Growth in Classical Galactosemia

Many genetic metabolic diseases are often associated with growth abnormalities, usually an impaired growth. Most often postnatal growth is affected. Disease intrinsic factors and diet-related deficiencies are probably the main causes of affected growth. One of the diseases where mild growth abnormalities have been noticed is classic galactosemia. Classic galactosemia is a hereditary disorder of galactose metabolism, caused by deficiency of one of the enzymes of the Leloir pathway, the main pathway responsible for galactose metabolism in the human body. Despite early diagnosis and galactose restriction, complications such as ovarian dysfunction, cognitive impairment, neurological sequelae, and mild growth impairment occur. The pathogenesis of these complications is not completely understood. Main proposed mechanisms are metabolites-induced damage, aberrant glycosylation of complex molecules, and epigenetic changes. Review of the available data on growth in this disease reveals that prenatal growth does not seem impaired whereas during postnatal growth decreased height in childhood and early adolescence in both genders have been reported. Predicted final height is less than target height in many patients, but predicted height can be reached as children can grow beyond the age of 18 years. Risk growth factors in this disease might be hormonal and diet related. Ovarian dysfunction (hypergonadotropic hypogonadism) and suboptimal hormonal replacement therapy in girls and delayed puberty in boys are likely to play a role. Other disease-related factors such as aberrant glycosylation of IGF-1 complex components have been proposed but so far there are no investigations to support this hypothesis. Growth might also be influenced by the soy-based galactose-restricted diet. Also, an intriguing question that needs further study is whether we are simply witnessing the coexistence of constitutional delay in classical galactosemia. Prospective studies in a larger number of patients from different populations are necessary to define the typical phenotype of growth in this disease.