Band 32, Heft 8

PHACE syndrome is an uncommon disorder of posterior fossa anomalies, cervicofacial infantile hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects. Endocrine abnormalities including hypopituitarism and ectopic thyroid were rarely described. In this article we review occurrence, onset, presenting symptoms, hormonal treatments and outcomes of all endocrine abnormalities in PHACE syndrome. Eleven of 20 (55%) had hypothalamic-pituitary dysfunction and 10 of 20 (50%) had thyroid dysgenesis. A thorough understanding of the endocrine manifestations is important for clinicians to early identify endocrine involvement in PHACE and develop plans for monitoring and treatment of its complications.

Background Arginine family amino acids (AFAAs) include glutamine (Gln) plus glutamate (Glu), ornithine (Orn), proline (Pro), citrulline (Cit) and arginine (Arg). We aimed to quantitate these amino acids in the blood of full-term infants in relation to their birth weight (BW) perinatally. Methods Breastfeeding full-term infants (n = 2000, 1000 males, 1000 females) with a BW of 2000–4000 g were divided into four equal groups: group A, 2000–2500 g; B, 2500–3000 g; C, 3000–3500 g and D, 3500–4000 g. Blood samples as dried blood spots (DBS) were collected on the third day of life and analyzed via a liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol. Results Gln plus Glu mean values were found to be statistically significantly different between males and females in all studied groups. The highest values of these amino acids were detected in both males and females in group D. Orn mean values were found to be statistically significantly different between males and females of the same BW in all groups except the last one. The lower mean value was determined in group A, whereas the highest was determined in group D. Cit and Arg mean values were determined to be almost similar in all studied groups. Conclusions Gln plus Glu and Orn blood concentrations were directly related to infants’ BW. Conversely, Cit and Arg did not vary significantly in all groups.

Background The beneficial effects of treating hypertriglyceridemic adults with omega-3 fatty acids have been reported. However, information regarding omega-3 treatment of pediatric patients is limited. To evaluate the efficacy and safety of administering omega-3 fatty acids (3 g/day for 12 weeks) to children/adolescents with obesity and hypertriglyceridemia. Methods A randomized, double-blind, placebo-controlled, parallel study involving pediatric patients (10–16 years old) with obesity and hypertriglyceridemia was conducted. The National Center for Health Statistics (CDC) defines obesity as a body mass index (BMI) ≥95th percentile. Subjects with triglyceride concentrations ranging from 150 to 1000 mg/dL were randomized into two groups: those receiving omega-3 fatty acids (eicosapentaenoic and docosahexaenoic acids) (n = 65) and those receiving a placebo (n = 65) for 12 weeks. Serum triglyceride concentrations were always measured from 8 to 9 am after a 12-h fast. Results By the end of treatment, triglyceride concentrations had decreased by 39.1% in the omega-3 group and 14.6% in the placebo group (p < 0.01). The incidence of adverse gastrointestinal events (e.g. flatulence, belching) was 41.2% and 6.2% in the omega-3 and placebo groups, respectively (p < 0.01). There were no serious drug-related adverse events. Conclusions Supplementation with 3 g/day of omega-3 fatty acids is a safe and effective option for treating hypertriglyceridemia in children and adolescents with obesity.

Background The purpose of this study was to assess the benefit of a short workshop addressing knowledge and confidence of inpatient caregivers (physicians and nurses) treating pediatric type 1 diabetes mellitus (T1DM) patients. Methods Questionnaires to determine familiarity with T1DM management and confidence in care were distributed at three university-affiliated medical centers. A 5-h practical-skills workshop was conducted at one center. Same questionnaires were filled out immediately after the workshop and 3 months later. Evaluation of knowledge was based on 16 multiple-choice questions, and confidence based on 10 categorical questions. Results Nurses and physicians (total 135, 106 women, 85 nurses) completed the questionnaires. The median knowledge score was 53.33 (40–66) and 46.7 (26.7–66.7) for nurses and physicians, respectively (p = 0.76). The confidence scores were 1.44 (1.1–1.9) and 1.56 (1.2–1.8), respectively (p = 0.7). More experience among nurses (>10 years) was associated with higher confidence scores (p = 0.04). Twenty-one physicians and 52 nurses, 66 women, attended the workshop. The median knowledge grade improved from 60 (47–67) to 81 (69–81), p < 0.001, immediately after, and to 69 (63–81), p < 0.001, 3 months post-workshop. The median confidence score improved from 1.8 (1.6–2) to 2.4 (2.1–2.6), p < 0.001, and to 2.2 (2–2.6), p < 0.001, respectively. There was no association with profession or seniority. Conclusions Knowledge and confidence in care of medical staff treating inpatient T1DM pediatric patients are lacking. Both improved significantly after the workshop, independent of seniority or profession.

