CVID54

Immunodeficiency-54 is a rare, autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased natural killer (NK) cell numbers, and recurrent viral infections, most commonly affecting the respiratory tract. Furthermore, affected individuals suffer from adrenal insufficiency, which may require corticosteroid replacement therapy. There is an increased susceptibility to tumor disease. Etiopathogentically, this symptomatology is based on a DNA repair defect (see Gineau et al. 2012), which is caused by mutaions in the MCM4 gene.

Eidenschenk et al (2006) described a large consanguineous family with NK cell deficiency in four members of three siblings related as first cousins, including one patient with Epstein-Barr virus (EBV)-induced lymphoproliferative disorder and two patients with severe pneumonitis likely of viral origin. The index patient presented at 18 months of age with failure to thrive, hepatomegaly, splenomegaly, and peripheral lymphadenopathy.

Known history was relatively benign viral infections in childhood, with recurrent respiratory infections, herpetic stomatitis, and molluscum contagiosum. At 2 years and 9 months of age, he developed an EBV-related lymphoproliferative disorder in the small intestine. The resulting tumor was surgically removed. Thereafter, he remained healthy until report age (9 years). Two of the 3 other affected family members had recurrent penuomia. All 4 affected family members had selective and profound deficiency of NK cells in the blood, in contrast to the 14 healthy family members tested. Three of the patients with NK deficiency were tested before an unusual infectious disease associated with EBV infection occurred.

In a follow-up of this clan, Gineau et al. (2012) found that all patients had low peripheral blood NK cell counts (less than 5% of normal), severe intra- and extrauterine growth retardation, microcephaly, and adrenal insufficiency requiring corticosteroid replacement therapy.

1. Casey JP et al (2012) Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet 49: 242-245.
2. Eidenschenk C et al (2006) A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am J Hum Genet 78: 721-727.
3. Gineau L et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest 122: 821-832.