Introduction
Skeletal dysplasias are a heterogeneous group of inherited disorders of mostly monogenic etiology. They affect skeletal development and lead to variable skeletal anomalies, often with short stature.(Krakow, 2015; Mortier et al., 2019) Some forms are associated with a spectrum of metabolic disturbances and extra-skeletal manifestations in the context of complex syndromes. The manifestations can include, but are not limited to hepatosplenomegaly, cardiomyopathy and pulmonary dysfunction.(Longo et al., 2013; Saenger, Czernichow, Hughes, & Reiter, 2007) Many of the metabolic disturbances observed in this group of disorders arise from perturbations of pathways involving modifications of proteins and lipids.(Sparks & Krasnewich, 2017) These modifications are important for stability or function of molecules including proteins which function in several tissues including cartilage and bone.(Stanley, 2011) For example, many skeletal disorders with prominent extra-skeletal manifestations involve defects in glycosylation.(Coman, Irving, Kannu, Jaeken, & Savarirayan, 2008; Kranz et al., 2007)
Several metabolic disorders with severe skeletal consequences have been identified and delineated. These include lysosomal storage disorders, mucopolysaccharidosis (OMIM#309900, OMIM#253200, OMIM#25300), mucolipidosis (OMIM#252600, OMIM#252605), and congenital disorders of glycosylation (OMIM#212065), among others. These disorders can be inherited in an autosomal recessive, autosomal dominant, X-linked recessive or X-linked dominant manner. The multisystemic defect due to error in metabolism in these and most other related disorders is progressive and severity of the disorder increases with age. Cognition and hearing ability can also be affected. In extreme cases, multi-organ failure and early death can occur.(Ballabio & Gieselmann, 2009; Eklund & Freeze, 2006) Although the molecular bases of many skeletal disorders are known, a significant number of others remain to be elucidated.
In this study, we explored the genetics of severe skeletal dysplasia in individuals from Pakistan and Iran. Patients in both families had features similar to mucopolysaccharidosis.