Natural killer cell and glucocorticoid deficiency with DNA repair defect is an autosomal recessive disorder characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of NK cells, and recurrent viral infections, most often affecting the respiratory ... Natural killer cell and glucocorticoid deficiency with DNA repair defect is an autosomal recessive disorder characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of NK cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer (summary by Gineau et al., 2012).
Bernard et al. (2004) described the first reported form of familial NK cell deficiency in 2 French sisters without persistent T-cell lymphopenia. The older child died from cytomegalovirus (CMV) infection at age 18 months, whereas the second child ... Bernard et al. (2004) described the first reported form of familial NK cell deficiency in 2 French sisters without persistent T-cell lymphopenia. The older child died from cytomegalovirus (CMV) infection at age 18 months, whereas the second child remained healthy at age 7 years and had a persistent lack of NK cells with no diagnosed viral infection. Both also had neutropenia, facial dysmorphia, and severe intrauterine growth retardation. One patient had transient T-cell lymphopenia. Eidenschenk et al. (2006) performed biochemical studies of peripheral immunologic cells derived from 1 of the patients reported by Bernard et al. (2004). Although NK cells could not be studied, T lymphocytes displayed excessive apoptosis, and T-cell blasts showed poor survival upon treatment with IL2 (147680) and IL15 (600554). The data suggested that an impaired survival response to IL2 and IL15 may account for the persistent lack of NK cells and transient CD8 T lymphopenia. Eidenschenk et al. (2006) described a large consanguineous kindred with NK cell deficiency in 4 members in 3 sibships related as first cousins, including 1 patient with Epstein-Barr virus (EBV)-driven lymphoproliferative disorder and 2 patients with severe pneumonitis of probable viral origin. The index patient presented at age 18 months with failure to thrive, hepatomegaly, splenomegaly, and peripheral lymphadenopathy. His condition may have reflected primary EBV infection. He had relatively benign viral infections of childhood, with recurrent respiratory tract infections, herpetic stomatitis, and molluscum contagiosum. At age 2 years and 9 months, he developed an EBV-related lymphoproliferative disorder in the small bowel, and the resulting tumor was surgically removed. He remained well thereafter up to the age of report (9 years). Two of the 3 other affected family members had frequent lung infections. All 4 affected family members presented with a selective and profound deficiency of NK cells in blood, unlike the 14 healthy family members tested. Three of the NK-deficient patients were tested before the onset of any unusual infectious disease associated with EBV infection. This kindred lived in Ireland, and its members were all of Irish Nomadic descent. In a follow-up of this kindred, Gineau et al. (2012) noted that all patients had low NK cell counts in peripheral blood (less than 5% of normal), severe intra- and extrauterine growth retardation, microcephaly, and adrenal insufficiency requiring corticosteroid replacement therapy. Hughes et al. (2012) reported 7 children from 3 kindreds within the Irish Traveller community who had NKGCD. All had isolated glucocorticoid deficiency, increased ACTH, and normal renin and aldosterone. The cortisol deficiency generally became apparent in childhood following a period of normal adrenal function. Affected children also had poor growth, short stature, and a specific NK deficiency. However, only 1 showed increased susceptibility to recurrent infections. Patient lymphocytes showed increased chromosomal breakage. Casey et al. (2012) reported further analysis of members of 3 clans from the Irish Traveller population, including the family reported by Eidenschenk et al. (2006). In the first highly consanguineous pedigree, there was intrauterine growth retardation, failure to thrive, clinodactyly, some episodes of hypoglycemia, and delayed bone age. In the second pedigree, which had been described by Eidenschenk et al. (2006), there was familial glucocorticoid deficiency, as well as natural killer cell deficiency and DNA repair disorder. In the third pedigree, affected individuals were referred for possible Russell-Silver syndrome (see 180860) but were