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.

Maturity onset diabetes of the young type 2 (MODY2): Insight from an extended family.

AIMS: To assess long-term outcome of patients with maturity onset diabetes of the young, type 2 (MODY2) in a unique large cohort of patients with the same genetic and environmental background. METHODS: We prospectively evaluated 162 patients aged 5 to 82 years, belonging to the same extended family living in the same village. All patients underwent molecular testing for the glucokinase (GCK) gene mutation identified in the proband, and were categorized into three groups (MODY2, type 2 diabetes and controls). RESULTS: The 5.5-year-old proband had the c.1278_1286del mutation in the GCK and was diagnosed with MODY2. Forty-two out of 162 participants were positive for the mutation and 39 had type 2 diabetes. Patients were followed for a mean 10.2 ± 3.7 years (range 0-14). Mean fasting blood glucose and HbA1c increased significantly over the years in MODY2 patients (133 vs. 146 mg/dL; 6.9% vs. 8.2%, respectively). Increase in HbA1c occurred only in the obese/overweight subgroups. Twenty-five percent of MODY2 patients developed diabetes complications, all were above 40 years of age. CONCLUSIONS: Although MODY2 commonly has a benign disease course, weight gain is a risk factor for diabetes complications, requiring life-long follow-up and in some patients, medical intervention.

Long-term outcome of loss-of-function mutations in thyrotropin receptor gene.

BACKGROUND: Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations. METHODS: The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH. RESULTS: Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time. CONCLUSION: SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.

[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.

A novel mutation in IGFALS, c.380T>C (p.L127P), associated with short stature, delayed puberty, osteopenia and hyperinsulinaemia in two siblings: insights into the roles of insulin growth factor-1 (IGF1).

BACKGROUND: The acid-labile subunit (ALS) protein is crucial for maintaining the circulating IGF/IGFBP system. Inactivating mutations of IGFALS result in IGF1 deficiency associated with growth retardation. Although the first IGFALS mutation in humans was described in 2004, only 16 mutations have been reported since. Moreover, the phenotype of affected patients as a consequence of ALS deficiency is still highly variable. We assessed whether children with idiopathic short stature (ISS) harbour mutations in IGFALS and characterized affected patients' phenotype. DESIGN: Sixty-five children with ISS were enrolled in the study. Serum ALS levels were measured by ELISA, and IGFALS was sequenced. RESULTS: A novel homozygous mutation in IGFALS, c.380T>C (p.L127P), was identified in two siblings of a consanguineous family. The proband, a 17·75-year-old male, was -1·9 SDS in height and -4·5 SDS in weight. Exaggerated stimulated GH (38 ng/ml) and extremely low IGF1 and IGFBP3 (<25 and <500 ng/ml, respectively) indicated GH insensitivity. Both affected siblings had low or no ALS (43 and 0 mU/ml, respectively). They were also mildly small for gestational age, severely underweight and showed osteopenia, insulin insensitivity and delayed and slow puberty progression. CONCLUSIONS: Acid-labile subunit deficiency due to IGFALS mutations is a rare cause of growth retardation in children. The unique combination of features presented by the two affected siblings emphasizes the important role of IGF1 in bone formation, insulin regulation and the pubertal process, in addition to its crucial effect on growth. Long-term follow-up is indicated since the clinical outcome with respect to osteoporosis, diabetes mellitus and fertility has not been recognized.

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.

Can auxology, IGF-I and IGFBP-3 measurements followed by MRI and genetic tests replace GH stimulation tests in the diagnosis of GH deficiency in children?

