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Hyperimmunoglobulinemia E Syndrome, Pediatric

Basics

Description

- Fungal infections: mostly mucocutaneous candidiasis - Typical organisms: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae - Opportunistic infections with Pneumocystis jiroveci pneumonia - Those with AR-HIES have viral skin infections, including molluscum, warts, and/or recurrent herpes.

- Rash - Present in newborn period - Can resolve or become eczematoid

- Facial features are noted in late childhood to early adolescence, including: - Asymmetric facies - Prominent forehead/chin - Wide-set eyes

- Total serum IgE of >2,000 IU/mL - Elevation may not be present in newborns. - Can decline to normal levels in adult years - Level does not correlate with disease severity.

Hyperimmunoglobulinemia E syndrome (HIES) is a primary immunodeficiency with markedly elevated serum IgE associated with recurrent skin abscesses, pulmonary infections, and eczematoid dermatitis.

Epidemiology

  • Rare
  • True incidence and prevalence is unknown; affects equal numbers of males and females

Risk Factors

Genetics

  • Autosomal dominant cases (AD-HIES) are caused by mutations in signal transducer and activator of transcription 3 (STAT3).
  • Autosomal recessive cases (AR-HIES) have mutations in the dedicator of cytokinesis-8 gene (DOCK8).
  • AR-HIES patients differ in phenotype from AD-HIES patients.
  • Sporadic cases do occur.

Pathophysiology

  • STAT3 is integral in secretion and signaling of multiple cytokines involved in proinflammatory and anti-inflammatory responses.
  • A failure of Th 17 cell differentiation and failure of IL-17 secretion makes patients susceptible to Candida infections.
  • Deficiency in IL-11 signaling results in tooth abnormalities and craniosynostosis.
  • DOCK8 deficiency results in failure of dendritic cells to migrate to lymph nodes and affects long-term memory B cells and viral-specific CD8+ T cells.

Diagnosis

History

  • Recurrent infectionsSkinAbscessesFurunclesCellulitisLymphadenitisSinopulmonary infectionsPneumonia with aberrant healing forming pneumatoceles and bronchiectasisFungal infections: mostly mucocutaneous candidiasisTypical organisms: Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzaeOpportunistic infections with Pneumocystis jiroveci pneumoniaThose with AR-HIES have viral skin infections, including molluscum, warts, and/or recurrent herpes.
  • RashPresent in newborn periodCan resolve or become eczematoid
  • Retention of primary teethDelayed exfoliation of 3 or more teeth in 70% of patients
  • Vascular anomaliesTortuosity, dilation, and aneurysms of medium-sized vessels

Physical Exam

  • Facial features are noted in late childhood to early adolescence, including:Asymmetric faciesProminent forehead/chinWide-set eyes
  • Dermatitis
  • Skeletal anomaliesScoliosisCraniosynostosisHyperextensible jointsOsteopenia leading to resultant bone fractures from minor trauma
  • Hard palate anomalies, high-arched palate

Diagnostic Tests & Interpretation

Lab

  • Total serum IgE of >2,000 IU/mLElevation may not be present in newborns.Can decline to normal levels in adult yearsLevel does not correlate with disease severity.
  • Peripheral eosinophiliaDoes not correlate with IgEPresent in >90% of patients
  • Immunoglobulin levelsIgG and IgM are usually normal.IgA may be normal or low.IgM is often decreased in AR-HIES.
  • Specific antibody response is variable.
  • Reduced CD45RO+ memory T cells and memory B cells with normal total lymphocyte counts
  • Neutropenia may be present in a subset of patients.

Imaging

CT of the lungs if history of pneumonia to look for bronchiectasis and/or pneumatoceles

Differential Diagnosis

  • Atopic dermatitis
  • Wiskott-Aldrich syndrome
  • Severe combined immunodeficiency (SCID)
  • Omenn syndrome
  • Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX)
  • Netherton syndrome

Treatment

Medication

  • Prophylactic antibiotics, typically trimethoprim/sulfamethoxazole, for prevention of staphylococcal infection
  • Immunoglobulin replacement therapy in the case of concomitant hypogammaglobulinemia
  • Consideration of antifungal prophylaxis if recurrent/chronic candida infections

Additional Therapies

General Measures

  • Implement good management of dermatitis with regular hydration and emollient use.
  • Control pruritus with antihistamines.
  • Dilute bleach baths to decrease staphylococcal skin colonization.
  • Promptly and aggressively treat all infections.
  • Physical therapy for joint pain related to hyperextensibility

Ongoing Care

Follow-up Recommendations

Patient Monitoring

Blood pressure monitoring in patients, especially those with known vascular anomalies, as hypertension is common

Complications

  • Parenchymal lung changes from aberrant healing. Pulmonary surgery to correct these is associated with an increased risk of further complications.
  • Increased chance of malignancy, most commonly lymphoma

Additional Reading

  • Buckley RH. The hyper-IgE syndrome. Clin Rev Allergy Immunol. 2001;20(1):139 " 154. [View Abstract]
  • Davis SD, Schaller J, Wedgwood RJ. Job 's syndrome: recurrent, "cold " , staphylococcal abscesses. Lancet. 1966;1(7445):1013 " 1015. [View Abstract]
  • Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29(3 " 4):123 " 130. [View Abstract]
  • Paulson ML, Freeman AF, Holland SM. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr Opin Allergy Clin Immunol. 2008;8(6):527 " 533. [View Abstract]
  • Yong PF, Freeman AF, Engelhart KR, et al. An update on the hyper-IgE syndromes. Arthritis Res Ther. 2012;14(6):228 " 237. [View Abstract]

Codes

ICD09

  • 288.1 Functional disorders of polymorphonuclear neutrophils

ICD10

  • D82.4 Hyperimmunoglobulin E [IgE] syndrome

SNOMED

  • 50926003 Job 's syndrome (disorder)

FAQ

  • Q: How do AD-HIES and AR-HIES differ?
  • A: Aside from arising from different mutations, AD-HIES has more skeletal and facial anomalies, whereas AR-HIES is more often associated with viral skin infections and has a higher chance of malignancy.
  • Q: Will HIES patients show signs typical of infection?
  • A: HIES patients may lack classical signs of infection such as warmth and redness. Skin infections have been referred to as "cold " abscesses.
  • Q: What are the other names for HIES?
  • A: HIES has been referred to as Buckley syndrome, Job-Buckley syndrome, and Job syndrome in the literature. In the initial 1966 case series, Davis and colleagues wrote that the "appearance of these patients and the history of recurrent abscesses and skin infections makes the name " Job 's syndrome ' seem suitable. " The reference is to the Biblical character Job, who was smote "with sore boils from the sole of his foot unto his crown " (Job, Chapter 2; Verse 7).