Disorders of post-squalene cholesterol biosynthesis leading to human dysmorphogenesis

Insights in molecular developmental biology in animals and humans are facilitating the understanding of pathophysiologic mechanisms in dysmorphogenesis or abnormalities in normal embryologic structural development. A milestone was recognition of the role of shh in morphogenesis of craniofacial structures, especially the development of holoprosencephaly. The dependence of hedgehog morphogens on cholesterol modification for normal hedgehog signaling function has particular relevance to disorders of cholesterol synthesis which manifest dysmorphogenesis. Four human disorders of morphogenesis (Smith-Lemli-Opitz syndrome, desmosterolosis, X-linked chondrodysplasia punctata, CHILD syndrome) have recently been shown to be caused by sterol abnormalities resulting from cholesterol biosynthesis enzyme deficiencies. This review summarizes the clinical, biochemical and molecular data in these disorders with an emphasis on understanding the pathophysiology of dysmorphogenesis.