Background Heart disease has been the leading cause of death for decades in the US population. Dyslipidemia is the most important risk factor for cardiovascular disease (CVD), and it often starts during childhood. Methods This cross-sectional study was performed in a growth assessment clinic in the city of Shiraz to determine the relation between body mass index (BMI) and dyslipidemia among children and teenagers aged 2–18 years. Nine hundred and eighty-nine children including 422 boys and 567 girls were selected. Results Adjusted for age and gender, total cholesterol (TC) (r = 0.172, p = 0.000), low-density lipoprotein cholesterol (LDL-c) (r = 0.176, p = 0.000), non-high-density lipoprotein cholesterol (non-HDL-c) (r = 0.227, p = 0.000) and triglycerides (TG) (r = 0.253, p = 0.000) showed a significant positive correlation with BMI Z-score, and HDL-c showed a significant negative correlation with BMI Z-score (r = −0.131, p = 0.000). Adjusted for age and gender, overweight and obese children were 1.882 times more likely to have high TC levels (p = 0.009), 2.236 times more likely to have high non-HDL-c levels (p = 0.000) and 3.176 times more likely to have high TG levels (p = 0.000) in comparison with children who had a healthy weight. Obese children had the highest percentage of isolated TG dyslipidemia (23.1%) and underweight children had the highest percentage of isolated HDL dyslipidemia (15.6%). Conclusions There is a strong link between atherosclerotic cardiovascular disease (ASCVD) and the level of blood lipids and between blood lipids and BMI Z-score. The first step in preventing ASCVD is the reduction of blood lipids, preventing weight gain and loss of extra weight.

Background Arterial stiffness is a consequence of aging, but there are several diseases that contribute to this process. The evaluation of pulse wave velocity (PWV) allows a dynamic evaluation of vascular distensibility and the detection of atherosclerosis at an early stage. It was intended to evaluate the PWV in children and adolescents with type 1 diabetes mellitus (T1DM) and to compare their outcome according to the type of treatment used. Methods Forty-eight patients were randomly selected. Inclusion criteria: T1DM, under intensive insulin therapy (multiple daily insulin administrations [MDI] or continuous insulin infusion system [CIIS]). Exclusion criteria: existence of another chronic pathology or microvascular complications. Echocardiography was performed and three measurements of PWV were done, with their mean calculated. Results Most of the children and adolescents presented a PWV ≥ the 75th centile. There was a statistically significant difference for hemoglobin A 1c (HbA 1c ) (7.8 in CIIS vs. 9 in MDI, p < 0.05). There were not statistically significant differences in the PWV between the two groups. This can be attributed to the fact that children with CIIS are those who previously presented greater glycemic instability. There was a significant correlation between PWV and disease duration (Pearson’s correlation coefficient [r] = 0.314, p = 0.036). Conclusions This study showed that in children and adolescents with T1DM, there is an important prevalence of arterial stiffness, translated by an increase in PWV. This increase in PWV appears to exist even in very young children with little disease evolution time.

