ABSTRACT
The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
Subject(s)
Intellectual Disability/genetics , Musculoskeletal Abnormalities/genetics , Osteochondrodysplasias/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Association Studies , Humans , Infant , Infant, Newborn , Intellectual Disability/diagnosis , Intellectual Disability/diagnostic imaging , Intellectual Disability/physiopathology , Male , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/diagnostic imaging , Musculoskeletal Abnormalities/physiopathology , Osteochondrodysplasias/diagnosis , Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/physiopathology , Radiography , Exome SequencingABSTRACT
A 25-year-old female was referred for short stature and joint deformities. Except for previous corneal transplantation, her medical history was unremarkable. Initial physical examination revealed the presence of a coarse facies, short neck, kyphosis, restricted joint movements and deformities, and cardiac murmur besides a normal intellect. Urine glycosaminoglycan levels were high, and blood enzyme assay indicated significantly low alpha-L-iduronidase levels. Mucopolysaccharidosis I (MPS I) was diagnosed and prompted the onset of enzyme replacement therapy (ERT), which significantly improved articular complaints, while cardiac pathology remained stable. At the eighteenth month of ERT, sudden vision loss developed. She spontaneously recovered her vision in a month. MPS I is a progressive disease, in which tissue accummulation of heparan and dermatan sulphate result from defective activity or lack of alpha-L-iduronidase. ERT in MPS I usually presents favourable outcomes or at least stabilization of symptoms. This present case qualifies as the first report ofa MPS I patient developing sudden vision loss under ERT. We suggest that further research studies are warranted for defining the efficiency and possible limitations of ERT.
