Immunodeficiency 26 With Or Without Neurologic Abnormalities

A number sign (#) is used with this entry because of evidence that immunodeficiency-26 (IMD26) is caused by homozygous or compound heterozygous mutation in the PRKDC gene (600899) on chromosome 8q11.

Clinical Features

Van der Burg et al. (2009) reported a Turkish girl, born of consanguineous parents, who was clinically diagnosed with severe combined immunodeficiency (SCID) at 5 months of age. She presented with recurrent candidiasis and lower respiratory tract infections, as well as a large oral aphthous lesion. B and T cells were virtually absent from peripheral blood, but NK cells were normal. Bone marrow analysis showed a complete block in B-cell differentiation, comparable to that observed in Artemis (DCLRE1C; 605988)-deficient SCID (602450), suggesting a defect in V(D)J recombination during immune development. Patient fibroblasts showed radiation sensitivity, with a particular defect in slow repair of DNA double-strand breaks (DSBs). The patient underwent successful hematopoietic bone marrow transplant. She had no signs of microcephaly or mental retardation.

Woodbine et al. (2013) reported a boy, born of unrelated parents, with SCID characterized by absent circulating B and T cells and normal NK cells. The patient had intrauterine growth retardation and presented with suspected sepsis and persistent oral and perineal candidiasis at age 3 weeks. He was microcephalic and had dysmorphic features, including prominent forehead, wide nasal bridge, deep-set eyes, long philtrum with thin upper lip, small chin, low-set ears, overlapping fingers, and postaxial polysyndactyly of the right foot. He showed little developmental progress, and he was found to have profound hearing loss and severe visual impairment. Brain imaging showed simplified gyral pattern, mild frontal pachygyria, small hippocampi, hypomyelinated white matter, thin corpus callosum, and cerebellar vermis hypoplasia. He died at age 31 months with intractable seizures.

Inheritance

The transmission pattern of IMD26 in the family reported by van der Burg et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Turkish girl with IMD26, van der Burg et al. (2009) identified a homozygous missense mutation in the PRKDC gene (L3062R; 600899.0001).

In a boy with IMD26 and profound neurologic abnormalities, Woodbine et al. (2013) identified compound heterozygous mutations in the PRKDC gene (A3574V, 600899.0002 and EX16del, 600899.0003). Functional studies were consistent with a loss of function, resulting in decreased protein expression, loss of kinase activity, and impaired nonhomologous end-joining (NHEJ) and DSB repair. Noting that animal models of Prkdc loss do not show neurologic abnormalities, Woodbine et al. (2013) postulated that DSB repair plays a role in nonhomologous recombination during neuronal development and maintenance in humans.

Animal Model

Scid with decreased T and B cells and normal NK cells due to mutations in or deficiency of Prkdc has been reported in mice (Araki et al., 1997; Kirchgessner et al., 1995) and Arabian foals (Wiler et al., 1995).