Background To evaluate the safety of fasting during the holy month of Ramadan among children and adolescent with type 1 diabetes (T1D). Methods A retrospective cohort study of 50 children and adolescents with T1D whose mean age was 12.7 ± 2.1 years was conducted. Twenty-seven patients (54%) were on multiple daily injections (MDI) insulin regimen and 23 (46%) were on insulin pump therapy. Before fasting for Ramadan, children and their families were evaluated and educated about diabetes management during Ramadan. Hemoglobin A 1c (HbA 1c ), weight, number of days fasted, hypoglycemia and hyperglycemia episodes, and emergency hospital visits were collected and analyzed after completing the month. Participants were compared according to the insulin treatment regimen and their glycemic control level before Ramadan. Results The children were able to fast 20 ± 9.9 days of Ramadan, and the most common cause for breaking the fast was mild hypoglycemia (7.8% among all cases). There was no significant difference between the two insulin regimen groups in breaking fast days, frequency of hypo- or hyperglycemia, weight and HbA 1c changes post Ramadan. Patients with HbA 1c  ≤ 8.5% were able to fast more days during Ramadan with significantly less-frequent hypoglycemic attacks as compared to patients with HbA 1c  > 8.5 (1.2 ± 1.5 vs. 3.3 ± 2.9 days of hypoglycemia, p = 0.01, respectively). Conclusions Fasting for children with T1D above the age of 10 years is feasible and safe in both pump and non-pump users, and well-controlled patients are less likely to develop complications. Education of the families and their children before Ramadan, along with intensive monitoring of fasting children during the month are crucial.

Background Diabetic nephropathy (DN) is a significant cause of morbidity and mortality in young adults with type 1 diabetes (T1D). Microalbuminuria (MA) is generally considered as the earliest manifestation of DN. However, it has been shown that MA may be temporary and not reflect permanent renal failure. For this reason, sensitive markers are needed for the detection of kidney damage in the early period. Urinary tubular injury markers increase in the early period of diabetes. These tubular markers are rather indicators of acute renal damage. The objective of this study was to measure the urinary netrin-1 level, a marker of tubular injury in children with normoalbuminuric (NA) T1D, and to determine its relationship with short-term fluctuations in blood glucose using fructosamine levels. Methods Netrin-1 levels in spot urine samples from 82 children with T1D (median age 13.6 years) without MA or hypertension and from 59 healthy controls (median age 11.3 years) with a similar distribution of age and body mass index (BMI) were compared. The relationship of the netrin-1 levels with diabetes parameters such as fructosamine, hemoglobin A 1c (HbA 1c ) or duration of diabetes was investigated. Results Urinary netrin-1 level was found to be higher in patients with T1D than in healthy controls (590 [interquartile range (IQR) = 811] pg/mg-creatinine [pg/mg-cr] and 396 [IQR = 742] pg/mg-cr, respectively) (p = 0.03). Urinary netrin-1 was found to correlate with HbA 1c (p = 0.007, r = 0.320) and fructosamine (p = 0.04, r = 0.310) but not with average HbA 1c in the last year (p = 0.14, r = −0.19), duration of diabetes (p = 0.83, r = 0.02) or other diabetes indices. Conclusions These results support the idea that tubular damage occurs early in the course of diabetes. However, the fact that netrin-1 is related to fructosamine and HbA 1c but not to the duration of diabetes or average HbA 1c in the last year may suggest that the tubular damage markers are affected by short-term fluctuations in blood glucose.

Background A wide range of reports on the incidence of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in children have been published worldwide. Reports from Saudi Arabia are limited. The aim of this study was to assess the incidence, clinical pattern and severity of DKA in children with newly diagnosed T1DM and the association of autoimmune conditions with initial DKA occurrence at King Abdulaziz Medical City – Jeddah. Methods This retrospective chart review was conducted during the period 2005–2015. All newly diagnosed T1DM children during the study period were investigated (n = 390). Data were collected on the demographic characteristics, body mass index (BMI), DKA severity, length of hospital stay and follow-up data on the type of diabetes therapy. Results The incidence of DKA among newly diagnosed T1DM pediatric patients was 37.7% (n = 147). Moderate and severe DKA cases were significantly higher among female children (p = 0.04). Patients diagnosed with DKA had lower BMI (20.87 ± 5.21) than their counterparts (p = 0.03). The median length of hospital stay was higher among severe DKA compared to moderate and mild cases (5.0, 4.5 and 4.0 days, respectively). Conclusions The incidence of DKA among newly diagnosed T1DM is still high compared to developed countries; however, it is relatively lower than previous reports in Saudi Arabia. Immediate interventions, such as awareness campaigns, are vital to reduce the burden of this preventable health sequela among children with DM.

