Hunter Syndrome · MPS II

Description

Mucopolysaccharidosis type II, MPS II, also called Hunter syndrome, is an X-linked recessive lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. The enzyme is encoded by IDS on chromosome Xq28. Reduced enzyme activity leaves dermatan sulfate and heparan sulfate undegraded inside lysosomes. Storage accumulates across connective tissue, bone, viscera, airway, heart, and, in severe disease, the central nervous system.

Because inheritance is X-linked recessive, almost all affected children are boys. Heterozygous girls are usually unaffected; rare symptomatic females have been reported in association with skewed X-inactivation or structural X chromosome variants. Pooled live-birth incidence is roughly 1 in 100,000 to 1 in 170,000 male births in registry and screening data.

Clinicians describe MPS II as a continuum, traditionally split into a severe phenotype with progressive cognitive decline and an attenuated phenotype with preserved cognition. Both phenotypes share somatic disease: coarsening facial features, hepatosplenomegaly, joint stiffness and contractures, short stature, dysostosis multiplex on skeletal radiographs, recurrent otitis media and hearing loss, airway obstruction, cardiac valve thickening, and corneal involvement that is usually milder than in MPS I. Severe MPS II adds neurodevelopmental regression, seizures, and behavioral changes, typically beginning between ages 2 and 4. Skin pebbling over the scapulae is a phenotypic feature of MPS II not seen in MPS I.

Detection is by enzyme assay on the dried blood spot or in leukocytes, with reflex to urinary glycosaminoglycan analysis and IDS gene sequencing. Several state newborn screening programs added MPS II in the past decade. As of May 2026, MPS II is under formal review by the federal Advisory Committee on Heritable Disorders in Newborns and Children for inclusion on the Recommended Uniform Screening Panel; status of the recommendation should be verified against the current ACHDNC and HRSA listing before any policy claim is repeated.

Treatments to date

Idursulfase, a recombinant human iduronate-2-sulfatase, was approved by the FDA in July 2006 as enzyme replacement therapy. It is given by weekly intravenous infusion. Idursulfase reduces hepatosplenomegaly, lowers urinary glycosaminoglycan excretion, and improves endurance and joint range of motion. The molecule does not cross the blood-brain barrier at standard intravenous doses, so intravenous idursulfase addresses non-central-nervous-system manifestations and does not alter the cognitive trajectory of severe Hunter syndrome.

Intrathecal idursulfase, idursulfase-IT, has been studied in clinical trials for the central nervous system component of severe MPS II. The Shire-Takeda Phase 2/3 program reported in 2021 did not meet its primary cognitive endpoint, and the regulatory path remains under discussion. Pabinafusp alfa, an iduronate-2-sulfatase fused to an anti-transferrin-receptor antibody designed to cross the blood-brain barrier, was approved in Japan in March 2021 for MPS II. Pabinafusp alfa is not approved by the FDA as of May 2026.

Hematopoietic stem cell transplant has a more limited evidence base in MPS II than in MPS I. Outcomes from earlier transplant cohorts were mixed for cognitive preservation, and HSCT is not a routine standard of care. Selected centers have revisited transplant in severe MPS II in light of better conditioning and supportive care, and registry follow-up continues.

AAV gene therapy programs targeting MPS II are in clinical development, including direct intrathecal and intravenous delivery approaches. None has reached FDA approval as of May 2026.

Supportive care includes airway management and adenotonsillectomy, hearing aids, cardiac valve surveillance, hydrocephalus monitoring, cervical spine imaging, orthopedic procedures, and physical and occupational therapy, coordinated through a multidisciplinary metabolic clinic.