Tall stature : morbidity, mortality and treatment outcomes

Tall stature is usually constitutional. In some cases excessive growth is caused by early puberty and in others by growth disorders such as Marfan syndrome or pituitary gigantism. Some individuals experience a substantial negative psychosocial impact from being tall which can cause them and their families to seek medical attention. Whether or not to reduce adult height is an ethical dilemma where the psychological benefits must be weighed carefully against possible health complications. For over half a century, adolescent boys and girls have been treated with high-dose sex steroids in an attempt to reduce their adult heights by inducing early growth plate closure. In the late 1990s, another treatment option was introduced, so called epiphysiodesis, where growth plate cartilage in the lower extremities was surgically destroyed to stop further growth in tall adolescents. The overall aim of this thesis was to evaluate health consequences of the two principally different methods to reduce further growth in extremely tall adolescents and to study how height affects health. In paper I we performed a cohort study of the cancer risk in 369 women who were assessed for tall stature during their adolescence at Swedish university hospitals between 1973 and 1993 and were followed for a median period of 27 years. Approximately half of them were treated with a median daily dose of 500 μg ethinyl oestradiol and the rest were untreated. The odds ratio (OR) for developing melanoma in treated compared to untreated was 6.1 (1.04-∞). The ORs for overall tumours and breast cancer were increased, but the risk estimates were imprecise. In paper II we studied the efficacy and safety of percutaneous epiphysiodesis, in 21 operated boys and girls who were followed until reaching adult height. When compared to prediction, adult height was reduced by 4.1+/-0.7 cm in treated girls (P<0.001) and 6.4 +/- 0.7 cm in treated boys (P<0.001), corresponding to a third of predicted remaining growth in both genders. No serious side effects were reported during follow-up. In paper III, the extensive Swedish population registers enabled us to study how height was associated with cancer and mortality in a very large cohort of five and a half million Swedish men and women born 1938-1991. Hazard ratio (HR) for any cancer per 10 cm increase in height was 1.19 (1.18, 1.20) in women and 1.11 (1.10, 1.12) in men. All 15 specific cancer sites studied were positively associated with height, melanoma most strongly so with HR 1.39 (1.35, 1.43) in women and 1.32 (1.28, 1.36) in men. Cancer mortality was increased with height in both genders whereas a number of other specific death causes, including cardiovascular disease, were decreased with height. Overall mortality was not notably affected by height in women, HR 0.98 (0.97 - 0.99), but decreased in taller men, HR 0.91 (0.90 - 0.92). In summary, this thesis contributes to the understanding of how an individual’s health is affected by height per se as well as by different height reduction therapies. This knowledge can facilitate better management of individuals who seek medical attention for tall stature

Common DNA variants predict tall stature in Europeans

Genomic prediction of the extreme forms of adult body height or stature is of practical relevance in several areas such as pediatric endocrinology and forensic investigations. Here, we examine 770 extremely tall cases and 9,591 normal height controls in a population-based Dutch European sample to evaluate the capability of known height-associated DNA variants in predicting tall stature. Among the 180 normal height-associated single nucleotide polymorphisms (SNPs) previously reported by the Genetic Investigation of ANthropocentric Traits (GIANT) genome-wide association study on normal stature, in our data 166 (92.2 %) showed directionally consistent effects and 75 (41.7 %) showed nominally significant association with tall stature, indicating that the 180 GIANT SNPs are informative for tall stature in our Dutch sample. A prediction analysis based on the weighted allele sums method demonstrated a substantially improved potential for predicting tall stature (AUC = 0.75; 95 % CI 0.72-0.79) compared to a previous attempt using 54 height-associated SNPs (AUC = 0.65). The achieved accuracy is approaching practical relevance such as in pediatrics and forensics. Furthermore, a reanalysis of all SNPs at the 180 GIANT loci in our data identified novel secondary association signals for extreme tall stature at TGFB2 (P = 1.8 x 10(-13)) and PCSK5 (P = 7.8 x 10(-11)) suggesting the existence of allelic heterogeneity and underlining the importance of fine analysis of already discovered loci. Extrapolating from our results suggests that the genomic prediction of at least the extreme forms of common complex traits in humans including common diseases are likely to be informative if large numbers of trait-associated common DNA variants are available