Hyper IgM syndrome

Hyper IgM Syndrome
Nattasasi Suchamalawong, MD.
18 September 2020
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

Outline
Definition
SurvillancePathogenesis
Epidemiology
Clinical manifestation
Prognosis
Treatment

Hyper-IgM syndromes
de la Morena et al. J Allergy Clin Immunol Practice 2016;4:1023-36
Immunodeficiency (recurrent infection) with
Marked elevation of serum IgM
with low or absent IgG, IgA, and IgE
or normal/moderately elevated IgM
with low but not absent other immunoglobulins
Mechanism : defect in Ig class switching recombination (CSR)

Class swicthing recombinant defects and
HIGM syndromes
ESID Registry - Working definitions for clinical diagnosis of PID November, 27, 2018
At least one of the following:
- increased susceptibility to infections(recurrentand/or opportunistic,including cryptosporidium)
- immune dysregulation(autoimmunity,lymphoproliferation,sclerosing cholangitis)
- cytopenia (neutropenia or autoimmune) - malignancy(lymphoma)
- affectedfamily member
AND marked decrease of IgG (measured at least twice)
AND normal or elevated IgM (measured at least twice)
AND defined causes of hypogammaglobulinemia have been excluded
AND no evidence of profound T-cell deficiency
AND no evidence of Ataxia telangiectasia (cafe-au lait spots, ataxia, telangiectasia, raised AFP)

Epidemiology
R.Yazdani et al. Clinical Immunology 198 (2019) 19–30
- US X-HIGM registry, the prevalence of X-HIGM was approximately
1 in 1,000,000 live births
- X-linked Hyper-IgM syndrome (X-HIGM), which is caused by CD40L mutations,
is the most common form of HIGM and accounts for about 65–70% of all case
(2:1,000,000 in males )
- Globally, all forms of HIGM constitute 0.3–2.9% of all patients with PIDs.
- European Society for Immune Deficiency (ESID) demonstrated that
3.08% of PID patients enrolled had CSR defects, the most prevalent being
CD40L deficiency with a frequency of 1.16%

Epidemiology
Durandy and Kracker. Class-switch recombination defect. Stiehm’s
immune deficiencies, 2014
CD40-ligand deficiency is the
most common CSR-D

Incidence in Thailand
P. Benjasupattanan et al. J Clin Immunol. 2009; 29:357-364.
O. Luecha et al. J Allergy Clin Immunol. 2012.
Primary Immunodeficiency Diseases; A 20 Years
Experience in a Tertiary University Hospital at Ramathibodi

B cell responses to antigen
Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018
T- independent response
T- dependent response

Class Switching Recombination (CSR)
3 Important steps
1.) Induction of CSR : primary & secondary stimuli
2.) Double-strand breaking (DSB) : Cleavage of S region
3.) Resolution of DSB (S-S synapsis) : recombination
M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36

2.Double-Strand Breaking
(DSB): molecular
AID - Activation-induced cytidine deaminase
UNG - Uracil N glycosylase
APE - Apurinic/Apyrimidinic endonuclease

Mechanism of
heavy chain
isotype switching
Abbas,Abul K. Cellular and molecular
immunology, 9th ed, 2018
I = initiator of transcription S = switch region

Isotype class
switching
Regulated by cytokine
from helper T cells

Affinity maturation

Pathogenesis
Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 february

Pathogenesis
R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30

PID with elevated IgM
Congenital Acquired
- Multiple myeloma, CLL, lymphoma
-Nephrotic syndrome
-Congenital rubella syndrome
-Medications: calcineurin inhibitors and
phenytoin
-Autoimmune diseases: AIHA, Primary
biliary cirrhosis, Multiple sclerosis,
cryoglobulinemia
- Classic : HIGM types 1 to 5 (CD40L,AID,CD40,UNG)
- Other defect in CSR : MSH6 deficiency , PMS2 deficiency , APDS
, INO 80 defect
- NEMO (defects in nuclear factor kappa B essential modulator)
- Syndromes associated with HIGM & Low IgG
Ataxia telangiectasia (AT)
Nijmegen breakage syndrome (NBS)
Cernunnos/XRCC4-like factor

