Liora Lazar

Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the Bayley-Pinneau method.

This study was designed to determine the benefit of therapy on final height (FHt) in girls with central precocious puberty (CPP). A total of 102 patients were evaluated--28 untreated, 26 treated with cyproterone acetate (CyA), and 48 treated with GnRH analogue (GnRHA)-and their achieved FHt was compared to the respective target height (THt). Of the untreated girls, half (14/28) had a slow course of puberty and reached THt +/- 0.5 SD (FHt 160.2 +/- 7.1, THt 159.5 +/- 6.6 cm); the other half (14/28) had an accelerated course of puberty with a FHt well below THt (FHt 150.8 +/- 4.3, THt, 159.2 +/- 5.9 cm) and in most cases (14/28) below the height-SDS of both parents. The treated girls (both regimens) reached THt above (CyA group: FHt 157.8 +/- 5.1, THt 156.8 +/- 5.1 cm; GnRHA group: 159.6 +/- 6.3, THt 157.7 +/- 5.7 cm). We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years. Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used, regardless of the advanced bone age of the patients.

SERUM GROWTH HORMONE BINDING PROTEIN ACTIVITY IN HEALTHY NEONATES, CHILDREN AND YOUNG ADULTS: CORRELATION WITH AGE, HEIGHT AND WEIGHT

Serum growth hormone binding protein (GHBP) activity was estimated in healthy neonates (n=6), children and adolescents (n=97) and young adults (n=19). GHBP activity was measured by incubating 125I‐hGH (human growth hormone) (˜ 25 000 c. p. m.) with serum (100 μ1) in the presence and in the absence of excess unlabelled hGH, followed by separation of specifically bound 1251‐hGHBP complexes from free 125I‐hGH by gel filtration on Ultrogel AcA44 minicolumns. The results are expressed as the percentage specific binding relative to an adult reference serum (%RSB), after correction for endogenous hGH of the unknown serum. The between‐assay coefficients of variation for two sera of %RSB activity of 51.2 and 115.4% were 6.0 and 7.0% respectively. In neonates, low values of serum GHBP were found (%RSB = 27.1 ± 5.0 SEM) followed by a major rise during the first 6 years of life to a mean value (%RSB = 68.3 ± 4.1 SEM) which more than doubled that of neonates. Thereafter, values rose progressively throughout childhood and puberty to reach maximum values in young adults (%RSB =95.0 ± 3.1 SEM). A novel observation was that serum GHBP activity correlated significantly with height standard deviation score (SDS) (males: r= 0.77, P < 0.001; females: r= 0.56, P= 0.01) and weight SDS (P < 0.001) for both sexes before puberty. During puberty GHBP correlated only with weight SDS in males (r=0.60, P < 0.01). In all age groups studied, no correlation could be found between serum GHBP and height velocity.

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

CONTEXT Because clinical manifestations of thyroid disorders are variable and subtle in children and adolescents, thyroid function tests are often repeated in patients with nonspecific symptoms. OBJECTIVES The 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. METHODS A 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. RESULTS Results 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). CONCLUSIONS In 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

CONTEXT The 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). OBJECTIVE The 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. DESIGN In 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. RESULTS A 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. CONCLUSION A 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

OBJECTIVE To evaluate the clinical characteristics, course, and outcome of differentiated thyroid carcinoma (DTC) in pre-pubertal children compared with adolescents. STUDY DESIGN The 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. RESULTS A 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. CONCLUSION DTC 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.

