Table 2.

Disorders to Consider in the Differential Diagnosis of X-Linked Hyper IgM Syndrome (HIGM1)

Gene(s)Differential
Disorder		MOIClinical Features of Differential Disorder
Overlapping w/HIGM1Distinguishing from HIGM1
AICDA
(AID)		HIGM2 (OMIM 605258)ARAbnormalities in B-cell differentiation → recurrent URTI, LRTI, GI infections
  • Opportunistic infections rare
  • Lymphoid hyperplasia common; incl: hepatomegaly, splenomegaly, giant germinal centers, follicular hyperplasia.
  • Autoimmunity w/hemolytic anemia more common 1
Note: Clinical course milder in HIGM4 than in HIGM2 2
HIGM4 (OMIM 608184)AD 3
  • Recurrent URTI, LRTI
  • ↓ production of IgG, abnormalities in B cell differentiation 2
CD40 HIGM3 (OMIM 606843)ARClinically indistinguishable w/recurrent bacterial infections & opportunistic infections w/P jirovecii, Cryptosporidium, & sclerosing cholangitis 4Clinically indistinguishable 4
UNG HIGM5 (OMIM 608106)ARRecurrent bacterial infectionsHIGM5 resembles HIGM2 in the ↑ in lymphoid hyperplasia compared to HIGM1. 2
MSH6 Constitutional mismatch repair deficiency (See Lynch Syndrome.)AR↑ or normal IgM, ↓ or normal IgG, normal B cell counts, & normal memory B cells w/↓ class-switched B cells
  • No recurrent infections
  • ↑ risk for cancers incl colorectal cancer, hereditary nonpolyposis colon cancer, & endometrial cancer
PMS2 Constitutional mismatch repair deficiency (See Lynch Syndrome.)AR
  • Recurrent infections
  • ↑ or normal IgM w/↓ IgG & IgA
  • Normal B cell counts but ↓ memory B cells
  • Café au lait spots
  • Colorectal adenocarcinoma
CD19
CD81
CR2
ICOS
IKZF1
IL21
IRF2BP2
LRBA
MS4A1
NFKB1
NFKB2
TNFRSF13B
TNFRSF13C 		Common variable immunodeficiency (CVID) (OMIM PS607594)AR
AD
  • Recurrent sinopulmonary infections
  • ↓ immunoglobulins incl IgG & IgA
  • CD40LG protein may be ↓.
  • No CD40LG pathogenic variant
  • May be assoc w/↓ number of total T cells or ↓ T-cell function 5
ADA
AK2
CD3D
CD3E
CD247
CORO1A
DCLRE1C
IL2RG
IL7R
JAK3
PRKDC
PTPRC
RAG1
RAG2 6		Severe combined immunodeficiency (SCID)
(See X-Linked SCID & Adenosine Deaminase Deficiency.)		AR
XL		All SCIDs must be considered in infants presenting w/P jirovecii pneumonia.
  • Most forms of SCID present w/absent T-cell function, quantitative abnormalities of T lymphocyte populations, & markedly ↓ mitogen function.
  • Hypomorphic RAG2 variants reported in a male w/clinical & immunologic studies suggestive of HIGM 7
AGMX2
BLNK
BTK
CD79A
CD79B
IGHM
IGLL1
LRRC8A
PIK3R1
TCF3
SLC39A7 8		Agammaglobulinemia
(See X-Linked Agammaglobulinemia [XLA].)		AR
AD
XL
  • Males w/agammaglobulinemia should be considered in differential of HIGM1.
  • XLA typically presents in 1st yr of life w/recurrent bacterial infections
Most individuals w/agammaglobulinemia lack circulating B cells.
IKBKG
(NEMO)		Ectodermal dysplasia & immunodeficiency 1 (OMIM 300291)XL
  • Serious infections, incl opportunistic infections, are a common complication at any age.
  • Variable immunoglobulins from agammaglobulinemia to normal or ↑ IgM, ↓ IgG, & low/↑ IgA w/↓ memory B cells
  • IKBKG-related hyper IgM syndrome is generally assoc w/hypohydrotic ectodermal dysplasia. 9
  • Invasive disease by MRSA & MSSA; osteopetrosis, lymphedema; conical shaped teeth
PIK3CD Activated PI3 kinase-δ syndrome (OMIM 615513]AD
  • Recurrent infections w/S pneumoniae or H influenzae
  • Chronic lung disease
  • ↑ IgM, ↓/normal IgG/IgA
  • ↓ class-switched memory B cells
  • Lymphoid hyperplasia
  • Lymphopenia, ↓ T/B cell counts
  • Severe response to herpes family virus (EBV, CMV, HSV, VZV)
ATM Ataxia-telangiectasia AR
  • Recurrent URTI/LRTI, malignancy
  • Normal/↑ IgM, normal to ↓ IgG/IgA, normal to ↓ T/B cells
  • Ataxia, telangiectasias, hypotonia, dysarthria, radiosensitivity
  • Lymphopenia, ↑ α-fetoprotein, variable mitogen & antigen response
NBN Nijmegen breakage syndrome AR
  • Recurrent URTI/LRTI, malignancy, autoimmune conditions (primarily hemolytic anemia)
  • Variable immunoglobulins w/agammaglobulinemia to ↓ IgG/IgA & normal/↑ IgM
Microcephaly, facial features, short stature, café au lait spots, vitiligo, radiosensitivity
INO80 INO80 deficiency 10 (OMIM 610169)
  • Recurrent bacterial infections
  • COPD
  • ↓ IgG & IgA
  • ↓ class-switched memory B cells
Normal CD40LG protein expression & no CD40LG pathogenic variant

AD = autosomal dominant; AR = autosomal recessive; COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; H = Haemophilus; HIGM = hyper IgM syndrome; LRTI = lower respiratory tract infection; MOI = mode of inheritance; P = Pneumocystis; S = Streptococcus; URTI = upper respiratory tract infection; XL = X-linked

1.
2.
3.

An autosomal dominant form of hyper IgM syndrome has been reported in four unrelated families with an identical pathogenic nonsense variant (p.Arg190Ter) in AICDA (reference sequence NM_020661​.2) [Durandy et al 2005].

4.
5.

See Park et al [2011], Yong et al [2011], and Abbott & Gelfand [2015] for current reviews of CVID.

6.

Note: A growing list of rare causes of SCID-like phenotypes include pathogenic variants in the following additional genes: CD3G, CD8A, CHD7, CIITA, DOCK8, FOXN1, LCK, LIG4, MTHFD1, NHEJ1, ORAI1, PGM3, PNP, PRKDC, RFXANK (RFX-B), RFX5, RFXAP, RMRP, SLC46A1, STIM1, TBX1, TTC7A, ZAP70.

7.
8.
9.
10.

From: X-Linked Hyper IgM Syndrome

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