Background X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 ( NR0B1 )/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 ( DAX1 ) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients. Methods Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed. Results Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1 , Duchenne muscular dystrophy ( DMD ), glycerol kinase ( GK ) and melanoma antigen, family B, 16 ( MAGEB16 ) genes. Conclusions Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.

Background The present study was designed to evaluate the metabolic profile, cardiovascular risk factors and quality of life in children with congenital adrenal hyperplasia (CAH) and compare it with age- and sex-matched controls. Methods Fifty-two patients aged 3–21 years with classic CAH due to 21-hydroxylase deficiency were included in the study. Metabolic profiling was done for 36 cases and compared with 28 healthy age- and sex-matched controls. Quality of life was assessed in all 52 children and their parents using a validated Pediatric Quality of Life Inventory (PedsQL) questionnaire and was compared with normative data from the same population. Results The median age was 12 years with 14 (27%) males and 38 (73%) females. Out of the total 52 patients, 35 (67%) had salt wasting and 17 (33%) had simple virilising CAH. The median height standard deviation score (SDS) of cases was similar to that of controls (−0.72 vs. −0.64, p = 0.57) and 81% of females had normal pubertal status indicating a good control of the disease. Weight SDS, body mass index (BMI) SDS, mean diastolic blood pressure and insulin resistance were significantly higher in cases when compared to controls (0.31 vs. −0.3; 0.96 vs. 0.17; 67.8 ± 10.49 vs. 61 ± 8.49 and 2.1 vs. 0.95, respectively). The quality of life was significantly reduced in all domains as per parents’ perspective, whereas the children reported reduced quality of social and school functioning. There was no significant correlation between quality of life and metabolic parameters. Conclusions Children with CAH despite a reasonably good control of the disease have a higher cardiovascular risk and reduced quality of life when compared to healthy controls.

Background There is little evidence of the effects of early treatment with growth hormone (GH) in infants with Prader-Willi syndrome (PWS). A prospective study was conducted to assess the safety of GH therapy in infants younger than 2 years of age with PWS. Methods A total of 14 patients with PWS started treatment with GH under the age of 2 years and were followed over a 2-year period. A deletion of chromosome 15 was present in nine infants (64.3%) and maternal uniparental disomy 15 in five infants (35.7%). The median age at start of GH treatment was 9.6 months (interquartile range [IQR] 9.0–18.3 months). Changes in height standard deviation score (SDS), body mass index (BMI) SDS and subcapsular and tricipital skinfolds in the follow-up period were evaluated with a mixed-model regression analysis using the Package R. Results There were no fatal adverse events. A significant decrease (p < 0.001) in tricipital and subcapsular skinfold thickness, with an upward trend of height SDS and a downward trend of BMI SDS, was observed. Infants who started GH before 15 months of age started walking at a median of 18.0 [17.0–19.5] months vs. 36.6 [36.3–37.8] months for those who began treatment with GH after 15 months of age (p = 0.024). Conclusions GH treatment in infants with PWS less than 2 years of age is safe and improved body composition. Infants who received GH before the age of 15 months started to walk earlier.

Background Phenylketonuria (PKU) is one of the most common types of inborn error of metabolism. The mainstay of therapy for PKU has been dietary phenylalanine (Phe) restriction. Sapropterin dihydrochloride has been shown to be effective in reducing Phe levels in PKU patients. Methods This study was a clinical trial performed in the pediatric endocrine clinic of Imam Reza Hospital, Mashhad, Iran. Results All children between 1 and 10 years of age with a diagnosis of PKU whose serum Phe levels were between 120 and 360 μmol/L, in Khorasan Razavi province in the north-east of Iran, were enrolled. Twenty-four patients were enrolled in the study. Intervention : A free diet for 72 h was allowed and then a 20-mg/kg/day dose of Kuvan ® was administered. More than 30% reduction in blood Phe levels was described as responsive. Eight patients responded to the loading test and were eligible for the second stage of the study. In this stage, Phe powder in combination with Kuvan was provided. Patients’ serum Phe was measured weekly for 3 months. All eight patients showed Phe tolerance in 3 months, and their serum Phe levels remained within the range. Conclusions Treatment with Kuvan can help reduce blood Phe levels in our pediatric PKU population and allows patients to follow a more liberal diet.

