Diagnostic Yield of Critical Sample and Elective Fast-Test in Children After a Hypoglycemic Event: Experience From a Single Center in Israel.

OBJECTIVE: To determine the diagnostic yield of the critical sample and fast-tests as dynamic function tests for the work-up of hypoglycemia in children. METHODS: A retrospective record review of children (0-18 years) with a diagnosis of hypoglycemia (glucose ≤ 50 mg/dL) was performed. A comparison of results of critical sample (obtained during an episode of hypoglycemia) and fast-test (performed to induce hypoglycemia in fasting state) was done. RESULTS: In 317 patients with hypoglycemia, data of 89 critical samples and 52 fast-tests were taken. Only 7 (7.8%) patients who underwent critical sample testing received an endocrine or metabolic diagnosis. No confirmatory diagnoses were made using the fast-tests. Idiopathic ketotic hypoglycemia was detected in 33/89 (37.1%) of critical samples and 21/52 (40.4%) of fast-tests. The completeness of workup including the hormonal and metabolic profile was <80% in both tests. CONCLUSION: The confirmatory yield of critical sample was better than fast-test. The processing of metabolic analytes was incomplete in a few, suggesting the need to rationalize the dynamic function testing.

Pediatricians' confidence level in diagnosing and treating children with atopic dermatitis in Israel, based on a self-efficacy survey.

Atopic dermatitis (AD) is one of childhood's most common skin conditions. Although pediatricians often diagnose and manage it, more than half refer even mild cases to dermatologists. In this study, we aimed to evaluate pediatric residents' and pediatricians' self-confidence regarding their ability to diagnose and manage AD. A cross-sectional questionnaire study was conducted with Israeli pediatric residents and pediatricians in 2022. The questionnaire was designed to distinguish participants with high vs. low self-confidence characteristics regarding their ability to diagnose and treat AD. In total, 171 participants completed the questionnaire (59.4% women; age, 41.1 ± 10.6 years); 39.1% of the participants were residents, while 60.9% were board-certified pediatricians. Overall, 64.4% of the responders reported below or average confidence (score ≤ 3, on a scale of 1-5) in diagnosing and treating AD in children. The group with higher self-confidence was significantly older (44.39 vs. 39.14 years, P = 0.003), had more years of experience in evaluating pediatric AD (P = 0.004), had trained in dermatology during their residency (P = 0.02) with a longer training period (P = 0.01), and with more than three training methods (P = 0.009). Multivariable logistic regression analysis showed that high self-confidence was associated with age older than 40 years and training in dermatology during residency (odds ratios = 5.63 [P = 0.04] and 3.36 [P = 0.05], respectively).  Conclusion: Most pediatric residents and pediatricians were not particularly confident in treating children with AD. Those with high self-confidence were older, had been exposed to more patients, and had been trained in dermatology during their residency with various methods and for longer periods. Therefore, we encourage the implementation of a training program in dermatology during pediatric residency programs. What is Known: • Atopic dermatitis (AD) is one of childhood's most common skin conditions and often presents to pediatricians for diagnosis and management. • Many pediatricians refer children with even mild cases of AD to dermatologists. What is New: • Most pediatric residents and pediatricians report low confidence in diagnosing and treating pediatric AD. • Physicians with high self- confidence were older, exposed to more AD patients, and had been trained in dermatology during their residency with various methods and for longer periods. Therefore, the implementation of a training program in dermatology during pediatric residency programs is warranted.

GH treatment in pediatric Down syndrome: a systematic review and mini meta-analysis.

Objective: To analyze and determine the safety and efficacy of growth hormone (GH) treatment in Down syndrome (DS) pediatric patients and to weigh ethical aspects involved. Design: Systematic review and mini meta-analysis of the literature. Methods: A search was performed in PubMed, Embase, Scopus, and PsycINFO through August 2022. Eligible studies included those who answered at least one of the following two questions: 1) What is the effect of growth hormone treatment in children with Down syndrome? 2) What are the ethical arguments in favor and against growth hormone treatment for children with Down syndrome? Multiple reviewers independently screened each article for eligibility. Results: In total sixteen reports detailed medical effects of GH treatment in pediatric DS patients and eight studies dealt with ethical aspects of GH treatment. Treatment with GH resulted in significantly higher growth velocity in patients with DS. The ethical complexity is great but does not present insurmountable difficulties to the therapeutic option. Conclusions: As GH treatment is safe and effective for short-term height growth, GH therapy should be considered in long-term treatment of DS children.

