History

According to the US X-linked immunodeficiency with hyper–immunoglobulin M [XHIGM] Registry (2003), the initial presentation of patients with XHIGM usually involves increased susceptibility to infection.^[4]Two prominent clinical problems are Pneumocystis jiroveci pneumonia (PJP) and neutropenia. Nearly one half of patients with XHIGM presented with PJP prior to, or at the time of, diagnosis.

Among all infections, pneumonia is the most common, occurring in more than 80% of patients. Other infections frequently observed in patients with XHIGM include sinusitis (43%), otitis (43%), recurrent and/or protracted diarrhea (34%), CNS infections (14%), sepsis (13%), hepatitis (9%), and sclerosing cholangitis (6%). Other, less common, infections include cellulites, subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection, molluscum contagiosum, warts, and Candida esophagitis.
Microbial pathogens that cause pneumonia include P jiroveci (59%), cytomegalovirus (CMV) (3%), adenovirus (2%), Pseudomonas species (3%), herpesvirus type 1 (2%), respiratory syncytial virus (2%), histoplasmosis (2%), Pneumococcus species (2%), Staphylococcus species (2%), Haemophilus influenzae type b (2%), and other unknown pathogens (27%). Infections with Mycobacterium bovis or atypical Mycobacterium species have been reported.
Pathogens that cause diarrhea include Cryptosporidium species (21%), Giardia lamblia (8%), rotavirus (8%), Clostridium difficile (4%), Yersinia enterocolitica (4%), and other unknown pathogens (63%).
Causes of CNS infection include echovirus (27%), Cryptococcus species (9%), Pneumococcus species (9%), and other unknown causes (55%). Neurological deterioration in cognitive functions, ataxia, and hemiplegia associated with progressive meningoencephalitis has been described in patients with CNS infection due to enteroviruses or CMV. One case with rapidly progressing multifocal leukoencephalopathy due to JC virus infection has been reported.^[7]Cerebral toxoplasmosis was the very first presenting event in a middle aged man that lead to the diagnosis of XHIGM.
Hepatitis occurred in a significant number of patients (7 of 79 patients) in the US XHIGM Registry; causative agents included hepatitis C virus, echovirus, histoplasmosis, and Bartonella species.
Cryptosporidium infection was the etiology of sclerosing cholangitis in 80% of patients.
Chronic diarrhea without identifiable infectious agents that leads to failure to thrive is common. Some patients may need parenteral nutrition. Intestinal nodular lymphoid hyperplasia and inflammatory bowel disease have been reported. Chronic hepatitis frequently progresses to cirrhosis and liver failure. Oral ulcers, gingivitis, proctitis, and perianal ulcers have also been described.
Neutropenia was the most common hematologic finding (63-68%). Nearly one half of patients had chronic neutropenia, whereas others had cyclic or episodic neutropenia. In 38% of patients with neutropenia, it was present at the time of diagnosis. Antineutrophil antibodies were negative. Bone marrow examination revealed maturation arrest of the myeloid lineage at the promyelocyte-myelocyte stage. In 48% of patients with neutropenia, oral ulcers were occasionally present. Anemia and/or thrombocytopenia also occurred but with much less frequency than neutropenia.
Hepatocellular carcinoma and carcinoid tumor of the pancreas were reported. Lymphoma, neuroectodermal tumor of the colon, and gastroenteropancreatic neuroendocrine tumors have also been reported. Neuroendocrine carcinomas associated with XHIGM are rapidly progressing and have been found in the pancreas, liver, intestine, and lymph nodes.^[8]
Seronegative arthritis, degenerative encephalopathy, hypothyroidism, and autoimmune nephropathy have been reported in patients with XHIGM. In the European XHIGM Registry, generalized lymphadenopathy was reported in 7 of 56 patients. Osteopenia is a prominent and previously underappreciated feature of XHIGM.^[9]CD40L mediated T-cell priming is required in induction of osteoclast differentiation, and CD40L deficiency may contribute to an imbalance in bone mineral homeostasis. Patients may present with spontaneous rib fractures without obvious antecedent trauma history.
A mild phenotype presenting with neutropenia, intermittent fever, and recurrent oral ulcerations is associated with hemizygous sequence variant in the CD40L gene. At age 12 years, one patient experienced only pseudomonas sepsis and uncomplicated bronchiolitis.^[10]

Physical

Physical examination findings are related to the manifestation of infection and/or associated conditions.

