Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur.
Mucopolysaccharidosis type VI (MPS VI) (Maroteaux–Lamy syndrome; Online Mendelian Inheritance in Man: 253200) is an autosomal recessive disease caused by deleterious variants in arylsulfatase B (ARSB), causing deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB, Enzyme Commission number 184.108.40.206), a lysosomal enzyme that degrades glycosaminoglycan dermatan sulfate (DS).1 Affected individuals are cognitively normal. The disorder is clinically heterogeneous. Most patients present early with a severe or rapidly advancing form characterized by early onset of coarse facial features, corneal clouding, macrocephaly, hepatosplenomegaly, hernias, joint restriction, cervical spine compression, and respiratory failure. Patients with attenuated or slowly progressive MPS VI may present with short stature, carpal tunnel syndrome, and hip dysplasia. Facial dysmorphisms are mild or absent, although corneal clouding is typical.2 The prevalence of MPS VI ranges from 0.05 cases in 100 000 live births in Scandinavian countries3 to 25 in 100 000 live births in Northeastern Brazil.4 A definitive diagnosis may be delayed because of subtle symptoms, absence of coarse facial features, and lack of knowledge.5 We discuss the process and barriers encountered during the diagnosis of MPS VI in 4 individuals from 3 families with attenuated MPS VI.
Patients were enrolled from centers in Brazil (Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul) and the United States (Mayo Clinic, Rochester, MN). Clinical data were extracted from the electronic medical records. All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients (or their parents) included in the study. The study was approved by the Institutional Review Board of the Mayo Clinic.
A summary of the patients’ clinical and demographic information is in Table 1.
The patient is a 19-year-old woman born to nonconsanguineous parents. Her developmental milestones were normal, and she has an unrevealing family history. At age 3 years, she was referred to orthopedics for gait disturbance and was diagnosed with hip dysplasia and bilateral femoral head avascular necrosis (Fig 1A). Spinal radiographs revealed scoliosis, and MRI detected bilateral hip dysplasia. At age 10 years (Fig 2), she was referred to genetics when mucopolysaccharidosis screening revealed positive results with elevated glycosaminoglycan excretion (122 μg/mg per mmol creatinine; normal range: 26–97). Subsequently, ARSB activity was found to be deficient (13 μmol per hour per mg protein; normal range: 72–176), and genetic analysis of ARSB was used to detect compound heterozygosity for the NM_000046.4(ARSB):c.311A>C, p.Gln104Pro and NM_000046.4(ARSB):c.438G>A, p.Trp146* variants confirming MPS VI. Noteworthy, a second sulfatase was tested to exclude multiple sulfatase deficiency. Follow-up studies revealed mild aortic stenosis, a median nerve lesion, dysostosis multiplex (Fig 1B), and peripheral corneal opacities. Respiratory parameters were normal. From the time of diagnosis, she was managed regularly with clinical assessments and biochemical tests, but enzyme replacement therapy (ERT) was not initiated. At age 15 years, echocardiogram revealed mitral and aortic valve thickening. Left ventricular dysfunction was detected. Spirometry and abdominal ultrasound were normal. Cervical MRI revealed narrowing of the cervical canal but no spinal compression. Ophthalmologic evaluation was used to detect mild corneal opacities. She developed pain in the hips and fatigue. Because of worsening symptoms, ERT was prescribed, and after 4 years of treatment, the cardiac findings are stable; the 6-minute walk test, spirometry, and laboratory examinations are normal; and her joint mobility and endurance significantly improved.
The patient is a 12-year-old girl (Fig 3), born to nonconsanguineous parents, who was referred to Medical Genetics Service for evaluation of progressive joint pain; contractures of the metacarpophalangeal, proximal, and distal joints; radial deviation of the wrists; and corneal clouding since the age of 5 years. She had an unremarkable early childhood. She underwent urine mucopolysaccharidosis screening at the age of 7, which was normal. Given the concern for a lysosomal disorder, another mucopolysaccharidosis screen was requested, which revealed a mild elevation of glycosaminoglycan (11.1 mg/mmol creatinine; normal: <10) and mildly elevated DS in her urine. Further evaluation revealed that she had stable thickening of the mitral valve and 2 papillary muscles and mild mitral stenosis. She had significant pain in her wrists, knees, and ankles, and a history of decreased flexibility in all joints. Radiographs revealed thickened ribs, several shorted vertebrae, and hip dysplasia (Fig 4). Whole-exome sequencing (WES) was used to identify 1 paternally inherited variant of uncertain significance in ARSB (NM_000046.4(ARSB):c.928A>G, p.Asn310Asp). No other variants of interest were reported, but after careful reevaluation of the WES data, a maternally inherited variant of uncertain significance was found (NM_000046.4(ARSB):c.310C>A, p.Gln104Lys). Given high suspicion of a lysosomal disorder and compound heterozygous variants in ARSB, analysis of ARSB activity via lysosomal enzyme panel was completed. Initially, enzyme testing was reported as normal because of an issue with buffers used in the enzymatic analysis. Repeat enzymatic testing revealed total absence of ARSB activity, confirming MPS VI. ERT was prescribed and is ongoing.6
Patients C and D
Patients C and D are first cousins (Fig 5) who had presenting symptoms thought to be secondary to Morquio disease (mucopolysaccharidosis type IV), which was initially diagnosed after biochemical testing and bone biopsy at 5 years of age. Patient C is a 37-year-old man with short stature, progressive joint stiffness and pain, corneal clouding, dysostosis multiplex (Fig 6), decreased pulmonary function, heart valve thickening, and mildly coarse features. There was minimal organomegaly. Patient D is a 42-year-old man (Fig 7A) with similar symptoms to his cousin’s, although he has a history of severe mitral stenosis that was repaired when he was 37 years old and required hip replacement (Fig 7B) in the same year. The patients were evaluated by a geneticist who ordered a panel of mucopolysaccharidosis enzymes for patient C, which revealed decreased activity of ARSB (2.78 μmol per hour per mg protein; normal range: 8.1–38). Unfortunately, because of insurance issues, we were not able to perform genetic analysis for this family. Currently, they are in the process of initiating therapy with the proper recombinant enzyme.
