Mucopolysaccharidosis Type Iva

Clinical characteristics.

The phenotypic spectrum of mucopolysaccharidosis IVA (MPS IVA) is a continuum that ranges from a severe and rapidly progressive early-onset form to a slowly progressive later-onset form. Children with MPS IVA have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years, often first manifesting as kyphoscoliosis, knock-knee (genu valgum), and pectus carinatum; the slowly progressive form may not become evident until late childhood or adolescence often first manifesting as hip problems (pain, stiffness, and Legg Perthes disease). Progressive bone and joint involvement leads to short stature, and eventually to disabling pain and arthritis. Involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, visual impairment from corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment. Children with MPS IVA have normal intellectual abilities at the outset of the disease.

Diagnosis/testing.

The diagnosis of MPS IVA is established by analysis of N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity or by the identification of biallelic pathogenic variants in GALNS on molecular genetic testing.

Management.

Treatment of manifestations: Enzyme replacement therapy (elosulfase alfa, or Vimizim™) is available, although the long-term effects of this treatment on the skeletal and non-skeletal features of MPS IVA are not yet known. Evaluation and management of individuals with MPS IVA are best undertaken by multiple specialists, coordinated by a physician specializing in the care of persons with complex medical problems. Physiatrists, physical therapists, and occupational therapists help optimize mobility and autonomy. Psychological support can optimize coping skills and quality of life; educational professionals can optimize the learning environment for a medically fragile individual. Surgical intervention is often required for lower extremity malalignment, hip subluxation and/or hip pain, upper cervical spine instability, and/or progressive thoracolumbar kyphosis. Upper extremity management may include stabilizing external wrist splints or partial or complete wrist fusion. Cardiac valve involvement may require placement of a bioprosthetic or prosthetic valve. Upper-airway obstruction and obstructive sleep apnea are managed by removal of enlarged tonsils and adenoids; diffuse narrowing of the airway may require positive airway pressure and/or tracheostomy. The outcome following keratoplasty for corneal opacification varies. Hearing loss is often treated initially with ventilation tubes and later with hearing aids.

Prevention of secondary complications: Potential pre- and postoperative anesthetic concerns secondary to spine anomalies and difficult airway management need to be anticipated. All affected individuals should receive influenza and pneumococcal immunizations as well as routine immunizations. Bacterial endocarditis prophylaxis is recommended for those with a prosthetic cardiac valve, prosthetic material used for cardiac valve repair, or previous infective endocarditis.

Surveillance: For those on ERT: physical examination at least every six months; annual assessment of quality of life parameters and pulmonary function tests. For all individuals: annual endurance tests to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems; annual assessment of upper and lower extremities for functionality and malalignment, hips for dysplasia/subluxation and thoracolumbar spine for kyphosis; neurologic examination and cervical spine radiographs every six months to assess for spinal cord compression; yearly whole-spine MRI with flexion-extension views every one to three years. Perform annual evaluation of heart rate with electrocardiogram and echocardiogram every one to three years depending on disease course. Annual assessment for obstructive sleep apnea and pulmonary function; monitor nutritional status using MPS IVA-specific growth charts. Perform vision and eye exam at every visit, dental evaluation every six to 12 months, and annual audiogram.

Agents/circumstances to avoid: Excessive weight gain; beta blockers.

Genetic counseling.

MPS IVA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Mucopolysaccharidosis IVA (MPS IVA) should be suspected in an individual with the following findings on medical history, physical examination, skeletal radiographs, and ophthalmologic examination; and suggestive laboratory findings [Wood et al 2013].

Medical history

• No distinctive clinical findings at birth
• History of adenoidectomy, tonsillectomy, hernia repair, ear ventilation tubes (general findings for all MPS disorders)
• History of cervical spine decompression and/or fusion or a history of surgery for limb alignments (unique to MPS IVA among all MPS disorders)
• Respiratory compromise (sleep apnea, endurance limitations, snoring)
• Cardiac valve abnormalities
• Dental abnormalities

Physical examination. In severe MPS IVA the following findings are usually observed between ages one and three years; in slowly progressive MPS IVA the following findings may not become evident until as late as the second decade of life:

• Marked disproportionate short stature with short trunk and normal limbs (arm span exceeds height)
• Ulnar deviation of the wrists (Figure 1 and Figure 2)
• Pectus carinatum and flaring of the lower rib cage (Figure 3 and Figure 4)
• Gibbus (short-segment structural thoracolumbar kyphosis resulting in sharp angulation of the back), kyphosis, and scoliosis
• Genu valgum (knock-knee) (Figure 5)
• Hypermobile joints
• Waddling gait with frequent falls

Figure 1.

