Hurler Syndrome

Etiology

Hurler syndrome is an autosomal recessive disorder due to a defective gene which encodes for the enzyme alpha-L-iduronidase (IUDA) that is located on chromosome 4.[1]

Epidemiology

The incidence of Hurler syndrome is approximately 1 in 100,000 births.[1] Male and female children are equally affected. All races and ethnicities are at risk of inheriting the disease.

Pathophysiology

Hurler syndrome is caused by a deficiency of a lysosomal enzyme, IUDA, which aids in the breakdown of dermatan sulfate and heparin sulfate (GAG). This finally results in the accumulation of large amounts of GAG in the body, eventually causing the cells to become severely dysfunctional leading to death. The deposition of GAG causes enlargement and thickening of various organs like the heart, spleen, liver, muscles, connective tissues, joints, and the central nervous system causing severe functional impairment.

Hurler Syndrome is considered as MPS I. The presentation and course of the disease vary due to underlying IUDA mutations and a consequent residual degree of enzyme activity. MPS I is further subdivided into three subtypes. 

1. Hurler syndrome (MPS I H): This is the most common and severe form. Patients develop symptoms shortly after birth and progress rapidly. The symptoms include developmental delay, cognitive decline, characteristic coarse facial features, joint stiffness and contractures, short stature, and cardiac and hepatic disease. Patients usually die within the first year of life.[2]
2. Hurler-Scheie syndrome (MPS I H-S): This is an intermediate phenotype, typically diagnosed at 2 to 6 years of age. Facial features are less coarse than Hurler syndrome. Achilles tendon contractures lead to toe walking. Hepatosplenomegaly causes respiratory compromise. Patients often develop spondylolisthesis and kyphoscoliosis. The meninges are thickened and cause compression of the cervical spinal cord (pachymeningitis cervicalis), leading to weakness or paralysis.[3] Those affected usually have mild cognitive impairment. Life expectancy usually extends into the late teens or early twenties. Death is usually due to respiratory failure.
3. Sheie syndrome (MPS IS): This is a rare and mild phenotype. The physical symptoms of Sheie syndrome are similar to Hurler and Hurler-Sheie syndromes, but patients have normal intelligence. Most patients die before the age of 25 to 30 years.

History and Physical

Children with Hurler syndrome are usually not born with signs but develop symptoms during the first year of life. Developmental delay may become apparent by the age of 1 to 2 years, with a maximum functional age of 2 to 4 years. The average age of mortality is 5 years, and nearly all patients die before 10 years of age.

• General appearance: Characteristic features include coarse facies, enlarged head with prominent frontal bones, widely placed eye sockets with protruding eyes, flat appearance of the nasal bridge, enlarged lips, and wide-open eyes. The neck is typically short and stiff. These characteristic features were formerly described traditionally in the medical literature by the term gargoylism.
• Neurological manifestations: Children have a progressive developmental delay before 2 years of age and lose previously acquired skills. GAGs are deposited in the meninges and spinal cord. This results in obstruction of CSF thereby causing high pressure communicating hydrocephalus and convulsions. Odontoid dysplasia and anterior C1-C2 subluxation occur frequently and can cause cord compression and sudden death.
• Respiratory manifestations: Patients often develop frequent ear, sinus, and pulmonary infections with thick secretions that lead to frequent emergency department visits and hospitalizations. Soft tissue thickening in the nose, pharynx, tonsils, and adenoids along with abnormalities in the tracheal cartilage causes progressive airway obstruction and sleep apnea. In some patients, sleep apnea is unrecognized and can cause significant hypoxemia at night, leading to complications like pulmonary hypertension and cor pulmonale.[4]
• Cardiac manifestations: These include cardiomyopathy, endocardial fibroelastosis, valvular regurgitation, and heart failure. GAG deposition within the blood vessels causes diffuse narrowing of the coronary arteries. Some untreated patients develop irregular lesions of the aorta. Most patients with severe Hurler syndrome die from heart failure before the age of 10.[2] It has been recommended that patients undergo cardiac evaluation every 1 or 2 years after an initial diagnosis of Hurler syndrome.
• Gastrointestinal manifestations: Swallowing might become difficult due to GAG deposition in the muscle tissue of the tongue, resulting in macroglossia which might impair speech. Patients also develop umbilical and inguinal hernias within several months of life, often one of the first clinical signs. Hepatosplenomegaly is also noted.
• Musculoskeletal system: Patients may be of normal height during infancy but stop growing by the age of 2 years. They may not reach a height of greater than 4 feet. Skeletal abnormalities occur by about 6 months but become more clinically obvious by 10 to 14 months. A rapidly enlarging head size due to craniosynostosis and hyperostosis of the skull is usually seen. They may experience debilitating spine and hip deformities, abnormal bone and cartilage development (particularly spine and hands), carpal tunnel syndrome, and joint stiffness. Abnormal curvature of the lower spine, giving a hunchback appearance called Gibbus (dorsal kyphosis) deformity, is common. Patients may develop progressive joint stiffness and contractures, which limit mobility and are painful. Cervical myelopathy is seen due to congenital vertebral anomalies and atlantoaxial subluxation. Vertebral bodies are characteristically hypoplastic and show anteroinferior beaking on radiological examination. Patients usually develop typical skeletal abnormalities, known as dysostosis multiplex.
• Ocular manifestations: Clouding of the cornea occurs due to structural alteration of the corneal stroma and derangement of collagen fibrils thereby leading to blindness. Retinal degeneration and optic nerve compression can also occur within the first year of life.
• Hearing manifestations: GAGs build up in tubes of the middle ear and further prevent them from draining properly, leading to recurrent ear infections. Patients usually develop combined conductive and sensorineural hearing loss.[5][6]
• Integumentary manifestations: Hair is often coarse and more abundant than in normal children. Bluish birthmarks known as Mongolian spots are common.

