High Prevalence of Hearing Impairment in Primary Congenital Hypothyroidism.

BACKGROUND: An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation. METHODS: Audiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies. RESULTS: HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT4) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT4 levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 µg/dL, p = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies. CONCLUSIONS: Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT4 therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.

The evolving role of whole-exome sequencing in the management of disorders of sex development.

OBJECTIVE: Disorders of sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. METHODS: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. RESULTS: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two atients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. CONCLUSIONS: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management - and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

Favorable outcomes following early onset oral miglustat in early infantile Niemann Pick Type C.

Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in NPC1. Their considerably discrepant neurological disease courses were dependent on the timing of initiation of miglustat treatment. The outcomes support the significant role of early treatment with miglustat in the disease course of early infantile NPC and suggest that therapy should be considered even before the occurrence of neurological involvement. Moreover, this report emphasizes the importance of early diagnosis, in light of the availability of a potential disease-modifying medication.

Long-Term Follow-Up and Outcomes of Autoimmune Thyroiditis in Childhood.

Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable. Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time. Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral. Results: Mean follow-up was 8.1 years (range 0-29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT4) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83-84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T4 at presentation was the only predictor of outcome over time. Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT4 therapy at the end of the study was free T4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases.

Prevalence and Predictors of Growth Impairment and Short Stature in Pediatric-Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Growth impairment is common in children with inflammatory bowel diseases (IBD). However, the magnitude of short stature at adulthood is not well characterized. We aimed to determine the prevalence and predictors of growth impairment at diagnosis and adulthood in children with IBD. METHODS: Height z-scores at diagnosis of IBD and at adulthood among 291 children with Crohn's disease (CD) and 125 with ulcerative colitis (UC) were retrieved retrospectively and compared to matched controls. Growth impairment at diagnosis was defined as height z-score for age less than or equal to -1 and short stature at adulthood as less than or equal to -2. RESULTS: Mean height z-score at adulthood in subjects with CD or UC was significantly different from controls although mean height did differ in males only (CD 172.3 cm ± 6.7, UC 172.7 cm ± 5.3, controls: 174.2 cm ± 7.3, p = 0.003 and p = 0.047, respectively). Diagnosis prior to final stage of puberty and male gender were risk factors for being short statured at adulthood in CD (mean difference [MD] 2.5, p = 0.013 and MD 6.25, p = 0.001, respectively) and UC (MD 4.9, p = 0.011 and MD 3.3, p = 0.034, respectively). CONCLUSION: Increased proportion of pediatric-onset IBD patients has growth impairment at adulthood. Male gender and diagnosis prior to puberty were found to impose risk for reduced adult height in both diseases.

[IS THE PREVALENCE OF CHILDHOOD OBESITY IN ISRAEL SLOWING DOWN?].

BACKGROUND: Childhood and adolescent obesity is an ongoing problem in the Western World and has increased dramatically over the last four decades. Similar trends have been observed in Israel, but only limited data has been available on the prevalence of obesity. The rise in the prevalence of childhood obesity is mainly attributed to the change in lifestyle including increased intake of fast food and lowered extent of physical activities. OBJECTIVE: To determine the current prevalence of childhood and adolescent obesity in Northern Israel and to compare results to former years. METHODS/DESIGN: We conducted an analysis of weight, height and body mass index (BMI, in two separate periods: between the years 2010-2012 and 2005-2007, using the electronic medical records of the Clalit Health Services. A total of 94,239 subjects were enrolled between the ages of 2-18 years. RESULTS: Twenty four percent of the children had a BMI above the 85th centile and 10.5% were found to be obese. The prevalence of obesity was higher in males as compared to females [11.5% vs. 9.5%, respectively, p<0.0001). Obesity peaked in girls at age 9 and in boys at age 11 (33%, 30.5%, respectively). The prevalence of overweight and obesity was significantly higher in urban regions when compared with rural regions in all age groups. Among the age groups of 2-5 and 6-11 years, the Jewish population showed a higher rate of overweight and obesity as compared to the Arab population (age group 2-5 years: obesity 9.6% vs. 8.3%, respectively, p=0.15; above 85th centile: 22.2% vs. 19.6%, respectively, p<0.0001; age group 6-11 years: obesity 12.9% vs. 10.5%, respectively, p<0.0001; above 85th centile: 26.5% vs. 23.4%, respectively, p<0.0001). No increase in the prevalence of obesity was observed between the years 2005-2007 and 2010- 2012 and above the age of 6 years a trend towards a decrease in the prevalence of obesity and overweight has been shown. CONCLUSIONS: A high prevalence of overweight and obesity has been shown in northern Israel. The prevalence was high for all age groups. The finding that there was no increase in the prevalence of obesity during the last 5 years may suggest that obesity has reached its peak.