A Novel Mutation in the ADAMTS10 Associated with Weil-Marchesani Syndrome with a Unique Presentation of Developed Membranes Causing Severe Stenosis of the Supra Pulmonic, Supramitral, and Subaortic Areas in the Heart.

Weill-Marchesani syndrome (WMS) is a rare genetic inherited disorder with autosomal recessive and dominant modes of inheritance. WMS is characterized by the association of short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia and ectopia of the lenses, and, occasionally, heart defects. We investigated the genetic cause of a unique and novel presentation of heart-developed membranes in the supra-pulmonic, supramitral, and subaortic areas, creating stenosis that recurred after their surgical resection in four patients from one extended consanguineous family. The patients also presented ocular findings consistent with Weill-Marchesani syndrome (WMS). We used whole exome sequencing (WES) to identify the causative mutation and report it as a homozygous nucleotide change c. 232T>C causing p. Tyr78His in ADAMTS10. ADAMTS10 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 10) is a member of a family of zinc-dependent extracellular matrix protease family. This is the first report of a mutation in the pro-domain of ADAMTS10. The novel variation replaces a highly evolutionary conserved tyrosine with histidine. This change may affect the secretion or function of ADAMTS10 in the extracellular matrix. The compromise in protease activity may thus cause the unique presentation of the developed membranes in the heart and their recurrence after surgery.

Effect of Paediatric Atopic Dermatitis on Parental Sleep Quality.

Data on the impact of paediatric atopic dermatitis on parental sleep are scarce. The aim of this study was to examine the effects of paediatric atopic dermatitis on the quality of parents' sleep. This cross-sectional study included parents of patients with atopic dermatitis and parents of healthy children who completed validated Pittsburgh Sleep Quality Index questionnaires. The study and control groups were compared, as were results for mild and moderate atopic dermatitis with severe atopic dermatitis, mothers and fathers, and different ethnic groups. A total of 200 parents were enrolled. Sleep latency was significantly longer in the study group compared with the control group. Sleep duration was shorter in the parents of the mild AD group compared with the moderate-severe and control groups. Parents in the control group reported more daytime dysfunction than parents in the AD group. Fathers of children with AD reported more sleep disturbance than mothers.

GHRH-GH-IGF1 axis in pediatric Down syndrome: A systematic review and mini meta-analysis.

Objective: To analyze and determine the quality of functioning in different components of GHRH-GH-IGF1 axis in children with Down syndrome (DS). Design: Systematic review and mini meta-analysis of the literature. Methods: A search was performed in PubMed, Embase, Scopus, and PsycINFO through August 2022. Eligible studies included pediatric patients with DS who had undergone any laboratory evaluation of the GHRH-GH-IGF1 axis. Two reviewers independently screened articles for eligibility. Results of each type of test were weighed together in patients both with and without DS and were pooled using a random effects meta-analysis. Results: In total, 20 studies assessed the GHRH-GH-IGF1 axis function. A defect in three major components of GHRH-GH-IGF1 axis was found in a significant proportion of pediatric DS patients. Conclusions: A significant portion of short-stature pathogenesis in children with DS is associated with impaired GHRH-GH-IGF1 axis function.

Pediatric psoriasis negatively influences parental sleep quality.

