Evaluation of cardiac autonomic dysfunctions in children with type 1 diabetes mellitus.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes, impacting the autonomic nerves that regulate the heart and blood vessels. Timely recognition and treatment of CAN are crucial in averting the onset of cardiovascular complications. Both clinically apparent autonomic neuropathy and subclinical autonomic neuropathy, particularly CAN pose a significant risk of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Notably, CAN can progress silently before manifesting clinically. In our study, we assessed patients with poor metabolic control, without symptoms, following the ISPAD 2022 guideline. The objective is is to determine which parameters we can use to diagnose CAN in the subclinical period. METHODS: Our study is a cross-sectional case-control study that includes 30 children diagnosed with T1DM exhibiting poor metabolic control (average HbA1c > 8.5% for at least 1 year) according to the ISPAD 2022 Consensus Guide. These patients, who are under the care of the pediatric diabetes clinic, underwent evaluation through four noninvasive autonomic tests: echocardiography, 24-h Holter ECG for heart rate variability (HRV), cardiopulmonary exercise test, and tilt table test. RESULTS: The average age of the patients was 13.73 ± 1.96 years, the average diabetes duration was 8 ± 3.66 years, and the 1-year average HbA1c value was 11.34 ± 21%. In our asymptomatic and poorly metabolically controlled patient group, we found a decrease in HRV values, the presence of postural hypotension with the tilt table test, and a decrease in ventricular diastolic functions that are consistent with the presence of CAN. Despite CAN, the systolic functions of the ventricles were preserved, and the dimensions of the cardiac chambers and cardiopulmonary exercise test were normal. CONCLUSIONS: CAN is a common complication of T1DM, often associated with the patient's age and poor glycemic control. HRV, active orthostatic tests, and the evaluation of diastolic dysfunctions play significant roles in the comprehensive assessment of CAN. These diagnostic measures are valuable tools in identifying autonomic dysfunction at an early stage, allowing for timely intervention and management to mitigate the impact of cardiovascular complications associated with T1DM.

A novel graphene oxide-based fluorescence method for detection of urine glycosaminoglycans.

Glycosaminoglycans (GAGs) serve as a biomarker for mucopolysaccharidoses disease. In this study, a novel fluorometric method was developed to measure total GAGs in urine. Graphene oxide (GO) and rhodamine B (RhB), a cationic fluorescent dye, were employed in the development of the method. RhB attaches to the GO surface via electrostatic attraction, leading to the quenching of its fluorescence upon the establishment of the RhB-GO complex. However, the presence of GAGs prompts a resurgence of intense fluorescence. The linear range of the method is between 5.00 and 70.00 mg/L. The total GAG levels of urine samples analyzed using the method agree with the results of the biochemistry analysis laboratory (65.85 and 79.18 mg/L; 73.30 ± 1.76 and 72.21 ± 2.21). The method is simple, accurate, and sensitive and may be used for both first-step diagnosis of the mucopolysaccharidoses and detection of individual GAGs for studies of GAG-related research and other biological applications.

Ambulatory blood pressure monitorisation in children with recombinant growth hormone treatment.

OBJECTIVES: It is safe to use recombinant growth hormone in children. Studies have shown it to be effective and safe, except for a few side effects in the short and long term after treatment. The present study investigated the presence of hypertension in pediatric patients receiving growth hormone treatment using 24 h ambulatory blood pressure monitoring (ABPM). METHODS: This study is a single-center, retrospective study. Eighty-four patients aged 5-16 years who received growth hormone treatment for at least 3 months, who underwent 24 h ABPM were analyzed. They were compared with 67 patients who had no risk factors for hypertension. RESULTS: In the study, 84 rhGH-treated patients (45.2 % male, 54.8 % female) and 67 healthy control groups (49.3 % male, 50.7 % female) were analyzed. The mean age of the patient group was 10.83±2.85 years and the mean age of the healthy control group was 13.1±2.93 years. The diagnostic classification of the patients receiving treatment was as follows: 66.6 % (n=56) partial growth hormone deficiency, 22.6 % (n=19) growth hormone deficiency, 7.1 % (n=6) bioactive growth hormone, 2.3 % (n=2) idiopathic short stature, 1.1 % (n=1) low birth weight for gestational age (SGA). Body mass index was significantly lower in the treated group (p=0.013). The duration of treatment was 6.04±4.9 months. Daytime diastolic blood pressure was significantly lower in the treated group (p=0.001). There was no correlation between BMI and ABPM parameters in the treatment group and the control group. CONCLUSIONS: The present study shows that growth hormone treatment is safe in terms of high blood pressure.

