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Hyper-IgE recurrent infection syndrome 4, autosomal recessive(HIES4B)

MedGen UID:
1673363
Concept ID:
C5193141
Disease or Syndrome
Synonyms: HYPER-IgE RECURRENT INFECTION SYNDROME 4B, AUTOSOMAL RECESSIVE; HYPER-IgE SYNDROME 4B, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS
 
Gene (location): IL6ST (5q11.2)
 
Monarch Initiative: MONDO:0032796
OMIM®: 618523

Definition

Hyper-IgE syndrome-4B with recurrent infections (HIES4B) is an autosomal recessive immunologic disorder characterized by early childhood onset of recurrent infections and skeletal abnormalities, including craniosynostosis and scoliosis. Patients are mainly susceptible to bacterial infections that affect the respiratory tract, skin, and eye. Immunologic workup shows increased serum IgE, intermittent eosinophilia, and impaired IL6 (147620) and IL27 (608273) downstream signaling that affects the development and function of certain B- and T-cell populations, as well as the acute-phase response; IL11 (147681) signaling in fibroblasts is also affected (summary by Shahin et al., 2019). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see HIES1 (147060). [from OMIM]

Clinical features

From HPO
Clubbing
MedGen UID:
57692
Concept ID:
C0149651
Anatomical Abnormality
Broadening of the soft tissues (non-edematous swelling of soft tissues) of the digital tips in all dimensions associated with an increased longitudinal and lateral curvature of the nails.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Neurodevelopmental delay
MedGen UID:
868344
Concept ID:
C4022738
Finding
Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.
Craniosynostosis syndrome
MedGen UID:
1163
Concept ID:
C0010278
Disease or Syndrome
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
Arthropathy
MedGen UID:
7190
Concept ID:
C0022408
Disease or Syndrome
Any disorder of the joints.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Joint contracture of the hand
MedGen UID:
56382
Concept ID:
C0158113
Finding
Contractures of one ore more joints of the hands meaning chronic loss of joint motion due to structural changes in non-bony tissue.
Isolated scaphocephaly
MedGen UID:
82712
Concept ID:
C0265534
Congenital Abnormality
Scaphocephaly is a subtype of dolichocephaly where the anterior and posterior aspects of the cranial vault are pointed (boat-shaped). Scaphocephaly is caused by a precocious fusion of sagittal suture without other associated synostosis.
Thoracolumbar scoliosis
MedGen UID:
196671
Concept ID:
C0749379
Anatomical Abnormality
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Eczematoid dermatitis
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Increased count of eosinophils in the blood.
Keratitis
MedGen UID:
44013
Concept ID:
C0022568
Disease or Syndrome
Inflammation of the cornea.
Increased circulating IgE concentration
MedGen UID:
116018
Concept ID:
C0236175
Finding
An abnormally increased overall level of immunoglobulin E in blood.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Food allergy
MedGen UID:
1635115
Concept ID:
C4554344
Disease or Syndrome
Primary food allergies primarily occur as a result (most likely) of gastrointestinal sensitization to predominantly stable food allergens (glycoproteins). A secondary food allergy develops after primary sensitization to airborne allergens (e. g., pollen allergens) with subsequent reactions (due to cross-reactivity) to structurally related often labile allergens in (plant) foods.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch

Professional guidelines

PubMed

Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT
J Clin Immunol 2015 Feb;35(2):189-98. Epub 2015 Jan 28 doi: 10.1007/s10875-014-0126-0. PMID: 25627830

Recent clinical studies

Etiology

Eken A, Cansever M, Okus FZ, Erdem S, Nain E, Azizoglu ZB, Haliloglu Y, Karakukcu M, Ozcan A, Devecioglu O, Aksu G, Arikan Ayyildiz Z, Topal E, Karakoc Aydiner E, Kiykim A, Metin A, Cipe F, Kaya A, Artac H, Reisli I, Guner SN, Uygun V, Karasu G, Dönmez Altuntas H, Canatan H, Oukka M, Ozen A, Chatila TA, Keles S, Baris S, Unal E, Patiroglu T
Allergy 2020 Apr;75(4):921-932. Epub 2019 Oct 31 doi: 10.1111/all.14081. PMID: 31596517Free PMC Article
Al-Shaikhly T, Ochs HD
Immunol Cell Biol 2019 Apr;97(4):368-379. Epub 2018 Nov 19 doi: 10.1111/imcb.12209. PMID: 30264496
Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
Zhang Q, Su HC
Curr Opin Pediatr 2011 Dec;23(6):653-8. doi: 10.1097/MOP.0b013e32834c7f65. PMID: 21970826Free PMC Article
Gatz SA, Benninghoff U, Schütz C, Schulz A, Hönig M, Pannicke U, Holzmann KH, Schwarz K, Friedrich W
Bone Marrow Transplant 2011 Apr;46(4):552-6. Epub 2010 Jul 12 doi: 10.1038/bmt.2010.169. PMID: 20622910

