X-Linked Hyper Igm Syndrome

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of HIGM1 syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of CD40LG is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• An immunodeficiency multigene panel that includes CD40LG and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by immunodeficiency, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Additional Confirmatory Testing

Measurement by flow cytometry of CD40 ligand (CD40L) protein expression after in vitro stimulation of T cells. In the resting state, only a low level of CD40L protein expression is seen on normal CD4+ T cells. After in vitro stimulation:

• Controls show increased expression (up-regulation) of CD40L protein in the majority of CD4+ T cells which is determined by monoclonal anti-human IgG to CD40L.
  Note: Infants younger than age six months may not express normal amounts of CD40L protein [Gilmour et al 2003].
• Persons with HIGM1 do not show increased expression of CD40L protein in CD4+ T cells.

NOTE: This testing should not be used as the only diagnostic test when HIGM1 is suspected. Up to 32% of individuals with HIGM1 may have normal extracellular domains of CD40L detected by this laboratory measure, which uses CD40L binding; but the intracellular signaling pathway from CD40L is nonfunctional, and thus genetic testing is required for diagnosis [Lee et al 2005].

Males

The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years [Winkelstein et al 2003].

Presentation. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are also (though less commonly) seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder [Lee et al 2005, Leven et al 2016, de la Morena et al 2017].

Infection. Increased susceptibility to recurrent bacterial infections consisting of upper- and lower-respiratory tract infections is seen in 75%-80% of affected individuals (typically streptococcus pneumonia and pseudomonas), otitis in 42%, and sinusitis in 36% [Leven et al 2016]. Susceptibility to invasive fungal infections (primarily Candida, Cryptococcus, and Histoplasma) is also increased. Boys with HIGM1 are also at a significant risk for opportunistic infections from Pneumocystis jirovecii (PJP; formerly known as Pneumocystis carinii) and gastrointestinal infection with Cryptosporidium parvum.

Pneumocystis jirovecii pneumonia is the first clinical symptom of HIGM1 in more than 40% of infants with the disorder and is shown as the pathogenic organism in roughly 30% of individuals with HIGM1 [Levy et al 1997, Lee et al 2005, de la Morena 2016, Leven et al 2016] and accounts for 10%-15% of the mortality associated with HIGM1 [Levy et al 1997, Winkelstein et al 2003].

The presentation of HIGM1 across different ethnic backgrounds and in different countries has been shown to be consistent in the infectious organisms at present across all individuals with HIGM1 but they are also at risk for the pathogens that are endemic to their specific region [Cabral-Marques et al 2014, Wang et al 2014, Rawat et al 2018, Tafakori Delbari et al 2019].

Gastrointestinal manifestations. Chronic diarrhea is the most frequent GI complication of HIGM1, occurring in approximately 20%-30% of affected males [Winkelstein et al 2003, Leven et al 2016]. Recurrent or protracted diarrhea may result from infection with Cryptosporidium parvum or other microorganisms; however, in at least 50% of males with recurrent or protracted diarrhea, no infectious agent can be detected [Winkelstein et al 2003, Leven et al 2016]. Poor growth is a serious complication of chronic diarrhea. Additionally, aphthous ulcers can be present in 21% of affected males [Leven et al 2016].

Hematologic and immunologic abnormalities. Neutropenia occurs in roughly 45%-50% of males with HIGM1, with anemia seen in 10%-15% and thrombocytopenia in 5% [Levy et al 1997, Lee et al 2005, Cabral-Marques et al 2014, Leven et al 2016]. Severe aplastic anemia secondary to parvovirus B19 has been found, but was reported as the initial finding in individuals with a milder phenotype and later age of presentation [Seyama et al 1998, Leven et al 2016, de la Morena 2016].

The total number of B cells in circulation is normal, however, there is a marked reduction of class-switched memory B cells [Agematsu et al 1998]. Furthermore, some individuals with HIGM1 may show progressive loss of B and NK cell populations over time, which can contribute to the increased morbidity [Lougaris et al 2018]. Defective oxidative burst of both neutrophils and macrophages have been reported – the result of impaired interaction between neutrophils, macrophages and, activated T lymphocytes through CD40 and CD40LG [Cabral-Marques et al 2018].

Histologic examination of lymph nodes shows absence of germinal center formation.

Neurologic involvement. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of males with HIGM1 [Levy et al 1997, Cabral-Marques et al 2014, Leven et al 2016]. However, in at least half of affected individuals a specific infectious agent cannot be isolated [Winkelstein et al 2003].

Hepatobiliary disease. Liver disease, a serious complication of HIGM1, historically was observed in more than 80% of affected males by age 20 years [Hayward et al 1997] but with adequate screening and treatment of Cryptosporidium infections, that number may now be lower [Leven et al 2016]. Hepatitis and sclerosing cholangitis occur in 6%-10% of affected individuals. CD40, the receptor to which CD40Ligand (CD40L) binds, has been shown to be expressed on bile duct epithelium; chronic infection with Cryptosporidium or other inflammatory changes are thought to contribute to sclerosing cholangitis and malignant transformation [Hayward et al 1997, de la Morena 2016, Leven et al 2016].

Oncologic disease. Malignancies occur in approximately 5% of individuals with HIGM1 and are associated with high mortality [Winkelstein et al 2003, de la Morena 2016, Leven et al 2016]. Malignancies reported in individuals with HIGM1 include neuroendocrine tumors of the GI tract, colon cancer, bile duct carcinomas, hepatocellular carcinomas, hepatoma, adrenal adenomas, and adenocarcinomas of the liver and gall bladder [Hayward et al 1997, Winkelstein et al 2003, Filipovich & Gross 2004, Erdos et al 2008, Leven et al 2016, Nicolaides & de la Morena 2017].

Males with HIGM1 are also at increased risk for acute myelogenous leukemia and lymphoma, particularly Hodgkin disease associated with Epstein-Barr virus infection [Filipovich & Gross 2004].

Other (rarely) reported complications of HIGM1 include autoimmune retinopathy, cutaneous granulomas, and disseminated cutaneous warts [Gallerani et al 2004, Schuster et al 2005, Ho et al 2018].

Life span. The current reported median survival time from diagnosis is 25 years [de la Morena et al 2017]. Pneumocystis jirovecii pneumonia in infancy, liver disease, and malignancies in adolescence or young adulthood are important contributors to mortality [Levy et al 1997, Winkelstein et al 2003, de la Morena 2016, Leven et al 2016].

Hematopoietic stem cell transplant (HSCT) is the only curative therapy available for HIGM1. In a retrospective series of 130 affected individuals who had undergone HSCT, overall survival, event-free survival, and disease-free survival rates were respectively 78.2%, 58.1%, and 72.3% five years post HSCT [Ferrua et al 2019].

Heterozygous Females

Typically, heterozygous females are asymptomatic but on immunologic testing have been shown to have reduced expression of CD40L on activation of CD4+ T lymphocytes. Those females with more dramatic reduction in circulating lymphocytes with CD40L due to skewed X-chromosome inactivation can have a presentation similar to HIGM1 or common variable immunodeficiency [Hollenbaugh et al 1994, de Saint Basile et al 1999, Lobo et al 2002].