ß-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11ß-hydroxylase deficiency CAH.

Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.

Evaluation of hypothalamic-pituitary function in children following acute bacterial meningitis.

BACKGROUND: Previous studies in adults and case reports in children have shown increased frequency of hypothalamo-pituitary dysfunction after infectious diseases of the central nervous system. The aim of this study was to evaluate the function of hypothalamo-pituitary axis in children with a history of bacterial meningitis. METHODS: Patients diagnosed with bacterial meningitis between April 2000 and June 2011 was included. Baseline and stimulated hormonal tests were performed as required for hormonal evaluations following a diagnosis of meningitis. RESULTS: Pituitary function was assessed following a period of 8-135 months (mean 53 months) after bacterial meningitis. Thirty-seven cases (27 male, 15 pubertal) with mean age of 11.1 ± 4.4 years were included. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. Baseline cortisol and low dose ACTH stimulation revealed normal adrenal functions in all patients. Gonadotropin deficiency was not detected in any of the pubertal cases. Four cases (10.8%) had low IGF1 and IGFBP3 z-scores (<-2 SD) according to age, sex and Tanner stage, but peak GH response in clonidin test was >10 ng/ml in three of them suggesting neurosecretary dysfunction of GH in these cases. The fourth case has died before the test. No one had TSH deficiency and diabetes insipidus, only one case had mild hyperprolactinemia. CONCLUSIONS: Our findings suggest that hypothalamo-pituitary dysfunction is not as common in childhood as in adulthood. The most remarkable finding was neurosecretary dysfunction of GH in some cases.

Cardiovascular Risk Factors in Adolescents with Type 1 Diabetes: Prevalence and Gender Differences

Objective: Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in patients with type 1 diabetes (T1D). Children with T1D have a similar or higher prevalence of being overweight (OW) or obese (Ob) compared to healthy peers. The aim of this study was to determine the prevalence of CVD risk factors in children and adolescents with T1D and the impact of obesity and sex differences on these factors. Methods: Data of patients aged 10-21 years and who had been using intensive insulin therapy with a diagnosis of T1D for at least three years were evaluated. Patients were divided into normal weight (NW), OW and Ob groups based on body mass index percentiles. Risk factors for CVD (obesity, dyslipidemia, hypertension) were compared between groups, and impact of gender was also analyzed. Results: Data of 365 patients (200 girls, 54.8%), were evaluated. Prevalence of OW/Ob was 25.9% and was significantly higher in girls (30.6% vs 20.1%, p<0.001). Rate of hypertension was highest in OW/Ob girls followed by OW/Ob boys, and similar in NW girls and boys (p=0.003). Mean low density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels were highest in OW/Ob girls, followed by OW/Ob boys, NW girls and NW boys, respectively (p<0.001 and p<0.001, respectively). Mean high density lipoprotein-cholesterol (HDL-c) levels were similar among groups. Rates of high LDL-c and TG were similar between OW/Ob girls and boys and higher than NW girls, followed by NW boys (p<0.001 and p<0.001, respectively). The rate of low HDL-c was similar in OW/Ob girls and boys, and higher than NW girls, followed by NW boys (p<0.001). Overall, girls were 1.9 times more likely than boys to have two or more risk factors for CVD. Factors associated with risk for CVD in multiple logistic regression analyses were being a girl, followed by higher daily insulin dose, higher hemoglobin A1c, and longer duration of diabetes (r=0.856; p<0.001). Conclusion: In spite of the increased prevalence for obesity in both sexes, the trend for CVD risk factors was greater in Ob girls, followed by Ob boys and NW girls. Girls with T1D are more likely to be OW/Ob and to have CVD risk than boys, highlighting the need for early intervention and additional studies to elucidate the causes.

Epidemiology of type 1 diabetes mellitus in children and adolescents: A 50-year, single-center experience.

BACKGROUND: Global variations in epidemiology of type 1 diabetes mellitus (T1DM) exist. This study is designed to examine demographic and clinical features of T1DM over the past 3 decades as well as evolving trends in epidemiology over last 50 years. METHODS: Clinical characteristics of 925 patients with T1DM over last 30 years (1990-2019) were evaluated and compared to previously published data of 477 patients diagnosed between 1969 and 1990 from one of the major referral centers for diabetes in Turkey. RESULTS: Mean age at diagnosis decreased from 9.5 ± 4.0 to 7.1 ± 3.6 years within the past 50 years (p < .001). Age at diagnosis peaked at 12-14 years between 1969 and 1990, then fell to 10-11.9 years between 1990 and 1999, and to 4-5.9 years between 2000-2009 and 2010-2019 (p = .005). Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage between the ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. A total of 47.5% of patients had ketoacidosis, 38.2% had ketosis, and 14.3% had only hyperglycemia. 23% of patients had severe diabetic ketoacidosis (DKA), whereas 42% had moderate. Over last 3 decades, there has been no change in frequency of ketoacidosis at presentation, but there has been significant decline in severity (p = .865, and p < .001, respectively). Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis. DKA was more frequent and severe in patients <6 years of age (p = .005, and p < .001, respectively). CONCLUSION: Age at diagnosis shifted to younger ages in T1DM in the past 50 years. Half of patients had ketoacidosis at diagnosis and frequency of presentation with DKA did not decrease, but severity decreased slightly. Increase in prevalence of T1DM in the younger age group and the fact that half of patients present with DKA indicate that awareness should be increased in terms of early diagnosis and treatment.

