Familial glucocorticoid deficiency is a rare autosomal recessive disorder characterized by an inability of the adrenal cortex to produce cortisol in response to stimulation by adrenocorticotropic hormone (ACTH). Affected individuals typically present within the first few months of ... Familial glucocorticoid deficiency is a rare autosomal recessive disorder characterized by an inability of the adrenal cortex to produce cortisol in response to stimulation by adrenocorticotropic hormone (ACTH). Affected individuals typically present within the first few months of life with symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, hypoglycemia, convulsions, and shock. The disease is life-threatening if untreated (summary by Meimaridou et al., 2012). For a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200).
Meimaridou et al. (2012) studied patients from 15 families with glucocorticoid deficiency (GCCD), all of whom were negative for mutation in genes known to cause GCCD. The patients, who were diagnosed between 6 months and 40 months of ... Meimaridou et al. (2012) studied patients from 15 families with glucocorticoid deficiency (GCCD), all of whom were negative for mutation in genes known to cause GCCD. The patients, who were diagnosed between 6 months and 40 months of age, presented with hyperpigmentation, high ACTH levels, and low cortisol levels, but with normal renin and aldosterone levels. All patients in whom an ACTH stimulation test was performed failed to mount a suitable response.
In the proband of a family with glucocorticoid deficiency (GCCD) mapping to chromosome 5p13-q12, Meimaridou et al. (2012) performed targeted exome sequencing followed by filtration, which yielded 5 variants for validation; only 1, a missense mutation in the ... In the proband of a family with glucocorticoid deficiency (GCCD) mapping to chromosome 5p13-q12, Meimaridou et al. (2012) performed targeted exome sequencing followed by filtration, which yielded 5 variants for validation; only 1, a missense mutation in the NNT gene (607878.0001), was homozygous in the affected individual, heterozygous in the unaffected parents, and absent in controls. Homozygosity for a 1-bp deletion or a missense mutation in NNT (607878.0002 and 607878.0003, respectively) was identified in affected individuals from 2 more families with GCCD mapping to chromosome 5. Sequencing the NNT gene in 100 individuals with GCCD of unknown etiology revealed homozygosity or compound heterozygosity for 18 more mutations in 12 kindreds (see, e.g., 607878.0004-607878.0006). Functional analysis in mutant mice suggested that impaired adrenal steroidogenesis and the development of GCCD are due to defective oxidative stress responses.