Ghrelin and growth hormone secretagogue receptor (GHSR) genes are not commonly involved in growth or weight abnormalities in an Israeli pediatric population.

CONTEXT AND OBJECTIVE: Ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), have key roles in appetite control and growth regulation. To date, only few mutations of GHSR have been identified in children with obesity and short stature. We hypothesized that mutations in ghrelin or GHSR will result in disrupted growth and weight regulation in children. DESIGN: A total of 98 subjects (38 females and 60 males) were enrolled with failure to thrive (FIT) (n=9), GH deficiency (GHD) (n=44), idiopathic short stature (ISS) (n=22) or obesity (n=23). The coding exons of both ghrelin and GHSR genes were screened for mutations by sequencing. RESULTS: Seven different sequence changes were identified in GHSR, two of them novel and five described previously. One previously described sequence change (p.L72M) in the ghrelin gene was identified in five patients; however, the same variant was identified at a higher rate in controls. A high rate of sequence changes was shown in ghrelin and its receptor, GHSR, in our population, but none of these changes affected the coding region of the protein. CONCLUSIONS: Despite the major role of ghrelin in growth and appetite regulation, our results indicate that mutations in ghrelin and GHSR do not explain short stature and weight regulation disorders in children in our population.

[The burden and outcomes of acute bronchiolitis among young children hospitalized in Israel].

BACKGROUND: Acute bronchiolitis (AB) is a significant indication for hospitalization during the winter period. Underlying conditions increase risk for severe manifestations. AIMS: To estimate the burden and outcomes of AB in northern Israel. METHODS: A prospective study was performed between 1.12.2005 - 31.3.2006. Previously healthy children younger than 2 years of age, hospitalized with the diagnosis of AB, in three hospitals in northern Israel, were included in this study. RESULTS: Overall, 465 children (93%) out of 500 children who were hospitalized due to AB and comprised 18% of all hospitalizations during the study period, were included. A pathogen was identified in 91% of cases. A single pathogen was identified in 243 (52%) cases; 2-4 pathogens were found in 176 (39%) children. Common pathogens were respiratory syncytial virus (RSV) and Rhinovirus in 346 (75%) and 129 (28%), of which 192 (41%) and 37 (8%) were sole pathogens respectively. Complete data were available for 390 (82%) children, of whom 78% were younger than 6 months. Patients were hospitalized for 4 +/- 4.4 days; 15 children were treated in intensive care. There was one mortality. An X-ray was performed in 94% of cases. Most children were treated with multiple regimens including intravenous fluids, O2 supplement, physiotherapy, bronchodilators, steroids and antibiotics. Bronchiolitis was attributed to 18% of hospitalizations. On a national scale, assuming that the policy of hospitalization is similar, 4100 children were hospitalized due to AB. This reflects 4% of all hospitalized children a year in Israel and attributing to 16,400 hospitalizations. CONCLUSIONS: AB is associated with a huge burden, during a short period of the year, on pediatric departments, mainly attributed by infants younger than 6 months of age. The development of effective vaccine against RSV may significantly reduce the burden of morbidity.