Patients with chronic diarrhea may present with failure to thrive.
Patients with pulmonary infections may have cough, tachypnea, dyspnea, retraction, accessory muscle use, hypoxia, or abnormal breath sound on auscultation.
Lymphadenopathy may be present.
Jaundice, pruritus, and hepatomegaly may be present.
Oral mucosal and perirectal ulcerations may be present, especially in patients with concomitant neutropenia.

Causes

XHIGM is caused by mutation in the gene (CD40LG) that codes for CD40 ligand (CD40L: CD154), a T-cell surface molecule required for T-cell–driven immunoglobulin class-switching by B cells. CD40LG is located on the long arm of the X chromosome (Xq26-27.2). CD40LG belongs to the tumor necrosis factor superfamily. More than 100 unique mutations of CD40LG have been reported.

In most patients, activated T lymphocytes fail to express CD40L.
About 20% of patients with XHIGM express non-functional CD40L on T cells, which can bind anti–CD40L monoclonal antibodies. Therefore, these patients may require testing of the capability of T cells to bind to CD40, using CD40-Ig fusion protein. The final molecular diagnosis may depend on sequence analysis of CD40L using complementary DNA (cDNA) or genomic DNA. (ref.36,37)
A case report described a patient with XHIGM due to mutation in the promotor region resulting in decreased transcription of CD40L. Sequence analysis of CD40LG genomic DNA showed no mutations.^[11]
In a minority of patients, milder mutations that allow binding of CD40 at reduced intensity are associated with less severe clinical course. Among these, a few cases presented with parvovirus B19–related anemia.
CD40-CD40L interactions may be involved in the selection of T-cell repertoire and priming of T cells, and absence of CD40-CD40L interaction may result in defective development of regulatory T cells (T-reg). This may cause development of autoimmune manifestations in patients with XHIGM.
Neutropenia is a common feature of XHIGM and may result from a defective, stress-induced, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules. Autoantibodies to neutrophils are generally absent.
CD40-CD40L interactions are important in hematopoiesis and innate/adaptive immunity. CD40-CD40L interactions may have a critical role in the development of effector cell functions on monocytes, CD34⁺ multilineage progenitor cells, and endothelial cells. The generation of dendritic cells that prime immune reactions during antigen-driven responses to pathogenic invasion also depends on functional CD40 molecules.

Differential Diagnoses

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Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003 Nov. 82(6):373-84. [QxMD MEDLINE Link].
Matamoros Flori N, Mila Llambi J, Espanol Boren T, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997 Jul. 17(4):333-9. [QxMD MEDLINE Link].
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Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. 2007 Feb. 64(2):273-6. [QxMD MEDLINE Link].
Erdos M, Garami M, Rakoczi E, et al. Neuroendocrine carcinoma associated with X-linked hyper-immunoglobulin M syndrome: report of four cases and review of the literature. Clin Immunol. 2008 Dec. 129(3):455-61. [QxMD MEDLINE Link].
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Cabral-Marques O, Arslanian C, Ramos RN, et al. Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis. J Allergy Clin Immunol. 2012 Mar. 129(3):778-86. [QxMD MEDLINE Link].
Cunningham CK, Bonville CA, Ochs HD, et al. Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr. 1999 May. 134(5):584-8. [QxMD MEDLINE Link].
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Media Gallery

During the primary antibody response, B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. This process occurs largely in an antigen-independent way (pro-B cells, pre-B cells). Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations; class-switch recombination (switching from IgM to IgG, IgA, or IgE) and somatic hypermutation (introduction of point mutations in the V regions of the Ig genes, the antigen-biding sites, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies). The secondary antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the interaction between CD40L (CD154) expressed on activated CD4+ T cells and CD40 expressed on B cells.
Chest radiograph of a 22-year-old patient with X-linked hyper-IgM syndrome.
Chest radiograph (laterval view) of 22-year-old patient with X-linked hyper-IgM syndrome.
Chest CT scan of a 22-year-old patient with X-linked hyper-IgM syndrome.