Ulnar deviation of both wrists and joint enlargement in a male age 15 years with MPS IVA

Figure 2.

Shortened forearm and ulnar deviation of the wrist in a male age 15 years with MPS IVA

Figure 3.

Pectus anomaly and short neck in a male age 15 years with MPS IVA

Figure 4.

Lateral view of chest showing severe pectus carinatum in a male age 15 years with MPS IVA

Figure 5.

Severe genu valgum (knock-knee) in a male age 15 years with MPS IVA

Skeletal radiographs

• Odontoid hypoplasia with subsequent cervical instability (Figure 6)
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture) (Figure 7)
• Gibbus (structural kyphosis) with wedging of one or more adjacent vertebrae) (Figure 7)
  Note: The radiographic abnormalities of the lumbar spine can be detected at birth in infants with rapidly progressive disease [Tomatsu et al 2011].
• Scoliosis
• Pectus carinatum or (less frequently) excavatum
• Short ulnas, ulnar deviation of the radial epiphysis, and delayed bone maturation
• Short metacarpals with the proximal ends of the second to fifth metacarpals rounded or pointed [White et al 2014]
• Flared iliac wings, flattening of femoral epiphyses (Figure 8), and coxa valga
  Note: Skeletal abnormalities are observed before physical abnormalities [Montaño et al 2007, Tomatsu et al 2011].

Figure 6.

Lateral cervical spine x-ray of a female age six years with MPS IVA. Note hypoplastic odontoid (dashed line highlights that the odontoid does not extend superiorly within the C1 ring); platyspondyly (vertebral flattening) (double arrows); and anterior (more...)

Figure 7.

Lateral spine x-ray of a female age eight years with MPS IVA. Note platyspondyly (flattened vertebrae) with anterior beaking (arrow).

Figure 8.

Hip x-ray of a female age eight years with MPS IVA. Note bilateral irregular flattening of the capital femoral epiphyses (thin arrows), irregular dysplastic acetabuli with lateral joint subluxation (thick arrows).

Ophthalmologic examination. Visual impairment secondary to corneal clouding, astigmatism, and/or retinopathy

Suggestive laboratory findings

• Qualitative urine glycosaminoglycan (GAG) analysis, which uses thin layer chromatography or electrophoresis to identify specific types of GAG [Wood et al 2013], demonstrates keratan sulfate and chondroitin 6-sulfate.
  Note: The presence of keratan sulfate (on qualitative analysis) with or without abnormal quantitative urine GAGs has been observed in some affected individuals.
• Quantitative urine GAG analysis, which measures the total amount of GAG, demonstrates:
  • Elevated keratan sulfate (KS), indicating deficiency of either the enzyme N-acetylgalactosamine 6-sulfatase (in MPS IVA) or the enzyme B-galactosidase (in MPS IVB);
    Note: Urine KS levels in younger individuals (≤18 years) is higher than in older individuals due to the decrease in cartilage formation in older persons [Harmatz et al 2013].
  • Elevated chondroitin 6-sulfate (C6S), indicating deficiency of the enzyme N-acetylglactosamine 6-sulfatase (MPS IVA).
• Urine keratan sulfate analysis is more sensitive than standard dye-based total GAG quantitative analysis and may be used to replace urine total GAGs in the future.
• Both qualitative and quantitative urine GAGs can be normal in some affected individuals. Thus, further enzymatic or molecular evaluation of a child with clinical evidence of MPS IV is warranted even when GAG analysis is normal.

Establishing the Diagnosis

The diagnosis of MPS IVA is established in a proband with: (1) low N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity in cultured fibroblasts or leukocytes OR (2) biallelic pathogenic variants in GALNS identified on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of GALNS is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes GALNS and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

N-acetylgalactosamine 6-sulfatase (GALNS) enzyme activity can be used when:

• Clinical findings strongly indicate MPS IVA and urine GAG analysis is normal; AND/OR
• Molecular genetic testing fails to identify biallelic pathogenic variants in GALNS.