BACKGROUND: One-third of psoriasis cases occur in the pediatric population. Pediatric psoriasis has a negative long-term impact on the quality of life of children and their families. However, data regarding the impact of pediatric psoriasis on parental sleep quality are scarce. OBJECTIVES: This study examined the effects of pediatric psoriasis on the quality of parents' sleep compared to parents of healthy, non-psoriatic children. METHODS: A cross-sectional questionnaire study was conducted from September 2020 to November 2021, using the validated Pittsburgh Sleep Quality Index (PSQI). The study population included parents of patients aged 2-18 years diagnosed with psoriasis and parents of healthy children of the same gender and ethnicity. We further compared sleep quality between parents of children with mild and moderate-to-severe psoriasis, and fathers to mothers. RESULTS: A total of 301 parents were enrolled; 151 parents of 83 children diagnosed with psoriasis and 150 parents of 124 healthy controls. Parents of children with psoriasis had significantly longer sleep latency (p = 0.031), worse subjective sleep quality (p = 0.043), and greater use of sleep medications (p < 0.001). The comparison between parents of moderate-severe with mild psoriatic children as well as mothers with fathers showed no statistical significance. CONCLUSION: Poor sleep quality was demonstrated among parents of children diagnosed with psoriasis compared to parents of healthy children. This finding is crucial for the direction of treatment efforts regarding parental well-being and functioning.

Comparison of glucagon stimulation test and low dose ACTH test in assessing hypothalamic-pituitary-adrenal (HPA) axis in children.

INTRODUCTION: Children with a pituitary hormone deficiency are at risk for secondary adrenal insufficiency (AI). A stimulation test is usually performed for diagnosing AI, evaluating both the hypothalamic-pituitary-adrenal and growth hormone (GH)-IGF-1 axes. This single test is preferred by clinicians and is considerably more tolerable by patients. The objective of this study was to evaluate the glucagon stimulation test (GST), which is commonly used to assess both axes. Its diagnostic capability for GH deficiency is high and well accepted, however its utility for determining secondary AI has not been well established. METHODS: This retrospective study involved 120 patients under 18 years of age with short stature who had undergone both a GST and low dose ACTH stimulation test (LDACTH test). Twenty-six children who had more than 6 months elapsed between the two tests were excluded from the study. The study was conducted on patients of the Pediatric Endocrinology Department at Soroka University Hospital, a tertiary medical centre in Beer Sheva, Israel. Statistical analyses were carried out via IBM SPSS (v. 22), with a significance level determined at p < .05. RESULTS: Different cortisol cut-off values were assessed for GST and it was determined that the highest combined sensitivity and specificity yielded a cut-off point of 320 nmol/L (56% sensitivity and 83% specificity) while the currently accepted cut-off value (500 nmol/L) yielded 100% sensitivity and 6% specificity. CONCLUSION: The results of this study show that GST is not an optimal tool for diagnosing secondary AI. Therefore, clinicians using this test should interpret its results with caution.

Hypoparathyroidism-retardation-dysmorphism syndrome-Clinical insights from a large longitudinal cohort in a single medical center.

Background: Hypoparathyroidism, retardation, and dysmorphism (HRD) Syndrome is a rare disease composed of hypoparathyroidism, retardation of both growth and development, and distinctive dysmorphic features. Here, we describe the long-term morbidity and mortality in a large cohort of HRD patients and suggest recommendations for follow up and treatment. Methods: Medical records of 63 HRD syndrome patients who were followed at Soroka Medical Center during 1989-2019 were reviewed retrospectively. Information regarding demographics, medical complications, laboratory findings, and imaging studies was collected. Results: The mortality rate was 52%. The main causes of death were infectious diseases including pneumonia, septic shock, and meningitis. Multiple comorbidities were found including brain anomalies in 90% of examined patients (basal ganglia calcifications, tightening of corpus callosum, Chiari malformation, hydrocephalous, and brain atrophy), seizures in 62%, nephrocalcinosis and/or nephrolithiasis in 47%, multiple eye anomalies were recorded in 40%, bowel obstructions in 9.5%, and variable expression of both conductive and senso-neural hearing loss was documented in 9.5%. Conclusion: HRD is a severe multisystem disease. Active surveillance is indicated to prevent and treat complications associated with this rare syndrome.

TSHB R75G is a founder variant and prevalent cause of low or undetectable TSH in Indian Jews.

