This was a cross-sectional study of 34 pediatric patients with MPS who attended the neurometabolic clinic at Cairo University Children Hospital, from January 2013 to June 2014. The study was approved by the Institutional Ethics Committee. The study was performed according to the principles of the Declaration of Helsinki (2008). Informed consent was obtained from all the parents. The mean age ±standard deviation of the participants was 5.7 ± 3.77 years and number of male patients was 23. The measurement of enzyme activities was done to confirm different types of MPS. Enzymatic assays were carried out according to the methods described by Kresse et al., [15].

All patients were subjected to thorough medical history assessments that included family history and a three-generation pedigree analysis of parental consanguinity and any similarly affected family members. Full clinical examination was done to detect features of MPS disorders.

Skeletal survey was conducted for all cases to detect evidence of skeletal abnormalities [Table/Fig-1a,b]. Quantitative and electrophoretic analysis of urinary (GAGs) as well as enzymatic analysis for types of MPS was done to measure the activities of α-L-iduronidase, iduronate-2-sulfatase, α-N-acetylglucosaminidase, galactosamine-6-sulfatase, arylsulfatase B in the White Blood Cells [Table/Fig-2].

[Table/Fig-1]:

(a) Skeletal survey of a five-year-old girl with type VI. Enlarged cranium-J shaped sella turcica-enlarged heart-wide ribs-dorsolumber gibbus at D12/L1-anterior breaking of vertebral bodies. (b) The same patient’s hand- wide metacarpal, proximal and middle phalanges-pointed proximal ends of the second to fifth phalanges.

Electrocardiogram (ECG) was performed for all cases in the supine, left lateral position using General Electric (GE, Vivid-5) system with probe 3 or 5 MHz (multi-frequency transducer) according to the age of patient, having tissue velocity imaging capabilities. The electrocardiography was connected to time the cardiac cycle events. The examination consisted of M-mode, two-dimensional, pulsed-wave and colour Doppler blood flow velocity assessments of the cardiac valves.

Other investigations, such as Magnetic Resonance Imaging (MRI) of brain and spine was done. Auditory brain stem evoked potential was obtained from those MPS patients with hearing problems (otitis media) and median nerve conduction velocity was done to diagnose cases of carpal tunnel syndrome.

Statistical Package for Social Science (SPSS) program version 17 was used for data analysis. Data was described in terms of mean ± standard deviation (±SD), or frequencies (number of cases) and percentages when appropriate.

The study was conducted on 34 patients, aged 0.9–16 years; the mean age (±standard deviation) of the participants was 5.7 ± 3.77 years, with 23 male and 11 female. There were 19 cases of MPS I (55.9%), 3 cases of MPS II (8.8%), 2 cases of MPS III (5.9%), 6 cases of MPS IV (17.6%) and 4 cases of MPS VI (11.8%). A total of 13 (38%) patients have positive family history of similar condition. Coarse facial features were present in all cases of Hunter and Sanfilippo Syndrome and were the most common finding in Hurler cases (70%). Corneal clouding was seen in Hurler and Hunter patients while absent in Sanfilippo, Morquio and Maroteaux-Lamy patients. Heart Murmur was heard in nine (9/34) cases (26%), with higher prevalence in Maroteaux-Lamy patients (50%). Hyperactivity was apparent in Sanfilippo cases. Median nerve conduction velocity showed bilateral median nerve neuropathy of axonal nature, in 6 patients (17.6%). It ranges between moderate to severe degrees. The findings of clinical characteristics are represented in [Table/Fig-3].

ECG was performed in all patients. Cardiac abnormalities were detected in 15 patients (44%) such as mitral valve lesions, pulmonary hypertension, concentric left ventricle hypertrophy/dilatation, tricuspid regurge and/or aortic regurge. Mitral regurge (47%) followed by pulmonary hypertension (40%) were the most common findings among MPS patients [Table/Fig-4]. We encountered 3 patients with MPS I in whom the predominating heart problems were infiltration of the valvular cusps, ventricular hypertrophy and/or dilatation leading to mitral valve insufficiency and pulmonary hypertension. Cardiac lesions in various types of MPS are shown in [Table/Fig-5]. ECG showed ST segment depression-abnormality and negative T-wave, in cases of concentric Left ventricle hypertrophy.

