title: Familial glucocorticoid deficiency due to compound heterozygosity of two novel MC2R mutations.
abstract: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. A 2-year-old adopted Chinese girl presented with hypertonic seizures associated with hypoglycemia, skin hyperpigmentation, muscle weakness and mild jaundice. Hormonal analyses revealed high ACTH, low serum cortisol along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered, although further episodes occurred with infection. To date, her physical and neurocognitive development progress is normal. A clinical diagnosis of FGD was given. We undertook MC2R and MRAP mutation screening. Two novel MC2R mutations were identified: p.D107G localized in the transmembrane region, predicted to be trafficking-competent but is unable to bind to ACTH, and p.R145C, situated in the second intracellular loop, predicted to be trafficking-defective.
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Aza-Carmona
authors.forename: Ana Coral
authors.initials: AC
authors.lastname: Barreda-Bonis
authors.forename: Julio
authors.initials: J
authors.lastname: Guerrero-Fernández
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Casado
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gracia
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency*; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2; D004247:DNA; D006854:Hydrocortisone