Paediatric-onset and adult-onset Graves' disease share multiple genetic risk factors.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disease (AITD) with a peak incidence between 30 and 50 years of age. Although children and adolescents may also develop the disease, the genetic background of paediatric-onset GD (POGD) remains largely unknown. Here, we looked for similarities and differences in the genetic risk factors for POGD and adult-onset GD (AOGD) as well as for variants associated with age of GD onset. MATERIALS AND METHODS: A total of 1267 GD patients and 1054 healthy controls were included in the study. Allele frequencies of 40 established and suggested GD/AITD genetic risk variants (39 SNPs and HLA-DRB1*03) were compared between POGD (N = 179), AOGD (N = 1088) and healthy controls. Subsequently, multiple linear regression was used to explore the relationship between age of GD onset and genotype for each locus. RESULTS: We identified six POGD risk loci, all of them were also strongly associated with AOGD. Although for some of the analysed variants, including HCP5 (rs3094228), PRICKLE1 (rs4768412) and SCGB3A2 (rs1368408), allele frequencies differed nominally between POGD and AOGD patients, these differences were not significant after applying multiple testing correction (Pcor  = 0.05/40 = 1.25 × 10-3 ). Regression analysis showed that patients with higher number of HCP5 risk alleles tend to have a significantly earlier onset of GD (P = 6.9 × 10-5 ). CONCLUSIONS: The results of our study revealed that POGD and AOGD share multiple common genetic risk variants. Moreover, we demonstrated for the first time that HCP5 polymorphism is associated with an earlier age of GD onset in a dose-dependent manner.

[Woman 19-old with hirsutism, obesity and acanthosis nigricans]. / Chora lat 19 z hirsutyzmem, otyloscia i zmianami skórnymi o typie rogowacenia ciemnego.

19-year-old hirsute woman with obesity, skin lesions with features of acanthosis nigricans around neck, armpits, thoracic cage and wrists escalating for couple of months, elevated testosterone and insulin plasma levels was admitted to hospital to perform diagnostic approach. The final diagnosis was hyperandrogenism-insulin resistance-acanthosis nigricans syndrome (HAIR-AN syndrome), considered as a subtype of policystic ovary syndrome (PCOS) and impaired glucose tolerance. HAIR-AN is characterized by coexistence of: hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). These symptoms are result of increased insulin and androgens levels. Due to accompanying complications (obesity, hyperglycemia, hyperlipidemia, infertility) patients with HAIR-AN syndrome should be monitored and treated. Rarely acanthosis nigricans, especially when occurs rapidly and extensively, may be a paraneoplastic disorder. Life style modification with BMI reduction was recommended and metformin, a drug improving sensitivity to insulin, was administered. Patient should be monitored due to possible complications of obesity, diabetes and hyperinsulinemia.

Genotype-phenotype correlations in Graves' disease.

Graves' disease (GD) is a heterogeneous autoimmune disease affecting with varying degrees of severity the thyroid gland, orbital tissues and skin. The pathogenesis of GD involves a complex interplay between multiple genetic, environmental and endogenous factors. Although the genetic predisposition to GD is well established, the significance of genotype-phenotype correlations and the role of epigenetic modifications in the disease pathogenesis remains largely unknown. In this review, we provide an up-to-date overview of genotype-phenotype correlations and summarize possible clinical implications of genetic and epigenetic markers in GD patients. We will specifically discuss the association of genetic markers and epigenetic modifications with age of GD onset, severity of Graves' hyperthyroidism and the development of clinically evident Graves' orbitopathy.

Insulin autoimmune syndrome.

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Life-threatening hypophosphataemia secondary to zoledronic acid implementation in a middle-age patient who presented with advanced osteolysis in the course of multiple myeloma.

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