[Table/Fig-4]:

Echocardiographic findings in MPS Patients.

TR; Tricuspid Regurge, MR; Mitral Regurge, AR; Aortic regurge

One patient with Hunter disease died at the age of 10 years. His echo showed mitral regurge and dilated left ventricle. His death was thought to be related to the cardiac abnormalities.

MRI of brain and spine, were available in 31 cases [Table/Fig-6]. Out of 31, 24 cases (77%) have abnormal findings. Demyelination, incomplete myelination and dysmyelination are described in 11/31 patients (35%). Abnormal dorsolumbar vertebra was described in 2(6%) cases, while four patients (13%) had venticulomegaly; one of whom had ventriculoperitoneal shunt operation.

Cardiac abnormalities have been observed in patients with MPS of any types. However, an early diagnosis is difficult due to joint stiffness, respiratory system involvement or skeletal malformations that limit exercise capacity and mask the underlining heart failure [16]. The most frequent MPS type in Egyptian children was type I (56%). The anatomical changes of cardiovascular systems were common in all types of MPS patients. In another study, among Taiwanese children, the most common type was type II (43%) [17]. In this study, the heart murmur was heard in 26% of our patients with MPS. Mitral regurgitation was the most common echo finding. Rigante and Signi found clinical evidence in most cases that have moderate-to-severe somatic disease [9]. Thickening of the valve leaflets, commonly leads to mitral and aortic regurgitation rather than stenosis [3].

It has been suggested that, cardiomyopathy and valve defects occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries [5]. Histologically, cytoplasmic vacuolation may be observed in cells of mitral valves, in coronary arteries and in the aorta; electron-microscopically, the same cardiomyocytes may appear enlarged or packed with electron-lucent cytoplasmic vacuoles, which are stored undegraded GAGs [17]. The deformed valves showed mitral or aortic leaflets thickening and calcification, and may lead to various severities of stenosis or regurgitation. Pulmonary hypertension is the second echo finding in our patients. There was a strong association between the accumulation of dermatan sulphate and the presence of valvular dysfunction, and pulmonary hypertension [18]. Rheumatic mitral valve was diagnosed in one patient however, these findings could be attributed to infiltration of polysaccharides or mucosubstances instead of rheumatic involvement [10]. Moreover, multi-system disease involving the dermatological, musculoskeletal, cardiac and gastrointestinal system could suggest storage disease [19]. Cardiovascular abnormalities among patients with MPS III were rare and less severe than among other groups [20]. Similar to our study, one of those has mild tricuspid regurge.

Valvular deformation and thickening, thick interventricular septum and diastolic dysfunction were found to worsen with age [17]. Insofar, ECG and Echo should be done regularly during follow-up of MPS patients [21]. Valvular lesions causing valvular stenosis or insufficiency are an indication for infectious endocarditis prophylaxis before surgical and dental treatment [22]. Valvular disease, myocardial thickening, systemic and pulmonary hypertension [18] or narrowing of the coronary arteries with ischemia, all contribute to instances of sudden cardiovascular collapse [9].

Treatment options for MPS include, either haematopoietic stem cell transplantation, which is useful for selected patients or recombinant I.V enzyme replacement therapy. ERT is available for MPS I, II, VI [6], and recently for type IV [23]. ERT may alter the course of ventricular hypertrophy but cardiac valve pathology is usually unresponsive or, at best, stabilized [24]. In Taiwanese study of patients with MPS VI, ERT reduced urinary GAG and had positive effects on cardiac hypertrophy and diastolic dysfunction [25]. Early ERT may prevent valve disease, a fact that emphasizes the importance of early diagnosis and treatment in MPS [3].

Echocardiography is a key diagnostic technique for evaluation of valves, ventricular dimensions and function; even among asymptomatic patients. Serial ECG in patients with MPS are recommended to assess ventricular function and the progression of cardiac abnormalities. Prompt diagnosis and treatment are mandatory before irreversible damage.