Objective: Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-stimulating hormone (TSH), cause congenital hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function but abrogates its detection by some immune detection-based platforms, leading to erroneous diagnosis of hyperthyroidism. We set out to identify and determine the carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine the possible founder origin of this variant worldwide, and to determine the phenotypic effects of its heterozygosity. Design: Molecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort. Methods: TSHB p.R75G variant tested by Sanger sequencing and restriction fragment length polymorphism (RFLP). Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays. Results: Clinically euthyroid individuals with low or undetectable TSH levels from three apparently unrelated Israeli Jewish families of Bene Israel ethnicity, originating from the Mumbai region of India, were found heterozygous or homozygous for the p.R75G TSHB variant. Extremely high carrier rate of p.R75G TSHB in Bene Israel Indian Jews (~4%) was observed. A haplotype block of 239.7 kB in the vicinity of TSHB shared by Bene Israel and individuals of South Asian origin was detected. Conclusions: Our findings highlight the high prevalence of the R75G TSHB variant in euthyroid Bene Israel Indian Jews, demonstrate that heterozygosity of this variant can cause erroneous detection of subnormal TSH levels, and show that R75G TSHB is an ancient founder variant, delineating shared ancestry of its carriers.

Multiple Endocrine Deficiencies are Common in Hypoparathyroidism-Retardation-Dysmorphism Syndrome.

CONTEXT: The rare hypoparathyroidism-retardation-dysmorphism (HRD) syndrome (OMIM #241410) is caused by the mutated tubulin chaperone E (TBCE) gene. This gene encodes a critical protein in the microtubule assembly pathway. OBJECTIVE: To evaluate the endocrine profile of patients with HRD. METHODS: The study used a retrospective analysis of a large cohort of patients in a single university medical center. Sixty-three patients were diagnosed with HRD during 1990 to 2019; 58 of them had an endocrine evaluation. MAIN OUTCOME MEASURES: We investigated somatic growth parameters, the prevalence of hypoglycemia, growth hormone deficiency, hypothyroidism, hypogonadism, and cortisol deficiency. RESULTS: All patients were born small for gestational age, and severe growth retardation was found in all patients with mean height standard deviation score (SDS) of -8.8 (range: -5.1 to -15.1) and weight SDS -18 (range: -5.1 to -61.2). Serum insulin-like growth factor-1 concentrations were very low among the 21 studied patients: -2.32 SDS (range: -0.6 to -2.7). Four out of 14 (28%) investigated patients had growth hormone deficiency, and 55% of patients were hospitalized due to symptomatic hypoglycemia. Adrenal glucocorticoid insufficiency was diagnosed in 22% of those tested. Hypothyroidism was found in 36% of patients. Both hypogonadotrophic and hypergonadotrophic hypogonadism were observed. The main magnetic resonance imaging findings were small anterior pituitary gland, small hippocampus, brain atrophy, thin corpus callosum, Chiari type I malformation, and septo-optic dysplasia. CONCLUSION: Multiple endocrine abnormalities are common in patients with HRD syndrome. Periodic screening of thyroid and adrenal functions is recommended.

Urinary tract infections in children < 2 years of age hospitalized in a tertiary medical center in Southern Israel: epidemiologic, imaging, and microbiologic characteristics of first episode in life.