In addition, establishing a diagnosis of MPS IVA by enzyme analysis may aid in interpretation of sequencing variants of unknown significance. GALNS enzyme activity can be measured in cultured fibroblasts or leukocytes. Because each laboratory has its own normal range of enzyme activity, results from different laboratories cannot be directly compared. The level of residual enzyme activity may correlate with disease severity.

Note: (1) Low enzyme activity can be caused by other disorders including:

• Multiple sulfatase deficiency (MSD), i.e., deficient activity of several sulfatases (including GALNS). Thus, when GALNS enzyme activity is abnormal, additional sulfatase enzymes need to be assayed to evaluate for MSD.
• Mucolipidosis II and mucolipidosis III (see GNPTAB-Related Disorders, ML III Gamma). Mucolipidosis II and mucolipidosis III impair mannose-6-phosphate lysosomal enzyme targeting, leading to low lysosomal enzyme activities in fibroblasts, high lysosomal enzyme activities in plasma, and relatively unchanged lysosomal enzyme activities in leukocytes.

(2) Because the clinical manifestations of MPS IVA and MPS IVB are indistinguishable, it is customary to measure B-galactosidase enzyme activity at the same time.

Clinical Description

Mucopolysaccharidosis type IVA (MPS IVA) comprises a clinical continuum ranging from a severe and rapidly progressive form to a slowly progressive form. In the past, the two forms were distinguished by height, the subjective assessment of severity of bone deformity, and survival [Tomatsu et al 2011]; however, neither clinical nor biochemical findings can provide clear distinctions between the two forms and, thus, the MPS IVA phenotype should be considered a continuum from severe to slowly progressive.

Affected children have no distinctive clinical findings at birth. The severe form is usually apparent between ages one and three years. The slowly progressive form may not become evident until late childhood or adolescence [Montaño et al 2007].

In both forms, the initial presentations vary and may be a single finding or several findings. Kyphoscoliosis, knock-knee (genu valgum) (Figure 5), and pectus carinatum (Figure 3 and Figure 4) are the most common initial manifestations of the severe form [Montaño et al 2007]. In contrast, hip problems including pain and stiffness (due to collapse and flattening of the proximal femoral epiphysis) are common initial manifestations of the slowly progressive form [Hecht et al 1984, Wraith 1995, White et al 2014].

Because descriptions of the natural history of MPS IV published in the past may not have distinguished between MPS IVA (Morquio syndrome type A; accounting for >95% of affected individuals) and MPS IVB (Morquio syndrome type B; <5% of affected individuals), the following information is relevant to both MPS IVA and MPS IVB.

While the skeletal findings of MPS IVA are the hallmark findings, involvement of other organ systems can lead to significant morbidity, including respiratory compromise, obstructive sleep apnea, valvular heart disease, hearing impairment, corneal clouding, dental abnormalities, and hepatomegaly. Compression of the spinal cord results in neurologic involvement especially when disease is recognized later in life [reviewed in Neufeld & Muenzer 2001, Tomatsu et al 2011, Solanki et al 2013].

Coarse facial features are also present but milder than in other mucopolysaccharidoses (see Differential Diagnosis).

Children with MPS IVA typically have normal intellectual ability.

Ligamentous laxity and joint hypermobility are distinctive features of MPS IVA, and are rare among other storage disorders.

Genotype-Phenotype Correlations

Genetic alterations in GALNS that are predicted to severely affect protein function, such as deletions and nonsense variants, are common in individuals with rapidly progressive growth failure [Montaño et al 2007, Morrone et al 2014].

In contrast, affected individuals with more conservative genetic changes, such as p.Thr312Ser, are more likely to have a milder phenotype, likely due to retained partial enzymatic activity [Yamada et al 1998].

Individuals homozygous for c.898+1G>C generally have a slowly progressive course [Tomatsu et al 2005].

Nomenclature

Much of the older literature and more complete natural history studies were performed prior to understanding the basis of MPS IVA (N-acetylgalactosamine 6-sulfatase deficiency or biallelic GALNS pathogenic variants) and MPS IVB (B-galactosidase deficiency or biallelic GLB1 pathogenic variants). Thus, the term MPS IV refers to individuals with a clinical diagnosis without an enzymatic and/or molecular diagnosis, whereas the more specific terms MPS IVA and MPS IVB refer to individuals with an enzymatic and/or molecular diagnosis.

Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio syndrome type A, was initially characterized by Morquio [1929] and Brailsford [1929].

MPS IVA and MPS IVB are known as Morquio syndrome type A and type B, respectively.

Prevalence

MPS IVA is rare. The prevalence in Australia has been estimated at 1:926,000, whereas the prevalence in the UK has been estimated at 1:599,000. The birth prevalence for MPS IVA ranged from 1:71,000 to 1:179,000 across multiple countries [Leadley et al 2014]. In one German study, the incidence of MPS IVA was 1:270,000 and that of MPS IVB less than 1:1,000,000 [Baehner et al 2005]. Similarly, the incidence of MPS IVA in Italy was estimated at 1:300,000 live births [Caciotti et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type IVA (MPS IVA), the following evaluations are recommended [Hendriksz et al 2013, Solanki et al 2013, Hendriksz et al 2015]:

• Baseline neurologic examination to assess for signs of spinal cord compression
• Plain radiographs
  • Baseline radiographs of the cervical spine, including anterior-posterior (AP), neutral lateral, and flexion-extension views
  • Baseline AP and lateral radiographs of the entire spine
  • Baseline AP and frog leg lateral radiographs of the pelvis
  • Baseline AP standing radiographs of the lower extremities; in individuals who are able to stand independently and have signs of lower extremity misalignment, baseline standing lower extremity alignment radiograph from hip to ankle
• MRI
  • Baseline MRI of the entire spine (neutral position) focusing on potential sites of cord compression (occipitocervical, cervicothoracic, and thoracolumbar)
  • Flexion-extension MRI of the cervical spine when clinically indicated – for example, if cervical spine instability is suspected on plain radiographs:
    • Because MRI is usually performed under sedation or anesthesia, cervical spine radiographs should be obtained prior to anesthesia to evaluate for upper cervical spine instability.
    • In individuals with cervical spine instability suspected on plain film or those with inconclusive radiographic findings, flexion-extension cervical spine MRI can be used to evaluate for cord compression.
    • Flexion-extension MRI can identify dynamic changes in canal diameter leading to cord compression.
    • Mackenzie et al [2013] demonstrated that cervical spine flexion-extension MRI under sedation/anesthesia in children with skeletal dysplasia was safe under adequate supervision and the result was useful for surgical decision making.
• Evaluation by:
  • A physiatrist (i.e., specialist in physical medicine and rehabilitation [PM&R]) to assess mobility and autonomy. Endurance tests including six-minute walk test (6MWT) or timed 25-foot walk test (T25FW) in patients with limited ambulation have been used to evaluate functional status of the cardiovascular, pulmonary, musculoskeletal, and nervous systems. 6MWT and T25FW should be performed at the time of diagnosis.
  • A physical therapist to assess joint range of motion and mobility
  • An occupational therapist to assess activities of daily living such as the functional dexterity test (FDT). Baseline upper extremity strength assessments should be performed, including grip strength assessed by dynamometer and pinch strength assessed by a pinch meter [White et al 2014].
• Consultation with a clinical geneticist and/or genetic counselor
• Electrocardiogram and echocardiogram. If coronary artery involvement is suspected, noninvasive stress imaging should be performed [Braunlin et al 2011, Hendriksz et al 2013].
• Baseline pulmonary function and polysomnography, with evaluation by a pulmonologist
• Audiology evaluation
• Dental evaluation
• Ophthalmology evaluation to assess visual acuity and intraocular pressure; slit lamp examination and posterior segment examination for retinopathy
• Plotting of height and weight on growth charts specific for MPS IVA [Montaño et al 2007, Montaño et al 2008]
• Pain assessment and quality of life questionnaires

Treatment of Manifestations

Management of individuals with MPS IVA is best undertaken by the following multiple specialists, coordinated by a physician specializing in the care of individuals with complex medical problems:

• Physiatrist (specialist in physical medicine and rehabilitation [PM&R]) to optimize mobility and autonomy
• Physical therapist to optimize mobility
• Occupational therapist to optimize autonomy
• Psychological support to optimize coping skills and quality of life
• Educational professions to optimize learning in a medically fragile individual
• Consideration of referral to family therapy to help normalize the experience for the affected individual, parents, sibs, and extended family members
• Home care for affected individuals with multiple medical equipment needs
• Hospice for end-of-life care