Band 32, Heft 2

Background Short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency is a rare inborn error of metabolism with uncertain clinical significance. As it leads to C5-carnitine (i.e. isovalerylcarnitine, 2methylbutyrilcarnitine, or pivaloylcarnitine) elevation, SBCAD deficiency is detectable at newborn screening, requiring differential diagnosis from isovaleric acidemia and pivalic acid administration. Increased urinary excretion of 2-methylbutyrylglycine (2MBG) is the hallmark of SBCAD deficiency. Methods We report two cases of SBCAD deficiency and provide a review of the available literature on this condition. Results Two siblings newly diagnosed with SBCAD deficiency are reported. Newborn screening allowed the early diagnosis in the second-born (C5=0.5 μmol/L, normal 0.05–0.3 μmol/L) and addressed selective screening in the 5-year asymptomatic brother (C5=1.9 μmol/L). Both patients showed increased urinary excretion of 2MBG and two mutations in the ACADSB gene (c.443C>T/c.1145C>T). Currently, both the patients are asymptomatic. Longitudinal biochemical monitoring of the two patients while on treatment with carnitine (100 mg/kg/day) was provided. Based on our experience and the literature review (162 patients), SBCAD deficiency is symptomatic in about 10% of reported patients. Clinical onset occurs in newborns or later in life with seizures, developmental delay, hypotonia, and failure to thrive. On longitudinal follow-up, epilepsy, developmental delay, microcephaly, and autism can develop. Acute metabolic decompensation due to catabolic stressors can occur, as observed in one newly reported patient. Fifteen mutations in the ACADSB gene are known, including the newly identified variant c.1145C>T (p.Thr382Met), variably associated to the phenotype. In the Hmong population, SBCAD deficiency is highly prevalent, mostly due to the founder mutation c.1165A>G, and is largely asymptomatic. Conclusions Although mostly asymptomatic, considering SBCAD deficiency as a non-disease in non-Hmong subjects appears unsafe. Catabolic situations can precipitate acute metabolic decompensation. Carnitine supplementation and valproate avoidance appear to be indicated. Providing an emergency protocol for the management of acute catabolic episodes seems reasonable in asymptomatic patients with SBCAD deficiency. Longitudinal follow-up is recommended.

Background Type-1 diabetes mellitus (T1DM) causes endothelial dysfunction and early atherosclerosis, which can result in premature coronary artery disease. The aim of this study was to determine the impact of glycemic control, vascular oxidative stress and inflammation on vascular health in adolescents with T1DM. Methods This was a cross-sectional study in adolescents with age- and sex-matched T1DM who were ≥12 years and were at least 2 years post-diagnosis. Recruitment was balanced to include individuals with hemoglobin A 1c (HbA 1c ) ≤8.5% (n=27) or with HbA 1c ≥9.5% (n=25). Biomarkers of inflammation were measured in the blood including C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), E-selectin, fibrinogen and tumor necrosis factor-α (TNF-α). Carotid intima media thickness (cIMT) and peripheral arterial tonometry (PAT) were assessed. Results Plasma E-selectin level was significantly different between the two groups with higher levels in the group with HbA 1c ≥9.5% (65.0±27.7 ng/mL vs. 48.8±21.5 ng/mL, p=0.02). Though cIMT and PAT were not significantly different between the groups, Pearson correlation showed a significant direct relationship between rising HbA 1c and mean right cIMT (p=0.02; r=0.37), PAT (p=0.03, r=0.31) and fibrinogen (p=0.03, r=0.03). Conclusions Elevated E-selectin level is an early marker of oxidative stress in T1DM patients with an elevated HbA 1c level. Suboptimal glycemic control as evidenced by a rising HbA 1c causes early atherosclerosis.

