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Autosomal recessive hyper-IgE syndrome

ORPHA169446
Synonym(s) AR-HIES
Autosomal recessive HIES
Hyperimmunoglobulin E syndrome type 2
Non-skeletal hyper-IgE syndrome
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • D82.4
OMIM
UMLS
  • C1968689
MeSH -
MedDRA -

Summary

Autosomal recessive hyper IgE syndrome (AR-HIES) is a very rare severe primary immunodeficiency disorder characterized by the clinical triad of highly elevated serum IgE levels, recurring staphylococcal skin abscesses, and recurrent pneumonia. The clinical triad is shared with the more frequent autosomal dominant HIES syndrome (AD-HIES; see this term), but other features such as persistent cutaneous viral infections are unique to AR-HIES.

AR-HIES accounts for only a small number of HIES cases, with about 130 affected families reported to date. The syndrome affects males and females equally.

In addition to the clinical triad, AR-HIES includes extreme hypereosinophilia, susceptibility to viral infections such as herpes simplex and herpes zoster, molluscum contagiosum and human papillomavirus, which are extensive, difficult to control and mutilating, and a severe dermatitis that may often be superinfected with S. aureus or, in less frequent cases, with herpes simplex (eczema herpeticum). Other clinical features such as involvement of the central nervous system (facial paralysis, hemiplegia, ischemic infarction, and subarachnoid hemorrhage), autoimmune effects, and vascular disorders are variably associated. Poor growth and failure to thrive appears to be common. Unlike AD-HIES, 50-70% of patients develop severe allergies, including anaphylaxis to food and environmental antigens, and about 30% have asthma. Although eosinophilia is a common finding in both AD- and AR-HIES, it tends to be more severe in the AR variant. The dental, skeletal and connective tissue anomalies, as well as the characteristic facies and pneumatoceles which are present in AD-HIES are rarely seen in AR-HIES. There is an increase risk of malignancies.

Homozygous mutations of the dedicator of the cytokinesis 8 DOCK8 (9p24.3) gene are responsible for many, although not all, cases. Since the discovery that loss-of-function mutations in DOCK8 underlie AR-HIES, an estimated more than 100 patients worldwide have been identified. DOCK8 deficiency appears to impair CD4+and CD8+T-cell proliferative responses, as well as B- and T-cell memory.

Due to the great variety of clinical features of DOCK8 deficiency, early diagnosis can be challenging and genetic testing may be essential.

The differential diagnosis includes the more common AD-HIES caused by STAT3 mutations, as well as other conditions that can be associated with high serum IgE, such as Wiskott-Aldrich syndrome (WAS), IPEX (Immunodysregulation - Polyendocrinopathy - Enteropathy - X-linked) syndrome, Netherton syndrome, severe combined immunodeficiency (SCID) (see these terms), and HIV-infection.

Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

AR-HIES follows autosomal recessive transmission and is more common in consanguineous families.

The therapeutic approach involves prevention and management of infections with long-term administration of systemic antibiotics and antivirals. Recently it has been shown that hematopoietic stem cell transplantation (HSCT) may be curative.

Prognosis in this form of the disorder is poor with most patients not reaching adulthood if untreated. AR-HIES has high mortality due to sepsis, CNS infections, and early onset of malignancies.

Expert reviewer(s)

  • Pr Bodo GRIMBACHER
  • Dr Cristina WOELLNER

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Detailed information

Review article
  • EN (2011)
Article for general public
  • EN (2013)
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