Severe Combined Immunodeficiency With Microcephaly, Growth Retardation, And Sensitivity To Ionizing Radiation

A number sign (#) is used with this entry because T cell-negative, B cell-negative, natural killer (NK) cell-positive severe combined immunodeficiency (SCID) with microcephaly, growth retardation, and sensitivity to ionizing radiation (IR) is caused by mutation in the NHEJ1 gene (611290). A presumably hypomorphic mutation in the NHEJ1 gene (611290.0005) results in SCID with sensitivity to ionizing radiation, but without microcephaly or growth retardation.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.

Clinical Features

Buck et al. (2006) reported 5 patients in which SCID was associated with microcephaly and growth retardation. Severe growth retardation and dystrophy were observed in 4 of the 5 patients, and microcephaly was present in all 5 patients at birth. Dysmorphic features and various malformations were observed in 4 of the 5 patients. Recurrent infections occurred in all 5 patients and were lethal in 2. All 5 patients had hypogammaglobulinemia with severe B and T lymphocytopenia, but normal NK cell levels. Circulating naive T cells were absent, and CD45RO (151460)-positive memory T cells had impaired function. Patient fibroblasts showed variable but increased sensitivity to IR at least as great as that observed in other radiosensitive conditions. Formation of IR-induced foci and IR-induced cell cycle checkpoints were normal in patient fibroblasts. V(D)J recombination was defective in patient fibroblasts, but the defect was less severe than that in Artemis (DCLRE1C; 605988)-deficient RS-SCID (602450). In vitro assays showed a defect in the NHEJ pathway in the absence of LIG4 (601837) deficiency in all 5 patients.

Mapping

SCID with microcephaly, growth retardation, and sensitivity to IR is caused by mutations in the NHEJ1 gene, which maps to chromosome 2q35 (Buck et al., 2006).

Molecular Genetics

Buck et al. (2006) identified mutations in the NHEJ1 gene (611290.0001 to 611290.0004) in all 5 patients they reported with SCID, microcephaly, growth retardation, and sensitivity to IR. Patient fibroblasts showed normal sensitivity to IR and normal V(D)J recombination following complementation with wildtype NHEJ1.

Ahnesorg et al. (2006) identified an inactivating frameshift mutation in the NHEJ1 gene (611290.0005) in the 2BN cell line derived from a patient with SCID and sensitivity to IR, but no microcephaly and only mild developmental delay (Dai et al., 2003). They could not rule out the possibility that the mutation did not totally inactivate NHEJ1 activity and that some NHEJ1 protein with residual function was made from alternative downstream translational initiation codons. Callebaut et al. (2006) also suggested that 2BN cells harbor a hypomorphic mutation through translation reinitiation at a downstream methionine.