Diagnosis

Jacob M, Masood A, Abdel Rahman AM
Int J Mol Sci 2023 Jan 26;24(3) doi: 10.3390/ijms24032406. PMID: 36768728Free PMC Article
Özyurt K, Atasoy M, Ertaş R, Ulaş Y, Akkuş MR, Kiraz A, Hennies HC
Turk J Pediatr 2019;61(4):604-607. doi: 10.24953/turkjped.2019.04.020. PMID: 31990481
Al-Shaikhly T, Ochs HD
Immunol Cell Biol 2019 Apr;97(4):368-379. Epub 2018 Nov 19 doi: 10.1111/imcb.12209. PMID: 30264496
Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
Zhang Q, Su HC
Curr Opin Pediatr 2011 Dec;23(6):653-8. doi: 10.1097/MOP.0b013e32834c7f65. PMID: 21970826Free PMC Article

Therapy

Ozgur TT, Asal GT, Gurgey A, Tezcan I, Ersoy F, Sanal O
J Pediatr Hematol Oncol 2007 May;29(5):327-9. doi: 10.1097/MPH.0b013e318059c236. PMID: 17483712

Prognosis

Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, Tavakol M, Eslamian MH, Gharagozlou M, Movahedi M, Ghadami M, Hamidieh AA, Azizi G, Yazdani R, Afarideh M, Ghajar A, Havaei A, Chavoshzadeh Z, Mahdaviani SA, Cheraghi T, Behniafard N, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Mansouri M, Mesdaghi M, Babaie D, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari N, Ahanchian H, Khoshkhui M, Soheili H, Dabbaghzadeh A, Shirkani A, Nasiri Kalmarzi R, Mortazavi SH, Tafaroji J, Khalili A, Mohammadi J, Negahdari B, Joghataei MT, Al-Ramadi BK, Picard C, Parvaneh N, Rezaei N, Chatila TA, Massaad MJ, Keles S, Hammarström L, Geha RS, Aghamohammadi A
J Allergy Clin Immunol 2018 Apr;141(4):1450-1458. Epub 2017 Sep 12 doi: 10.1016/j.jaci.2017.06.049. PMID: 28916186
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT
J Clin Immunol 2015 Feb;35(2):189-98. Epub 2015 Jan 28 doi: 10.1007/s10875-014-0126-0. PMID: 25627830
Zhang Q, Su HC
Curr Opin Pediatr 2011 Dec;23(6):653-8. doi: 10.1097/MOP.0b013e32834c7f65. PMID: 21970826Free PMC Article
Gatz SA, Benninghoff U, Schütz C, Schulz A, Hönig M, Pannicke U, Holzmann KH, Schwarz K, Friedrich W
Bone Marrow Transplant 2011 Apr;46(4):552-6. Epub 2010 Jul 12 doi: 10.1038/bmt.2010.169. PMID: 20622910
Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, Wintergerst U, Hauser M, Klein B, Schwarz K, Schmid I, Albert MH
Klin Padiatr 2010 Nov;222(6):351-5. Epub 2010 Nov 5 doi: 10.1055/s-0030-1265135. PMID: 21058221

Clinical prediction guides

Kumar Jindal A, Sil A, Aggarwal R, Tyagi R, Mondal S, Singh A, Barman P, Chawla S, Loganathan SK, Gupta K, Vinay K, Mahajan R, Saikia B, Kaur G, Sharma R, Saka R, Bhatia A, Sankhyan N, Pandiarajan V, Pilania R, Dhaliwal M, Sharma S, Vyas S, Suri D, Rawat A, Singh S
Clin Exp Dermatol 2024 Feb 14;49(3):226-234. doi: 10.1093/ced/llad345. PMID: 37815217
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L, Kostyuchenko L, Genel F, Kütükcüler N, Karaca N, Gonzalez-Granado L, Abbott J, Al-Zahrani D, Rezaei N, Baz Z, Thiel J, Ehl S, Marodi L, Orange JS, Sawalle-Belohradsky J, Keles S, Holland SM, Sanal Ö, Ayvaz DC, Tezcan I, Al-Mousa H, Alsum Z, Hawwari A, Metin A, Matthes-Martin S, Hönig M, Schulz A, Picard C, Barlogis V, Gennery A, Ifversen M, van Montfrans J, Kuijpers T, Bredius R, Dückers G, Al-Herz W, Pai SY, Geha R, Notheis G, Schwarze CP, Tavil B, Azik F, Bienemann K, Grimbacher B, Heinz V, Gaspar HB, Aydin R, Hagl B, Gathmann B, Belohradsky BH, Ochs HD, Chatila T, Renner ED, Su H, Freeman AF, Engelhardt K, Albert MH; inborn errors working party of EBMT
J Clin Immunol 2015 Feb;35(2):189-98. Epub 2015 Jan 28 doi: 10.1007/s10875-014-0126-0. PMID: 25627830
Zhang Q, Su HC
Curr Opin Pediatr 2011 Dec;23(6):653-8. doi: 10.1097/MOP.0b013e32834c7f65. PMID: 21970826Free PMC Article
Ozgur TT, Asal GT, Gurgey A, Tezcan I, Ersoy F, Sanal O
J Pediatr Hematol Oncol 2007 May;29(5):327-9. doi: 10.1097/MPH.0b013e318059c236. PMID: 17483712
Grimbacher B, Schäffer AA, Holland SM, Davis J, Gallin JI, Malech HL, Atkinson TP, Belohradsky BH, Buckley RH, Cossu F, Español T, Garty BZ, Matamoros N, Myers LA, Nelson RP, Ochs HD, Renner ED, Wellinghausen N, Puck JM
Am J Hum Genet 1999 Sep;65(3):735-44. doi: 10.1086/302547. PMID: 10441580Free PMC Article

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