Background To describe the complications and long-term results in patients with multiple endocrine neoplasia type 2A (MEN 2A) syndrome in whom a prophylactic thyroidectomy was performed, in relation to the recommendations of the American Thyroid Association (ATA). Methods A retrospective study of 14 patients with MEN 2A thyroidectomized between 2000 and 2017. We reviewed demographic, clinical, analytical and radiological data. Postoperative complications and long-term follow-up were analyzed. Results We treated eight boys and six girls with a median age of 5 years old (range 2–10). The predominant genetic mutation belonged to codon 634 (8/14, 57.14%). Total thyroidectomy (TT) without cervical lymphadenectomy was performed in all patients. A right upper parathyroidectomy was performed in one patient due to intraoperative suspicion of increased volume. Histological study revealed no alterations. Two patients presented transient hypocalcemia postoperatively and no patient had permanent hypocalcemia or nerve damage. Pathological anatomy confirmed medullary thyroid microcarcinoma in 5/14 patients: all carrying codon 634 mutation and three of them with preoperative basal calcitonin levels <20 pg/mL. No recurrences or metastases have been detected after a mean follow-up of 8 years. A patient with codon 634 mutation developed a unilateral pheochromocytoma at 25 years of age. No patient has presented hyperparathyroidism. Conclusions Prophylactic thyroidectomy without cervical lymphadenectomy is an effective and safe preventive treatment in patients with MEN 2A syndrome when it is performed by experienced surgeons in reference centers.

Background The American Thyroid Association (ATA) recommendations for the follow-up of thyroid nodules with benign fine needle aspiration (FNA) cytology in children are largely based on adult data, despite well-characterized differences between thyroid nodules in adults and children. We aimed to determine the optimal time interval for repeat evaluation of an FNA-benign thyroid nodule in a pediatric patient. Methods This is a retrospective chart review of patients <19 years of age from 2003 to 2013 with a benign thyroid nodule by FNA cytology. Results We identified 43 patients with benign thyroid nodule cytology on FNA. The average age at diagnosis was 15.6 years, with female predominance (91%). Initial ultrasound (US) findings showed an average nodule size of 2.5 cm, 10% with calcifications, 37% hyperemia, 29% hypoechogenicity and 7% lymphadenopathy. Follow-up US was done in 42%. The first follow-up US occurred on average at 15 months after the initial US. Four patients had nodules with significant growth over time. One patient with papillary thyroid carcinoma (PTC) on final pathology initially had a decreasing nodule size, and then a subsequent increase in the nodule size after 4.5 years. Thyroid nodules were surgically removed in 33% with the final pathology showing a benign cytology in four patients, follicular adenoma in eight patients and PTC in two patients. Conclusions The majority of patients with benign thyroid nodules had no significant increase in nodule size in the first year of follow-up, including one patient who was subsequently found to have PTC. We recommend follow-up US at 1 year after initial presentation in low-risk pediatric patients with benign thyroid nodule cytology.

We present a case of an unusual delayed multi-systemic reaction, following treatment with pamidronate. Although serious adverse reactions have been reported with pamidronate use, such a severe reaction, late in the course of pamidronate treatment, has not been described before. An 11-month-old boy with severe and complex osteogenesis imperfecta (OI) presented with hyperpyrexia and respiratory distress 10 days after his fifth cycle of pamidronate. He had significant derangement of his biochemical parameters including a positive urine myoglobin. His respiratory distress was out of proportion to his chest radiograph changes. Bilevel positive airway pressure (BiPAP) and paediatric intensive care (PICU) admission were required. He was extensively investigated to exclude other diagnoses, but all of these investigations were negative. The reaction resembled rhabdomyolysis. He made a full recovery with only supportive management.

Nonbullous congenital ichthyosis erythroderma (CIE) is an autosomal recessive disorder of ineffective keratinization. We present a unique case of a 16-year-old female with CIE who developed Cushing disease (CD) at age 13 with concomitant worsening of her skin disease. After transsphenoidal resection of her pituitary adenoma, she had both resolution of her Cushing symptoms and significantly milder skin manifestations of her CIE. To the best of our knowledge, this is the first reported case of a patient with both CD and CIE, one that is important in demonstrating the role of glucocorticoids in this disorder.

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.