CLASSIC HIGM SYNDROMES: X-Linked HIGM
(HIGM type 1; CD40Ligand gene)
● Mutations in CD40 Ligand gene (CD40LG) on Xq26.3
● The most common and well-recognized form of HIGM syndrome

X-Linked HIGM: Clinical manifestations
● Onset: childhood, up to 40s
● Prevalence 1: 1,000,000
● > 80% recurrent upper and lower respiratory tract infections
● 40% gastrointestinal manifestations : chronic diarhea
● Others: Neutropenia, common and may be intermittent
Parvovirus aplastic anemia
Liver disease and sclerosing cholangitis are “red flags” for HIGM and important predictor of mortality
● Opportunistic infections : in young infants : Pneumocystis jirovecii infection.
Cryptosporidium infection >> associated sclerosing cholangitis.
● Malignancy: frequently classified as neuroendocrine tumor
Pathology : biopsy LN not seen germinal center.
Common
H.Buckley ,S.orange et al.Primary immune deficiency .middleton’s Allergy (9th edition) 2019

Predictor of Mortality
Vian Azzu & Lucinda Kennard et al. J ALLERGY CLIN IMMUNOL JANUARY 2018

GI manifestations in X-Linked HIGM

Neutropenia in XHIGM
Rawat et al.Clin Immunol .2018 October ;195:59-66.
▪ Etiology of neutropenia is not known in XHIGM
▪ CD40-40L interaction play a role in myelopoiesis >> neutropenia
▪ An arrest of myelopoiesis at promyelocyte or myelocyte
▪ Treatment : recombinant G-CSF : increase neutrophil counts and
significantly reduction in infection
▪ Presence of neutropenia probably did not influence mortality outcome
▪ Survival rates in XHIGM following HSCT : have proven to be superior
compared to patient who are not transplanted

Cabral-Marques et al.J Allergy Clin Immunol 2018;142:1571-88.
Patients with XHIGM caused by CD40L deficiency often present
with episodic, cyclic, or chronic neutropenia, suggesting abnormal
neutrophil development.
CD40L-deficient patients are susceptible to life-threatening
infections caused by opportunistic pathogens, suggesting
impaired phagocyte function
Similar to CD40L-deficient patients, CD40L knockout mice were
found to have impaired neutrophil responses.
In parallel, we demonstrated that soluble CD40L induces the
promyelocytic cell line to proliferate and mature

X-Linked HIGM: Treatment
● Curative treatment: hematopoietic stem cell transplantation (HSCT)
● IVIG replacement
● Prevention of opportunistic infections:
○ Pneumocystis jirovecii: Trimethroprim- sulfamethoxazole
○ Cryptosporidium: chlorine-tolerant
- Drinking only boiled ± filtered water - Avoidance of public swimming pools, lakes, and ponds
- Limiting contact with livestock - Practicing extra caution when traveling
- Prophylactic use of azithromycin: not recommended
● Prognosis : 20% survival by age 25 year

Causes of death in patients undergoing HSCT
Infection 2
Acute GVHD 1
Liver failure 1
Mitsui-Sekinaka, et al. J Allergy Clin Immunol. 2015 Oct;136(4):1018-24.

Mitsui-Sekinaka, et al. J Allergy Clin Immunol. 2015 Oct;136(4):1018-24.
Conclusion:
- Prognosis of XHIGM was poor
- HSCT showed significant benefit
- Younger patients received HSCT had
significantly higher survival, event-free
survival, and disease-free survival rate.
Overall survival Event-free survival
Disease-free
survival

J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292.
Conclusion
- General prognosis of XHIGM is poor
- Liver disease is a significantpredictor of poor prognosis
- HSCT showed no significant survival benefit, but did improve performance status
- Younger age and absence of liver disease are predictor of good HSCT outcome
Non-
HSCT
HSCT
Overall study
(176)
109
(62%)
67
(38%)
North American 52 36
South American 20 5
Europe 25 26
Other 12 0
Large sample of patient with XHIGM to
1.Compare long term overall survival of Pt treated with/ w/o HSCT
2.Clinical factor associatedmortality risk

E Table 1. Affected Organ/System involvement at diagnosis for patients with XHIGM (N=176).
Patients may have been described as having more than one organ/system involved.

