The constellation of skeletal deformities in a family with mixed types of mucopolysaccharidoses

Abstract

Introduction:A 13-year-old child was clinically diagnosed with mucopolysaccharidosis type VI—Maroteaux–Lamy syndrome (MPS VI) at the age of 5 years, and the diagnosis was confirmed biochemically and genetically (homozygous mutation in ARSB gene). At that time, his older brother manifested with increasing severe mental retardation. His urinary glycosaminoglycan excretion in urine was elevated, but there was only 1 mutation in the ARSB gene defining him as a healthy carrier of MPS VI. The 15-year-old boy was born with dysmorphic facial features, cleft lip and palate, and multiple contractures associated with profound skeletal deformities manifested, severe mental retardation, and seizures, leading to the diagnosis of cerebral palsy from birth on.Clinical and radiographic phenotypic characterization was the baseline tool to document the older sibling, parents, and relatives, all of them examined at the Orthopaedic Hospital of Speising, Vienna, Austria. The family history (from maternal and paternal sides) showed >10 subjects with variable clinical histories of hyperactivity and attention deficit disorder, depression, and a diversity of skeletal abnormalities, such as dysplastic spondylolisthesis, discovertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age).Methods:Eleven patients in a family with interrelated marriages (two male siblings of 15 and 13-year-old), parents and relatives over three generations were enrolled. One of the siblings was diagnosed with Maroteaux-Lamy syndrome at the age of five-years and mutation of the ARBS gene has been encountered. The older sibling manifested at birth craniofacial abnormalities associated with multiple contracture and seizures. Cerebral palsy was the suggested diagnosis. Clinical and radiographic phenotypes were the baseline tool to document the older sibling, parents and relatives at the orthopaedic Hospital of Speising, Vienna, Austria. These were followed by whole Exome sequencing in three family subjects.Results:A series of genetic studies in the older sibling showed homozygous mutation in GNS gene compatible with MPS IIID. Both parents are first related and were found to be heterozygous for N-acetylglucosamine-6-sulfatase GNS gene. Family history showed more than 10 subjects with variable clinical presentations such as dysplastic spondylolisthesis, disco-vertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age).Conclusion:Owing to the multiple systemic involvements, a genetic cause was suspected and a molecular genetic investigation by using whole-exome-sequencing method in 3 family subjects (trios) was performed: the 15-year-old boy and his parents. A homozygous splice-site-mutation in the GNS gene could be found, compatible with mucopolysaccharidosis–Sanfillipo syndrome (type IIID). Both parents are first related and were now found also to be heterozygous for the GNS gene mutation found in the...

Epidemiology of Mucopolysaccharidoses Update

“…The splice site mutation, c.1098+1G>A, was found in the GNS gene in the parent and their child. The constellation of the clinical malformation and skeletal abnormalities were inconsistent with previously reported in MPS IIID patients [ 106 ]. An in vitro study was performed to detect the mutation spectrum of the GNS gene, the ramifications of which found a homozygous nonsense mutation R355X (1063C→T) [ 107 ].…”

Precision Medicine for Lysosomal Disorders

“…Meanwhile, MPS IV-, MPS VI-, or pycnodysostosis-associated genes could be included in a general skeletal dysplasia panel [18]. Whole-exomesequencing (WES) is a standard diagnosisprocedureinmanyplacesandlikewiseisusedtofindnovelgenesassociatedwithrareconditions, such as the newly discovered MPStype (mucopolysaccharidosis-plussyndrome, MPSPS) [20,21], expanding the recognized phenotypic spectrum of known LDs [22,23] and elucidating complex phenotypes [24]. Moreover, several LDs remain undiagnosed after extensive genetic and biochemical investigations due to a wide phenotypic spectrum of nonspecific manifestations or lack of available clinical tests, so WES may be used to identify undiagnosed patients [25].…”