diagnosed with familial glucocorticoid deficiency (FGD; see 202200) on the basis of the development of increased pigmentation and subsequent biochemical investigations. Eventually, Casey et al. (2012) tested members of all 3 clans for the 3 different phenotypes (i.e., familial glucocorticoid deficiency, DNA repair disorder, and NK cell deficiency) and found that some who had FGD also had low levels of NK cells, and some showed defective DNA repair. The DNA repair disorder was classified as mosaic Fanconi anemia (FA; see 227650), but the patients did not have the typical mosaic FA test result or the expected clinical features of the disorder. In mosaic FA, patients have 2 subpopulations of cells, one of which is hypersensitive to crosslinking agents, while the other behaves normally in response to these agents. Upon testing, patients with mosaic FA have some cells with high levels of DNA damage and others that are completely normal. However, often the patients reported by Casey et al. (2012) had a relatively low level of DNA damage in a minority of cells. The observed chromosome breakage was greater than that expected from a healthy individual but less than that of mosaic FA. O'Riordan et al. (2008) had described the endocrine abnormalities in some of these patients. Eight of the 10 patients studied by Casey et al. (2012) had been small for gestational age (SGA). The majority had microcephaly, failure to thrive, and hyperpigmentation; all had short stature. Two had low growth hormone levels, 2 were normal, and the others were not tested. Two had episodes of hypoglycemia; there was 1 person without evidence of hypoglycemia, and the others were not tested. Five patients had biochemical evidence of mosaic Fanconi anemia; in 2 evidence was unclear, 2 were either untested or unknown, and 1 patient had no biochemical evidence of this abnormality. Six patients had evidence of NK cell deficiency and the others were not tested.
In affected members of 2 consanguineous kindreds within the Irish Traveller community with NK cell and glucocorticoid deficiency with DNA repair defect, Gineau et al. (2012) identified a homozygous mutation in the MCM4 gene (602638.0001). One of the ... In affected members of 2 consanguineous kindreds within the Irish Traveller community with NK cell and glucocorticoid deficiency with DNA repair defect, Gineau et al. (2012) identified a homozygous mutation in the MCM4 gene (602638.0001). One of the families had previously been reported by Eidenschenk et al. (2006). In vitro functional expression studies indicated that the mutation resulted in translation of a hypomorphic isoform. Cells transfected with the mutant allele showed a lower proportion of cells in the G1 and S phases and a higher proportion of cells in the G2/M phase compared to controls. The findings suggested that mutant MCM4 adversely disrupted the coordination of DNA replication and impaired the normal control of the prevention of re-replication, with an impact on the mitotic phase. Patient cells showed increased genomic instability and increased DNA breakage compared to control. Hughes et al. (2012) identified the same homozygous truncating mutation in 8 children from 3 consanguineous Irish Traveller kindreds with NKGCD. Casey et al. (2012) identified homozygosity for the same mutation in the MCM4 gene in 10 individuals from 3 clans from the Irish Traveller population manifesting natural killer cell deficiency, DNA repair disorder, and familial glucocorticoid deficiency.
O'Riordan et al. (2008) identified 9 children with familial glucocorticoid deficiency among 22,557 individuals in the Irish Traveller population, yielding a disease prevalence of 1 in 2,506 with a carrier frequency of 1 in 25. In the 4- ... O'Riordan et al. (2008) identified 9 children with familial glucocorticoid deficiency among 22,557 individuals in the Irish Traveller population, yielding a disease prevalence of 1 in 2,506 with a carrier frequency of 1 in 25. In the 4- to 15-year old group, the prevalence increased to 1 in 665, with a carrier frequency of 1 in 13. The study focused on endocrinologic features, and the diagnosis was based on high ACTH and low cortisol levels with normal levels of renin and aldosterone. Initial biochemical testing, up to 2.5 years of age, was normal in all patients except 1; the mean age at diagnosis was 5 years. Clinical history indicated that most had hyperpigmentation, short stature, and a history of failure to thrive.