Yael Lebenthal

Natural History of Thyroid Function Tests over 5 Years in a Large Pediatric Cohort

CONTEXTnBecause clinical manifestations of thyroid disorders are variable and subtle in children and adolescents, thyroid function tests are often repeated in patients with nonspecific symptoms.nnnOBJECTIVESnThe objective of the study was to determine the natural history of initial abnormal TSH and define populations at greater risk for developing a subsequent thyroid dysfunction.nnnMETHODSnA total of 121,052 of 1.043 million outpatients aged 0.5-16 yr insured by the Clalit Health Medical Organization had a TSH determination in 2002 and follow-up to 2007. Extracted from the Clalit Health Medical Organization database were their demographic data, referral diagnoses, and laboratory results (TSH, free T(4), thyroid antibodies). Excluded were patients with overt hypothyroidism or hyperthyroidism on initial testing.nnnRESULTSnResults of 96.5% of initial serum TSH concentrations were normal (0.35-5.5 mIU/liter), 0.2% were low (<0.35 mIU/liter), 2.9% elevated (>5.5 to <or=10 mIU/liter), and 0.4% highly elevated (>10 mIU/liter). The frequency of TSH testing increased with age and female gender. During follow-up, repeated (two to more than four) TSH tests were performed in 45.7% of the patients. In the second TSH determination, normal TSH was documented in 40, 73.6, and 78.9% of those whose initial serum TSH was highly elevated, elevated, and low, respectively, and in 97% of those with normal initial TSH. Predictive factors for a sustained highly elevated TSH were initial TSH greater than 7.5 mIU/liter (P = 0.014) and female gender (P = 0.047).nnnCONCLUSIONSnIn the pediatric population, initial normal or slightly elevated TSH levels are likely to remain normal or spontaneously normalize without treatment. Patients with initial levels greater than 7.5 mIU/liter, particularly girls, are at a greater risk for sustained abnormal TSH levels.

A Novel Loss-of-Function Mutation in GPR54/KISS1R Leads to Hypogonadotropic Hypogonadism in a Highly Consanguineous Family

CONTEXTnThe G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH).nnnOBJECTIVEnThe objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood.nnnDESIGNnIn six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood.nnnRESULTSnA new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up.nnnCONCLUSIONnA novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.

Differentiated Thyroid Carcinoma in Pediatric Patients: Comparison of Presentation and Course between Pre-pubertal Children and Adolescents

OBJECTIVEnTo evaluate the clinical characteristics, course, and outcome of differentiated thyroid carcinoma (DTC) in pre-pubertal children compared with adolescents.nnnSTUDY DESIGNnThe records of 10 pre-pubertal and 17 pubertal patients in whom DTC was diagnosed and who were observed in our tertiary pediatric endocrine clinic were reviewed. Extension of tumor at presentation, treatment modality, course, and outcome were analyzed.nnnRESULTSnA positive family history of DTC was more prevalent in the pre-pubertal group (P = .037). At diagnosis, they had a greater degree of extrathyroid extension (P = .012), lymph node involvement (P = .009), and lung metastases (P = .009). The extent of surgery was similar in both groups, whereas the weight-adjusted radioiodine (I(131)) ablative dose was higher in the pre-pubertal group (P = .004). During the median follow-up of 5 years, the overall survival rate was 100% for both groups, with no significant difference in evidence of residual tumor after initial therapy or the recurrence rate.nnnCONCLUSIONnDTC has a more aggressive presentation in pre-pubertal children. Rigorous initial surgical and I(131) treatment, followed by thyrotropin suppression, was found to result in an outcome similar to that achieved in the pubertal group.

Treated and untreated women with idiopathic precocious puberty: long-term follow-up and reproductive outcome between the third and fifth decades

Central precocious puberty (CPP), treated or untreated, may have implications in adulthood.

Interrelationship of Extent of Precocious Adrenarche in Appropriate for Gestational Age Girls with Clinical Outcome

OBJECTIVEnTo assess the interrelationship between extent of adrenarche at presentation in girls with precocious adrenarche (PA) born appropriate for gestational age and their growth pattern, pubertal course and adult height.nnnSTUDY DESIGNnWe reviewed clinical and laboratory data from medical charts of 85 girls with PA aged 5.0 to 8.8 years at referral, stratified in 3 subgroups according to bone age (BA) minus chronological age (CA) ≤0 years; 0 1 year.nnnRESULTSnExtent of pubarche and dehydroepiandrosterone-sulfate levels were greatest in the BA-CA >1 subgroup (P=.02, P=.008, respectively), who also were taller at diagnosis (P=.002) and during childhood (P=.01). In all subgroups, pubertal onset was within normal range; menarche occurred earlier than in control subjects (P<.02); all attained adult height within their mid-parental height range. Predicted adult height was overestimated in girls with BA ≤CA (P=.04) and underestimated with BA-CA >1 (P<.001).nnnCONCLUSIONSnAlthough a more pronounced adrenarche and BA advancement at diagnosis in girls with PA born appropriate for gestational age had an impact on their pre-pubertal growth pattern, it was not associated with early and rapid progression of puberty or reduced adult height. This reassuring clinical course indicates that PA is a benign condition, irrespective of the extent of adrenarche at presentation. Adult height prediction is unreliable in PA.

