Autosomal Recessive Hyper-IgM with CD40 Mutations
A few unrelated families with autosomal recessive hyperimmunoglobulin M caused by mutations of CD40 have been reported. Affected members have similar clinical and laboratory findings as those with CD40L mutations. Treatment and prognosis of CD40 deficiency is similar to XHIGM.
Autosomal Recessive Hyper-IgM Syndrome Caused by an Intrinsic B-Cell Defect
AID is expressed only in B cells undergoing CSR or SHM and is thought to affect DNA editing.18 Because of milder symptoms, the diagnosis of AID deficiency is often established later in life.
AID-deficient patients present with recurrent bacterial infections, mostly affecting the upper and lower respiratory tract. In contrast to patients with XHIGM, AID-deficient individuals have an excellent long-term prognosis, especially if given IVIg prophylaxis. Most affected individuals present with striking lymphoid hyperplasia involving tonsils and lymph nodes as a result of marked follicular hyperplasia. The number of circulating T- and B-cell subsets are normal, including normal proportion of memory B cells; however, all CD27+ memory B cells fail to isotype switch and express IgM and IgD. Mutations of AID affect the entire gene and include missense, nonsense mutations, and small deletions.
UNG is expressed in proliferating cells, including B cells undergoing CSR. Following AID-induced deamination of cytosine into uracil residues on single-stranded DNA, UNG deglycosylates and removes uracil residues, thus leading to a single-stranded DNA break. The repair of the DNA nick leads to successful CSR and SHM. Because AID and UNG are functionally closely linked, lack of UNG results in a clinical phenotype similar to AID deficiency. The three UNG deficient patients reported to date have a history of frequent bacterial infections, lymphadenopathy, and an excellent response to IVIg therapy.18
X-Linked Anhydrotic Ectodermal Dysplasia with Immunodeficiency Caused by Mutations of Nemo
Anhydrotic (or hypohidrotic) ectodermal dysplasia is a rare syndrome with partial or complete absence of sweat glands, sparse hair growth, and abnormal dentition. A subset of these patients has an X-linked mode of inheritance and immunodeficiency characterized by low-serum IgG levels, variably elevated IgM levels, and decreased antibody responses. This syndrome results from mutations in the IKBKG gene encoding NEMO, a key subunit of IB-kinase that regulates NF-B dimerization and nuclear transfer.19 Most affected boys have a hypomorphic NEMO mutation that allows some function, and present with bacterial (Streptococcus pneumoniae, S. aureus) and often atypical mycobacterial infections. Loss-of-function mutations cause the X-linked dominant condition of incontinentia pigmenti in females and are embryonically lethal in males.
A review of 72 individuals with NEMO mutations has demonstrated a wide spectrum of clinical phenotypes.20 Thirty-two different mutations of NEMO were identified, with 70 percent being associated with ectodermal dysplasia, 86 percent with serious pyogenic infections, 39 percent with mycobacterial infections, 19 percent with serious viral infections, and 21 percent with inflammatory bowel disease. One-third of this cohort of NEMO patients died prematurely (mean age: 6.4 years).
Treatment with IVIg is useful but does not prevent the occurrence of serious complications. Symptomatic treatment depends on those complications