BACKGROUND/AIMS: GH levels < 10 ng/ml in response to two different GH stimulation tests (GHSTs) are traditionally used to identify children with GH deficiency (GHD). Since GHSTs are imprecise, other diagnostic tools have been proposed. We assessed whether auxology, IGF-I and IGFBP-3 measurements followed by brain MRI and genetic analysis can replace the current diagnostic approach. METHODS: Fifty-three children diagnosed with GHD by two different GHSTs. GH-1 gene was sequenced. RESULTS: At presentation, 17% of patients were with height above -1.5 SD and 28% above -2.0 SD; 50% had IGF-1 concentration above -1.5 SD and 58% above -2.0 SD; 59% had pituitary anomalies demonstrated by MRI. Fourteen patients harbored the heterozygous R183H mutation, one patient had the N47D mutation and one had a novel F25Y mutation in GH-1. Using cut-off levels of -1.5 SD for height, IGF-I and IGFBP-3 excluded the diagnosis of GHD in 17, 68 and 79% of the children, respectively; a cut-off of -2 SD excluded 28, 88 and 96%, respectively. Further brain MRI and genetic tests excluded 81-96% and 96-100%, respectively, of children currently diagnosed with GH. CONCLUSION: Use of the tested approach, which avoids carrying out two GHSTs, would exclude most children currently diagnosed with GHD. Until better tools become available, we recommend identifying GHD in children by an integrated approach combining phenotype, auxological parameters, hormonal measurements and two separate GHSTs, with MRI and genetic tests to support the diagnosis.

Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene.

CONTEXT: G to A transition at position 6,664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial isolated GH deficiency type II (IGHD II). OBJECTIVES: The objective of the study was to assess the phenotype-genotype correlation of subjects affected with IGHD II caused by a G6664A mutation in 34 affected members of two large families. DESIGN AND PATIENTS: Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by restriction fragment length polymorphism. RESULTS: Twenty-four of the 52 members from family 1 and 10 of 14 from family 2 carried the same G6664A mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter [-2.6 vs. -0.1 sd score (SDS), P < 0.0001] and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, P < 0.0001), compared with normal-genotype family members. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 (mean -2.8 SDS), with five members being of normal height (>-2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although one of these subsequently demonstrated GH insufficiency (6.5 and 3.7 ng/ml). The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age (chronological age - bone age), age at diagnosis, peak GH response, and IGF-I levels. CONCLUSIONS: These detailed phenotypic analyses show the variable expressivity of patients bearing a G6664A mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. Our findings raise a new dilemma in the guidelines for the diagnosis of GH deficiency and the indications for GH therapy.

Growth hormone receptor sequence changes do not play a role in determining height in children with idiopathic short stature.

BACKGROUND/AIMS: In children with short stature, in whom growth hormone deficiency has been excluded, the presence of a normal or elevated growth hormone concentration concomitant with low insulin-like growth factor I suggests growth hormone insensitivity (GHI). Previous reports suggest that heterozygous mutations in the growth hormone receptor gene (GHR) may account for about 5% of children with idiopathic short stature (ISS). In the present study we have attempted to determine whether mutations in the GHR explain the short stature and growth retardation in a cohort of children with ISS and characteristics suggesting GHI. METHODS: For the present study 33 children with clinical and biochemical characteristics of GHI were selected from a cohort of 150 children of short stature. Molecular analysis of the GHR was performed using a single-strand conformation polymorphism technique and sequencing. Ten different sequence changes in 19 (58%) out of 33 children were identified, 9 of them novel and 1 that had been described previously. RESULTS: Two changes were found in exons 2 and 6. The known polymorphism of exon 6 (G168) was significantly more common in the control subjects than in our study group (63.5 vs. 30%; p < 0.0001). In the intronic sequences 8 previously undescribed DNA changes were found. The screening of the affected children's family members revealed that both normal and short stature members carried the same variants. The study group did not significantly differ from the controls in retention (GHRfl) or exclusion (GHRd3) of exon 3. CONCLUSION: Our study suggests that sequence changes of the GHR are common in children with ISS. The presence of these sequence changes in the control subjects as well as in normal stature family members indicates that these changes represent a simple polymorphism of the GHR. Such DNA changes are more prevalent than previously recognized, and they do not seem to play a contributory role in the etiology of short stature.