Mucopolysaccharidosis in Children: Clinical Case and Viva Q&A

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Clinical Case of Mucopolysaccharidosis in Children

Clinical Case: Mucopolysaccharidosis Type II (Hunter Syndrome)

A 4-year-old boy, Alex, is brought to the pediatric clinic by his parents with concerns about his developmental delays and frequent respiratory infections. His parents report the following:

  • Coarse facial features that have become more pronounced over the past year
  • Delayed speech development and difficulty understanding simple instructions
  • Recurrent upper respiratory tract infections (6 episodes in the last 12 months)
  • Enlarged liver and spleen noticed during a recent well-child visit
  • Stiff joints, especially in the hands, limiting fine motor skills
  • Umbilical and inguinal hernias repaired at age 2

Physical examination reveals:

  • Height and weight below the 3rd percentile for age
  • Coarse facies with a broad nose, thick lips, and enlarged tongue
  • Macrocephaly (head circumference above 97th percentile)
  • Hepatosplenomegaly
  • Limited range of motion in multiple joints
  • Mild hearing loss detected during audiometry

Initial investigations:

  • Skeletal survey: Dysostosis multiplex, including J-shaped sella turcica and paddle-shaped ribs
  • Echocardiogram: Mild mitral and aortic valve thickening
  • Urinary glycosaminoglycans (GAGs): Elevated, predominantly dermatan sulfate

Based on the clinical presentation and initial findings, mucopolysaccharidosis type II (Hunter syndrome) is suspected. Enzymatic assay confirms deficiency of iduronate-2-sulfatase, establishing the diagnosis. Genetic testing reveals a pathogenic variant in the IDS gene, confirming X-linked inheritance.

Management plan includes multidisciplinary care, enzyme replacement therapy with idursulfase, and genetic counseling for the family.

Clinical Presentations of Mucopolysaccharidosis in Children

Varieties of Clinical Presentations of Mucopolysaccharidosis in Children

  1. MPS I (Hurler, Hurler-Scheie, and Scheie syndromes)

    • Coarse facial features, macrocephaly
    • Progressive cognitive decline (in Hurler syndrome)
    • Corneal clouding, retinal degeneration
    • Recurrent upper respiratory infections, obstructive sleep apnea
    • Hepatosplenomegaly, umbilical and inguinal hernias
    • Joint stiffness and contractures
    • Cardiac valve abnormalities
    • Dysostosis multiplex (skeletal deformities)

  2. MPS II (Hunter syndrome)

    • Coarse facial features, macrocephaly
    • Behavioral problems and developmental regression (in severe form)
    • Hearing loss
    • Recurrent respiratory infections, airway obstruction
    • Hepatosplenomegaly
    • Joint stiffness and contractures
    • Carpal tunnel syndrome
    • Cardiac valve disease and cardiomyopathy

  3. MPS III (Sanfilippo syndrome)

    • Mild coarsening of facial features
    • Severe behavioral problems (hyperactivity, aggression)
    • Progressive cognitive decline and developmental regression
    • Sleep disturbances
    • Seizures
    • Mild skeletal abnormalities
    • Hearing loss

  4. MPS IV (Morquio syndrome)

    • Short stature with disproportionate trunk
    • Skeletal dysplasia (genu valgum, kyphoscoliosis)
    • Joint laxity
    • Odontoid hypoplasia with atlantoaxial instability
    • Corneal clouding
    • Preserved intellect
    • Cardiac valve abnormalities

  5. MPS VI (Maroteaux-Lamy syndrome)

    • Coarse facial features
    • Short stature
    • Corneal clouding
    • Hepatosplenomegaly
    • Joint stiffness and contractures
    • Cardiac valve disease
    • Spinal cord compression
    • Normal intelligence

  6. MPS VII (Sly syndrome)

    • Coarse facial features
    • Hydrops fetalis in severe cases
    • Hepatosplenomegaly
    • Short stature
    • Joint stiffness
    • Cardiac abnormalities
    • Variable cognitive impairment

  7. MPS IX (Hyaluronidase deficiency)

    • Soft tissue masses
    • Short stature
    • Mild coarsening of facial features
    • Joint pain and swelling
    • Normal intelligence
Viva Questions and Answers on Mucopolysaccharidosis in Children

Viva Questions and Answers on Mucopolysaccharidosis in Children

  1. Q: What is the underlying pathophysiology of mucopolysaccharidoses?

    A: Mucopolysaccharidoses (MPS) are caused by deficiencies in lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs). This results in the accumulation of partially degraded GAGs within lysosomes, leading to cellular dysfunction and progressive tissue and organ damage.

  2. Q: Name the four main types of glycosaminoglycans involved in MPS disorders.

    A: The four main types of glycosaminoglycans involved in MPS disorders are:

    1. Dermatan sulfate
    2. Heparan sulfate
    3. Keratan sulfate
    4. Chondroitin sulfate

  3. Q: What is the inheritance pattern of MPS disorders?

    A: Most MPS disorders are inherited in an autosomal recessive pattern. The exception is MPS II (Hunter syndrome), which is X-linked recessive.

