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Hunter Syndrome and Hemophilia A: A Case of Two X-Linked Syndromes Occurring in One Individual 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
We report a case of Hunter syndrome (mucopolysaccharidosis II or MPS II) and hemophilia A occurring in the same individual. Most reports of concurrently occurring X-linked syndromes have been found in contiguous gene deletion syndromes. There has only been one case reported of two X-linked conditions occurring in the same individual that are not part of a contiguous gene deletion syndrome. We present a unique case of concurrent dual genetic diagnoses in a male patient.

 

Case Presentation
A 20-month-old male presented to us with a history of frequent bruising and hematomas. On clinical evaluation, the patient had macrocephaly, frontal bossing, broad ribs, and coarse facial features (thick eyebrows, broad nasal base with depressed nasal bridge, thick lips, poor dentition, and widely spaced teeth), and therefore a diagnosis of a lysosomal storage disorder was suspected. Our patient also presented with hepatosplenomegaly, umbilical hernia, frequent ear infections and mixed conductive/ sensorineural hearing loss (diagnosed via tympanograms, OAEs, and ABRs).

Diagnostic Workup
His initial workup found a low Factor VIII and prolonged PTT. MPS enzyme activity panel revealed low iduronate-2 sulfatase activity (0.83 mol/L/hr; Ref: Normal > 5.21 umol/L/hr). A skeletal survey showed broad joints, and an abdominal US showed hepatosplenomegaly. Both an echocardiogram and brain MRI were initially normal. Gene panel testing revealed two separate pathogenic variants, a frameshift variant in the IDS gene (c.1216_1217del;p.Leu406Phefs*24), associated with X-linked mucopolysaccharidosis II and an intronic variant in the F8 gene (c.5219+3A>G) associated with hemophilia A.

Treatment and Management
Currently, the patient is treated with weekly infusions of Idursulfase (Elaprase®), which is an enzyme replacement therapy for patients with Hunter syndrome, as well as Emicizumab (Hemlibra®) for hemophilia A. A multidisciplinary team of specialists is involved in this patient’s care. He has received myringotomy tubes for recurrent ear infections and serial casting for hand, ankle, and elbow contractures.

Outcome and Follow-Up
The patient has responded well to treatments for Hemophilia A treatments with no further symptomatic episodes of bleeding. Although he is receiving therapy for Hunter's syndrome, he has developed thickened aortic and mitral valves as well as enlarged tonsils and adenoids. He is followed by developmental pediatrics for a diagnosis of autism spectrum disorder and associated speech language disorder, and he currently receives speech therapy and ABA therapy at elementary school.

Discussion
This is the first reported case of hemophilia A and Hunter syndrome occurring together as concurrent genetic diagnoses. The incidence of hemophilia A has been found to be 1 in 5000 live male births and the incidence of Hunter syndrome is estimated to be 1 in 162000 live male births. Thus, we can estimate the incidence of both hemophilia A and Hunter syndrome occurring in an individual to be 1 in 810 million live male births. In general, the incidence of two concurrent monogenic diseases occurring together has been estimated to be 10-8 to 10-14 through population genomics and hyper-rare disease concepts. Although it is exceedingly rare for two concurrent unlinked genetic disorders to occur in one individual, it should always be considered when the clinical presentation does not fit a single diagnosis. It can especially be a diagnostic challenge when two or more independent genetic variations in an individual produce a distinct phenotype on clinical evaluation.

Conclusion
In conclusion, it is important to evaluate for all differential diagnoses with a reasonable modicum of suspicion in a patient presenting with a wide array of symptoms while considering that each symptom may be attributed to a different diagnosis. This case demonstrates well that a degree of diagnostic uncertainty is an essential part of diagnostic modification and refinement.

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