The packet lists IDS as the gene associated with MPS II, with a ClinGen gene-disease validity classification of DEFINITIVE, located on the X chromosome. The inheritance pattern recorded in the packet is X-linked. GeneReviews describes the disease as almost exclusively reported in males and reports rare clinical manifestations in females. GeneReviews also states that penetrance in males is complete and that family history consistent with X-linked inheritance includes no male-to-male transmission.

GeneReviews reports limited information on genotype-phenotype correlations. Males with complete absence of functional enzyme from gene deletion or complex gene rearrangements (about 17% of affected individuals) are described as invariably manifesting the neuronopathic phenotype.

GeneReviews states that the diagnosis cannot be established on clinical findings alone, because clinical and radiographic findings vary widely and the evolution of manifestations is often a better indicator.

Newborn screening: GeneReviews reports that screening for MPS II is primarily based on iduronate 2-sulfatase (I2S) enzyme activity in dried blood spots, that activity below the laboratory cutoff is considered positive and leads to follow-up biochemical or molecular testing, and that screening is performed in the United States and Taiwan.

Suggestive findings: GeneReviews lists short stature, hepatosplenomegaly, joint contractures, coarse facies, frequent ear and airway infections and umbilical hernia as nonspecific clinical findings, commonly appearing between 18 months and four years. A skeletal survey showing dysostosis multiplex is a radiographic finding, and urine glycosaminoglycan analysis showing large amounts of dermatan sulfate and heparan sulfate is a laboratory finding. GeneReviews notes these findings are not specific to MPS II and that the urine profile is similar to that seen in MPS I.

Confirmation: In a male proband, GeneReviews describes diagnosis by identification of absent or reduced I2S enzyme activity in leukocytes, fibroblasts or plasma, with normal activity of at least one other sulfatase documented because low I2S activity is also present in multiple sulfatase deficiency. Identification of a hemizygous IDS pathogenic or likely pathogenic variant also confirms the diagnosis in a male proband. In a female proband, a heterozygous IDS pathogenic or likely pathogenic variant is described as usually establishing the diagnosis. GeneReviews states that absence of a known family history does not preclude the diagnosis.

The packet lists idursulfase (ELAPRASE), a BLA product regulated by CDER, as FDA-approved on 2006-07-24 with an active market status. GeneReviews describes intravenous idursulfase, a recombinant form of human iduronate 2-sulfatase, as enzyme replacement therapy approved in the United States and the European Union for MPS II. GeneReviews reports positive effects on functional capacity (six-minute walk distance and forced vital capacity), liver and spleen volumes, and urine glycosaminoglycan excretion, and reports that survival in idursulfase-treated individuals in the Hunter Outcome Survey was longer than in untreated individuals. GeneReviews states that idursulfase does not cross the blood-brain barrier, so no effect on central nervous system disease is anticipated.

Surveillance: GeneReviews states that because all persons with MPS II face the same organ failure issues, with timing dependent on severity, the frequency of monitoring cannot be generalized, and that the evaluations in its surveillance table are likely indicated at least yearly beginning in early to mid-childhood.

The packet also lists several orphan drug designations for MPS II. A designation is not an approval, and the packet records one of these as withdrawn. Other treatment details are not certified in this packet.

GeneReviews describes outcomes by phenotype at the population level. In neuronopathic MPS II, cognitive deterioration together with progressive airway and cardiac disease usually results in death in the first or second decade of life. In non-neuronopathic MPS II, the central nervous system is minimally or not affected, and survival into the early adult years with normal intelligence is described as common. GeneReviews also reports significant variability in age of onset and rate of progression, and that the time of organ failure depends on severity. The packet does not certify an age-of-onset category.

The packet lists active clinical trial records for MPS II on ClinicalTrials.gov, including studies sponsored by industry and academic groups. Examples with certified records include NCT05208281 (A Multi-cohort Study of Safety, Efficacy, PK and PD of GNR-055; Phase 2; active, not recruiting; AO GENERIUM), NCT05371613 (Tividenofusp Alfa (DNL310) versus Idursulfase; Phase 2; active, not recruiting; Denali Therapeutics), NCT04573023 (JR-141, STARLIGHT; Phase 3; active, not recruiting; JCR Pharmaceuticals), NCT07236606 (RGX-121-3102 gene therapy; Phase 3; active, not recruiting; REGENXBIO), and NCT02254863 (cord blood-derived cell study; Phase 1; recruiting; Joanne Kurtzberg, MD). GeneReviews also describes a number of interventions under evaluation for MPS II. Active clinical trials for this condition are listed on ClinicalTrials.gov.