Using the Internet-based upload blood glucose monitoring and therapy management system in patients with type 1 diabetes.

The aim of this study is to assess the impact of the internet-based upload blood glucose monitoring and therapy management system (Carelink®) in patients with type 1 diabetes. Diabetic patients treated with pump infusion forxa0≥3xa0months were prospectively randomized to use the CareLink® with (4xa0months) and without (4xa0months) diabetes-team initiated contact (nxa0=xa036, intervention group) or to continue standard care for 4xa0months and then transfer to the CareLink® without diabetes-team initiated contact (nxa0=xa034, control group). In the first 4xa0months, treatment was adjusted monthly by the same team in both groups. Main outcome measures were HbA1c level and scores on the Diabetes Treatment Satisfaction and Diabetes Quality of Life Questionnaires. Patients who submittedxa0<3 times during each 4-month segment were considered noncompliant. Mean patient age was 14.02xa0±xa05.33xa0years; mean diabetes duration, 6.4xa0±xa04.7xa0years; median duration of pump treatment, 2.5xa0years. After 4xa0months, mean HbA1c level decreased from 8.75xa0±xa00.84 to 8.45xa0±xa00.90xa0% in the intervention group (pxa0=xa00.013) and from 8.65xa0±xa00.57 to 8.37xa0±xa00.73xa0% in the control group (pxa0=xa00.054). Within the intervention group, the difference in the change in HbA1c levels between compliant and noncompliant patients was significant (8.17xa0±xa00.81 vs. 8.99xa0±xa00.85xa0%, pxa0=xa00.017). Only in the compliant subgroup was the decrease from baseline significant (pxa0=xa00.006). Similar findings were noted in the control group at 8xa0months (pxa0<xa00.05 and pxa0=xa00.018, respectively). There were no significant changes in questionnaire scores at 4 or 8xa0months in either group. Use of the CareLink® system is associated with significantly improved glycemic control in compliant patients, with no apparent effect on patient satisfaction or quality of life.

Familial type 1 diabetes mellitus - gender distribution and age at onset of diabetes distinguish between parent-offspring and sib-pair subgroups.

Lebenthal Y, de Vries L, Phillip M, Lazar L. Familial type 1 diabetes mellitus—gender distribution and age at onset of diabetes distinguish between parent‐offspring and sib‐pair subgroups.

Metabolic control by insulin detemir in basal-bolus therapy: treat-to-target study in children and adolescents with type 1 diabetes.

To assess the efficacy and safety of insulin detemir administered once vs. twice daily in children and adolescents with type 1 diabetes mellitus.

The glucokinase mutation p.T206P is common among MODY patients of Jewish Ashkenazi descent.

Gozlan Y, Tenenbaum A, Shalitin S, Lebenthal Y, Oron T, Cohen O, Phillip M, Gat‐Yablonski G. The glucokinase mutation p.T206P is common among MODY patients of Jewish Ashkenazi descent.

Natural History of Idiopathic Advanced Bone Age Diagnosed in Childhood: Pattern of Growth and Puberty

Background: Significant idiopathic bone age (BA) advancement is defined as BA >2 SD above the mean chronological age (CA) with no underlying etiology. BA advancement due to endocrinopathies is associated with early puberty and compromised adult height (AHt), necessitating treatment. The natural history of idiopathic BA advancement is not well-established. Aim: To determine the pattern of growth and puberty, and validity of AHt prediction in idiopathic BA advancement. Methods: Fifty-five prepubertal patients (20 boys aged 6.7 ± 2.2 years, 35 girls aged 6.4 ± 2.0 years) evaluated between 1985 and 2008 were found to have idiopathic BA advancement. Assessed during follow-up were: BA, height (Ht), weight (Wt), pubertal course and predicted AHt (PAHt). Attained AHt was compared to PAHt and to midparental Ht (MPHt). Results: Throughout follow-up, BA-SDS (SD score) significantly declined (p < 0.001), Ht-SDS significantly decreased (p = 0.006) and Wt-SDS did not change. Pubertal onset, duration and growth were within the normal range. Attained AHts did not differ significantly from MPHts (boys: 172 ± 6.7 vs. 171 ± 6.1 cm; girls: 160.5 ± 6.5 vs. 159.0 ± 6.8 cm). PAHts using the ‘accelerated’ tables of Bayley and Pinneau were accurate. Conclusion: Idiopathic BA advancement differs from BA advancement with underlying endocrinopathy in evolution of BA progression (decline in BA-SDS), growth pattern, validity of AHt prediction and uncompromised AHt. This indicates that it requires minimal clinical monitoring and usually does not mandate treatment.