Title: An Exploratory Study of Physical Phenotype, Biomarkers and Psychosocial Health Parameters in Boys with Klinefelter Syndrome
Description: Klinefelter Syndrome (KS) is a genetic condition that occurs only in males. In adult men, KS is associated with reproductive, cardiometabolic, bone and psychosocial health problems that are believed to emerge during peri-puberty. In children, the condition is under-diagnosed and not well understood due to the wide-ranging spectrum of physical features. Although pediatric studies are rare, androgen deficiency is believed to underlie many of the KS-related abnormalities in both physical and emotional well-being. The purpose of this dissertation was to systematically describe the physical and psychosocial health of peri-pubertal boys with KS. Aim I of the study was to explore associations between physical and psychosocial health while Aim II explored body composition and bone mineral density. For Aim I, a cross-sectional exploratory study examining the associations between physical phenotype, reproductive hormones, cardiometabolic risk factors, and psychosocial health was conducted in a sample of 43 boys with KS between the ages of 8 and 18 years.

Physical examination, laboratory and self-administered psychosocial health data were analyzed using descriptive statistics and univariate and multivariate linear regression techniques. For Aim II, a retrospective chart review examining body composition and bone mineral density (BMD) was conducted of 20 KS patients ages 8-18 years who attended a pediatric endocrine practice at a Columbia University-affiliated hospital. Aim I participants demonstrated a range of physical phenotype features. On average, boys showed at least 5 KS physical traits. Gonadotropins were elevated without androgen deficiency in most boys. Adverse cardiovascular risk factors were observed in about a third of the boys with higher frequency in pubertal boys. Quality of life and self-esteem scores were low compared to reference standards; average scores for self-concept and depression were within the normal range. Physical phenotype was inversely associated with quality of life, but not with the other measures of psychosocial health.

Low testosterone was associated with interpersonal problem subscale of the Children's Depression Inventory, but not for other psychosocial measures. Serum testosterone was not associated with cardiometabolic biomarkers. For Aim II, boys with KS demonstrated a higher mean body fat by Dual Energy Xray Aborptiometry (DEXA) compared to a healthy reference group and overall mean normal lumbar spine BMD. Four of the oldest boys demonstrated lower BMD than expected for age. Findings from this study suggest that in peri-pubertal boys with KS, phenotype may adversely influence quality of life especially with respect to school and physical function. The adverse psychosocial health of boys with KS may not be related to androgen deficiency. Biomarkers of cardiometabolic risk were most evident in pubertal boys. Testosterone does not appear to be a main mediating factor in cardiometabolic risk in this age group. KS boys may have increased fat as measured by DEXA and normal BMD. The onset of bone loss present in KS men may begin in late adolescence.

The implications from this study include recommendations that primary care providers and developmental specialists become more familiar with the clinical pattern of KS as represented by physical, hormonal as well as behavioral signs and symptoms. In primary care, it is recommended that complete genital examination including testicular volume measurement be conducted during well-child visits and that karyotype be ordered on boys who show a high index of suspicion for this diagnosis. A multidisciplinary team-approach for management KS-related symptoms needs to be created for each child and family affected by KS with integration of services between pediatrician, endocrinologist, developmental, psychological and school specialists. It is also recommended that boys with KS be referred for baseline bone mineral assessment during adolescence.