A Rare Case of Monogenic Obesity due to a Novel Variant in the ADCY3 Gene: Challenges in Follow-up and Treatment.

Adenylate cyclase 3 (ADCY3) gene alterations have been found to be associated with obesity. However, few patients with homozygous mutations have been reported so far, and the follow-up procedure and treatment options have not been clarified. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 µIU/mL, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A(p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient's weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount's disease and acanthosis nigricans were distinctive, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur even at young ages. More data regarding the follow-up process and treatment of these patients are needed.

Investigation of (Epi)genetic causes in syndromic short children born small for gestational age.

Intrauterine onset syndromic short stature constitutes a group of diseases that pose challenges in differential diagnosis due to their rarity and clinical as well as molecular heterogeneity. The aim of this study was to investigate the presence of (epi)genetic causes in children born small for gestational age (SGA) and manifesting clinically undiagnosed syndromic short stature. The study group comprised twenty-nine cases selected from the syndromic SGA cohort. Various analyses were performed, including chromosomal microarray (CMA), methylation-specific-multiple ligation probe amplification for chromosomes 6,14 and 20, and whole exome sequencing (WES). Pathogenic copy number variants (CNVs) on chromosomes 2q13, 22q11.3, Xp22.33, 17q21.31, 19p13.13 and 4p16.31 causing syndromic growth disturbance were detected in six patients. Maternal uniparental disomy 14 was identified in a patient. WES was performed in the remaining 22 patients, revealing pathogenic variants in nine cases; six were monoallelic (ACAN, ARID2, NIPBL, PIK3R1, SMAD4, BRIP1), two were biallelic (BRCA2, RFWD3) and one was hemizygous (HUWE1). Seven of these were novel. Craniofacial dysmorphism, which is an important clue for the diagnosis of syndromes, was very mild in all patients. This study unveiled, for the first time, that ARID2 mutatios can cause syndromic SGA. In conclusion, a high (55.2%) diagnosis rate was achieved through the utilization of CMA, epigenetic and WES analyzes; 15 rare syndromes were defined, who were born with SGA and had atypical and/or mild dysmorphic findings. This study not only drew attention to the association of some rare syndromes with SGA, but also introduced novel genes and CNVs as potential contributors to syndromic SGA.

A very early onset MNGIE-like syndrome with POLG1 mutation and accompanying leukoencephalopathy.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a well-known mitochondrial depletion syndrome. Since Van Goethem et al. described MNGIE syndrome with pathogenic POLG1 mutations in 2003, POLG1 gene became a target for MNGIE patients. Cases with POLG1 mutations strikingly differ from classic MNGIE patients due to a lack of leukoencephalopathy. Here we present a female patient with very early onset disease and leukoencephalopathy compatible with classic MNGIE disease who turned out to have homozygous POLG1 mutation compatible with MNGIE-like syndrome, mitochondrial depletion syndrome type 4b.

Angiotensin (1-7) peptide replacement therapy with plasma transfusion in COVID-19.