Evaluation

Diagnosis of this condition is based on a thorough clinical examination and measurement of urinary GAG levels which is a useful screening test. A positive test is suggestive of an MPS, but false-negative results are common.[18] Positive family history is often present.

Enzyme activity assays based on cultured fibroblasts, leukocytes, plasma, and serum are confirmatory and are considered the gold standard. By using an enzyme assay or DNA analysis, it is sometimes possible to distinguish Hurler syndrome from the other closely related MPH I subtypes, along with symptom severity and age of onset should be considered, establishing a specific diagnosis.

Prenatal diagnosis: Measurement of enzyme activity in cultivated chorionic villus or amniocytes can be used for the prenatal diagnosis.[7]

Gene sequencing can be done to identify the mutations in families at risk so that patients can be offered genetic counseling and carrier testing to allow for more informed family planning.

Treatment / Management

Most therapies for Hurler syndrome are directed towards treatment of complications and are not specific for an underlying abnormality.

• Enzyme replacement therapy: Recombinant human alpha L- iduronidase (Aldurazyme) is given as a weekly intravenous injection. Better outcomes can be achieved if it is given before severe complications ensue.[8] It is used for patients with the Hurler and Hurler-Scheie forms of MPS I and moderate-to-severe symptoms in patients with Scheie form.
• Hematopoietic stem cell transplant (HSCT): HSCT is the progressive replacement of enzyme-deficient hematopoietic cells with donor-derived enzyme competent cells. It is the ideal treatment for patients who are under 2 years of age and in selected patients over this age limit as it can prolong the survival. HSCT decreases hepatosplenomegaly, airway obstruction, CSF pressures and increases joint mobility, cardiac function, and improves or stabilizes hearing (mostly in young patients). HSCT is more effective at preventing disease progression than reversing the established disease.[8]
• Additional management of Hurler syndrome is supportive and includes surgical interventions like adenotonsillectomy; hernia repair; ventriculoperitoneal shunt; cardiac valve replacement; carpal tunnel release; spinal decompression; physical, occupational, and speech therapies; respiratory support such as continuous positive pressure ventilation with oxygen supplementation (CPAP); hearing aids; and medications for pain and gastrointestinal disturbances. Corneal transplants can be done for vision problems; however, surgery in patients with Hurler syndrome often presents with complications related to anesthetic procedures.
• Newer therapies: Research is ongoing with gene therapy in animal models, which includes the delivery of iduronidase enzyme gene by using viral vectors.[9] It demonstrated correction of disease in the liver, spleen, and brain effects to a certain extent. Gene therapy may provide a future alternative human treatment for MPS disorder.
(B3)

Differential Diagnosis

• Hunter syndrome (mucopolysaccharidosis type 2): Patients present with similar features as in Hurler syndrome, but patients with Hunter syndrome present in later onset with a slower clinical course and absence of corneal manifestations.
• Sly syndrome (mucopolysaccharidosis type 6): This a rare disorder shares similar clinical features as Hurler syndrome. Mental retardation may be mild or absent. Hydrops fetalis is a most common presentation, and usually, patients do not survive to diagnosis.

Prognosis

The life expectancy of MPS with a median age is 8.7 years. The survival rate is varied based on bone marrow transplantation. Patients who received successful bone marrow transplantation had a 2-year survival rate of 68% and 10-year survival rate of 64% when compared to those individuals who did not receive the transplants. They had a significantly decreased life expectancy, with the median age of 6.8 years.