Clinical Immunology

Symptoms and Differential Diagnosis: What to Expect and How It Compares

At a Glance

AD-IL6ST deficiency can cause eczema, very high IgE, recurrent skin or lung infections, and bone or dental differences, but severity varies widely—even within one family. Symptoms overlap with other Hyper-IgE syndromes, so specialist assessment and genetic testing are needed.

Because autosomal dominant (AD) partial IL6ST deficiency is a newly recognized condition, understanding your symptoms can feel like putting together a puzzle. This disorder is a form of Hyper-IgE syndrome (HIES), but it has a unique “flavor” because it specifically disrupts the GP130 protein, a critical hub for immune and growth signals ^[1]^[2].

The Core Symptoms: Immune, Skin, and Bone

The symptoms of AD-IL6ST deficiency typically fall into three main categories: skin and allergies, infections, and skeletal issues. Because this disease is incredibly rare, much of what we know is reported in a small number of individuals or extrapolated from broader HIES groups.

Skin and Allergic Manifestations

Many individuals with this condition experience skin challenges that often start in early childhood:

Severe Eczema: Intensely itchy, inflamed skin that may be difficult to manage with standard creams ^[1].
High IgE and Eosinophilia: Lab tests often show very high levels of IgE (an allergy antibody) and eosinophils (allergy-related white blood cells) ^[1].
Cold Abscesses: Some develop skin boils or abscesses that lack the typical redness, warmth, and pain of a normal infection—these are often called “cold abscesses” ^[1].

Infection Profile

The immune system’s “muffled” response makes patients susceptible to specific types of germs:

Staphylococcal Infections: Staphylococcus aureus (Staph) is a common cause of skin and lung infections in this condition ^[1].
Fungal Issues: Some patients struggle with recurrent yeast infections (candidiasis), while others face a risk of Aspergillus mold infections in the lungs ^[1].
Lung Complexity: Recurrent pneumonia can lead to structural changes, such as bronchiectasis (scarred, widened airways) ^[3].

Skeletal and Dental Features

Because the GP130 protein also helps coordinate bone and tissue growth, unique physical traits have been reported:

Retained Primary Teeth: “Baby teeth” may not fall out on their own, requiring a dentist to pull them so adult teeth can emerge ^[1].
Bone Health: Some patients have a history of fractures, scoliosis (spinal curvature), or joint hyperextensibility (being “double-jointed”) ^[1].
Facial Features: Over time, some individuals may develop subtle distinct facial features ^[1].

Variable Expressivity: Unpredictable Severity

One of the most confusing aspects of AD-IL6ST deficiency is variable expressivity. Even within the same family—where everyone has the exact same genetic mutation—one person may have severe lung disease while another has only mild eczema ^[4].

Research suggests the clinical course is unpredictable. While modifier genes, environmental factors, and the amount of “residual signaling” may influence severity, it is impossible to perfectly predict how the disease will show up for you based solely on your specific variant ^[4]^[5].

How AD-IL6ST Compares to Other Syndromes

Doctors must distinguish AD-IL6ST from other types of HIES. It is critical to note that clinical symptoms alone cannot distinguish these disorders—they overlap heavily, and diagnosis always requires specialist assessment and genetic testing.

Condition	Key Differences and Overlaps
STAT3-LOF (Job Syndrome)	The most similar to AD-IL6ST. Both share high IgE, eczema, and bone issues. However, STAT3 is the “messenger” inside the cell, while IL6ST is the “antenna” on the surface ^[1]^[2].
DOCK8 Deficiency	These patients have much higher risks for viral skin infections (like severe warts or herpes) and are more likely to develop asthma and food allergies ^[6]^[7].
ZNF341 Deficiency	This looks almost identical to STAT3-LOF but tends to have milder bone and tooth issues ^[8].
Biallelic (AR) IL6ST	This is the “recessive” form where both gene copies are broken. It is often much more severe and can include craniosynostosis (early fusing of the skull bones) or life-threatening issues in newborns ^[3]^[9].
PGM3 Deficiency	Often involves broader immune problems and may include intellectual disability or more severe skeletal changes ^[10].

The “Muffled” Alarm System Safety Check

A critical thing to understand about AD-IL6ST is that your body’s “alarm system” for infection is dampened. Because your IL-6 signaling is partially blocked, you might have a severe infection without a high fever or high CRP (C-Reactive Protein) levels ^[1]^[11]. However, never assume that normal labs mean you do not have an infection. Your fever and CRP CAN still rise, and you must rely on symptoms, breathing changes, and your physician’s assessment rather than laboratory numbers alone.