Background As per the International Society for Pediatrics and Adolescent Diabetes (ISPAD) census, diabetic ketoacidosis (DKA) is the most frequent cause of diabetes-related death. In developing countries, DKA-related mortality rate ranges from 6% to 24% (Onyiriuka AN, Ifebi E. Ketoacidosis at diagnosis of type 1 diabetes in children and adolescents: frequency and clinical characteristics. J Diabetes Metab Disord 2013;12:47) in contrast to 0.15%–0.31% in the Western world (Poovazhagi V. Risk factors for mortality in children with diabetic ketoacidosis from developing countries. World J Diabetes 2014;5:932–93.). In developing countries like Pakistan, the situation is more perplexing owing to uncertain or under-reported statistics about the spectrum of the disease and its prevalence, coupled with limited access to medical care and experts as well as less awareness. These limitations restrict our ability to develop interventions that are patient-centered. Our main objective was to determine the severity, clinical features, bio-chemical findings and outcomes of DKA in children aged 1 month to 16 years. Subjects and methods This retrospective study included the analysis of medical and laboratory records from patients’ medical charts and the electronic database of all children aged 1 month to 16 years with newly diagnosed type-1 diabetes mellitus (T1DM) complicated with ketoacidosis, who presented to the emergency department (ED) at the Aga Khan University Hospital (AKUH), between January 2009 and December 2014. Results Diabetes mellitus complicated with DKA was the predominant diagnosis (n=113 [75.83%]) among endocrine diseases in children visiting the ED. Our study witnessed an increase in the incidence of DKA particularly after 5 years of age, with more severity in females. In our study, the mortality rate was 3.4%. Conclusions Considering the high incidence and mortality rate, it is emphasized that DKA should be considered in differential diagnosis. An awareness campaign for both general pediatricians and physicians as well as for the public is needed for better outcomes.

Background Diabetes and hepatosteatosis are dramatically increasing in childhood. Non-alcoholic fatty liver disease (NAFLD) is defined as a common disorder in adulthood, especially with type-2 diabetes and metabolic syndrome, while very few studies are available on liver health in children with type-1 diabetes. Patients and methods One hundred and ten (52 males and 58 females) patients with type-1 diabetes aged between 8 and 18 years were examined. The lipid profile, liver enzymes and hepatobiliary ultrasound findings of patients were investigated in terms of hepatopathies. Patients diagnosed with fatty liver were evaluated by pediatric gastroenterology specialists for the differential diagnosis and exclusion of other etiologies. The relationships between hepatopathy and age, pubertal status, the duration of diabetes and glycemic control were evaluated. Results Hepatopathy was found in 17 (15.5%) patients. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were normal and did not correlate with the ultrasonography (USG) findings. Hyperechogenicity detected by USG, whether it is true fat or glycogen hepatopathy, was found to be associated with “poor glycemic control” independently of age, puberty status and the duration of diabetes. Conclusions This study contributes to the literature in terms of the relationship between liver health and glycemic control in pediatric type-1 diabetes. Hepatopathies were releated with poor glycemic control independently of the duration of diabetes. This suggested that liver disorders should be considered as one of the subacute complications of diabetes. It was concluded that routine screening for comorbidities and complications in type-1 diabetes should also include hepatobiliary USG, as liver enzymes alone are inadequate for detecting hepatopathies.

Objective To compare the effects of mass effects in situ (MEIS) and after neurosurgery (ANS) on neuroendocrine function in children with craniopharyngioma. Methods We retrospectively investigated 185 cases of children with craniopharyngioma who underwent neurosurgical treatment at the Beijing Tiantan Hospital from 2011 to 2016. The neuroendocrine function of patients was compared before and after tumor removal. Results Compared with the MEIS, the incidence of growth hormone insulin-like growth factor 1 axis dysfunction (47.03% vs. 57.30%), pituitary-thyroid axis dysfunction (20.00% vs. 50.27%), pituitary-adrenal axis dysfunction (18.38% vs. 43.78%) and diabetes insipidus (26.49% vs. 44.86%) was significantly increased in the ANS status. The incidence of hyperprolactinemia significantly decreased from 28.11% in the MEIS status to 20.54% in the ANS status. Compared with the MEIS group, changes in appetite, development of diabetes insipidus, body temperature dysregulation, sleeping disorders, personality abnormalities and cognitive abnormalities were more frequent after ANS, yet no statistically significant differences were found. Conclusions Endocrine dysfunction is common in children with craniopharyngioma. Both MEIS and ANS can be harmful to neuroendocrine function, and neurosurgical treatment may increase the level of neuroendocrine dysfunction.

