The aim of this project was to determine the genetic basis of two interesting syndromes, segregating in large pedigrees. These syndromes presented with interesting features including some ENT problems that formed part of the presenting phenotype. Better understanding of the molecular basis of these conditions might explain the pleiotropic effects of mutation in a single gene on various tissues in the body. The specific conditions being studied were (a) Pachydermoperiostosis (Primary Hypertrophic Osteoarthropathy, PHO) and (b) a novel syndrome with mental retardation, epilepsy, spastic paraplegia, sensorineural hearing loss and early onset obesity. 2.1 Pachydermoperiostosis (Primary Hypertrophic Osteoarthropathy) Introduction: Affected individuals belonging to consanguineous families with PHO came to my attention because of features such as thickening of facial and scalp skin leading to aesthetic facial deformities. Another phenotype in these families was digital clubbing, an ancient clinical sign, the aetiopathogenesis of which has been much debated but still remained unexplained at the molecular level. The aim of this project was to identify the PHO gene(s). Methods: Autozygosity mapping was used to identify the PHO gene. Results: The PHO gene was localized to chromosome 4q33-q34 and three novel biallelic inactivating mutations were identified in HPGD, encoding the enzyme 15-hydroxyprostaglandin dehydrogenase. In two families segregating the HPGD mutations in a pseudo-dominant manner, affected patients were found to have marked clubbing and markedly elevated levels of urinary PGE2, while heterozygous patients with mild or no clubbing had a more varied and moderate elevation in the level of urinary PGE2. Conclusions: The fact that PHO results from persistently raised levels of PGE2 secondary to deficiency of 15-hydroxyprostaglandin dehydrogenase suggests that hypertrophic osteoarthropathy secondary to other pathologies may also be mediated by altered prostaglandin metabolism. Mutation testing of HPGD and measurement of urinary PGE2 levels may avoid morbidity from invasive searches for occult pathology in patients presenting with idiopathic clubbing.