Roland Pfaeffle

Reference intervals for TSH and thyroid hormones are mainly affected by age, body mass index and number of blood leucocytes, but hardly by gender and thyroid autoantibodies during the first decades of life

OBJECTIVES The purpose of our study was to establish reference intervals for thyroid function tests in children and adolescents and to identify factors that may influence the limits of these intervals. METHODS TSH, FT3, FT4, T3, T4, t-uptake, TPO-antibody (TPO-Ab) and TG-antibody (TG-Ab) levels were determined in blood of 1004 infants, children and adolescents by the Elecsys system (Roche). RESULTS A distinct overall age-dependent decrease of analyte levels was found for all parameters investigated. Puberty was accompanied by an increase of TSH, FT3 and T3 levels. Results of T4 and t-uptake were significantly higher in girls compared to boys. The exclusion of children with increased TPO-Ab and TG-Ab had no significant effect on the limits of the reference interval. We found that besides age, BMI-SDS but also white blood cells count and gender played a role in the prediction of analyte variation. CONCLUSIONS Covariates like BMI-SDS and white blood cell count should be taken into consideration when interpreting TSH and thyroid hormone measurements as well whereas gender and TPO-Ab or TG-Ab play a minor role.

Effects of Dehydroepiandrosterone Therapy on Pubic Hair Growth and Psychological Well-Being in Adolescent Girls and Young Women with Central Adrenal Insufficiency : A Double-Blind, Randomized, Placebo-Controlled Phase III Trial

CONTEXT AND OBJECTIVE The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy. DESIGN AND PATIENTS A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication. INTERVENTION Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16). MAIN OUTCOME MEASURES Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months. RESULTS In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P < 0.006), and of its 24 h urinary metabolite levels (P < 0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P < 0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P < 0.048). DHEA was well tolerated. CONCLUSIONS In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.

An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree.

Background: Mutations in the insulin-like growth factor-I (IGF-I) receptor (IGF1R) have been associated with prenatal and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate homeostasis. Methods: We investigated clinical, endocrine and metabolic parameters in four family members carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old male (index case), his sister and two paternal aunts. Results: All family members showed a variable degree of impairment in prenatal growth, with birth weight standard deviation scores (SDS) between –1.65 and –2.37 and birth length SDS between –1.78 and –3.08. Their postnatal growth was also impaired, with height SDS between –1.75 and –4.86. The index case presented high IGF-I levels during childhood and adolescence and delayed bone age. The index case and his two paternal aunts had impaired glucose tolerance (IGT) associated with a variable degree of alterations in insulin sensitivity and secretion. In contrast, the index case’s sister, who had had IGT during pregnancy, showed normal glucose metabolism but reduced insulin sensitivity. Conclusion: This is the first study showing an association between a novel IGF1R mutation and a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism.

Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry

CONTEXT Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. OBJECTIVE We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. DESIGN AND SETTING In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. PATIENTS We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. RESULTS Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 μg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 μg/l. For ID-MS, cutoffs of 5.48 μg/l (22k GH) and 7.43 μg/l (total GH) were ascertained. CONCLUSION The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

Background/Aims: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. Methods: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5–72.7 (median 16.6) years from 60 kindreds. Results: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0–20.7) and median volume was 127.6 mm3 (range 7.5–3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. Conclusion: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

Activating TSH-receptor mutation (Met453Thr) as a cause of adenomatous non-autoimmune hyperthyroidism in a 3-year-old boy.

Several mutations of the TSH-receptor gene have been described in a variety of thyroid diseases. Particularly in children and adolescents, somatic or germ cell mutations may lead to hyperthyroidism. In these cases, molecular analysis of the TSHR gene provides important information for further clinical management. We report a 3-year-old boy with a rare somatic TSHR mutation causing autonomous adenoma of the thyroid gland in order to illustrate how the genetic analysis of the lesion impacted on the surgical strategy. The patient presented with a left neck mass, negative thyroid autoantibodies, and unifocal autonomy on thyroid scan. He underwent local resection of the adenoma. Genetic workup demonstrated a somatic mutation of TSHR. Exons 9 and 10 of the TSHR gene (chromosome 14q3) from peripheral blood DNA and toxic thyroid adenoma tissue DNA were amplified by PCR and analyzed by denatured gradient gel electrophoresis (DGGE). DGGE from the EDTA blood sample showed no difference compared to the wild-type, whereas material extracted from the tissue sample showed a mutation in exon 10. Direct sequencing of the PCR product from the tissue demonstrated a heterozygous mutation in codon 453 (ATG-->ACG), leading to a substitution of methionine by threonine. The genetic appraisal of resected thyroid tissue in cases with nonautoimmune hyperthyroidism is important to formulate surgical and medical treatment plans. In cases with somatic mutations of the TSHR, simple resection of the adenoma is sufficient, whereas total thyroidectomy should be considered in patients with germ cell mutations.

A novel homozygous HESX1 mutation causes panhypopituitarism without midline defects and optic nerve anomalies.

Abstract Objective: There are many genes reported to have been associated with combined pituitary hormone deficiencies, but mutations in HESX1strongly correlate with septo-optic dysplasia. Our aim was to determine the cause of panhypopituitarism in our patient. Patients and methods: We studied an 8-month-old child having panhypopituitarism. The coding exons of PIT1, PROP1, LHX3, and HESX1 genes were amplified. Direct sequencing was done after denaturing HLPC. Results: We identified a novel homozygous mutation (R160H) within the homeodomain of HESX1, which, to our knowledge, is the first to be described in humans. Neuroimaging studies revealed anterior pituitary aplasia, a normal posterior pituitary gland, and a thin pituitary stalk but no midline abnormalities. Optic nerve studies showed no pathology. This mutation is also carried in the parents of the affected child in a heterozygous pattern, suggesting an autosomal recessive inheritance. Conclusion: These data demonstrate that homozygous HESX1 mutation causing an R160H substitution can result in panhypopituitarism without midline defects.

Thyroid disorders revisited.

Thyroid disorders are still a cause of health concerns, major illness, and comorbidities in neonates, children and adolescents around the world. Neonatal screening programs involve testing for congenital hypothyroidism usually using thyroid stimulating hormone (TSH) measurements in dried blood spots, and in developed countries, it is clinically and ethically mandatory to install neonatal screening programs for hypothyroidism. Also, as far as obese children are concerned, families and doctors alike tend to automatically ask about a child’s thyroid status. In addition, fatigue in a schoolchild is frequently met with concerns about whether or not there was an underlying thyroid dysfunction. However, most of the time, common causes such as psychosomatic illness or normal exhaustion are the reason for tiredness and thyroid function in these children are quite normal. Both hypothyroidism and hyperthyroidism may occur early in life, and thyroid cancer is of relevance in paediatric oncology and may be either sporadic or related to radiation be it after cancer treatments or environmental radiation exposure (Chernobyl accident and alike). However, overall clinically relevant disorders of the thyroid are still rather uncommon: congenital hypothyroidism occurs at a frequency of 1 in 3000, hypothyroidism in Hashimoto’s thyroiditis occurs in 1 in 2000, and lastly hyperthyroidism usually related to Graves’ disease is detected in 1 in 100,000 children and adolescents (1). Importantly, the relationship between different thyroid disorders is sometimes not completely understood as is shown by the cooccurrence of papillary thyroid cancer in patients with hyperthyroidism (2) and/or with autoimmune polyglandular syndrome (3). Lastly standardized reference values for serum concentrations of anti-thyroid peroxidase and anti-thyroglobulin antibodies and most importantly for TSH and thyroid hormones in relation to age, body mass index and to a much smaller extent to gender are to be employed when one investigates children’s thyroid status and health (4). The number of leucocytes in blood is related to thyroid hormone serum concentrations (5). In this issue of the Journal of Paediatric Endocrinology and Metabolism, scientific novelties and surprising clinical findings related to thyroid disorders are the focus of nine articles that will be introduced.

Puberty – genes, environment and clinical issues

In the context of human development and human lifespan puberty is defined as the transition period from childhood to adulthood. During puberty dramatic and substantial changes with respect to somatic, mental, behavioral and cognitive as well as social, psychological and economic dimensions occur in the individual. At the same time, the individual recognizes the group and the society in which he or she lives in new dimensions and a broader context. Somatic development, growth acceleration and deceleration occur during pubertal development. In females, menarche occurs during puberty and in males, an increase in testicular volume is testimony to the fact that the individual is indeed becoming fertile. The onset and progression of puberty, i.e. the speed with which an individual will accomplish fecundity and fertility and complete maturation, has been found to be determined by genetic variants of a number of genes. Some of these genes encode neuropeptides, neurotransmitters and their receptors and signaling components that serve as a clock and time keeper in the central nervous system [1–3]. In addition to the intrinsic factors that determine the onset and progression of puberty in the individual, external or extrinsic factors also play a substantial role in regulating puberty and pubertal development. Extrinsic factors include cultural, psychological, nutrition-related and environmental chemicals. Amongst chemicals occurring in, for example, plastic wrappings, toys, water and soil, the so-called endocrine-disrupting chemicals are suspected not only to influence pubertal development but also to influence gender identity, the development of internal and external genitalia, metabolic health and neurocognitive development [4]. Precocious and late puberty are often cause for concern for patients, parents, families and peers. Often, late puberty is related to late and/or slow development which occurs constitutionally and has a strong genetic component: often, children who enter puberty late have parents who have done so as well. Importantly, a large number of chronic diseases may slow puberty onset and/ or progression. Cystic fibrosis, chronic rheumatoid diseases, inflammatory bowel disease and renal, cardiac and pulmonary disorders may all impair pubertal development [2]. In this issue of our journal, excellent reports by experts in this field are presented that increase our knowledge in regard to several aspects of puberty and modulation of puberty progression.

Turner syndrome - working together with patients and their families.

Turner syndrome is one of the most common human variants of chromosome number or chromosomal deletion syndromes. The affected individuals rely on family and peer support and very frequently do need medical support from a variety of different medical specialists: geneticists, pediatricians, cardiologists, endocrinologists, hearing and speech therapists, diabetologists, gastroenterologists, hepatologists and psychologists might be asked for help (1–3). Specific therapeutic interventions may become necessary during all periods of life. In addition, transition of care during adolescence frequently poses a problem as family physicians, adult endocrinologists and gynecologists may be ill prepared to take over the care of women with Turner syndrome. In some countries there is still even a lack of adult physicians that are knowledgeable and willing to provide care for women with Turner syndrome (4, 5).