Mucopolysaccharidoses are a group of chronic progressive disorders with multisystem affection and a fatal disease course; each disorder results from the significant deficiency of 1 of the 10 known enzymes that contribute to the lysosomal degradation of glycosaminoglycans [1]. Mucopolysaccharidosis type I is a common form of mucopolysaccharidosis; it accounts for nearly 15% of all mucopolysaccharidosis cases and occurs secondarily to a deficiency in α-L-iduronidase enzyme activity and the subsequent intracellular accumulation of dermatan and heparan sulfate [2]. Mucopolysaccharidosis type I is an autosomal recessive disorder with a progressive course and multisystem involvement [3]. The condition is associated with a wide range of phenotypic and clinical features. However, there are three distinct phenotypes of mucopolysaccharidosis type I—the Hurler, Hurler-Scheie, and Scheie syndromes (Scheie syndrome is the most severe form of mucopolysaccharidosis type I) [4]. Patients with mucopolysaccharidosis type I can present with characteristic facial features, cognitive and neurological impairments, hearing impairments, eye problems, cardiomyopathy, heart failure, recurrent respiratory infections, acute and chronic liver failure, joint contractures, and cervical instability, and spinal stenosis [2]. Further, patients with mucopolysaccharidosis type I are at higher risk of morbidity and mortality during anesthesia and surgical interventions [5].

The diagnosis of mucopolysaccharidosis type I depends on the detection of glycosaminoglycans in urine and a significant deficiency in the activity of the α-L-iduronidase enzyme. Alongside biochemical analysis, molecular tests play a critical role in the identification of the genotype of mucopolysaccharidosis; knowing the genotype can aid in the identification of the phenotype, genetic counseling, and prenatal diagnosis [6]. With regard to mucopolysaccharidosis diagnosis, different methods are available for the early diagnosis of mucopolysaccharidosis type I. These methods are based on the detection of deficient enzyme activity via dried blood spot (DBS) punches. DBS punching is a blood sampling technique in which a drop of blood is dried and placed on filter paper (a DBS card) [7]. These blood samples can be shipped to central laboratories—those in the same country or those from abroad—to be analyzed by using different methods such as enzymatic assays and confirmatory molecular testing, as in our study. Conventional fluorometric methods are widely available techniques for the detection of enzymatic activity; however, they have limited value due to their inability to test multiple enzymes simultaneously [8]. Tandem mass spectrometry (MS/MS) methods, which quantify lysosomal enzyme activity, have exhibited high diagnostic accuracy for the detection of lysosomal storage disorders (LSDs) and have a high capacity for multiplex testing [9]. Recent reports have also introduced new, cheap, and feasible MS/MS-based methods for the mass detection of mucopolysaccharidosis type I [10,11].

All mucopolysaccharidosis types are characterized by musculoskeletal manifestations in the form of joint stiffness, reduced joint mobility, carpal tunnel syndrome, and bone abnormalities [12]. Idiopathic short stature is widely considered as the main feature of mucopolysaccharidosis type I [13]; in previous studies, children with mucopolysaccharidosis type I constantly had growth measure values that were below the normal percentiles for age and sex and independent of disease severity and the age of onset [14,15]. Since the underlying cause of idiopathic short stature can indeed be undiagnosed mucopolysaccharidosis type I, it is critical to identify patients with mucopolysaccharidosis type I among screened patients with idiopathic short stature. Therefore, the primary objective of our study is to determine the prevalence of mucopolysaccharidosis type I disease in a high-risk group (ie, patients with idiopathic short stature). The secondary objectives are to describe the demographic profiles and clinical characteristics of patients with mucopolysaccharidosis type I and to describe other comorbid conditions in patients with mucopolysaccharidosis type I.

Our protocol was reviewed and approved by the IRB of King Fahd Medical City and funded by Sanofi Genzyme Saudi Arabia. According to our sample size calculation, we expect that at least 800 patients from different sites in Saudi Arabia will be enrolled in our study.

The early diagnosis of mucopolysaccharidosis followed by early treatment can have a huge impact on patients’ quality of life; previous reports have demonstrated that the early initiation of treatment is the most important factor for slowing the progression of the disease [2]. Enzyme replacement therapy, when delivered early in the disease process, has alleviated many systematic signs and symptoms of mucopolysaccharidosis. This is possibly due to the prevention of permanent tissue damage resulting from excessive substrate deposition [20]. Since many mucopolysaccharidosis type I symptoms are often unspecific, many patients, especially those with undiagnosed mucopolysaccharidosis type I or an attenuated form of the disease, are either misdiagnosed or diagnosed later in the course of the disease (ie, after precious time has been lost due to inappropriate treatment and after irreplaceable organ damage has occurred) [21]. At some point during the course of the disease, patients with mucopolysaccharidosis consult rheumatologists. As such, rheumatologists should be aware of clinical manifestations that raise the suspicion of a mucopolysaccharidosis diagnosis. Thus, we found it imperative to assess the prevalence of mucopolysaccharidosis type I among high-risk patients, such as pediatric patients with idiopathic short stature.