HSCT
Non HSCT
W/O liver
disease
liver disease

No HSCT
HSCT

FIG 4. Karnofsky/Lansky scores
(as percentages) of surviving patients with XHIGM.
P < .001
Non HSCT
HSCT

Kaplan-Meier estimates of post transplantation survival by year of diagnosis:
before 1993 (1964-1992) and after 1993 (1993-2013).
HSCT outcome by year of diagnosis

Management
Ferrua and Galimberi et al. J Allergy Clin Immunol 2019;143:2238-53.
-HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before
organ damage development.
-Myeloablative conditioning is associated with better overall survival
CD40 ligand (CD40L) deficiency, an X-linked primary
immunodeficiency, causes recurrent sinopulmonary,
Pneumocystis and Cryptosporidium species infections.
Long-term survival with supportive therapy is poor.
Currently, only curative treatment is
“ Hematopoietic stem cell transplantation (HSCT) ”

Management

Management
Result & Conclusion
- HSCT can be curative in patients with CD40L deficiency, with the best outcome
if performed before 10 years of age and without organ damage, especially
sclerosing cholangitis.
- Superior OS was achieved with matched donors. HSCT early after diagnosis and
use of myeloablative regimens resulted in greater OS and DFS. EFS resulted
improved with MSDs, MAC, and BM as stem cell source.
- Reduced intensity and nonmyeloablative conditioning were associated with
poor donor cell engraftment.

Clinical trial therapy based on correcting
CD40/CD40L pathway
• In a mouse model of HIGM1, treatment with human recombinant CD40L protein
protected the mice from opportunistic infections, restored the mice’s ability to make
gamma globulin and improved survival.
• Three children with HIGM were administered recombinant CD40L. The specific Ab
responses to T cell-dependent Ag was still absent.
• Ab synthesis recovered partially in a mouse model , this may not predict the
outcome in humans.
• Gene therapy was supposed to be the fundamental therapeutic solution for
HIGM; however, gene therapy for HIGM still remains at the animal testing stage
Meng et al. Innate Immunity.2018 Vol.24 : 4-10.

Management
Hubbard et al.Blood. MAY 2016;volume127(number 21):2513-2522.
Gene therapy
• The CD40LG locus can be specifically targeted and repaired in primary human T
cells by insertion of a spliced CD40LG complementary DNA.
• Gene editing restores regulated CD40L expression in X-HIGM T cells,
reconstituting B-cell immunoglobulin class switching

Autosomal-recessive HIGM type 2
(activation-induced cytidine deaminase [AID])
● Biallelic mutation in AID (or AICDA) on chromosome 12p13, rare : 20% of CSR-D
● Defect intrinsic to B cell CSR
● AID also important in controlling of autoreactive B cell
● Early onset recurrent sinopulmonary infections (similar to XHIGM)
● Hallmark : Lymphadenopathy ,diffuse lymphoid hyperplasia
● No opportunistic infections (≠ XHIGM)
● Histology : Giant germinal centers
● Autoimmune cytopenia :
Hemolytic anemia , thrombocytopenia

(activation-induced cytidine deaminase [AID])
Treatment
● Regular IVIG replacement : reduce frequency of infection
● IVIg replacement : not prevent lymphadenopathy , autoimmune
● N0 PCP prophylaxis : AID deficiency (pure B cell defect)
● If Life-threatening autoimmunity : Corticosteroid , anti CD20 monoclonal
antibodies