Challenges During the Coronavirus Disease 2019 Pandemic: Diabetes Control and Psychosocial Issues in Children with Type 1 Diabetes Mellitus and Their Mothers.

OBJECTIVE: Governments have enforced restrictions to prevent the spread of coronavirus dis- ease 2019, which has affected lifestyle and psychosocial well-being. The aim of this study is to examine the psychosocial dimensions of children with type 1 diabetes mellitus and lifestyle changes in the face of the pandemic. MATERIALS AND METHODS: Sixty school-aged children with type 1 diabetes mellitus were included to evaluate socioeconomic status, lifestyle changes, and psychological state after a 3-month school closure, using a questionnaire as well as scales in children and mothers [Depression-Anx iety-Stress Scale (short-form), Revised Child Anxiety-Depression Scale (parent-version), The Perceived Stress Scale in Children] via a Google® Form. The effect of pre-pandemic glycemic control on lifestyle and factors affecting HbA1c change were also investigated. RESULTS: The percentage of mothers having scale scores above the cutoff in terms of stress, anxiety, and depression were 18.3%, 23.3%, and 33.3%, respectively. Mother's and children's anxiety, depression, and stress scores were positively correlated. Employed mothers had higher depression scores. Paternal unemployment increased the anxiety of the mothers. Seventy-eight percent (n = 46) of the mothers thought that diabetes in their children increased the risk of coro- navirus disease 2019 infection, and children of these mothers had higher depression, anxiety, and stress scores(P = .01, P < .01, P < .01). The majority of participants were adversely affected by coronavirus disease 2019 in terms of daily routines and dietary compliance. Patients with poor-controlled type 1 diabetes mellitus deteriorated more in terms of diet compliance (P = .01). CONCLUSION: Coronavirus disease 2019 affects the psychosocial dimensions in the family of chil- dren with type 1 diabetes mellitus. The psychosocial impact is reflected within the family and may affect diabetic control. Thus, it should be handled within the context of family. The provi- sion of proper information and guidance to parents may be crucial to alleviate the psychosocial burden on the family during the pandemic.

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.

Assessment of gonadotrophin suppression in girls treated with GnRH analogue for central precocious puberty; validity of single luteinizing hormone measurement after leuprolide acetate injection.

OBJECTIVE: Intravenous GnRH stimulation test has often been used as gold standard test for the evaluation of hypothalamic-pituitary-gonadal axis in the diagnosis of central precocious puberty (CPP) and in the assessment of pubertal suppression. However, this test is time-consuming, costly and uncomfortable for the patients. We aimed to analyse the validity of single LH sample 90 min after GnRH analogue (GnRHa) administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut-off level for LH indicating adequate suppression. DESIGN: Prospective study. PATIENTS AND METHODS: One hundred and forty-two patients with CPP were included in this study. Peak LH level during iv GnRH stimulation test after the third dose of GnRHa was compared with LH level 90 min after injection of the 3rd dose of GnRHa. RESULTS: There was a positive correlation between LH level following a GnRHa injection and peak LH during standard iv GnRH stimulation test (r = 0·83; P < 0·0001). A LH value of 2·5 mIU/ml or less 90 min after GnRHa injection was considered to be the cut-off for the determination of pubertal suppression (sensitivity and specificity was 100% and 88%, respectively). In 117 patients, gonadotrophin suppression was existed according to both GnRHa and iv GnRH tests. In 25 patients, gonadotrophin suppression was not found in the GnRHa test. However, 16 of them were suppressed according to the iv GnRH test. CONCLUSION: Single LH determination 90 min after GnRHa administration using a cut-off level of 2·5 mIU/ml reflects pubertal suppression with a high sensitivity and specificity. However, this test may fail to show pubertal suppression in some cases. Those patients who appear to be inadequately suppressed should be reassessed using standard iv GnRH stimulation test for optimal dose adjustment.

Evaluation of serum kisspeptin levels in girls in the diagnosis of central precocious puberty and in the assessment of pubertal suppression.