AIM: To determine whether convalescent angiotensin (1-7) peptide replacement therapy with plasma (peptide plasma) transfusion can be beneficial in the treatment of critically ill patients with severe coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: Case series of 9 critically ill patients with laboratory-confirmed COVID-19 who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment. Peptide plasma: Plasma with angiotensin (1-7) content 8-10 times higher than healthy plasma donors was obtained from suitable donors. Peptide plasma transfusion was applied to 9 patients whose clinical status and/or laboratory profile deteriorated and who needed intensive care for 2 days. RESULTS: In our COVID-19 cases, favipiravir, low molecular weight heparin treatment, which is included in the treatment protocol of the ministry of health, was started. Nine patients with oxygen saturation of 93% and below despite nasal oxygen support, whose clinical and/or laboratory deteriorated, were identified. The youngest of the cases was 36 years old, and the oldest patient was 85 years old. 6 of the 9 cases had male gender. 3 cases had been smoking for more than 10 years. 4 cases had at least one chronic disease. In all of our cases, SARS CoV2 lung involvement was bilateral and peptide plasma therapy was administered in cases when oxygen saturation was 93% and below despite nasal oxygen support of 5 liters/minute and above, and intensive care was required. Although it was not reflected in the laboratory parameters in the early period, 8 patients whose saturations improved with treatment were discharged without the need for intensive care. However, a similar response was not obtained in one case. Oxygen requirement increased gradually and, he died in intensive care process. An increase of the platelet count was observed in all cases following the peptide plasma treatment. CONCLUSION: In this preliminary case series of 9 critically ill patients with COVID-19, administration of plasma containing angiotensin (1-7) was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.

Can we predict risk for cardiac involvement in paediatric inflammatory multi-system syndrome?

INTRODUCTION: Increasing recognition of paediatric inflammatory multi-system syndrome is a cause of concern. This study aimed to evaluate children with paediatric inflammatory multi-system syndrome and compare the clinical and laboratory features of children with and without cardiac involvement. MATERIAL AND METHODS: We conducted a prospective single-centre study including 57 (male 37, 65%) patients with paediatric inflammatory multi-system syndrome at a tertiary care hospital between November, 2020 and March, 2021. The mean age was 8.8 ± 4.5 years (range, 10 months-16.7 years). RESULTS: The most frequent symptoms were fever (100%), abdominal pain (65%) and diarrhoea (42%). SARS-CoV-2 PCR and serology tests were positive in 3 (5%) and 52 (91%) patients, respectively. Eight patients required intensive care support. Nineteen patients (33%) had cardiac involvement (valvular regurgitation in 15, left ventricular systolic dysfunction in 11 and coronary artery dilation in 1). The presence and duration of cough and intensive care admissions were significantly higher in children with cardiac involvement than those without it. The cut-off values of troponin T, pro-brain natriuretic peptide and interleukin 6 for predicting cardiac involvement were 11.65 ng/L (95% confidence interval, 0.63-0.90; sensitivity, 0.63; specificity, 0.84; area under the curve: 0.775, p = 0.009), 849.5 pg/mL (95% CI, 0.54-0.86; sensitivity, 0.63; specificity, 0.63; area under the curve: 0.706, p = 0.009) and 39.8 pg/mL (95% CI, 0.54-0.85; sensitivity, 0.63; specificity, 0.60; area under the curve: 0.698, p = 0.023), respectively. CONCLUSIONS: Cardiac involvement in children with paediatric inflammatory multi-system syndrome is common. The risk of cardiac involvement can be predicted by troponin T, pro-brain natriuretic peptide and interleukin 6 levels.

Treatment of COVID-19 patients with quercetin: a prospective, single center, randomized, controlled trial.

Scientific research continues on new preventive and therapeutic strategies against severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). So far, there is no proven curative treatment, and a valid alternative therapeutic approach needs to be developed. This study is designed to evaluate the effect of quercetin in COVID-19 treatment. This was a single-centre, prospective randomized controlled cohort study. Routine care versus QCB (quercetin, vitamin C, bromelain) supplementation was compared between 429 patients with at least one chronic disease and moderate-to-severe respiratory symptoms. Demographic features, signs, laboratory results and drug administration data of patients were recorded. The endpoint was that QCB supplementation was continued throughout the follow-up period from study baseline to discharge, intubation, or death. The most common complaints at the time of hospital admission were fatigue (62.4%), cough (61.1%), anorexia (57%), thirst (53.7%), respiratory distress (51%) and chills (48.3%). The decrease in CRP and ferritin levels was higher in the QCB group (all Ps were < 0.05). In the QCB group, the increase in platelet and lymphocyte counts was higher (all Ps were < 0.05). QCB did not reduce the risk of events during follow-up. Adjustments for statistically significant parameters, including the lung stage, use of favipiravir and presence of comorbidity did not change the results. While there was no difference between the groups in terms of event frequency, the QCB group had more advanced pulmonary findings. QCB supplement is shown to have a positive effect on laboratory recovery. While there was no difference between the groups in terms of event frequency, QCB supplement group had more advanced pulmonar findings, and QCB supplement is shown to have a positive effect on laboratory recovery/results. Therefore, we conclude that further studies involving different doses and plasma level measurements are required to reveal the dose/response relationship and bioavailability of QCB for a better understanding of the role of QCB in the treatment of SARS CoV-2.