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Table 1. Clinical and Immunologic Features of Hyper-IgM Syndromes ^[12]

	XHIGM	CD40 defect	EDA-ID	AR-AID	AID- Cter	AID-Δ C	UNG defect	CSR defect- upstream from DNA cleavage	CSR defect-downstream from DNA cleavage
Defect	CD40LG	CD40	NEMO	AICDA	AICDA	AICDA	UNG	Unknown	Unknown
Inheritance	XL	AR	XL	AR	AR	AD	AR	AR	AR
Lymphadenopathy	-	-	-	++	++	++	+	+	+
Opportunistic Infection	+	+	-	-	-	-	-	-	-
Autoimmunity	±	±	+	+	+	+	-	-	+
Serum IgM	N or ↑	N or ↑	N or ↑	↑ ↑	↑ ↑	↑	↑ ↑	N or ↑	N or ↑
CD40-induced CSR	N	UD	Variable	UD	UD	UD	UD	UD	UD
SHM	↓	↓	Variable	↓ ↓	N	N	N but biased	N	N

Table.

Brand (Manufacturer)	Virus Inactivation process	pH; Additives *	Osmolality (mOsm/kg)	Parenteral Form & Final Concentrations	IgA Content ( µg/ml)	IV or SC
Bivigam (Biotest Pharmaceuticals)	Cold ethanol fractionation, solvent/detergent, nanofiltration	4.0-4.6; glycine, polysorbate 80	Unspecified	Liquid 10%	< 200 µg/mL	IV
Flebogamma DIF(Grifols)	Pasteurization, solvent/detergent, nanofiltration, fractionation, low pH treatment	5.0-6.0; D-Sorbitol	240-370	Liquid 5%, 10%	< 50µg/mL in a 5% solution, < 100µg/mL in a 10% solution	IV
Gammagard S/D Low IgA (Baxter)	Cold ethanol fractionation, solvent/detergent	6.4-7.2; Albumin, glycine, glucose, PEG, tri-n-butyl phosphate, octoxynol, polysorbate 80	5%=636; 10%=250	Lyophilized powder 5%, 10%	< 1µg/mL in a 5% solution	IV
Gammaplex (Bio Products Laboratory)	Solvent/detergent, nanofiltraion, low pH incubation	4.8-5.1; D- sorbitol, glycine, polysorbate 80	420-500	Liquid 5%	< 10 µg/mL	IV
Octagam (Octapharma)	Cold ethanol fractionation, solvent/detergent, pH4 treatment	5.1-6.0; maltose	310-380	Liquid 5%	< 200 µg/mL	IV
Privigen (CSL Behring)	pH 4 incubation, nanofiltration, depth filtration	4.6-5.0; L-proline	240-440	Liquid 10%	< 25 µg/mL	IV
Gammagard Liquid (Baxter)	Solvent/detergent, nanofiltration, low pH incubation at elevated temp	4.6-5.1; glycine	240-300	Liquid 10%	37 µg/mL	IV or Subcutaneous
Gamunex-C (Grifolis)	Caprylate precipitation, depth filtration, chromatography, pH 4 incubation	4-4.5; glycine	258	Liquid 10%	46 µg/mL	IV or Subcutaneous
Gammaked (Kedrion Biopharma)	Caprylate precipitation, depth filtration, chromatography, low pH incubation	4.0-4.5; glycine	258	Liquid 10%	46 µg/mL	IV or Subcutaneous
Cuvitru (Shire)	Fractionation, SD treatment, nanofiltration, low pH treatment	4.6-5.1; glycine	280-292	Liquid 20%	80 µg/mL	Subcutaneous
Hizentra (CSL Behring)	Cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography	4.6-5.2; L-proline, polysorbate 80	380	Liquid 20%	< 50 µg/mL	Subcutaneous
HyQvia (Baxter Healthcare)	Solvent/detergent, nanofiltration, low pH incubation	4.6-5.1; recombinant human hyaluronidase (pH 7.4)	240-300; (290-350)	Liquid 10%	37 µg/mL	Subcutaneous
Xembify (Grifolis)	Cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography, low pH incubation	4.1-4.8 polysorbate 80	280-404	Liquid 20%		Subcutaneous