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.