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. 2016 Jun;53(6):403-18.
doi: 10.1136/jmedgenet-2015-103322. Epub 2016 Feb 23.

Clinical course of sly syndrome (mucopolysaccharidosis type VII)

Adriana M Montaño  1 , Ngu Lock-Hock  2 , Robert D Steiner  3 , Brett H Graham  4 , Marina Szlago  5 , Robert Greenstein  6 , Mercedes Pineda  7 , Antonio Gonzalez-Meneses  8 , Mahmut Çoker  9 , Dennis Bartholomew  10 , Mark S Sands  11 , Raymond Wang  12 , Roberto Giugliani  13 , Alfons Macaya  14 , Gregory Pastores  15 , Anastasia K Ketko  16 , Fatih Ezgü  17 , Akemi Tanaka  18 , Laila Arash  19 , Michael Beck  19 , Rena E Falk  20 , Kaustuv Bhattacharya  21 , José Franco  22 , Klane K White  23 , Grant A Mitchell  24 , Loreta Cimbalistiene  25 , Max Holtz  26 , William S Sly  27
Affiliations

Clinical course of sly syndrome (mucopolysaccharidosis type VII)

Adriana M Montaño et al. J Med Genet. 2016 Jun.

Abstract

Background: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data.

Methods: We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease.

Results: We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS.

Conclusions: MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy.

Keywords: Clinical genetics; Genetics; Metabolic disorders.

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Figures

Figure 1
Figure 1
Serial pictures of a male patient who survived a stormy early course, beginning with neonatal hydrops and subsequently progressed more slowly with cognitive impairment, hepatosplenomegaly, obstructive airway disease, heart valve abnormalities and dysostosis multiplex including progressive hip dysplasia. This patient died undergoing anaesthesia from a dental procedure at age 12 years, which is a complication from which these patients often suffer. (A) 2.5 months old, (B) 6 months old, (C) 1 year old, (D) 3 years old, (E) 5 years old, (F) 6 years old, (G) 7 years old, (H) 8 years old, (I) 9 years old and (J) 11 years old. Photographs of the deceased patient were obtained and approved for publication with maternal consent. X-rays are shown below in the section clinical course of the disease (figures 12 and 13).
Figure 2
Figure 2
Clinical symptoms found in (A) head and neck, (B) eyes, and (C) ear, nose and throat of patients with mucopolysaccharidosis VII (MPS VII) disease.
Figure 3
Figure 3
Clinical symptoms related to lungs and heart.
Figure 4
Figure 4
Musculoskeletal signs and symptoms in patients with mucopolysaccharidosis VII (MPS VII).
Figure 5
Figure 5
Thoracolumbar abnormalities in patients with mucopolysaccharidosis VII (MPS VII).
Figure 6
Figure 6
Major neurological features of patients with mucopolysaccharidosis VII (MPS VII).
Figure 7
Figure 7
(A) Length for age in boys (0–36 months) affected with mucopolysaccharidosis VII (MPS VII). (B) Stature for age in boys (2–18 years) affected with MPS VII. Data are compared with normal growth charts from the CDC.
Figure 8
Figure 8
(A) Length for age in girls (0–36 months) affected with mucopolysaccharidosis VII (MPS VII). (B) Stature for age in girls (2–18 years) affected with MPS VII. Data are compared with normal growth charts from the CDC.
Figure 9
Figure 9
Comparison of birth weight of patients with mucopolysaccharidosis VII (MPS VII).
Figure 10
Figure 10
(A) Weight for age in boys (0–36 months) affected with mucopolysaccharidosis VII (MPS VII). (B) Weight for age in boys (2–18 years) affected with MPS VII. Data are compared with normal growth charts from the CDC.
Figure 11
Figure 11
(A) Weight for age in girls (0–36 months) affected with mucopolysaccharidosis VII (MPS VII). (B) Weight for age in girls (2–18 years) affected with MPS VII. Data are compared with normal growth charts from the CDC.
Figure 12
Figure 12
Spine films in a patient with mucopolysaccharidosis VII (MPS VII) demonstrate findings common to all forms of MPS at age 7 years (A and B) and age 8 years (C and D). Anteroposterior views (A and C) reveal mild scoliosis (arrow) and broad ribs. The lateral films (B and D) demonstrate irregular anterior vertebral body growth, particularly at the L2 level (arrow).
Figure 13
Figure 13
Progressive hip dysplasia is seen in this patient with mucopolysaccharidosis VII (MPS VII). At age 7 years (A), the right hip shows subluxation with poor coverage, while the left hip is already dislocated and sits in a pseudoacetabulum (arrow). By age 8 years (C), an acetabular shelf procedure has been performed and by age 10 years (E), has not prevented further subluxation and femoral head erosion (arrow).
Figure 14
Figure 14
Distribution of surgical operations performed on patients with mucopolysaccharidosis VII (MPS VII) (n=21, 45.6% of total number of patients).
Figure 15
Figure 15
Distribution of causes of death by age. Causes included: Prenatal to 1 year, (50%) complications of hydrops fetalis, respiratory failure and renal failure; ages 1–5 years (5%), obstructive airway disease; ages 5–10 years (15%), heart disease, complications of bone marrow transplantation (BMT) and pulmonary failure; ages 10–15 (5%), decreased pulmonary function; and over 15 years of age, heart disease, pulmonary failure and/or obstructive airway disease, and aspiration/heart attack.
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