  4. Q: Describe the classic triad of symptoms in severe MPS I (Hurler syndrome).

    A: The classic triad of symptoms in severe MPS I (Hurler syndrome) includes:

    1. Coarse facial features
    2. Developmental delay/cognitive impairment
    3. Hepatosplenomegaly

  5. Q: What is the primary difference between MPS I and MPS II in terms of clinical presentation?

    A: The primary difference is that corneal clouding is typically present in MPS I but absent in MPS II. Additionally, MPS II affects only males due to its X-linked inheritance, while MPS I affects both sexes.

  6. Q: Which MPS type is characterized by severe behavioral problems and developmental regression with relatively mild somatic features?

    A: MPS III (Sanfilippo syndrome) is characterized by severe behavioral problems and developmental regression with relatively mild somatic features.

  7. Q: What is the characteristic skeletal finding in MPS IV (Morquio syndrome)?

    A: The characteristic skeletal finding in MPS IV (Morquio syndrome) is odontoid hypoplasia, which can lead to atlantoaxial instability and risk of spinal cord compression.

  8. Q: How does cognitive impairment differ among the various MPS types?

    A: Cognitive impairment varies among MPS types:

    • Severe in MPS I (Hurler), MPS II (severe form), and MPS III
    • Variable in MPS VII
    • Usually normal or mildly affected in MPS IV and MPS VI

  9. Q: What is dysostosis multiplex, and in which MPS types is it commonly observed?

    A: Dysostosis multiplex is a constellation of skeletal abnormalities including skull deformities, vertebral anomalies, and long bone deformities. It is commonly observed in MPS I, II, VI, and VII, but less prominent in MPS III and IV.

  10. Q: How is the diagnosis of MPS typically confirmed?

    A: The diagnosis of MPS is typically confirmed through a combination of:

    1. Elevated urinary glycosaminoglycan (GAG) levels
    2. Enzyme activity assay in leukocytes or fibroblasts showing deficiency of the specific enzyme
    3. Genetic testing to identify pathogenic variants in the relevant gene

  11. Q: What is the gold standard for prenatal diagnosis of MPS disorders?

    A: The gold standard for prenatal diagnosis of MPS disorders is molecular genetic testing of fetal DNA obtained through chorionic villus sampling or amniocentesis, especially when the familial pathogenic variant is known.

  12. Q: Describe the cardiac manifestations commonly seen in MPS disorders.

    A: Common cardiac manifestations in MPS disorders include:

    • Valve thickening and dysfunction (particularly mitral and aortic valves)
    • Left ventricular hypertrophy
    • Coronary artery narrowing
    • Cardiomyopathy
    • Conduction abnormalities

  13. Q: What are the main treatment modalities available for MPS disorders?

    A: The main treatment modalities for MPS disorders include:

    1. Enzyme replacement therapy (ERT)
    2. Hematopoietic stem cell transplantation (HSCT)
    3. Supportive care and management of specific symptoms
    4. Emerging therapies such as gene therapy and substrate reduction therapy

  14. Q: For which MPS types is enzyme replacement therapy currently available?

    A: Enzyme replacement therapy is currently available for:

    • MPS I (laronidase)
    • MPS II (idursulfase)
    • MPS IVA (elosulfase alfa)
    • MPS VI (galsulfase)
    • MPS VII (vestronidase alfa)

  15. Q: What are the limitations of enzyme replacement therapy in MPS disorders?

    A: Limitations of enzyme replacement therapy in MPS disorders include:

    • Inability to cross the blood-brain barrier, limiting effects on central nervous system manifestations
    • Need for frequent (usually weekly) intravenous infusions
    • High cost
    • Potential for immune reactions to the recombinant enzyme
    • Limited effect on certain tissues such as bone and cartilage

  16. Q: In which MPS type is hematopoietic stem cell transplantation (HSCT) considered the treatment of choice, and why?

    A: HSCT is considered the treatment of choice for severe MPS I (Hurler syndrome) when performed early (before 2.5 years of age). This is because HSCT can provide a continuous source of enzyme production, cross the blood-brain barrier, and potentially halt or slow cognitive decline.

  17. Q: What are the key components of multidisciplinary care for a child with MPS?

    A: Key components of multidisciplinary care for a child with MPS include:

    • Pediatric metabolic specialist coordination
    • Neurological and developmental assessments
    • Cardiology evaluations
    • Orthopedic management
    • Ophthalmological care
    • ENT and audiology assessments
    • Respiratory care, including sleep studies
    • Physical and occupational therapy
    • Genetic counseling for families

  18. Q: How does MPS II (Hunter syndrome) differ in its severe and attenuated forms?

    A: MPS II (Hunter syndrome) differs in its severe and attenuated forms as follows:

    • Severe form: Progressive cognitive impairment, behavioral problems, and developmental regression; typically diagnosed between 18 months and 4 years of age
    • Attenuated form: Normal or mildly impaired cognition; slower disease progression; may be diagnosed later in childhood or adolescence

  19. Q: What is the significance of joint stiffness and contractures in MPS disorders?

    A: Joint stiffness and contractures in MPS disorders are significant because:

    • They lead to reduced mobility and range of motion, affecting daily activities
    • They can cause pain and discomfort
    • They may contribute to skeletal deformities
    • They often require ongoing physical therapy and sometimes surgical intervention
    • They can impact overall quality of life and independence

  20. Q: Explain the pathophysiology of corneal clouding in MPS disorders.

    A: Corneal clouding in MPS disorders occurs due to:

    1. Accumulation of glycosaminoglycans (GAGs) within corneal stromal cells
    2. Disruption of normal collagen fibril organization in the corneal stroma
    3. Increased corneal thickness
    4. Alterations in corneal hydration

    These changes lead to decreased corneal transparency, resulting in visual impairment.

