Foot Catch-Up Growth in Prader–Willi Syndrome: A Model for Foot Growth Regulation in Normal Children

Abstract

This chapter proposes a new concept of foot growth regulation in addition to known endocrine and genetic factors. The Prader–Willi syndrome (PWS) is a genetically defined complex neurodevelopmental disorder characterized by short stature with small hands and feet, severe hypoactivity, progressive obesity, and endocrine disorders such as growth hormone deficiency. In PWS children as opposed to height, foot catch-up growth on growth hormone therapy is delayed and incomplete, contrasting to symmetric and complete catch-up growth observed in children with growth hormone deficiency, growth hormone insensitivity, and born small for gestational age. In hemiplegic and paraplegic children inactive legs are shorter than active legs. We therefore explored the hypothesis that in PWS children the relative reduction in foot length (FL) compared to height may be caused by reduced musculoskeletal loading reflecting severely reduced physical activity. In 37 PWS children we correlated foot length before and after 6 years of growth hormone therapy with parental and sibling’s FL, height and factors reflecting musculoskeletal loading such as weight for height (WfH), lean body mass (LBM), physical activity, and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, children were divided into age groups younger and older than 2.5 years. PWS children normalized height but not FL after 6 years of GHT. Parental FL correlation with PWS’s FL was lower than with sibling’s FL. In children older than 2.5 years FL positively correlated with WfH, LBM, and physical activity. In children younger than 2.5 years FL negatively correlated with age at onset of free walking. Foot catch-up growth on growth hormone therapy was slower in the younger compared to older children. We conclude that in PWS FL is positively associated with musculoskeletal loading. Small feet in PWS children before and during long-term growth hormone therapy may be more than just another dysmorphic feature, but possibly reflect decreased musculoskeletal loading influencing foot growth together with genetic and endocrine factors. Comparable to the “muscle-bone unit” explaining interdependency between bone remodeling and muscle strength, musculoskeletal loading impacts on foot growth, explaining about 25–50% of total variance of age-corrected FL. If our findings in PWS can be expanded to healthy children, the progressive reduction of physical activity observed over the last decades in healthy children may have consequences for FL of future generations.