Bone Mineral Density in Prader Willi Syndrome: A Search for Genetic Markers

Abstract

decreased BMD and bone mineral content (BMC) in PWS. Recently it has been shown that PW Snord 116 knockout mice show reduced bone formation indicating a possible link between the PW critical region and osteoporosis [10]. Since bone density and mineral content are highly variable among PWS individuals, other factors may contribute to the development of osteopenia and/or osteoporosis. Identifying risk factors for developing osteopenia or osteoporosis may allow early intervention prior to severe bone loss. The purpose of our study was to investigate polymorphisms of candidate genes previously shown to correlate with osteoporosis and/or bone disease and determine if similar associations are present in a PWS population. Materials and MethodsDNA samples were collected from 96 of 103 individuals above the age of 3 years with PWS followed at the Israeli national multidisciplinary PWS clinic at Shaare Zedek Medical Center, Jerusalem, Israel. There were Keywords: Prader-Willi syndrome; Osteoporosis; Osteopenia; Genetic markers of osteoporosis; Bone mineral density; DXA IntroductionPrader-Willi syndrome (PWS) is a complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The estimated prevalence is 1/10,000-1/30,000 [1]. Infants with PWS suffer from severe hypotonia, feeding difficulties, and failure to thrive (FTT) followed in later infancy or early childhood by excessive appetite with gradual development of obesity, short stature, hypogonadism, intellectual disabilities and behavioral problems [2].There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion in 65-75%, maternal uniparental disomy (UPD) in 20-30% and imprinting center defect in 1-3% of all cases [3,4]. PWS is the most common syndromic cause of life-threatening obesity and the first recognized disorder related to genomic imprinting. Muscle mass is decreased by 25-37%, which might partly explain the hypotonia [5]. Diabetes and scoliosis are common features of PWS [6]. Hypothalamic dysfunction has been implicated in many manifestations of this syndrome including hyperphagia, high pain threshold, sleepdisordered breathing, and multiple endocrine abnormalities including hypogonadism [7,8]. The etiology of hypogonadism in PWS (primary gonadal or hypothalamic) is heterogeneous [5].Increased fat mass and decreased lean body mass are characteristics of PWS. Several studies have demonstrated that individuals with PWS have lower bone mineral density (BMD) compared to normal controls [9]. Hypotonia, hypogonadism, growth hormone deficiency, and limited mineral and vitamin intake due to diet restrictions may contribute to the Abstract Introduction: Prader-Willi syndrome (PWS (is caused by lack of paternally expressed imprinted genes at chromosome 15q11.2-q13. Diminished (BMD) and osteoporosis are common in PWS. The purpose of this study was to determine whether polymorphisms in genes previously shown to correlate with bone mineral density (BMD), might explain the variable expression of abnormal...