  21. Q: What are the main respiratory complications seen in children with MPS disorders?

    A: The main respiratory complications in children with MPS disorders include:

    • Obstructive sleep apnea
    • Restrictive lung disease due to skeletal deformities
    • Recurrent upper and lower respiratory tract infections
    • Tracheobronchomalacia
    • Airway obstruction due to soft tissue hypertrophy and GAG deposition
    • Pulmonary hypertension (as a secondary complication)

  22. Q: How does enzyme replacement therapy (ERT) differ from hematopoietic stem cell transplantation (HSCT) in terms of their effects on the central nervous system in MPS disorders?

    A: The key difference is:

    • ERT: Does not cross the blood-brain barrier effectively, limiting its impact on central nervous system manifestations
    • HSCT: Can provide enzyme-producing cells that cross the blood-brain barrier, potentially halting or slowing cognitive decline, especially when performed early in life

  23. Q: What are the typical findings on skeletal surveys in children with MPS disorders?

    A: Typical findings on skeletal surveys in MPS disorders include:

    • Dysostosis multiplex
    • J-shaped sella turcica
    • Paddle-shaped ribs
    • Anterior beaking of vertebral bodies
    • Bullet-shaped phalanges
    • Hip dysplasia
    • Genu valgum (knock-knees)
    • Thickened skull
    • Short, broad long bones

  24. Q: Describe the typical progression of MPS III (Sanfilippo syndrome) and its impact on development.

    A: The typical progression of MPS III includes:

    1. Initial normal development in infancy
    2. Developmental plateau around 2-4 years of age
    3. Progressive cognitive decline and loss of language skills
    4. Behavioral problems, including hyperactivity and aggression
    5. Sleep disturbances
    6. Loss of motor skills and development of seizures in later stages
    7. Severe dementia and complete loss of ambulation by adolescence or early adulthood

  25. Q: What is the role of biomarkers in the diagnosis and monitoring of MPS disorders?

    A: Biomarkers play several roles in MPS disorders:

    • Diagnosis: Elevated urinary GAGs and specific enzyme deficiencies in blood or fibroblasts
    • Monitoring disease progression: Levels of specific GAG subtypes (e.g., dermatan sulfate, heparan sulfate)
    • Assessing treatment efficacy: Changes in biomarker levels following enzyme replacement therapy or HSCT
    • Emerging biomarkers: Lyso-Gb3 for Fabry disease, HS-NRE (heparan sulfate non-reducing end) for MPS III

  26. Q: How does MPS IV (Morquio syndrome) differ from other MPS types in terms of cognitive involvement?

    A: MPS IV (Morquio syndrome) differs from other MPS types in that:

    • Cognitive function is typically preserved
    • Intelligence is usually normal
    • There is no neurodegenerative component to the disease
    • The primary manifestations are skeletal and connective tissue abnormalities

  27. Q: What are the potential benefits and risks of intrathecal enzyme replacement therapy in MPS disorders?

    A: Potential benefits of intrathecal ERT include:

    • Direct delivery of enzyme to the central nervous system
    • Potential to address neurological manifestations not treatable with intravenous ERT
    • Possible cognitive and behavioral improvements

    Potential risks include:

    • Infection or bleeding associated with intrathecal administration
    • Immune reactions within the central nervous system
    • Potential for increased intracranial pressure
    • Long-term safety concerns (still under investigation)

  28. Q: Explain the concept of genotype-phenotype correlation in MPS disorders, using MPS I as an example.

    A: Genotype-phenotype correlation in MPS I:

    • Severe mutations (e.g., nonsense mutations) on both alleles typically result in Hurler syndrome (severe phenotype)
    • Combinations of severe and attenuated mutations often lead to Hurler-Scheie syndrome (intermediate phenotype)
    • Two attenuated mutations (e.g., missense mutations allowing residual enzyme activity) typically result in Scheie syndrome (attenuated phenotype)
    • However, exceptions exist, and other genetic and environmental factors can influence the phenotype

  29. Q: What are the current challenges and future directions in the treatment of MPS disorders?

    A: Current challenges and future directions include:

    • Improving central nervous system delivery of therapeutic enzymes
    • Developing gene therapy approaches for long-term enzyme production
    • Exploring substrate reduction therapy to decrease GAG production
    • Enhancing early diagnosis through newborn screening programs
    • Improving outcomes of hematopoietic stem cell transplantation
    • Developing combination therapies for synergistic effects
    • Addressing the high cost of current treatments
    • Managing long-term complications in patients with increased life expectancy
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