Background To develop a diagnostic assessment tool, using clinical, biochemical and sonographic markers, to help clinicians in the differential diagnosis of functional oligomenorrhea (FO) and endocrine-metabolic oligomenorrhea (EMO). Methods Sixty-two adolescents with oligomenorrhea without evident hormonal imbalances or severe energy deficit were selected. They were divided into two groups (EMO and FO) and they all underwent the following assessment: physical examination (height, weight, presence of hirsutism or acne), blood exams and transabdominal ultrasonography. The biochemical markers included: hemoglobin, thyrotropin stimulating hormone (TSH), prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), free (FT) and total testosterone (TT), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG). Uterine and ovarian volume, ovarian morphology, endometrial thickness and pulsatility index (PI) of uterine arteries were evaluated with ultrasound. Results Body mass index (BMI), hemoglobin, LH levels and LH/FSH ratio were significantly higher in women with EMO than in those with FO. Increased androgens values were found in the EMO group, but only A and FT were significantly different (p=0.04). Ovarian volume and uterine artery PI were the only ultrasound features significantly different, with higher values in the EMO population (p<0.05). Considering these variables, with a receiving characteristic operating curve, new cut-offs were calculated, and a diagnostic assessment tool elaborated (area under curve [AUC] 0.88, specificity 99%, sensibility 59%, p<0.001]. Conclusions This diagnostic tool, specific for adolescents, could be useful in the management of oligomenorrhea. Recognizing and distinguishing EMO and FO is very important in order to establish an appropriate treatment and a correct follow-up.

Background To compare the state of iodine nutrition among school age children (SAC) in high- (HSGs) and low-socioeconomic groups (LSGs) during a post iodation scenario in Kolkata. Methods Clinical examinations of the goiter, median urinary iodine (MUI), mean urinary thiocyanate (MUSCN) in SAC (6–12 years) from both sexes in the different socioeconomic groups were carried out and the iodine content of edible salt was measured. Results A total of 5315 SAC, of which 2875 SAC were from a HSG and another 2440 SAC from an LSG were clinically examined for goiter. In the HSGs the total goiter prevalence (TGP) was 3.2% and in the LSGs the TGP was 9.1% and the difference was statistically significant (p<0.001). The MUI of the HSGs was 242 μg/L as compared to 155 μg/L in the LSGs (p<0.001). MUSCN of the HSGs was 0.77±0.45 mg/dL while in the LSGs it was 0.94±0.44 mg/dL and the difference was statistically significant (p<0.01). In the HSGs 19.4% salt samples had 15–30 ppm iodine and 80.6% salt samples were above 30 ppm as compared to 26.3% salt samples which were below 15 ppm, 37.1% salt samples which were between 15 and 30 ppm and 36.6% salt samples which were above 30 ppm in the LSGs. Conclusions The population of the LSGs was clinically mildly iodine deficient having no biochemical iodine deficiency while in the HSGs it was more than the adequate requirement and the HSG children are possibly at risk of excess iodine induced thyroid diseases. Existing goiter prevalence in the LSGs was from their relatively high consumption of dietary goitrogens. Therefore, socioeconomic status plays a pivotal role in the management of iodine nutrition even in a post salt iodation scenario.

Background The objective of the study was to evaluate the long-term outcome of paediatric-onset hyperthyroidism with follow-up into adulthood and to identify any early predictors of a need for definitive therapy (DT). Methods In a retrospective analysis of patients diagnosed with hyperthyroidism under the age of 18 years and at follow-up, a comparison was made by categorising them into those who underwent definitive therapy (DT group), i.e. thyroidectomy/radioactive iodine (RAI), those who remained on antithyroid drugs (ATD) (CBZ group) and those who had complete remission (RE group). Results Sixty-one (49 females, 12 males) patients with a median age of 15.1 years (range: 3.6–18) at diagnosis were studied. The duration of the first course of ATD varied from <1 year (7%), 1–2 years (26%), >2 years (46%) and ATD never discontinued (21%). Disease relapsed in 69% of patients with <1 year of ATD vs. 79% with >2 years of ATD. At follow-up, the median duration since diagnosis was 8.75 years (range 2.0–20.7 years) and the median age at follow-up was 23.2 years (8–36 years). Thirty-three percent (20/61) had undergone DT (DT group) – with 16.5% (n=10) on RAI and 16.5% (n=10) on surgery, 36% (22/61) were on ATD (CBZ group), whilst 32% (19/61) had undergone full remission (RE group). The comparison did not identify any statistically significant difference for predictor factors at diagnosis including age, T4 and free T4 levels, thyroid peroxidise antibody levels (TPO) and the duration of the first course of carbimazole (CBZ) treatment. Conclusion Long-term complete remission of paediatric-onset hyperthyroidism in our study was 31%. There were no predictors identified that could help predict the long-term outcome, especially into adulthood.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT – high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H – low/normal TSH and low fT4), subclinical hypothyroidism (SH – high TSH and normal fT4), and hyperthyroidism (HyperT – low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

