STAT3-associated hyper-IgE syndrome

Definition: Autosomal dominant hyper-IgE recurrent infection syndrome is caused by mutation in the STAT3 gene (MIM.102582) (Job-Beckley syndrome).

Hyper-IgE recurrent infection syndrome is a primary immunodeficiency disorder characterized by chronic eczema, recurrent staphylococcal infections, increased serum IgE, and eosinophilia.

Patients have a distinctive coarse facial appearance, abnormal dentition, hyperextensibility of the joints, and bone fractures (Buckley et al., 1972; Grimbacher et al., 1999).

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE.

It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities.

A rash in the newborn period subsequently evolves into an eczematoid dermatitis.

Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatocoeles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. A characteristic facial appearance typically develops in adolescence.

Skeletal abnormalities include osteopenia, minimal trauma fractures, and scoliosis. Vascular abnormalities including middle-sized arterial tortuosity and aneurysms have been described.

Survival is typically into adulthood, but life span is often shortened. Most deaths are associated with Gram-negative (Pseudomonas) or fungal pneumonias. Lymphomas occur at an increased frequency.

Synopsis

 recurring bacterial infections of the skin and sinopulmonary tract
 elevation of circulating immunoglobulin E levels
 bacterial pulmonary abscess
 pneumatocele formation
 cavitating fungal abscess
 invasive fungal disease (20392475)
 cystic lung disease
 pneumonia

• Pseudomonas aeruginosa
• fungal organisms

 pulmonary fungal vascular invasion with fatal hemorrhage
 metastatic fungal disease

• Aspergillus fumigatus
• Scedosporium prolificans

 colonization of lung cavities (pneumatoceles) by Aspergillus sp. (16110817, 9264169)

• Aspergillus sp. infection (9827305)
• local invasion by Aspergillus sp. (16110817)
• rarely disseminated infection by Aspergillus sp. (16110817)

Diagnosis

Diagnosis requires a high index of suspicion based on clinical features, a clinical scoring system that includes both immunologic/infectious manifestations and skeletal/connective tissue abnormalities, and molecular genetic testing of STAT3, the only gene currently known to be associated with AD-HIES.

Treatment

The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and extent of involvement. Antiseptic therapies for the skin such as bleach baths are beneficial. Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of infections, culture of skin lesions and sputum samples helps direct therapy. Routine dental care is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth, routine screening of adolescents for early signs of scoliosis.

Genetics

AD-HIES is inherited in an autosomal dominant manner. To date, the majority of cases have been caused by de novo mutations. Each child of an individual with AD-HIES has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Etiology

 germline mutations of STAT3 (MIM.102582) in hyper-IgE syndrome (MIM.147060) (autosomal dominant hyper-IgE recurrent infection syndrome / Job-Buckley syndrome)

Clinical synopsis

 coarse facies
 asymmetric face
 prominent forehead
 mild prognathism
 hypertelorism
 broad nose
 thickening of the soft tissue of the nose
 high-arched palate
 retained primary teeth
 reduced resorption of primary tooth roots
 recurrent sinopulmonary infections
 joint hyperextensibility
 decreased bone mineral density
 recurrent fractures
 eczema, severe
 recurrent skin abscesses
 recurrent Staphylococcus aureus infections
 abscesses are ’cold,’ lacking erythema, heat, and swelling
 recurrent fungal infections
 increased serum IgE
 eosinophilia
 keratoconus (21703716)

 cutaneous anaomalies

• papulopustular rash on the face and scalp before the age of 2 months (67% of patients)
• neonatal papulopustular rash progressing to a chronic impetiginized eczematous dermatitis
• eczematous dermatitis before the age of 18 months (95%), mainly confined to the face, scalp, chest, and buttocks
• infected dermatitis (Staphylococcus aureus)
• chronic candidiasis of the oral mucosa and nails (59%)
• cutaneous herpes virus infections
• coarse facial skin with prominent follicular ostia resembling atrophoderma vermiculatum
• mucosal candidiasis (21346738)

 vascular anomalies (21494893, 17098478)

• congenital patent ductus venosus (17236905)
• bronchial artery aneurysm (7724285)
• coronary artery anomalies (21494893)
  • coronary artery tortuosity or coronary artery dilation (70% of HIES patients)
  • coronary artery aneurysms (37%) (17098478)
  • paucity of atherosclerosis
  • STAT3 can play an integral role in human vascular remodeling and atherosclerosis. (21494893)
  • coronary artery ectasia (17098478)
  • myocardial infarction (17098478)

 connective tissue anomalies and skeletal system anomalies

• characteristic facies
• scoliosis
• joint hyperextensibility
• retained primary dentition
• craniosynostosis
• osteopenia
• pathologic fractures

See also

 autosomal recessive HIES (MIM.243700), caused by mutation in the DOCK8 gene (MIM.611432)
 TYK2 deficiency (tyrosine kinase-2 deficiency) (MIM.611521), which is caused by mutation in the TYK2 gene (MIM.176941)

Online textbooks

 Autosomal Dominant Hyper IgE Syndrome. Freeman AF, Davis J, Hsu AP, Holland SM, Puck JM. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2010 Feb 23. PMID: 20301786 [Free]

References

 An adolescent with marked hyperimmuno-globulinemia E showing minimal change nephrotic syndrome and a STAT3 gene mutation. Miyazaki K, Miyazawa T, Sugimoto K, Fujita S, Yanagida H, Okada M, Takemura T. Clin Nephrol. 2011 Apr;75(4):369-73. PMID: 21426892

 Cutaneous findings in sporadic and familial autosomal dominant hyper-IgE syndrome: A retrospective, single-center study of 21 patients diagnosed using molecular analysis. Olaiwan A, Chandesris MO, Fraitag S, Lortholary O, Hermine O, Fischer A, de Prost Y, Picard C, Bodemer C. J Am Acad Dermatol. 2011 Jun 22. PMID: 21703716

 Coronary Artery Abnormalities in Hyper-IgE Syndrome. Freeman AF, Avila EM, Shaw PA, Davis J, Hsu AP, Welch P, Matta JR, Hadigan C, Pettigrew RI, Holland SM, Gharib AM. J Clin Immunol. 2011 Apr 15. PMID: 21494893

 Keratoconus associated with hyperimmunoglobulin E syndrome. Kim J, Netto MV. Cornea. 2004 Jan;23(1):93-6. PMID: 14701966

 Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Ling JC, Freeman AF, Gharib AM, Arai AE, Lederman RJ, Rosing DR, Holland SM. Clin Immunol. 2007 Mar;122(3):255-8. PMID: 17098478

 Bronchial artery aneurysm in hyperimmunoglobulinemia E syndrome. Connolly B, Manson D, Khattak S, Burrows P. Pediatr Radiol. 1994;24(8):592-3. PMID: 7724285