Hunter Syndrome

Overview

Plain-Language Overview

Hunter Syndrome is a rare genetic disorder that affects the body's ability to break down certain complex molecules called glycosaminoglycans. This leads to their buildup in various tissues, causing progressive damage. People with Hunter Syndrome often experience symptoms like distinctive facial features, joint stiffness, and heart problems. The condition primarily affects boys and usually appears in early childhood. Over time, it can impact growth, mobility, and organ function.

Clinical Definition

Hunter Syndrome, also known as mucopolysaccharidosis type II (MPS II), is an X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme iduronate-2-sulfatase. This enzyme deficiency results in the accumulation of dermatan sulfate and heparan sulfate within lysosomes, leading to progressive cellular and tissue dysfunction. Clinically, the syndrome presents with coarse facial features, hepatosplenomegaly, joint contractures, and cardiac valve abnormalities. Neurological involvement varies, with some patients exhibiting developmental delay and cognitive decline. The disease primarily affects males due to its X-linked inheritance pattern. Diagnosis is confirmed by demonstrating reduced iduronate-2-sulfatase activity in leukocytes or fibroblasts and identifying pathogenic mutations in the IDS gene. Radiographic findings often show dysostosis multiplex. The natural history includes progressive multisystem involvement, with severity ranging from attenuated to severe phenotypes. Management is supportive and may include enzyme replacement therapy to slow disease progression.

Inciting Event

none

Latency Period

none

Diagnostic Delay

Early symptoms are often nonspecific and overlap with other developmental disorders, leading to delayed recognition.
Lack of awareness about rare lysosomal storage diseases among clinicians contributes to diagnostic delay.
Variable severity and progression rates can obscure early diagnosis.

Clinical Presentation

Signs & Symptoms

Progressive developmental delay and cognitive decline.
Recurrent respiratory infections and obstructive airway disease.
Coarse facial features and macroglossia.
Hepatosplenomegaly causing abdominal distension.
Joint stiffness and contractures limiting mobility.

History of Present Illness

Progressive coarse facial features including a broad nose and thickened lips.
Developmental delay and behavioral problems such as hyperactivity.
Recurrent respiratory infections and obstructive airway symptoms.
Hepatosplenomegaly and joint stiffness causing limited mobility.
Hearing loss and cardiac symptoms like valvular heart disease may be present.

Past Medical History

History of frequent upper respiratory infections and otitis media.
Previous episodes of hernia repairs or other surgeries related to connective tissue abnormalities.
Delayed developmental milestones and learning difficulties.

Family History

X-linked recessive inheritance pattern with affected male relatives on the maternal side.
Carrier females may have no symptoms but can pass the mutation to offspring.
Family history of unexplained developmental delay or early death in males may be present.

Physical Exam Findings

Coarse facial features including a broad nose and thickened lips.
Hepatosplenomegaly detected on abdominal palpation.
Thickened, stiff skin and limited joint mobility.
Mild to moderate hearing loss on audiometric testing.
Short stature and a prominent forehead.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Hunter Syndrome is based on clinical features such as characteristic coarse facial features, hepatosplenomegaly, and joint stiffness, combined with biochemical evidence of deficient iduronate-2-sulfatase enzyme activity in leukocytes or fibroblasts. Genetic testing confirming mutations in the IDS gene supports the diagnosis. Radiologic evidence of dysostosis multiplex and elevated urinary glycosaminoglycans further aid in diagnosis.

Pathophysiology

Key Mechanisms

Hunter syndrome is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, leading to accumulation of glycosaminoglycans (GAGs) in tissues.
The buildup of heparan sulfate and dermatan sulfate within lysosomes causes progressive cellular and organ dysfunction.
X-linked recessive inheritance results in enzyme deficiency primarily affecting males.