The objectives of the study were to describe the epidemiologic, microbiologic, and imaging characteristics of first 44 UTI episode in hospitalized infants and children < 2 years of age. A UTI episode was diagnosed based on suprapubic aspiration or urinary catheterization and report of a significant bacterial growth of true uropathogens. Two thousand two hundred ninety-four UTI episodes were recorded during 2009-2013 in 1694 patients; 1350 (79.7%), 223 (13.2%), and 66 (3.9%) had one, two, and three episodes, respectively. Of 1955 pathogens isolated, the most frequent were E. coli, Klebsiella spp., and Enterococcus spp. (56.9%, 14.1%, and 11%, respectively). E. coli percentages increased with increase in patient age while Klebsiella spp. and Enterococcus spp. decreased with decrease in age. 136/344 (39.5%) renal ultrasound examinations performed were reported abnormal. The percentages of abnormal ultrasound examinations in Enterococcus spp.-UTI were higher than in E. coli and Klebsiella spp.-UTI (P < 0.001 and P = 0.007, respectively). The E. coli nonsusceptibility to ampicillin, TMP/SMX, ceftriaxone, amoxicillin/clavulanic acid, cefuroxime, and gentamicin was 71%, 31%, 14.9%, 14.7%, 7%, and 4.4%, respectively. Nonsusceptibility of Klebsiella spp. to ampicillin, amoxicillin/clavulanic acid, TMP/SMX, ceftriaxone, gentamicin, and cefuroxime was 98.7%, 10.4%, 9.5%, 8.4%, 4.8%, and 4.3%, respectively. E. coli nonsusceptibility to amoxicillin/clavulanate, TMP/SMX, and ciprofloxacin decreased during the study period. E. coli percentages increased and those of Klebsiella spp. and Enterococcus spp. decreased with increase in patient age. Enterococcus. spp.-UTI was associated with older age and more severe findings on renal ultrasound. E. coli and Klebsiella spp. nonsusceptibility to amoxicillin/clavulanate, TMP/SMX, cefuroxime, and ceftriaxone was low.

Validation of Contact-Free Sleep Monitoring Device with Comparison to Polysomnography.

STUDY OBJECTIVES: To validate a contact-free system designed to achieve maximal comfort during long-term sleep monitoring, together with high monitoring accuracy. METHODS: We used a contact-free monitoring system (EarlySense, Ltd., Israel), comprising an under-the-mattress piezoelectric sensor and a smartphone application, to collect vital signs and analyze sleep. Heart rate (HR), respiratory rate (RR), body movement, and calculated sleep-related parameters from the EarlySense (ES) sensor were compared to data simultaneously generated by the gold standard, polysomnography (PSG). Subjects in the sleep laboratory underwent overnight technician-attended full PSG, whereas subjects at home were recorded for 1 to 3 nights with portable partial PSG devices. Data were compared epoch by epoch. RESULTS: A total of 63 subjects (85 nights) were recorded under a variety of sleep conditions. Compared to PSG, the contact-free system showed similar values for average total sleep time (TST), % wake, % rapid eye movement, and % non-rapid eye movement sleep, with 96.1% and 93.3% accuracy of continuous measurement of HR and RR, respectively. We found a linear correlation between TST measured by the sensor and TST determined by PSG, with a coefficient of 0.98 (R = 0.87). Epoch-by-epoch comparison with PSG in the sleep laboratory setting revealed that the system showed sleep detection sensitivity, specificity, and accuracy of 92.5%, 80.4%, and 90.5%, respectively. CONCLUSIONS: TST estimates with the contact-free sleep monitoring system were closely correlated with the gold-standard reference. This system shows good sleep staging capability with improved performance over accelerometer-based apps, and collects additional physiological information on heart rate and respiratory rate.

Pediatric epilepsy and parental sleep quality.

STUDY OBJECTIVES: To evaluate the effects of pediatric epilepsy on sleep in parents of epileptic children. METHODS: Cohort design in which the sleep quality of parents of epileptic children (POEC) and parents of nonepileptic children (PONEC) in the month preceding recruitment were compared using the self-administered Pittsburgh Sleep Quality Index (PSQI). RESULTS: Mothers of epileptic children had a 7-fold occurrence of sleep disturbances when compared to mothers of non-epileptic children (OR = 6.66 CI 95% 1.10-70.08). The sleep characteristics that showed statistically significant differences were: sleep duration, sleep continuity, and self-evaluation of sleep quality (p < 0.05 for all parameters). No significant difference in sleep quality was found between fathers of epileptic children and fathers of nonepileptic children. CONCLUSIONS: Sleep disturbances are more common in mothers of epileptic children. The sleep quality of mothers to epileptic children should be considered in their comprehensive management, and if necessary, the sleep disturbance should be addressed.