Individuals with rapidly advancing MPS VI are diagnosed earlier than the individuals with slowly progressive disease because of the severity of symptoms, including facial dysmorphisms, short stature, bone changes, and pulmonary restriction. The clinical presentation of MPS VI is variable, and the attenuated form can present with a wide range of subtler symptoms that may remain unreported or undiagnosed for many years, especially if the clinician is not familiar with the disease. There are a few case reports and series of patients with the attenuated form of MPS VI in which authors focus on describing the clinical features of the patients.7,–10 Our aim of the current study is to provide insights into recognizing this disorder and the pitfalls to achieving the correct diagnosis.
Patient A struggled with gait disturbance because of hip dysplasia since childhood. She was evaluated by health providers and subspecialists who failed to diagnose her. After 7 years of symptoms, she was referred to a metabolic geneticist who ordered diagnostic tests for a possible storage disorder, including urine glycosaminoglycan excretion, quantitative assessment of DS, heparan sulfate, and keratan sulfate. Echocardiogram, pulmonary function testing, eye examination, and skeletal survey were helpful to detect comorbidities related to MPS VI and aided in the diagnosis and subsequent treatment. This case exemplified what is an adequate diagnostic workup for a patient with mucopolysaccharidosis. First, on the basis of the clinical phenotype, the clinician requested biochemical testing, including the analysis of a second sulfatase, and then the genetic analysis for confirmation of the disease.
For Patient B, her first symptom was corneal clouding, and her health providers considered a lysosomal disorder in the differential. However, because of an initially normal urinary mucopolysaccharidosis screen, she was thought to have a skeletal dysplasia and had been managed for 7 years without other metabolic investigations. Her joint pain and corneal clouding worsened, and she was referred to a biochemical geneticist who ordered a second urinary mucopolysaccharidosis screening, which revealed a mild glycosaminoglycan elevation. WES was used to detect a single variant in ARSB. However, after further review, a second variant was found. WES technology has limitations to detect variants in guanine-cytosine-enriched regions, mitochondria, deep intronic regions, and large structural variants. After biallelic mutations in ARSB were found, enzymatic activity analysis was repeated and revealed deficiency. Previous normal biochemical results were caused by an issue with buffers used in the assay, and when the problem was resolved, ARSB deficiency was confirmed. This case is important because it reveals that biochemical testing must be performed in reference centers with expertise in investigation of mucopolysaccharidosis. Also, because of physicians’ lack of awareness about individuals with MPS VI and normal-to-borderline excretion of glycosaminoglycan, the diagnostic workup followed a nonrational approach starting with WES and then using enzyme activity as a functional validation of the genetic findings.
Patients C and D had been diagnosed as having Morquio disease for >3 decades on the basis of significant skeletal dysplasia. Unfortunately, we did not have access to the previous testing performed that led to the erroneous diagnosis. In 2014, the US Food and Drug Administration and the European Medicines Agency approved a recombinant human enzyme as conventional ERT for patients with Morquio A (Vimizim [elosulfase alfa]; BioMarin Pharmaceutical Inc, Novato, CA). The patients were therefore referred for genetic evaluation and drug prescription. The geneticist sent specific enzymatic testing, attaining the diagnosis of MPS VI allowing for appropriate counseling and management.
There are pitfalls in the diagnosis of patients with the attenuated form of MPS VI. Providers should be aware of the signs and symptoms of MPS VI, including corneal clouding, short stature, and joint pain with joint restriction without inflammation. If findings of MPS VI are present, screening with urine glycosaminoglycans should be the first step, followed by enzymatic analysis of ARSB. Furthermore, when ARSB deficiency is detected, it should promptly be followed by the analysis of a second sulfatase to rule out multiple sulfatase deficiency, a disease without specific treatment at this moment. The provider should analyze clinical, imaging, biochemical, and genetic data in combination and must be aware that errors can happen in any step of the diagnostic process.
The most common presenting symptom in our series was bone abnormalities and pain. After follow-up studies, all patients had potentially life-threatening cardiac changes. On the basis of our cohort and others, increased awareness of attenuated MPS VI is needed. All providers need to be able to recognize signs and symptoms of MPS VI so that a diagnosis and treatment can be instituted. ERT has been shown to improve endurance, bone disease, growth pattern, and pulmonary function in patients with MPS VI.11 All of our patients had joint stiffness, bone changes, and pain in childhood, and because of delayed diagnosis and treatment, prognosis was likely worsened. There is evidence used to suggest that treating young patients with ERT prevents morbidities associated with disease.12
Dr Pinto e Vairo, Dr Conboy, and Dr Lanpher conceptualized and designed the case study, reviewed and collected patient data, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Barnett and Dr Klee conceptualized and designed the case study, conducted the initial and reevaluation of the whole-exome data, and reviewed and revised the manuscript; Dr de Souza and Dr Jones conceptualized and designed the case study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: Supported by the Mayo Clinic Center for Individualized Medicine, the Investigative and Functional Genomics Program, and the William O. Lund, Jr, and Natalie C. Lund Charitable Foundation.
We thank the patients and their families for participating in this study.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.