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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Immunology · STAT3-Deficient Hyper-IgE Syndrome

The Road to Certainty: Testing and Diagnosis

At a Glance

Diagnosing Job Syndrome (STAT3 HIES) requires both a physical evaluation using the NIH clinical score and genetic testing to confirm a STAT3 gene mutation. A full workup should also include an IgE blood test, a chest CT scan, and review by an immunologist.

Confirming a diagnosis of STAT3-deficient Hyper-IgE Syndrome (AD-HIES) requires looking at two different sets of evidence: the physical symptoms you can see (the clinical score) and the “blueprint” error you can’t see (genetic testing) [1][2].

The NIH Clinical Score (Grimbacher Score)

Before genetic testing was widely available, doctors used a points-based system developed by the National Institutes of Health (NIH) to determine the likelihood of Job Syndrome [1]. Points are awarded for features like very high IgE levels, “cold” abscesses, characteristic facial features, and retained baby teeth [3][4].

What the score means:

  • Less than 15: Job Syndrome is unlikely [1].
  • 16–39 points: Indeterminate or possible. The symptoms could be STAT3-HIES, but other tests are needed [1].
  • 40+ points: There is a very high probability of a STAT3 mutation [1][5].

The Gold Standard: Genetic Testing

While the NIH score is a great starting point, genetic testing is the only way to be 100% certain of the diagnosis [2][6]. Other genetic disorders can “look” like Job Syndrome but require radically different treatments [7][8]. Testing specifically searches for a “loss-of-function” mutation in the STAT3 gene [6][9].

Distinguishing the “Look-Alikes”

Several conditions share the “Hyper-IgE” name but have different underlying causes and risks:

Feature STAT3 Deficiency (Job Syndrome) DOCK8 Deficiency ZNF341 Deficiency
Inheritance Autosomal Dominant [10] Autosomal Recessive [11] Autosomal Recessive [12]
Viral Infections Rare [10] Common & Severe (Warts) [11] Rare [13]
Skeletal/Dental Common (Retained teeth) [14] Absent [14] Common [13]
Neurologic Risks Brain Aneurysms [15] Strokes, Brain Infections [11] Similar to STAT3 [12]

Your Diagnostic Completeness Checklist

Ensure your medical team has completed:

  1. Serum IgE Test: To confirm levels meet the criteria [16].
  2. Genetic Testing: A “Primary Immunodeficiency Panel” catches look-alikes [7][6].
  3. Baseline Imaging: A chest CT to check for lung cysts [17].
  4. Specialist Reviews: An evaluation by an immunologist [18].

For more on daily management, see Standard of Care: Protecting Your Health Every Day.

Common questions in this guide

What is the NIH clinical score for Job Syndrome?
The NIH clinical score, also known as the Grimbacher score, is a points-based system used to determine the likelihood of Job Syndrome. It awards points for features like high IgE levels, cold abscesses, and retained baby teeth. A score of 40 or higher indicates a very high probability of the condition.
How is STAT3-deficient Hyper-IgE Syndrome definitively diagnosed?
While the NIH clinical score helps assess the likelihood of the disease, genetic testing is the gold standard for a definitive diagnosis. This test specifically looks for a loss-of-function mutation in the STAT3 gene, which confirms the condition.
What is the difference between STAT3 deficiency and DOCK8 deficiency?
Both are types of hyper-IgE syndromes but have different genetic causes. STAT3 deficiency is inherited dominantly and often features retained baby teeth, while DOCK8 deficiency is inherited recessively and commonly causes severe viral infections like widespread warts.
What tests should I expect during a diagnostic evaluation for Job Syndrome?
A complete evaluation should include a serum IgE test, a primary immunodeficiency genetic panel, and a baseline chest CT scan to check for lung cysts. You should also be evaluated by an immunology specialist.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is my/my child's NIH clinical score, and which specific symptoms contributed to that number?
  2. 2.Is the genetic testing looking specifically for the STAT3 loss-of-function mutation?
  3. 3.How can we be absolutely sure this isn't DOCK8 deficiency or ZNF341 deficiency?
  4. 4.If we don't have a genetic answer yet, should we test for Th17 cell levels to help confirm the diagnosis?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (18)
  1. 1

    Identifying potentially undiagnosed individuals with hyper-IgE syndrome using a scoring system.

    Finkelshtain S, Cohen-Engler A, Rosman Y, et al.

    Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2024; (133(6)):696-702.e2 doi:10.1016/j.anai.2024.07.028.

    PMID: 39103119
  2. 2

    Whole-exome sequencing assists in the diagnosis of hyperimmunoglobulin E syndrome: Insights into dual genetic abnormalities.

    Li SY, Cao W, Ge Y, et al.

    Heliyon 2025; (11(4)):e42408 doi:10.1016/j.heliyon.2025.e42408.