(CD40 deficiency; TNFSFR5)
● Mutations in CD40, TNF Receptor Superfamily Receptor 5 (TNFRSF5), on 20q12-q13.12.
● Very rare <1% , affects both male ,female ; consanguineous families
● CD40 expressed in B cells, dendritic cells, monocytes, macrophages and other tissues such as
endothelial cells, neuronal cells, bronchial epithelial cells, and bile duct epithelial cells.
● It is crucial for cognate T-B-cell interactions
● Clinical phenotype is a combined immunodeficiency (similar to XHIGM)
● Treatment:
IVIG replacement
Antibiotic prophylaxis : PCP prophylaxis
HSCT(HLA identical donor) : may be less efficacious than
CD40L deficiency
H.Buckley ,S.orange et al.Primary immune deficiency .middleton’s Allergy (9th edition) 2019

● Associated with normal class switch recombination (CSR) but abnormal somatic
hypermutation (SHM)
● Unknown molecular mechanism, proposed to lie downstream of AID
● milder clinical phenotype than HIGM type 2
○ Sinopulmonary infections, sepsis, lymphadenitis, and osteomyelitis
○ Lymphadenopathy and autoimmunity along with myelodysplasia
● Management: Regular IVIG replacement : reduce frequency of infection

(Uracil-DNA-glycosylase [UNG])
● Very rare , UNG gene is located on chromosome 12q24.11
● Absence of UNG prevent DNA double-stranded breaks (DSBs) to form within the switch
region (S) and variable region (V)
● Clinical characteristics: similar to AID defects:
- Susceptibility to bacterial infections in early childhood
- Lymphoid hyperplasia
- Elevated levels of IgM with variable levels of IgG
● Treatment: Regular IVIG replacement : reduce frequency of infection
If Life-threatening autoimmunity : Corticosteroid , anti CD20 monoclonal antibodies

Classic : HIGM
M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36

DNA repair
genes mutation
● Mutator S homolog 6 (MSH6) deficiency
● PMS2 deficiency (mismatch repair gene; PMS2)
● Phosphoinositide 3-kinase δ syndrome
(activated PI3K-δ, activated PI3 Kinase-δ syndrome [APDS]; PIK3CD)
● Deficiency in the INO80 chromatin remodeling complex
R. Yazdani et al. The hyper IgM syndromes,
Clinical Immunology 198 (2019) 19–30
M.Teresa de la Morena et al.J allergy Clin Immunol
Pract 2016;4:1-23-36

Other defects in class switch recombination

Phosphoinositide 3-kinase δ syndrome
Jhamnani et al. CSR/HIGM Syndromes and PIK3 Defects. Frontiers in Immunology. Sep 2018
- PI3K pathway represent a distinctive subset of CSR/HIGM syndromes
- autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 >>
hyperactivation of the enzyme PI3Kδ-Akt pathway >> reduce antibody production & T cell
lymphopenia
- Clinical : combined immunodeficiency , recurrent sinopulmonary tract infection ,
recurrent and severe herpes infection (Hallmark)
Treatment
- prophylactic measures, such as antibiotics, antivirals
- Immunoglobulin replacement.
- Immunosuppressive therapy (control lymphoproliferation and/or autoimmunity)
: Rapamycin , Rituximab

Coulter and Cant. The Treatment of Activated PI3Kδ Syndrome. Frontiers in Immunology. Sep 2018
Treatment
- prophylactic measures, such as antibiotics, antivirals
- Immunoglobulin replacement.
- Immunosuppressive therapy (control lymphoproliferation and/or autoimmunity)
: Rapamycin , Rituximab

Jhamnani et al. CSR/HIGM Syndromes and PIK3 Defects. Frontiers in Immunology. Sep 2018
Treatment :
- PI3Kδ blockage : Idelalisib , Leniolosib
Study : In 2017 : Leniolisib, PI3K δ inhibitor >> therapeutic option in patients
with PIK3CD GOF mutations.
6 patients were treated 12-weeks period >> decreased lymphadenopathy
and splenomegaly.
- Curative treatment : HSCT
in 2017 : 81% survival 9/11 APDS patients who underwent HSCT in seven pediatric centers.
Acute GvHD was a common complication (81%),
2/3 (6/11) of APDS : surviving patients are off immunosuppressive therapy and
immunoglobulin replacement.

