Name: Immunodeficiency 54 | Acronym: IMD54
Alt. names: MCM4 deficiency | immunodeficiency-54 | Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency | Russell-Silver syndrome

Gene: MCM4 | MOI: Autosomal recessive | Mechanism of action: Loss of Function

No. of cases in DB: 20 | First reported in: 2012

Last updated on: 2023-03-29 16:10:48 by Xiao P. Peng

OMIM: 609981

Orphanet: 75391

MONDO: 0012383

DOID: 0111967

ClinGen: Moderate (2023-08-17)

Description

At least 8 unrelated kindreds with biallelic MCM4 loss-of-function have now been described in at least 4 studies, three of which report molecular genetic findings (PMID: 16532402, 22354167, 22354170, 22499342). Both pathogenic mutations described thus far are thought to lead to truncated Mcm4 proteins with loss of the N-terminal region whose post-translational modification is crucial for regulating pre-initiation complex assembly and replisome progression. This genome instability syndrome features severe intra-uterine growth retardation, postnatal failure to thrive, microcephaly, non-malignant lymphoproliferation, adrenal insufficiency or isolated glucocorticoid deficiency, hyperpigmentation, delayed bone age, and recurrent viral infections, often respiratory. Affected individuals may have increased cancer susceptibility as a consequence of their cellular genome instability. All patients have low peripheral blood NK cell counts (<5% of normal) with T and B cell counts being grossly unaffected. Patient lymphocytes also showed increased chromosomal breakage after treatment with DEB, mitomycin C, and nitrogen mustard but breakage rates remained relatively low and affecting only a minority of cells, unlike in Fanconi anemia patients.

Management

Antimicrobial prophylaxis may be considered for those with recurrent infections, while those with adrenal insufficiency and/or isolated glucocorticoid deficiency may require corticosteroid replacement therapy. There are currently no screening guidelines for managing the potentially increased malignancy risk.