Growth impairment in mucopolysaccharidoses

Abstract

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that affect regulation of glycosaminoglycan (GAG) processing. In MPS, the lysosomes cannot efficiently break down GAGs, and the specific GAGs accumulated depend on the type of MPS. The level of impairment of breakdown varies between patients, making this one of the many factors that lead to a range of clinical presentations even in the same type of MPS. These clinical presentations usually involve skeletal dysplasia, in which the most common feature is bone growth impairment and successive short stature. Growth impairment occurs due to the deposition and retention of GAGs in bone and cartilage. The accumulation of GAGs in these tissues leads to progressive damage in cartilage that in turn reduces bone growth by destruction of the growth plate, incomplete ossification, and imbalance of growth. Imbalance of growth leads to various skeletal abnormalities including disproportionate dwarfism with short neck and trunk, prominent forehead, rigidity of joints, tracheal obstruction, kyphoscoliosis, pectus carinatum, platyspondyly, round-shaped vertebral bodies or beaking sign, underdeveloped acetabula, wide flared iliac, coxa valgus, flattered capital femoral epiphyses, and genu valgum. If left untreated, skeletal abnormalities including growth impairment result in a significant impact on these patients' quality of life and activity of daily living, leading to high morbidity and severe handicap. This review focuses on growth impairment in untreated patients with MPS. We comprehensively describe the growth abnormalities through height, weight, growth velocity, and BMI in each type of MPS and compare the status of growth with healthy age-matched controls. The timing, the degree, and the difference in growth impairment of each MPS are highlighted to understand the natural course of growth and to evaluate future therapeutic efficacy.

Keywords: Glycosaminoglycans; Growth impairment; Lysosomal storage disorders; Mucopolysaccharidoses; Short stature.

Figure 1

Growth chart for patients with MPS II from birth to 18 years old, and comparison of mean height between the attenuated and severe phenotype. In Fig. 1A, the dotted line shows the mean height for healthy males and the solid line shows heights for MPS II patients. In Fig. 1B, the dotted line shows the mean height for patients with the attenuated phenotype and the solid line shows the mean height for patients with the severe phenotype. Arrows point to their respective percentile curve. Adapted from Patel et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [8]

Figure 2

Growth velocity from birth to 18 years of age in patients with MPS II. The dotted line shows the growth velocity of the normal control. The solid line shows the mean height velocity for patients with MPS II. Adapted from Patel et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [8]

Figure 3

Weight curve for patients with MPS II from birth to 18 years of age. In Fig. 3A, the dotted line shows the mean height for healthy males and the solid line shows weights for patients with MPS II. In Fig. 3B, the dotted line shows the mean weight for patients with the attenuated phenotype and the solid line shoes the mean weight for patients with the severe phenotype. Arrows point to their respective percentile curves. Adapted from Patel et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [8].

Figure 4

BMI curve for patients with MPS II from birth to 18 years of age. The dotted line shows the mean BMI for healthy males. The solid line shows BMIs for patients with MPS II. Arrows point to their respective percentile curves. Adapted from Patel et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [8].

Figure 5

Descriptive analysis of first measurements of height, weight, BMI and head circumference in untreated patients or before start of ERT in boys with Hunter syndrome. Adapted from Parini et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [10].

Figure 6

Analysis of height velocity in untreated patients or before the start of ERT in boys with Hunter syndrome. Adapted from Parini et al. (Mol Genet and Metab Rep 1; 2014, 5–18) [10].

Figure 7

Growth charts for length/height (cm) of boys (A) and girls (B) with MPS IVA from birth to 18 years of age (copyright permission from International Morquio Organization). The dotted line shows the 50th centile values for normal boys and girls. Adapted from Tomatsu et al. [6].

Figure 8

Growth velocity (cm/year) throughout childhood and adolescence of boys (A) and girls (B) with MPS IVA (copyright permission from International Morquio Organization). The gray line shows the height velocity values for normal boys and girls. Adapted from Tomatsu et al. [6].

Figure 9

Body weight (kg) of males (A) and females (B) with MPS IVA (copyright permission from International Morquio Organization). The dotted line shows the 50th centile values for normal males and females. Adapted from Tomatsu et al. [6].

Figure 10

Body mass index [weight (kg)/height² (m²)] for males (A) and females (B) with MPS IVA (copyright permission from International Morquio Organization). The dotted line shows the 50th centile values for normal males and females. Adapted from Tomatsu et al. [6].