The added values of our screening program include (1) the determination of the actual prevalence of mucopolysaccharidosis type I among children with idiopathic short stature, (2) the early detection of potentially disabling conditions among Saudi children (these data will provide a chance for early treatment and better prognoses), and (3) the increased awareness of Saudi pediatricians and primary care physicians with regard to how and when to suspect a mucopolysaccharidosis diagnosis in children.

We chose to conduct this epidemiological study in Saudi Arabia due to the peculiar characteristics of this country, which is located in the Arabian Peninsula and has a population of more than 28 million people. Recent reports have noted a trend toward a higher incidence of genetic disorders among Arab countries when compared to those of other parts of the world. These incidence rates also apply to the incidence of mucopolysaccharidosis type I. Recent global data show that the overall birth prevalence rate of mucopolysaccharidosis ranges from 1.04 to 4.8 infants per 100,000 live births. Additionally, reports from Europe show that the incidence rate of mucopolysaccharidosis is 1.56 infants per 100,000 live births [3]. This incidence rate is quite similar to the mucopolysaccharidosis incidence rates of Japan and other East Asian countries that were reported during the same period [22-24]. On the other hand, reports from Saudi Arabia show that the country has a higher incidence of mucopolysaccharidosis compared to those in the abovementioned reports. The first retrospective study from Saudi Arabia on this topic reported that the combined incidence rate of mucopolysaccharidosis type I and mucopolysaccharidosis type IV was 3.62 infants per 100,000 live births, and each disease type accounted for 21% of all mucopolysaccharidosis cases. Moreover, the birth prevalence of mucopolysaccharidosis III is 1.8 infants per 100,000 live births (11% of total cases) [25]. In addition, Al-Sannaa and colleagues [19] reported that the incidence rate of mucopolysaccharidosis diseases was 14 infants per 100,000 live births; with mucopolysaccharidosis type VI accounted for most of the mucopolysaccharidosis cases. A 13-year retrospective chart review reported an incidence rate of 14 infants per 100,000 live birth [26]. The incidence of mucopolysaccharidosis in Saudi Arabia appears to be even higher than those reported by other Arab countries; a previous report from Tunisia reported a mucopolysaccharidosis birth prevalence of 2.27 infants per 100,000 live births [27]. These high figures were postulated to stem from the higher incidence of congenital and genetic diseases in Arab countries compared to those of other parts of the world [28]; high consanguinity rates, which reach up to 60% in some regions; the high prevalence of hemoglobinopathies and metabolic disorders; relatively high maternal and parental ages; and the lack of proper genetic screening [28-30].

With regard to mucopolysaccharidosis diagnosis, different methods are available for the early diagnosis of mucopolysaccharidosis type I. These methods are based on the detection of deficient enzyme activity via DBS punches. Conventional fluorometric methods are widely available techniques for the detection of enzymatic activity; however, they have limited value due to their inability to test multiple enzymes simultaneously [8]. MS/MS methods, which quantify lysosomal enzyme activity, have exhibited high diagnostic accuracy for the detection of LSDs and have a high capacity for multiplex testing [9]. Recent reports have also introduced new, cheap, and feasible MS/MS-based methods for the mass detection of mucopolysaccharidosis type I [10,11]. Such advances in the diagnostic methods have encouraged other researchers to conduct several mucopolysaccharidosis type I neonatal screening programs; these researchers aim to evaluate the utility of mucopolysaccharidosis type I neonatal screening to determine whether such screening should be included in primary screening programs. From 2008 to 2013, a pilot screening program for mucopolysaccharidosis type I was conducted for 35,286 newborns from Taiwan. Only 2 neonates had a confirmed diagnosis of mucopolysaccharidosis type I. The rate of mucopolysaccharidosis type I incidence in Taiwan that was estimated from the results of this program was about 1:17,643 [31]. In the United States, several states have conducted pilot mucopolysaccharidosis screening programs. In a comprehensive program for LSDs that was conducted in Missouri, a multiplexing digital microfluidic fluorometric enzymatic assay was used to detect Pompe disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type I in 2013. Of the 43,701 screened newborns, 3 had a confirmed diagnosis of mucopolysaccharidosis type I, and 7 had pseudodeficiencies. In this Missouri program, the rate of mucopolysaccharidosis type I incidence (1:14,567) was similar to the incidence rate reported in a previous pilot study conducted in Taiwan (1:17,643) [32]. In Saudi Arabia, a national newborn screening program was established in 2005. This program covers inborn errors of metabolism, endocrine disorders, congenital heart defects, and hearing loss [33]. A recent 7-year retrospective study of 139 hospitals reported a higher rate of inborn errors of metabolism in Saudi Arabia compared to those in other parts of the world [34]. However, the inclusion of LSDs, including mucopolysaccharidosis type I, in Saudi Arabia’s newborn screening program has not yet been discussed.