Clinical, biochemical and genotypical characteristics in biotinidase deficiency.

OBJECTIVES: Hypotonia, lethargy, eczema, alopecia, conjunctivitis, ataxia, hearing loss, optic atrophy, cognitive retardation, and seizures can occur in patients with biotinidase deficiency, and it is inherited as autosomal recessive. The aim of this study was to evaluate the cases followed up with the diagnosis of biotinidase deficiency in our unit, in terms of clinical, biochemical and genetic analyses. METHODS: A total of 112 cases followed up in our centre with the diagnosis of biotinidase deficiency between August 2018-September 2020 were included in the study. Data were collected retrospectively. RESULTS: A total of 112 cases (55.4% male, mean age: 2.2 ± 2.8 years) diagnosed with biotinidase deficiency were evaluated. Diagnoses were made by newborn screening in 90.2% of the cases, by family screening in 4.5%, and by investigating symptoms in 5.4%. The most frequently (27.5%) detected mutations were c.1330G>C (p.D444H)/c.1330G>C (p.D444H) homozygous mutation, followed by (13.0%) c.1330G>C (p.D444H)/c.470G>A (p.R157H) compound heterozygous mutation, and (13.0%) c.470G>A (p.R157H)/c.470G>A (p.R157H) homozygous mutation. Biotinidase enzyme levels were found to be higher in patients with the p.D444H homozygous mutation than patients with other mutations. Biotin treatment was started in all patients with enzyme deficiency. CONCLUSIONS: Since the treatment is inexpensive and easily available, it is vital to detect this disease before symptom onset, especially findings related to the central nervous system, hearing and vision loss. In patients diagnosed with enzyme deficiency, the diagnosis should be definitively confirmed by genetic analysis.

Possible genotype-phenotype correlations in Niemann-Pick type C patients and miglustat treatment.

BACKGROUND AND PURPOSE: Niemann-Pick type C is a rare lysosomal storage disease caused by impaired intracellular cholesterol transport. The autosomal recessive disease is caused by mutations in NPC1 or NPC2 genes. METHODS: Clinical-laboratory features, genotype-phenotype correlation and miglustat treatment response of our patients diagnosed with early infantile Niemann-Pick type C were evaluated. RESULTS: In this article, four Niemann-Pick type C patients diagnosed in the early infantile period are presented. Common features of our patients were hepatomegaly, splenomegaly, cholestasis and retardation in motor development. Patients 1 and 2 are twins, with homozygous mutation c.2776G>A p.(Ala926Thr) in NPC1 gene and severe lung involvement. Lung involvement, which is mostly associated with NPC2 gene mutation in the literature, was severe in our patients and they died early. In patients 3 and 4, there were respectively c.2972del p.(Gln991Argfs*6) mutation in NPC1 gene and c.133C>T p.(Gln45*) homozygous mutation in NPC2 gene. In these two patients, improvement in neurological findings were observed with treatment of miglustat. CONCLUSION: In our twin patients, severe lung involvement was observed. Two of our four early infantile Niemann-Pick type C patients exhibited neurological gains with miglustat treatment.

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.

The frequency of and factors affecting functional gastrointestinal disorders in infants that presented to tertiary care hospitals.