Background An adequate maternal vitamin D (vitD) intake is rarely achieved in actual practice. The aim of this study was to assess maternal factors associated with neonatal vitD deficiency. Methods This is a single-institution prospective case-control study. Consecutive single-birth neonates admitted between September 2014 and February 2015 were prospectively enrolled. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured by spectrometry. The associations between neonatal vitD deficiency (defined as 25(OH)D <15 ng/mL) and several maternal characteristics, including body mass index (BMI) at delivery, education, health insurance status, birth season, sun exposure time, egg consumption, and vitD supplementation during pregnancy, were examined using multivariable logistic regression and their respective odds ratios (ORs) reported. Results A total of 125 mother-infant dyads were enrolled, with a gestational age of 36.8±2.7 weeks. Fifty-six percent (70/125) of the neonates had vitD deficiency. Maternal factors that were significantly associated with vitD deficiency included winter birth, insufficient sun exposure time, high maternal BMI at delivery, insufficient egg consumption, insufficient vitD supplementation during pregnancy, and disadvantaged health insurance. Disadvantaged insurance status and insufficient vitD supplementation during pregnancy were the two most influential factors of neonatal vitD deficiency, with an OR of 7.5 (95% confidence interval [CI], 2.0–37.6) and 7.0 (95% CI, 2.7–20.7), respectively. Conclusions Neonatal vitD deficiency is very rampant. An individualized vitD supplementation strategy may be developed by taking into consideration pregnant women’s socioeconomic status and lifestyles.

Background When evaluating peripubertal short stature patients, the interpretation of insulin-like growth factor 1 (IGF-1) levels based on chronological age (CA) can be inaccurate due to the influence of sex steroids and, presently, there is no evidence to support the assessment of IGF-1 values according to bone age (BA) and pubertal status (PS). Our objective was to assess the discriminatory performance of IGF-1 levels based on CA, BA and PS in the diagnosis of growth hormone (GH) deficiency. Methods We evaluated IGF-1 levels from 154 peripubertal short stature patients classified as GH deficient (GHD, n=23) or non-GHD (n=131). IGF-1 was assayed by a chemiluminescent immunometric assay and transformed into standard deviation scores (SDS) according to CA (IGF-1-SDS-CA), BA (IGF-1-SDS-BA) and PS (IGF-1-SDS-PS). Results The performances of IGF-1-SDS-CA, IGF-1-SDS-BA and IGF-1-SDS-PS in the receiver operator characteristics (ROC) curves were similar. There were greater accuracy and specificity of IGF-1-SDS-PS (98.4% and 93.3%, respectively) and IGF-1-SDS-BA (92.7% and 90.1%, respectively) when compared to IGF-1-SDS-CA (65.6% and 69.5%, respectively). The post-test probability of the IGF-1-SDS was also improved when compared to PS and BA – 44.8% (IGF-1-SDS-PS), 16.8% (IGF-1-SDS-BA) and 5.1% (IGF-1-SDS-CA), with similar negative predictive values. Conclusions The evaluation of IGF-1 levels based on CA has a higher sensitivity than those based on BA or PS, which justify its use as a screening tool. Additionally, IGF-1 assessed by PS has the best positive predictive power for GHD diagnosis in peripubertal age and could reduce the necessity of a second GH stimulation test.

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.

Background Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome (CS). It may occur sporadically or as part of a familial syndrome called Carney complex (CC). It is a rare entity, with fewer than 750 cases reported. Case presentation We describe the case of a 16-year-old otherwise healthy female referred to our endocrinology department for progressive weight gain. During investigation, an adrenocorticotropic hormone (ACTH) independent CS was identified and the possibility of an adrenocortical tumor was suggested. The histological exam of the left adrenal gland was compatible with PPNAD. Genetic study identified a novel pathogenic variant in the PRKAR1A gene. Her family history was then reviewed and her father had died prematurely due to a cardiac myxoma. Besides abnormal skin pigmentation, the girl presented no other features of CC. Conclusions Careful follow-up of these patients is important to detect other manifestations of CC and to prevent life-threatening comorbidities, like cardiac myxomas or malignant diseases. Genetic counseling of the patients and their siblings is also very important.

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto’s thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRβ gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto’s thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.