The mucopolysaccharidoses (MPS) comprise a heterogeneous family of rare, genetic lysosomal storage disorders that result in severe morbidity and reduced life expectancy. Emerging treatments for several of these disorders have triggered the search for clinically relevant biomarkers and clinical markers associated with treatment efficacy in populations and individuals. However, biomedical measures do not tell the whole story when characterizing a complex chronic disorder such as MPS. Health-related quality of life (HRQoL) tools that utilize patient reported outcomes to address patient parameters such as symptoms (pain, fatigue, psychological health), functioning (activity and limitations), or quality of life, have been used to supplement traditional biomedical endpoints. Many of these HRQoL tools have demonstrated that quality of life is negatively impacted in patients with MPS. There is both the opportunity and need to formally standardize and validate HRQoL tools for the different MPS disorders.

The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2-4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults.

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). 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. 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). 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 their older son. Therefore, both parents are heterozygous carriers for the ARSB gene mutation but also the GNS gene mutation. In the son with MPS VI, no mutation in the GNS gene was found, but the brother with MPS IIID was heterozygous for the ARSB gene mutation.We presume that the intrafamilial variability of clinical signs in different family members could be the result of various mutations in the ARSB/GNS genes in the carriers or potential modulating effects of other genes or differences in genetic backgrounds.

Background: The diagnostic process for children and adults manifesting a constellation of ectodermal abnormalities requires a conscientious and highly structured process. Material and Methods: Six girls (aged 6-month–8 years) and two older girls (aged 13 and 16 years) were born with variable skin lesions of varying intensities associated with noticeable cranial and skeletal malformation complexes. Cleft palate, abnormal dentition, and multiple papillomas were evident around the mouth, mostly bilateral but asymmetrical in the upper and lower limbs. Exaggerated frontal bossing (macrocephaly) and in some patients’ microcephaly with variable skeletal defects of the craniocervical junction and diverse forms of lower limb deformities of syndactyly, polydactyly, and split-hand/foot (ectrodactyly). Results: All patients manifested the constellation of abnormalities with variable intensities ranging between alopecia, papillomas, striated skin pigmentations split-hand/foot (ectrodactyly), and major bone defects. A 3D reconstruction CT scan was directed mainly to further scrutinize children with pseudo cleft lip, submucus cleft, and cleft palate. Interstingly, they manifested massive demineralization of the cranium associated with severely defective dentition. A spine 3D reconstruction CT scan in two girls showed marked cystic cavitation of the upper jaw associated with excessive cavitation of the mastoid, causing tremendous frailty of the mastoid bone. A 3D sagittal CT scan showed odontoid hypoplasia and C1-2 instability associated with the rudimentary atlas and the persistence of extensive synchondrosis of the cervico-thoracic spine. The overall clinical and radiological phenotypic characterizations were consistent with the diagnosis of focal dermal hypoplasia (Goltz syndrome). Two children manifested heterozygous mutations in the PORCN gene, chromosome Xp11. Conclusions: In this study, we believe it’s a good opportunity to share our novel scientific findings, which are intriguing and can be inspiring to readers, and to further aid the current scientific literature with exceptionally new unveiling results. This is the first comprehensive study of the cranio-skeletal malformation complex in children with GS.

Background: We describe patients who were recognized via conventional radiographs of the skull as manifesting wormian bones. Wormian bones are not a specific diagnostic entity and can be seen in variable forms of syndromic disorders. Materials and Methods: Seven children and three adults (of 10–28 years) were seen and diagnosed in our departments. The principal complaints for the pediatric and adult group were: ligamentous hyperlaxity, a history of delayed walking and occasional fractures, which later in life started to manifest a constellation of neurological symptoms such as nystagmus, persistent headache, and apnea. Conventional radiographs were the first traditional tools used to recognize wormian bones. We performed 3D reconstruction CT scans to further understand the precise etiology and the nature of these wormian bones and attempted to connect them with a broad spectrum of unpleasant clinical presentations. Our group of patients was consistent with the phenotypic and genotypic diagnoses of osteogenesis imperfecta type I and type IV as well as patients with multicentric carpotarsal osteolysis syndrome. Results: Three-dimensional reconstruction CT scan of the skulls confirmed that these worm-like phenotypes are in fact stemmed from the progressive softening of the sutures. The overall phenotype of the melted sutures is akin to overly stretched pastry. The most concerning sutures in this pathological process are the lambdoid. The overstretching of the lambdoid sutures was responsible for the development of sub-clinical basilar impression/invagination. Patients with certain forms of skeletal dysplasia such as osteogenesis imperfecta type I and IV manifested the heterozygous mutation of COL1A1/COLA2, shown as typical overstretching of the sutures. Similarly, patients with multicentric carpotarsal osteolysis syndrome with a heterozygous missense mutation of MAFB also manifested the phenotype of overly stretched pastry along the skull sutures. Conclusion: What we encountered via 3D reconstruction CT scan in our group of patients was entirely different than the traditional description that can be found in all relevant literature of the last decades. The worm-like phenomenon is in fact a pathological sequel occurring as a result of a progressive softening of the sutures, which results in the overstretching of the lambdoid sutures, a pathological process roughly similar to an overly stretched soft pastry. This softening is totally connected to the weight of the cerebrum (the occipital lobe of the cerebrum). The lambdoid sutures represent the weight-bearing zone of the skull. When these joints are loose and soft, they adversely alter the anatomical structures of the skull and lead to a highly hazardous derangement of the craniocervical junction. The latter causes the pathological upward invasion of the dens into the brain stem, leading to the development of morbid/mortal basilar impression/invagination.

Background: Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal form of skeletal dysplasia, characterized by abnormal craniofacial phenotype, short stature, and mesomelia of the upper and lower limbs. Methods: We describe two female patients with LWD. Their prime clinical complaints were severe bouts of migraine and antalgic gait. Results: Interestingly, via a 3D reconstruction CT scan we encountered several major anomalies. Notable features of craniosynostosis through premature fusion of the squamosal sutures and partial closure of the coronal sutures were the reason behind the development of abnormal craniofacial contour. A 3D reconstruction CT scan showed apparent bulging of the clavarium through the partially synostosed coronal and totally synostosed squamosal sutures. Additional deformities include deficient number of ribs (10 ribs on both sides), defective ossification of the ischium and dysplasia of the iliac-ischial junction, and coxa valga have been noted. Conclusions: The constellation of observed deformities can be considered as a novel features associated with LWD.