Okano et al.J Allergy Clin Immunol 2019;143:266-75.
Conclusion
30 yrs overall survival was 86.1%, but event-free
survival was 39.6%.
Indication HSCT : progressive combined
immunodeficiency or massive lymphoproliferation,
Complication : graft rejection

D. Notarangelo et al .J Allergy Clin Immunol 2019;143:91-3.
- survival rate in the 2 series was comparable (9/11 and 7/9,
respectively),
- complication severe graft-versus-host disease,
- Outcome significant improvement of humoral immunity.
- Transplantation from matched donors, use of more intense
conditioning, and inclusion of alemtuzumab might have
improved engraftment.
Administration of mTOR and PI3Kd inhibitors might represent a useful bridge therapy to
control immune dysregulation and bring patients to transplantation in better clinical status.

PID Syndrome associated with HIGM and low IgG
● Ataxia Telangiectasia (ataxia telangiectasia mutated [ATM])
● Nijmegen breakage syndrome (NBS1)
● Cernunnos/XRCC4-like factor deficiency (SCID T-B-SCID;
nonhomologous end-joining 1)

Syndromic HIGM
Treatment : no cure ,avoidance of ionizing radiation
Symptomatic & supportive physical & speech therapy
IVIG infusion (evidence immunodeficiency)
Treatment : IVIG infusion (immunodeficiency)
avoidance of ionizing radiation
Increase mortality : lymphoreticular
Treatment : IVIG infusion , antibiotic therapy , HSCT

Mutations in NEMO and IKBA can lead to NF-κB
signaling defects .
- X-linked Anhidrotic (hypohydrotic) Ectodermal
Dysplasia with Immunodeficiency (EDA-ID) :
mutations in NEMO/IKKγ gene.
leading to an abnormal expression of
multiple enzymes required for antibody switching
such as AID and UNG.
-Autosomal dominant mutations of IKBA/IκBα,
result in blockage of NF-κB release into the nucleus interfering with NF-κB and downstream CD40 signaling.
X-linked Anhidrotic ectodermal dysplasia with
immunodeficiency (EDA-ID)

● NEMO mutation : Hypohidrotic ectodermal dysplasia with immune deficiency;
anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and
lymphedema; inhibitor of kappa B kinase gamma)
Treatment : HSCT ,
IVIG replacement ,
antibiotic prophylaxis

•Study in 29 patient : 23 different hypomorphic IKBKG mutations.
•Engraftment was documented in 24 patients (83%),
and GVHD in 13 patients (45%)
•Global survival rate was 74% (22/29 Pts )at a median
follow-up after HSCT of 57 months.
•Preexisting mycobacterial infection and colitis
were associated with poor HSCT outcome.
Miot ,Imai et al. HSCT in 29 NEMO deficiency , Blood. 2017;130(12):1456-1467.
Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.
Transplantation did not appear to cure colitis, possibly as result of cell-intrinsic disorders of the
epithelial barrier.

Summary of management of HIGM syndrome
- Multiple therapeutic approaches to control the complications of HIGM syndromes,
including
- Immunoglobulin replacement therapy : decrease severity/frequency of infection
- Antimicrobial therapy
- PCP prophylaxis : Bactrim , IV/inhaled pentamidine
- Cryptosporidium infection : nitazoxanide and azithromycin , adequate hygiene
- Monitoring liver and biliary tract function : LFT , CBC , ultrasound , biopsy
- G-CSF (Granulocyte-colony stimulating factor) : if neutropenia
- CD40-agonist therapy
- Immune-suppressive therapy : AID , APDS
- HSCT : CD40 ligand deficiency , AR-CD40 deficiency , NEMO mutation , APDS
- Gene therapy : more complicated

Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome
Manifestation/
Concern
Treatment Considerations/Other
Recurrent
infections
•Immunoglobulin replacement IV or SC
• Initial dosing for IgG replacement: 0.4-0.6 g/kg every
3-4 wks for IV, or ≥100 mg/kg dose weekly for SCIg.
•Titrate IgG levels as for primary antibody deficiency
syndromes.
•Prophylactic antibiotics against opportunistic infections
include : P jirovecii
•Aggressively evaluate pulmonary infections (include use
of diagnostic bronchoalveolar lavage) to define specific
etiology.
Discussion re prophylactic use of
azithromycin or nitazoxanide for all
affected individuals for prevention
of Crypstosporidium is ongoing.
While not standard of care, it should
be considered for those living in /
traveling to an
area↑ Cryptosporidium rates.
Immunodeficiency
Only current curative treatment is HSCT, preferably at
age <10 yrs.
Modified conditioning regimens may
be needed in those w/preexisting
liver disease, & hepatic transplant
along w/HSCT may be required.
Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February

Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome
Manifestation/
Concern
Treatment
Chronic neutropenia Recombinant GCSF
Malnutrition &
poor growth
Total parenteral nutrition & consultation w/clinical dietary nutritionist may be
required to optimize caloric intake.
Sclerosing cholangitis
end-stage sclerosing cholangitis have been treated successfully with orthotopic liver
transplantation closely associated allogeneic bone marrow transplantation.
- Infectious etiologies need to be pursued & treated prior to transplantation.
Autoimmune disorders
Treatment of autoimmune disorders usually involves judicious use of
immunosuppressants tailored to individual's diagnosis.
Cancer
Treatment should follow standard protocols/therapies for individual cancers in
conjunction w/immunologist.

Disease Gene Ig G
replace
ment
HSCT Gene
therapy
PCP
prophylaxis
Note
Classic HIGM
HIGM1 CD40LG ✓ ✓ - ✓
- Avoid live vaccine,
- Blood product irradiation ,CMV neg
If neutropenia >> G-CSF
- Adequate hygiene ,drink boiled/filter waterHIGM3 CD40 ✓ ✓ - ✓
HIGM2 AID ✓ - - -
HIGM5 UNG ✓ - - -
DNA repair gene
mutation
MSH6 def
MSH6 ✓
- - -
PSM2 def PSM2 ✓ - - -
INO80 INO80 ✓ - - -
APDS PIK3CD ✓ ✓ - ✓ Reduction in lymphoproliferative
- mTOR inhibitor (Sirolimus)
- Selective PI3Kδ inhibitors (Leniolisib)
NEMO IKBKG ✓ ✓ - ✓
-Avoid live vaccine
-Fluconazole prophylaxis
Management in HIGM syndrome

Prognosis
-The Registry of the ESID on 56 affected males showed a 20% survival rate in individuals aged
~25 years .
-US X-HIGM Registry reported that 11 out of 61 surviving patients were aged >20 years.
-Cause of death was pneumonia, encephalitis or malignancy and liver failure secondary to
sclerosing cholangitis , cirrhosis.
-In a national study of morbidity and mortality of 38 Iranian HIgM patients, 10-years survival rate
was 67.8% and the most common cause of death is respiratory failure.

Recommended Evaluations Following Initial Diagnosis in X-Linked
Hyper IgM Syndrome
System/Concern Evaluation Comment
Hematology/
Immunology
•CBC w/differential
•IgG levels
•T, B, & NK cell numbers
For evidence of cytopenia
Pulmonary
Baseline chest radiograph &
pulmonary function testing
For chronic lung changes due to infection;
if present, consider pulmonology evaluation.
Gastrointestinal
PCR-based testing of stools
Nutritional assessment
For presence of Cryptosporodium or other
enteric pathogens; if present, consult
gastroenterologist.
Hepatobiliary
Baseline liver function testing & liver
/ biliary tree ultrasound
For evidence of hepatocyte dysfunction &
developing biliary dilation
Transplantation
All individuals should be offered
HLA typing at diagnosis.
For consideration of HSCT
Other Consultation clinical geneticist
Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February.