Involvement	Details
Organs	Heart involvement includes valvular thickening and cardiomyopathy.
	Liver and spleen enlargement occurs due to glycosaminoglycan storage.
	Airways are affected causing obstructive respiratory symptoms.
	Central nervous system involvement may cause cognitive impairment in severe cases.
Tissues	Connective tissue is thickened and dysfunctional due to glycosaminoglycan accumulation.
Tissues	Cartilage abnormalities contribute to joint stiffness and skeletal deformities.
Cells	Lysosomal cells are affected due to deficient iduronate-2-sulfatase leading to accumulation of glycosaminoglycans.
Cells	Macrophages accumulate glycosaminoglycans contributing to tissue inflammation and damage.
Chemical Mediators	Glycosaminoglycans (GAGs) such as dermatan sulfate and heparan sulfate accumulate abnormally in tissues.
Chemical Mediators	Inflammatory cytokines may be elevated secondary to tissue damage and contribute to disease progression.

Treatment

Pharmacological Treatments

Idursulfase (Elaprase)
- Mechanism: Enzyme replacement therapy providing recombinant iduronate-2-sulfatase to reduce glycosaminoglycan accumulation
- Side effects: infusion reactions, fever, headache, rash

Non-pharmacological Treatments

Regular physical therapy to maintain joint mobility and muscle strength.
Supportive respiratory care including airway clearance techniques to manage obstructive airway disease.
Educational and behavioral interventions to assist with cognitive impairment.
Surgical interventions such as carpal tunnel release or hernia repair when indicated.

Prevention

Pharmacological Prevention

Enzyme replacement therapy (ERT) with idursulfase to reduce GAG accumulation.

Non-pharmacological Prevention

Genetic counseling for families with a history of Hunter syndrome.
Early supportive therapies including physical therapy to maintain joint mobility.
Regular monitoring and management of cardiac and respiratory function.

Outcome & Complications

Complications

Cardiac failure secondary to valvular disease.
Airway obstruction leading to respiratory distress.
Neurological decline with progressive cognitive impairment.
Hepatic dysfunction due to massive hepatosplenomegaly.

Short-term Sequelae	Long-term Sequelae
Frequent upper respiratory infections. Progressive joint stiffness limiting daily activities. Mild to moderate hearing impairment.	Severe cognitive decline and developmental delay. Chronic heart failure due to valvular disease. Permanent airway obstruction requiring intervention. Disabling joint contractures and skeletal deformities.

Differential Diagnoses

Hunter Syndrome versus Hurler Syndrome (MPS I)

Hunter Syndrome	Hurler Syndrome (MPS I)
Absence of corneal clouding distinguishes Hunter syndrome from Hurler syndrome.	Corneal clouding is present, which is a hallmark of Hurler syndrome.
Milder or variable cognitive impairment is typical in Hunter syndrome compared to Hurler syndrome.	Severe developmental delay often appears earlier and is more pronounced in Hurler syndrome.
Iduronate-2-sulfatase deficiency is the enzymatic defect specific to Hunter syndrome.	Alpha-L-iduronidase deficiency is the enzymatic defect in Hurler syndrome.

Hunter Syndrome versus Morquio Syndrome (MPS IV)

Hunter Syndrome	Morquio Syndrome (MPS IV)
Cognitive impairment may be present in Hunter syndrome, unlike Morquio syndrome.	Normal intelligence is typical in Morquio syndrome, unlike Hunter syndrome.
Coarse facial features and hepatosplenomegaly are common in Hunter syndrome but not in Morquio syndrome.	Severe skeletal dysplasia with short-trunk dwarfism and odontoid hypoplasia is characteristic of Morquio syndrome.
Iduronate-2-sulfatase deficiency and accumulation of dermatan and heparan sulfate are seen in Hunter syndrome.	Keratan sulfate accumulation is the primary storage material in Morquio syndrome.

Hunter Syndrome versus Sanfilippo Syndrome (MPS III)

Hunter Syndrome	Sanfilippo Syndrome (MPS III)
Prominent somatic features including coarse facial features and hepatosplenomegaly are more evident in Hunter syndrome.	Severe central nervous system degeneration with early and profound neurocognitive decline is characteristic of Sanfilippo syndrome.
Variable cognitive impairment with slower progression compared to Sanfilippo syndrome.	Minimal somatic involvement such as mild skeletal abnormalities, unlike Hunter syndrome.
Dermatan sulfate and heparan sulfate accumulation is typical in Hunter syndrome.	Heparan sulfate accumulation predominates in Sanfilippo syndrome.