This study aimed to determine the prevalence of infantile functional gastrointestinal disorders (FGIDs) based on Rome IV diagnostic criteria, and to determine the associated patient demographic and nutritional characteristics. A total of 2383 infants aged 1-12 months which were evaluated by 28 general pediatricians and pediatric gastroenterologists on the same day at nine tertiary care hospitals around Istanbul, Turkey, between November 2017 and March 2018, were included in the study. Patients included consulted the pediatric outpatient clinics because of any complaints, but not for vaccines and/or routine well child follow-ups as this is not part of the activities in the tertiary care hospitals. The patients were diagnosed with FGIDs based on Rome IV diagnostic criteria. The patients were divided into a FGID group and non-FGID group, and anthropometric measurements, physical examination findings, nutritional status, risk factors, and symptoms related to FGIDs were evaluated using questionnaires. Among the 2383 infants included, 837 (35.1%) had ≥1 FGIDs, of which 260 (31%) had already presented to hospital with symptoms of FGIDs and 577 (69%) presented to hospital with other symptoms, but were diagnosed with FGIDs by a pediatrician. Infant colic (19.2%), infant regurgitation (13.4%), and infant dyschezia (9.8%) were the most common FGIDs. One FGID was present in 76%, and ≥2 FGIDs were diagnosed in 24%. The frequency of early supplementary feeding was higher in the infants in the FGID group aged ≤6 months than in the non-FGID group (P = 0.039).Conclusion: FGIDs occur quite common in infants. Since early diversification was associated with the presence of FGIDs, nutritional guidance and intervention should be part of the first-line treatment. Only 31% of the infants diagnosed with a FGID were presented because of symptoms indicating a FGID. What is Known: • The functional gastrointestinal disorders (FGIDs) are a very common disorder and affect almost half of all infants. • In infants, the frequency of FGIDs increases with mistakes made in feeding. When FGIDs are diagnosed in infants, nutritional support should be the first-line treatment. What is New: • This study shows that only a third of children presented to hospital because of the symptoms of FGIDs, but pediatricians were able to make the diagnosis in suspected infants after appropriate evaluation. • The early starting of complementary feeding (<6 months) is a risk factor for the development of FGIDs.

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.

Novel variants in Turkish patients with glycogen storage disease.

BACKGROUND: Glycogen storage diseases (GSD) are disorders of autosomal recessive carbohydrate metabolism, characterized by glycogen accumulation. The liver and muscle tissue are commonly affected but patients may present with different clinical manifestations. The presence of glycogen can be demonstrated in biopsies and definitive diagnosis can be made by enzymatic or molecular analysis. The aim of this study was to determine specific gene mutations in our cases with GSD. METHODS: Thirty-eight patients with clinical and laboratory diagnoses of GSD were studied. Thirty-two patients had undergone genetic analysis. In our study, a next-generation sequencing panel was used. RESULTS: Five novel variants of uncertain significance (VUS), which were likely to be pathogenic, were detected in seven patients. Two new pathogenic variations of c.927delT (p.Phe309LeufsTer4) homozygous and c.44C>G (p.Ser15Ter) homozygous in the G6PC gene were detected in two GSD type Ia patients. In our two non-sibling GSD type III patients, c.1439T>G (p.Leu480Arg) homozygous novel-VUS was detected in the AGL gene. In our GSD type IV patient, c.1054G>C (p.Asp352His) homozygous novel-VUS was detected in the GBE1 gene. In GSD type VI, two sibling patients had a c.1454A>G (p.Asn485Ser) homozygous novel-VUS change in the PYGL gene. CONCLUSIONS: We determined the gene mutations specific to cohorts in our cases with GSD. The novel pathogenic, likely pathogenic, and VUS changes identified will contribute to the relationship between the patients' clinical and laboratory findings.

The factors relevant to partial remission in children with type 1 diabetes mellitus after measles vaccination: A retrospective study.