Recommended Surveillance for X-Linked Hyper IgM Syndrome
System/Concern Evaluation Frequency
Hematology
CBC w/differential to monitor for
Cytopenia
At least every 6 months to yearly
if stable or any change in clinical status
Immunology
IgG levels
•IgG frequency depends on time needed to achieve
adequate IgG levels; similar to those with primary
antibody deficiency syndromes.
•Adults: at least yearly
Lymphocyte subpopulations: T,
B, & NK cell numbers
Given progressive T, B, & NK loss over time,
consider obtaining yearly in non-transplanted
adolescents & adults.
CD40L expression in
transplanted individuals
Monitor CD40L expression in activated T-cells at
least yearly in those who have had HSCT,
or if any change in clinical status.

Recommended Surveillance for X-Linked Hyper IgM Syndrome
System/Concern Evaluation Frequency
Pulmonary
Pulmonary function tests Yearly for those age >7 yrs or if change in clinical status
Chest radiograph w/follow up of
pulmonary infiltrates w/high-resolution
CT scan
As clinically indicated
Gastrointestinal
PCR-based testing of stools for
infectious etiologies
At least every 6 months or if diarrhea present or
exposure occurs
Liver function tests
•Children: at least every 4-6 months or if change in
clinical status
•Adults: at least 1-2 time/year or if change in clinical status
Liver ultrasound ≥1x/yr or if change in clinical status
•Monitor growth in children.
•Measure weight in adolescents &
adults at least 2 time/yr
•Children: at every visit; at least every 4-6 months
•Adolescents/adults: at least 2 times/year
•If any change in clinical status
Oncology Physical exam
•Children: at least every 4-6 months
•Adolescents/adults: at least 1-2 time/year
•Low threshold for lymph node biopsy

Disease Gene Inherit IgM Ig G/A/E Features
HIGM1 CD40LG XR N/↑ N/↓ Neutropenia 30%, Opportunistic infection
Sclerosing cholangitis Neuroendocrine tumorHIGM3 CD40 AR N/↑ N/↓
HIGM2 AID AR ↑↑ ↓ Lymphoid hyperplasia, giant germinal center, splenomegaly
Autoimmune cytopeniaHIGM5 UNG AR ↑↑ ↓
MSH6 def MSH6 AR N/↑ N/↓
Solid cancer (esp. colon)
PSM2 def PSM2 AR N/↑ N/↓
APDS PIK3CD AD ↑ N/↓ Lymphopenia, lymphoma, HSV infection, bronchiectasis
INO80 INO80 AR N ↓ COPD
Ataxia
telangiectasia
ATM AR N/↑ N/↓
Lymphopenia, cancer
Ataxia, telangiectasia, oculomotor apraxia, dysarthria
Nijmegen
breakage
NBS1 AR N/↑ ↓
Lymphopenia, cancer
Microcephaly, autoimmune cytopenia, café-au-lait, vitiligo
Cernunnos/XLF
SCID
NHEJ1 AR N/↑
↓
T- B- SCID Microcephaly, autoimmune cytopenia
NEMO IKBKG XR
Ig M: ↑ in 20%, may N/↓
Ig G: ↓ Ig A: may ↑
Non-tuberculous mycobacterial infection
Ectodermal dysplasia, osteoporosis, lymphedema
Summary of clinical and laboratory features

Durandy and Kracker. Class-switch recombination defect. Stiehm’s immune deficiencies, 2014

Treatment
of
HIGM
Meng et al. Innate Immunity.2018 Vol.24 : 4-10.
CD 154
NEMO

Hyper IgM syndrome

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