    PMID: 40028518
  3. 3

    Phenotypes of 126 Moroccan HIES patients according to NIH Score.

    Fadil I, Benhsaien I, El Bakkouri J, et al.

    La Tunisie medicale 2024; (102(10)):696-701 doi:10.62438/tunismed.v102i10.5148.

    PMID: 39441153
  4. 4

    Pediatric hyperimmunoglobulin E syndrome: A case series of 4 children in China.

    Fan H, Huang L, Yang D, et al.

    Medicine 2018; (97(14)):e0215 doi:10.1097/MD.0000000000010215.

    PMID: 29620631
  5. 5

    TH17 Cells in STAT3 Related Hyper-IgE Syndrome.

    Sharma S, Saikia B, Goel S, et al.

    Indian journal of pediatrics 2016; (83(10)):1104-8 doi:10.1007/s12098-016-2150-y.

    PMID: 27226025
  6. 6

    The genetics of hyper IgE syndromes.

    AlYafie R, Velayutham D, van Panhuys N, Jithesh PV

    Frontiers in immunology 2025; (16()):1516068 doi:10.3389/fimmu.2025.1516068.

    PMID: 40040707
  7. 7

    A set of clinical and laboratory markers differentiates hyper-IgE syndrome from severe atopic dermatitis.

    Kasap N, Celik V, Isik S, et al.

    Clinical immunology (Orlando, Fla.) 2021; (223()):108645 doi:10.1016/j.clim.2020.108645.

    PMID: 33301882
  8. 8

    Long term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job's syndrome.

    Carrabba M, Dellepiane RM, Cortesi M, et al.

    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2023; (19(1)):32 doi:10.1186/s13223-023-00776-5.

    PMID: 37081481
  9. 9

    Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.

    Asano T, Khourieh J, Zhang P, et al.

    The Journal of experimental medicine 2021; (218(8)) doi:10.1084/jem.20202592.

    PMID: 34137790
  10. 10

    AD Hyper-IgE Syndrome Due to a Novel Loss-of-Function Mutation in STAT3: a Diagnostic Pursuit Won by Clinical Acuity.

    Moens L, Schaballie H, Bosch B, et al.

    Journal of clinical immunology 2017; (37(1)):12-17 doi:10.1007/s10875-016-0351-9.

    PMID: 27844301
  11. 11

    An Update on Syndromes with a Hyper-IgE Phenotype.

    Bergerson JRE, Freeman AF

    Immunology and allergy clinics of North America 2019; (39(1)):49-61 doi:10.1016/j.iac.2018.08.007.

    PMID: 30466772
  12. 12

    A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

    Béziat V, Li J, Lin JX, et al.

    Science immunology 2018; (3(24)) doi:10.1126/sciimmunol.aat4956.

    PMID: 29907691
  13. 13

    Human hyper-IgE syndrome: singular or plural?

    Zhang Q, Boisson B, Béziat V, et al.

    Mammalian genome : official journal of the International Mammalian Genome Society 2018; (29(7-8)):603-617 doi:10.1007/s00335-018-9767-2.

    PMID: 30094507
  14. 14

    Hyper-IgE syndrome, 2021 update.

    Minegishi Y

    Allergology international : official journal of the Japanese Society of Allergology 2021; (70(4)):407-414 doi:10.1016/j.alit.2021.07.007.

    PMID: 34419355
  15. 15

    Hematopoietic Stem Cell Transplantation and Vasculopathy Associated With STAT3-Dominant-Negative Hyper-IgE Syndrome.

    Ponsford MJ, Clark J, Mock J, et al.

    Frontiers in pediatrics 2020; (8()):575 doi:10.3389/fped.2020.00575.

    PMID: 33014947
  16. 16

    [Hyper-IgE syndrome. Lessons from function and defects of STAT-3 or DOCK-8].

    Alcántara-Montiel JC, Vega-Torres BI

    Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993) 2016; (63(4)):385-396 doi:10.29262/ram.v63i4.217.

    PMID: 27795219
  17. 17

    Liver abscess in a boy with hyper IgE syndrome.

    Nandy S, Shah I

    Journal of family medicine and primary care 2016; (5(2)):491-492 doi:10.4103/2249-4863.192353.

    PMID: 27843873
  18. 18

    Intraoral and maxillofacial abnormalities in patients with autosomal dominant hyper-IgE syndrome.

    Tar I, Szegedi M, Krasuska-Sławińska E, et al.

    Central-European journal of immunology 2023; (48(3)):228-236 doi:10.5114/ceji.2023.130874.

    PMID: 37901871

This page provides educational information about testing and diagnostic criteria for STAT3 HIES. Always consult an immunologist or medical geneticist for official medical testing and diagnosis.

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