Common questions in this guide

What symptoms are common in AD-IL6ST deficiency?

Common features include severe eczema, high IgE, increased eosinophils, cold skin abscesses, and recurrent skin or lung infections. Some people also develop yeast or Aspergillus infections, recurrent pneumonia, retained baby teeth, fractures, scoliosis, or unusually flexible joints. Not everyone has the same combination or severity of findings.

Can a serious infection occur without a high fever or CRP?

Yes. Partial disruption of IL-6 signaling can blunt the fever response and reduce the rise in C-reactive protein, or CRP, during an infection. Normal temperature or CRP does not rule out a serious infection, so breathing changes, worsening symptoms, and a clinician’s assessment remain important.

How is AD-IL6ST deficiency distinguished from other Hyper-IgE syndromes?

AD-IL6ST deficiency can look similar to conditions such as STAT3-related Job syndrome, DOCK8 deficiency, and ZNF341 deficiency. Symptoms and routine laboratory findings alone cannot reliably distinguish them, so specialist evaluation and genetic testing are needed to identify the cause.

Can an IL6ST variant predict how severe the disease will be?

Not reliably. Relatives who carry the same IL6ST variant can have very different symptoms, ranging from mild eczema to significant lung disease. Other genes, environmental factors, and the amount of remaining immune signaling may influence the clinical course.

What bone and dental problems can occur with partial IL6ST deficiency?

Some people have primary teeth that do not fall out normally, as well as fractures, scoliosis, unusually flexible joints, or subtle facial differences. A dentist familiar with inherited immune disorders can help assess retained teeth and determine whether imaging or extraction is needed.

Can recurrent pneumonia lead to bronchiectasis in AD-IL6ST deficiency?

Yes. Repeated pneumonia can damage the airways and cause bronchiectasis, in which the airways become widened and scarred. This complication does not occur in everyone, but recurrent respiratory infections should be discussed with the treating clinician.

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References (11)

1
Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
Béziat V, Tavernier SJ, Chen YH, et al.
The Journal of experimental medicine 2020; (217(6)) doi:10.1084/jem.20191804.
PMID: 32207811
2
The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants.
Chen YH, van Zon S, Adams A, et al.
Journal of clinical immunology 2023; (44(1)):30 doi:10.1007/s10875-023-01603-7.
PMID: 38133879
3
A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.
Schwerd T, Twigg SRF, Aschenbrenner D, et al.
The Journal of experimental medicine 2017; (214(9)):2547-2562 doi:10.1084/jem.20161810.
PMID: 28747427
4
New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome.
Arlabosse T, Materna M, Riccio O, et al.
Journal of clinical immunology 2023; (43(7)):1566-1580 doi:10.1007/s10875-023-01517-4.
PMID: 37273120
5
Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome.
Ashihara K, Asano T, Takeuchi K, et al.
JCI insight 2025; (10(14)).
PMID: 40526438
6
The Child with Elevated IgE and Infection Susceptibility.
Freeman AF, Milner JD
Current allergy and asthma reports 2020; (20(11)):65 doi:10.1007/s11882-020-00964-y.
PMID: 32830295
7
Hyper-IgE syndromes in pediatrics: clinical spectrum, differential diagnosis, and management.
Mikulić S, Mihaljević MV, Kraljević D
Folia medica 2026; (68(4)) doi:10.3897/folmed.68.e173262.
PMID: 42677762
8
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
9
Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.
Chen YH, Grigelioniene G, Newton PT, et al.
The Journal of experimental medicine 2020; (217(3)) doi:10.1084/jem.20191306.
PMID: 31914175
10
A Novel Phosphoglucomutase-3 Gene Variant Causing Milder Phenotype in Two Families.
Gemici Karaaslan B, Benamar M, Ulas S, et al.
Journal of clinical immunology 2026; (46(1)).
PMID: 41904308
11
Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.
Chen YH, Zastrow DB, Metcalfe RD, et al.
The Journal of allergy and clinical immunology 2021; (148(2)):585-598 doi:10.1016/j.jaci.2021.02.044.
PMID: 33771552

This page is for informational purposes only and does not constitute medical advice about AD-IL6ST deficiency. An immunologist, genetic specialist, and other treating clinicians should interpret your symptoms, laboratory results, and infection concerns.