Premature Thelarche: Age at Presentation Affects Clinical Course but Not Clinical Characteristics or Risk to Progress to Precocious Puberty

OBJECTIVES To determine whether age at premature thelarche (PT) onset affects the clinical characteristics, course, and risk of progression to precocious puberty (PP). STUDY DESIGN Data regarding course of growth and puberty were retrieved from the medical files of 139 girls with PT followed up from 1995 to 2005. Analysis was based on age at PT appearance (birth, 1-24 months, and 2-8 years); course was categorized as regressive, persistent, progressive, or cyclic. RESULTS At diagnosis, height standard deviation score, bone age-chronological age ratio, and hormonal values were comparable in the 3 age groups. PT regressed in 50.8%, persisted in 36.3%, progressed in 3.2% and had a cyclic course in 9.7%. A progressive or cyclic course was significantly more prevalent among girls presenting after 2 years (52.6%) compared with girls presenting at birth (13.0%) or at 1 to 24 months (3.8%) (P < .001). PP occurred in 13% irrespective of age at PT presentation or clinical course. CONCLUSIONS Clinical and anthropometric characteristics at admission and risk of PP were similar in all girls with PT, regardless of age at onset. There are currently no clinical or laboratory tests that can predict the risk of progression to PP at presentation.

Precocious Puberty: Growth and Genetics

The precise neuroendocrine mechanisms underlying activation of hypothalamic-pituitary-gonadal (HPG) axis maturation are elusive. The wide age range of pubertal onset among normal individuals throughout the world may suggest that both genetic and environmental factors modulate the timing of puberty. Early activation of the HPG axis, termed central precocious puberty (CPP), causes psychosocial difficulties and may lead to compromised final height, especially if medical intervention is delayed. Although CPP is considered to be idiopathic in the majority of patients, we have recently reported a 27.5% prevalence of familial cases among 147 patients with idiopathic CPP. Segregation analysis of this cohort suggested an autosomal dominant transmission with incomplete sex-dependent penetrance. Allelic variants of candidate genes that regulate the timing of puberty may cause familial CPP. Detection of these genes will provide a tool for identification of children at risk of developing CPP, enabling early intervention with the aim of preventing its distressing outcomes.

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.

A novel mutation in PIT-1: phenotypic variability in familial combined pituitary hormone deficiencies.

Mutations in PIT-1 have been described in several cases of familial combined pituitary hormone deficiencies. This study describes a novel PIT-1 mutation that was found in two siblings of a highly consanguineous family of Israeli-Arab origin. The missense mutation (G688A) causes a lysine (K) to glutamic acid (E) substitution at codon 230. This codon resides in the first helix of the POU-homeodomain, which is directly involved in DNA binding. This amino acid is conserved in most homeodomain proteins, suggesting that the substitution disrupts the DNA-binding activity of the mutant protein. Two main observations are described: 1. The clinical presentation of the mutation involves intrauterine growth retardation. 2. One sibling had full deficency of growth hormone and thyroid stimulating hormone, whereas the other had only growth hormone deficiency. This is, to the best of our knowledge, a unique expression of a novel PIT-1 mutation.

PROP-1 Gene Mutation (R120C) Causing Combined Pituitary Hormone Deficiencies with Variable Clinical Course in Eight Siblings of One Jewish Moroccan Family

Background: PROP-1 gene mutations have been described in patients with combined pituitary hormone deficiencies (CPHD). Methods: Clinical follow-up and molecular analysis of the PROP-1 gene were performed in 4 affected sisters of one consanguineous family, in whom 8 members had CPHD. Results: The 4 sisters were homozygous for the same R120C mutation. Growth hormone and thyroid-stimulating hormone deficiencies were diagnosed concomitantly in all subjects, but at different ages (5.5–10.8 years). All 8 subjects exhibited complete gonadotropin deficiency with failure of spontaneous sexual maturation. Adrenocorticotropic hormone deficiency developed in only 2 sisters in the 3rd and 4th decades of life. Conclusions: The CPHD in this family, caused by an R120C mutation, was characterized by clinical phenotypic variability in terms of the severity of hormonal deficiencies and the time of their development. Identifying the mutation does not predict the clinical course. Therefore, continuous follow-up with repeated endocrine evaluations is mandatory to provide proper hormone substitution therapy.