We aimed to identify the determinants of partial remission in patients with type 1 diabetes mellitus (DM), and whether there is an influence of vaccination against measles on partial remission. This was a retrospective study consisting of consecutive patients diagnosed with type 1 DM followed-up from 1 September 2010, through 30 November 2011. The study included children vaccinated within 3 months after diagnosis, and children unvaccinated during the first 12 months of the disease. The daily insulin dose, hemoglobin A1c, and C-peptide levels, and whether children are in partial remission based on the insulin dose-adjusted HbA1c were recorded at diagnosis and 3, 6, 9, 12, 24, and 36 months. A total of 55 children with type 1 DM were analyzed. Thirty-one patients (56.4%) reached partial remission during the follow-up period, whereas 24 of them did not. Patients with diabetic ketoacidosis (DKA) at diagnosis were less likely to reach partial remission than patients without DKA (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.062-0.946; P = .038). Patients vaccinated against measles were more likely to be in partial remission than patients unvaccinated (OR, 4.2; 95% CI, 1.35-13; P = .011). Partial remission was significantly associated with the C-peptide level and insulin dosage at diagnosis P = .002; P = .013, respectively). The lack of DKA, higher C-peptide level, and lower insulin dosage at diagnosis, and vaccination against measles after diagnosis may have an influence on partial clinical remission in patients with new-onset type 1 DM.

Children with Hashimoto's Thyroiditis Have Increased Intestinal Permeability: Results of a Pilot Study

Increased intestinal permeability (IIP) precedes several autoimmune disorders. Although Hashimoto's thyroiditis (HT) is the most common autoimmune disorder, the role of IIP in its pathogenesis had received little attention. Zonulin plays a critical role in IIP by modulating intracellular tight junctions. Rise of serum zonulin levels were shown to indicate IIP in human subjects. In this case-control study, we examined the hypothesis that patients with HT have IIP. We studied 30 children and adolescents with HT, and 30 patients with congenital hypothyroidism (CH) matched for age, gender and body mass index (BMI). Serum zonulin levels, free thyroxine (fT4), thyroid stimulating hormone (TSH), anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were measured. Zonulin levels were significantly higher in patients with HT than patients with CH (59.1±22.9 ng/mL vs. 43.3±32.9 ng/mL, p=0.035). In patients with HT, zonulin levels were positively correlated with weight (r=0.406, p=0.03), BMI (r=0.486, p=0.006) and levothyroxine dose (r=0.463, p=0.02). In patients with CH, zonulin levels were positively correlated with age (r=0.475, p=0.008), weight (r=0.707, p<0.001), BMI (r=0.872, p<0.001) and levothyroxine dose (r=0.485, p=0.007). After adjusting for age, weight, TSH and fT4 levels, serum zonulin was only associated with levothyroxine dose in patients with HT (R2=0.36, p=0.05). In patients with CH, only weight was associated with zonulin levels (R2=0.62, p<0.001). In conclusion, higher zonulin levels in children and adolescents with HT suggested IIP in these patients. Additionally, the association between zonulin levels and levothyroxine dose might imply a relationship between serum zonulin and disease severity.

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.

Assessment of retinal thickness as a marker of brain masculinization in children with congenital adrenal hyperplasia: a pilot study.

Objective To investigate the relationship between brain masculinization and retinal thickness in children with congenital adrenal hyperplasia (CAH). Methods Forty-five patients with CAH aged between 4 and 18 years and 30 age-matched healthy controls were included in this prospective study. Macular area was examined with optical coherence tomography (OCT); central subfield thickness (CST), cube volume (CV) and macular retinal thickness (MT) were measured in each subject. A gender identity questionnaire (GIQ) was used for the evaluation of gender happiness index. Results Girls with CAH had a higher CV (p = 0.002) and MT (p = 0.003) than healthy girls. No significant difference was found between boys with CAH and healthy boys regarding the retinal thickness measurements. Mean CST, CV and MT were significantly higher in boys than in girls in the control group (p = 0.013, p < 0.001, respectively), but there was no significant difference in those parameters between girls and boys with CAH. The gender happiness index was not different between healthy boys and boys with CAH, but was significantly lower in girls with CAH than healthy girls (p = 0.01). Conclusions As retina is part of the brain, our finding appears to be a morphological evidence of the excess androgen exposure on brain structures in girls with CAH. In addition, we suggest using retinal thickness measurements as a marker of prenatal excess androgen exposure in future studies.