BACKGROUND: Onset of puberty is dependent on pulsatile secretion of gonadotropin releasing hormone (GnRH). The kisspeptin-GPR54 signaling system has a considerable role in GnRH physiology and induction of puberty. OBJECTIVES: To evaluate kisspeptin levels in girls with central precocious puberty (CPP) at the time of the diagnosis and during follow-up, to determine whether or not kisspeptin may serve as a marker for diagnosis and follow-up of CPP. PATIENTS AND METHODS: Kisspeptin levels of 28 girls with CPP were measured at the time of diagnosis and repeated at the 6th month of therapy after complete pubertal suppression and compared to kisspeptin levels of 13 age-matched prepubertal controls. RESULTS: Kisspeptin levels of girls with CPP (10.2 +/- 2.6 pg/mL) were higher than those in controls (8.6 +/- 1.5 pg/mL (p = 0.019). There was a significant decline in the kisspeptin levels (7.3 +/- 1.3 pg/mL) of girls with CPP after pubertal suppression (p < 0.0001). CONCLUSION: These findings suggest that kisspeptin levels can be used as corroborative evidence for diagnosis of CPP and a valuable parameter for monitoring treatment efficacy.

17beta-hydroxysteroid dehydrogenase type 3 deficiency as a result of a homozygous 7 base pair deletion in 17betaHSD3 gene.

17-beta-Hydroxysteroid dehydrogenase type 3 (17betaHSD-3) converts delta4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17betaHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17betaHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17betaHSD type 3, and she is the second reported case with this deletion.

Feminizing Adrenocortical Tumors as a Rare Etiology of Isosexual/Contrasexual Pseudopuberty

Objective: Estrogen-secreting adrenocortical tumors (ACTs) are quite rare with feminizing adrenocortical tumors (FATs) accounting for 0.37-2% of all ACTs. The aim was to evaluate clinical and hormonal characteristics of FATS as well as treatment options and follow-up in the pediatric age group. Methods: Medical records of children with ACTs presenting to a single center in the last two decades were reviewed. Literature review within Pubmed revealed 34 pediatric patients (22 boys) with FAT among 192 articles. Results: Among the 25 children presenting with ACTs in the last two decades, two new pediatric cases of FAT were identified, one benign and the other malignant, in two genders with different clinical presentations. Literature review showed that FATs are extremely rare tumors that are most commonly seen in men and boys presenting with gynecomastia. FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. While boys present with contrasexual pseudopuberty signs, girls present with isosexual pseudopuberty. A high estrogen level strongly supports diagnosis, while elevations in other adrenal hormones may be seen. FATs are usually malignant in adults and prognosis is generally very poor. However, in children approximately half are benign although assessment of malignant potential depends on clinical behavior of the tumor. FATs are very unpredictable so even after surgery long-term follow-up is required. FATs presenting in childhood may have a better prognosis than adult presentation tumors as most FATs in children are followed without recurrence of tumor. Conclusion: FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. FATs in childhood may have a better prognosis than in adult males.

Hyperinsulinism May Be Underreported in Hypoglycemic Patients with Phosphomannomutase 2 Deficiency

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.

Exercise performance in children and adolescents with cystic fibrosis with and without abnormal glucose tolerance: a single center cross-sectional study.

BACKGROUND: Abnormal glucose tolerance (AGT) in cystic fibrosis (CF) affects lung function and clinical parameters, including aerobic fitness. However, its effects on physical activity level (PAL), anaerobic power (AP), and muscle strength (MS) in children and adolescents are unknown. PURPOSE: To investigate aerobic fitness, PAL, AP, and MS in pediatric patients with mild-to-moderate CF and AGT. METHODS: The study included children and adolescents with CF aged 10-18 years. Participants underwent a pulmonary function test, quadriceps, and handgrip MS measurement, vertical jump test to assess AP, and six-minute walk test (6MWT) to assess aerobic fitness. Bouchard's Three-Day Physical Activity record was used to determine PAL. RESULTS: Height z-score (p = .006), 6MWT (p = .024), handgrip (p = .028), quadriceps MS (p = .044), and AP (p = .036) were significantly lower in AGT (n = 21) than normal glucose tolerance (NGT) (n = 19). In the AGT group, glycosylated hemoglobin (HbA1c) was significantly associated with forced expiratory volume in one second (FEV1) (p = .046). 6MWT distance (6MWD) was associated with height (p = .008), FEV1 (p = .001), forced vital capacity (FVC) (p = .001), forced expiratory flow from 25% to 75% (FEF25-75%) (p = .030), handgrip MS (p = .012), and PAL (p = .034). After adjusting for height and FEV1, the groups had similar 6MWD, MS, and AP (p > .05); also, insulin was associated with MS and AP but not with 6MWT or quadriceps MS. CONCLUSION: Measures of aerobic fitness, MS, and AP are lower in AGT, but after adjusting for height and FEV1, aerobic fitness, MS, and AP do not show substantial differences. Insulin sensitivity and resistance are associated with MS and AP.

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.

Pros of priming in the diagnosis of growth hormone deficiency.

Priming with sex steroids in stimulation tests for the diagnosis of GHD is still under debate. Most of the data on utility of priming during GH stimulation so far seem to support its use in the diagnosis of GHD in childhood. There is a propensity to treat growth retarded children who test subnormally to stimulation tests with GH. However, some studies analyzing the final height or height gain during GH treatment in such children failed to show any improvement in height. This paper summarizes previous studies on priming to analyze the utility of priming as a valid method to better the diagnostic capacity of the test.

Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL.