Saila Laakso

Premature Adrenarche - A Common Condition with Variable Presentation

Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature adrenarche (PA), clinical signs of androgen action appear before the age of 8/9 years in girls/boys, concurrently with the circulating DHEA(S) concentrations above the usually low prepubertal level. The most pronounced sign of PA is the appearance of pubic/axillary hair, but also other signs of androgen effect (adult type body odor, acne/comedones, greasy hair, accelerated statural growth) are important to recognize. PA children are often overweight and taller than their peers, and the higher prevalence of PA in girls than in boys is probably explained by higher female adiposity and peripheral DHEA(S) conversion to active androgens. PA diagnosis requires exclusion of other causes of androgen excess: congenital adrenal hyperplasia, androgen-producing tumors, precocious puberty, and exogenous source of androgens. PA has been linked with unfavorable metabolic features including hyperinsulinism, dyslipidemia, and later-appearing ovarian hyperandrogenism. Although this common condition is usually benign, PA children with additional risk factors including obesity should be followed up, with the focus on weight and lifestyle. Long-term follow-up studies are warranted to clarify if the metabolic changes detected in PA children persist until adulthood.

Serum androgen bioactivity is low in children with premature adrenarche

Background:Clinical findings in children with premature adrenarche (PA) correlate only partly with circulating levels of adrenal androgens. It is not known whether the prepubertal low circulating concentrations of testosterone (T) and dihydrotestosterone, together with those of adrenal androgens, are capable of activating the androgen receptor.Methods:This cross-sectional study was performed at a university hospital. Circulating androgen bioactivity was measured in 67 prepubertal children with clinical signs of PA and 94 control children using a novel androgen bioassay.Results:Circulating androgen bioactivity was low in the PA and control children. In the subgroup of children (n = 28) with serum T concentration over the assay sensitivity (0.35 nmol/l) and a signal in the androgen bioassay, we found a positive correlation between androgen bioactivity and serum T (r = 0.50; P < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a negative correlation with serum sex hormone–binding globulin concentration (r = −0.41; P < 0.05).Conclusion:Peripheral metabolism of adrenal androgen precursors may be required for any androgenic effects in PA. However, the limitations in the sensitivity of the bioassay developed herein may hide some differences between the PA and control children.

Polymorphism Pro12Ala of PPARG in Prepubertal Children with Premature Adrenarche and Its Association with Growth in Healthy Children

Background: The peroxisome proliferator-activated receptor-γ2 (PPARγ2) participates in the regulation of insulin sensitivity, and has connections to the GH-IGF system and ACTH-adrenal androgen axis. We hypothesized that PPARG Pro12Ala polymorphism leading to decreased receptor activity could contribute to the premature onset of adrenarche (PA). Methods: We performed a cross-sectional association study in 73 prepubertal children with PA and 97 age- and sex-matched healthy control children. Growth data, baseline hormone levels, and the values of oral glucose tolerance test (OGTT) were compared with PPARG genotypes. Results: We found no difference in the genotype distribution of PPARG between the PA and control children. The minor Ala12 variant was associated with lower current height SD scores (SDS) in the controls, but no similar association was seen in the PA children. Birth measures and current weight for height were equal between the genotype groups in both control and PA children. The Ala12 variant was associated with trends for a lower serum IGF-I level and lower serum insulin concentration at the 120-min time point of OGTT in control children. Conclusions: The Pro12Ala genotype of PPARG was not associated with PA. The minor Ala12 variant was associated with lower height SDS in healthy prepubertal children indicating its possible effects on growth.

Diverse Autoantibody Reactivity in Cartilage-Hair Hypoplasia

To the editor: Cartilage-hair hypoplasia (CHH) is a pleiotropic autosomal recessive disorder caused by mutations in the RMRP gene. Clinical features include short stature and metaphyseal bone dysplasia, as well as a range of extraskeletal manifestations such as hypotrichosis, bone marrow dysplasia, Hirschsprung disease, increased risk of cancer, and immune defects [1, 2]. The degree of immunodeficiency is highly variable, ranging from mild to severe forms such as severe combined immunodeficiency and Omenn syndrome [2]. Defective cellular immunity is common in CHH; however, impaired humoral immune responses have also been described [2, 3]. Patients frequently suffer from recurrent infections and immune dysregulation. Reported autoimmune sequelae of CHH include autoimmune hemolytic anemia, arthritis, immune thrombocytopenic purpura, as well as autoimmune hypothyroidism and enteropathy [1, 2]. The mechanisms behind the immune deficiency and dysregulation associated with CHH are still incompletely understood. Decreased AIRE expression and absence of FOXP3 T cells in the thymus have been implicated in the pathogenesis of Omenn syndrome in a CHH patient [4]. Cell cycle abnormalities, reduced thymic output, impaired lymphocyte proliferation, dysfunctional telomere machinery, and increased T cell apoptosis have also been associated with the immune defects seen in CHH [5, 6]. The role of autoantibody-mediated immune dysregulation, however, has not been determined. In order to evaluate whether autoantibodies contribute to CHH-related immune dysfunction, a protein microarray was performed on CHH patients in comparison to both healthy controls and patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). APECED is an autosomal recessive disorder caused by mutations in the AIRE gene, leading to various autoimmune disorders and chronic mucocutaneous candiasis [7]. Autoantibodies are a known contributor to APECED disease pathogenesis [7]. All individuals who participated, or their guardians, signed an informed consent, and the study was approved by the Institutional Review Boards at the referring institutions. Clinical and laboratory features of the evaluated CHH patients are reported in Supplemental Table S1. A panel of IgG autoantibodies was screened using an autoantibody array (University of Texas Southwestern Medical Center, Genomic and Microarray Core Facility) as previously described with minor modifications [8, 9]. Briefly, serum samples were diluted to 1:33 and incubated with the autoantigen array. Autoantibodies binding to antigens on the array were detected with Cy3 labeled anti-IgG at a laser wavelength of 532 nm. The array was scanned with GenePix® 4400A Microarray Scanner, and images analyzed using GenePixPro 6.0 software to generate GenePix Results (GPR) files. Averaged net Electronic supplementary material The online version of this article (doi:10.1007/s10875-017-0408-4) contains supplementary material, which is available to authorized users.

Testicular Function and Bone in Young Men with Severe Childhood-Onset Obesity

Background: Previous studies suggest increased risk for hypoandrogenism and fractures in men with obesity. We aimed to describe the effects of severe childhood-onset obesity on the cross talk between metabolic state, testes, and skeleton at late puberty. Methods: A cohort of adolescent and young adult males with severe childhood-onset obesity (n = 21, mean age 18.5 years) and an age-matched control group were assessed for testicular hormones and X-ray absorptiometry-derived bone mass. Results: Current median body mass indexes for the obese and control subjects were 37.4 and 22.9. Severe early-onset obesity manifested with lower free testosterone (median [interquartile range] 244 [194–332] vs. 403 [293–463] pmol/L, p = 0.002). Lower insulin-like 3 (1.02 [0.82–1.23] vs. 1.22 [1.01–1.46] ng/mL, p = 0.045) and lower ratio of testosterone to luteinizing hormone (2.81 [1.96–3.98] vs. 4.10 [3.03–5.83] nmol/IU, p = 0.008) suggested disrupted Leydig cell function. The degree of current obesity inversely correlated with free testosterone (τ = –0.516, p = 0.003), which in turn correlated positively with bone area at all measurement sites in males with childhood-onset obesity. Conclusions: Severe childhood-onset obesity is associated with impaired Leydig cell function in young men and lower free testosterone may contribute to impaired skeletal characteristics.

Oral Tongue Malignancies in Autoimmune Polyendocrine Syndrome Type 1

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Autoimmune polyendocrine syndrome type-1 (APS-1) (APECED, OMIM 240300) is a rare, childhood onset, monogenic disease caused by mutations in the Autoimmune Regulator (AIRE) gene. The overall mortality is increased compared to the general population and a major cause of death includes malignant diseases, especially oral and esophageal cancers. We here present a case series of four APS-1 patients with oral tongue cancers, an entity not described in detail previously. Scrutiny of history and clinical phenotypes indicate that chronic mucocutaneous candidiasis and smoking are significant risk factors. Preventive measures and early diagnosis are important to successfully manage this potentially fatal disease.