Objective: Description of the clinical, biochemical and genetic features of a Polish patient with familial glucocorticoid deficiency. Methods: Detailed clinical investigation, hormonal analysis and sequencing of the coding region of the melanocortin 2 receptor (MC2R) gene in this patient. Results: We report on a 3-month-old boy with familial glucocorticoid deficiency who presented at the age of 3 months with skin hyperpigmentation, muscle weakness, mild jaundice and constipation. Hormonal analyses revealed high ACTH and TSH serum concentrations, low serum cortisol concentration along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered completely. His physical and mental development progresses normally. Genetic analysis disclosed a novel compound heterozygous MC2R mutation p.Leu46fs and p.Val49Met. Conclusion: The heterozygous p.Leu46fs mutation adds to the small number of MC2R nonsense mutations and is the first frameshift mutation within the first transmembrane domain of the receptor. According to molecular modeling the Val49Met mutation results in a structural change of the first transmembrane domain and in a potential novel interaction of the transmembrane domains I and VII.

Keywords:
Familial glucocorticoid deficiency, Isolated glucocorticoid deficiency, Hereditary unresponsiveness to ACTH, MC2R
1.
Shepard TH, Landing BH, Mason DG: Familial Addison’s disease: case reports of two sisters with corticoid deficiency unassociated with hypoaldosteronism. Am J Dis Child 1959;97:154–162.
2.
Weber A, Clark AJ: Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet 1994;4:585–588.
3.
Weber A, Toppari J, Harvey R, Klann RC, Shaw NJ, Ricker AT, Nanto-Salonen K, Bevan JS, Clark AJ: Adrenocorticotropin receptor gene mutations in familial glucocorticoid deficiency: relationships with clinical features in four families. J Clin Endocrinol Metab 1995;80:65–71.
4.
Clark AJ, Weber A: Adrenocorticotropin insensitivity syndromes. Endocr Rev 1998;19:828–843.
5.
Clark AJ, Metherell LA, Naville D, Begeot M, Huebner A: Genetics of ACTH insensitivity syndromes. Ann Endocrinol (Paris) 2005;66:247–249.
6.
Metherell LA, Chan LF, Clark AJ: The genetics of ACTH resistance syndromes. Best Pract Res Clin Endocrinol Metab 2006;20:547–560.
7.
Metherell LA, Chapple JP, Cooray S, David A, Becker C, Ruschendorf F, Naville D, Begeot M, Khoo B, Nurnberg P, Huebner A, Cheetham ME, Clark AJ: Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet 2005;37:166–170.
8.
Genin E, Huebner A, Jaillard C, Faure A, Halaby G, Saka N, Clark AJ, Durand P, Begeot M, Naville D: Linkage of one gene for familial glucocorticoid deficiency type 2 (FGD2) to chromosome 8q and further evidence of heterogeneity. Hum Genet 2002;111:428–434.
9.
Prusis P, Schiöth HB, Muceniece R, Herzyk P, Afshar M, Hubbard RE, Wikberg JE: Modeling of the three-dimensional structure of the human melanocortin 1 receptor using an automated method and docking of a rigid cycling melanocyte-stimulating hormone core peptide. J Mol Graph Model 1997;15:307–317.
10.
Skrabanek L, Campagne F, Weinstein H: Building protein diagrams on the web with the residue-based diagram editor RbDe. Nucleic Acids Res 2003;31:3856–3858.
11.
Elias LL, Huebner A, Pullinger GD, Mirtella A, Clark AJ: Functional characterization of naturally occurring mutations of the human adrenocorticotropin receptor: poor correlation of phenotype and genotype. J Clin Endocrinol Metab 1999;84:2766–2770.
12.
Naville D, Barjhoux L, Jaillard C, Faury D, Despert F, Esteva B, Durand P, Saez JM, Begeot M: Demonstration by transfection studies that mutations in the adrenocorticotropin receptor gene are one cause of the hereditary syndrome of glucocorticoid deficiency. J Clin Endocrinol Metab 1996;81:1442–1448.
13.
Naville D, Weber A, Genin E, Durand P, Clark AJ, Begeot M: Exclusion of the adrenocorticotropin (ACTH) receptor (MC2R) locus in some families with ACTH resistance but no mutations of the MC2R coding sequence (familial glucocorticoid deficiency type 2). J Clin Endocrinol Metab 1998;83:3592–3596.
14.
Huebner A, Elias LL, Clark AJ: ACTH resistance syndromes. J Pediatr Endocrinol Metab 1999;12(suppl 1):277–293.
15.
Elias LL, Huebner A, Metherell LA, Canas A, Warne GL, Bitti ML, Cianfarani C, Clayton PL, Savage MO, Clark AJ: Tall stature in familial glucocorticoid deficiency. Clin Endocrinol (Oxf) 2000;53:423–430.
16.
Imamine H, Mizuno H, Sugiyama Y, Ohro Y, Sugiura T, Togari H: Possible relationship between elevated plasma ACTH and tall stature in familial glucocorticoid deficiency. Tohoku J Exp Med 2005;205:123–131.
17.
Sheehan AG, Martin SR, Stephure D, Scott RB: Neonatal cholestasis, hypoglycemia, and congenital hypopituitarism. J Pediatr Gastroenterol Nutr 1992;14:426–430.
18.
Choo-Kang LR, Sun CC, Counts DR: Cholestasis and hypoglycemia: manifestations of congenital anterior hypopituitarism. J Clin Endocrinol Metab 1996;81:2786–2789.
19.
Leblanc A, Odievre M, Hadchouel M, Gendrel D, Chaussain JL, Rappaport R: Neonatal cholestasis and hypoglycemia: possible role of cortisol deficiency. J Pediatr 1981;99:577–580.
20.
Lacy DE, Nathavitharana KA, Tarlow MJ: Neonatal hepatitis and congenital insensitivity to adrenocorticotropin (ACTH). J Pediatr Gastroenterol Nutr 1993;17:438–440.
21.
Tiosano D, Pannain S, Vassart G, Parma J, Gershoni-Baruch R, Mandel H, Lotan R, Zaharan Y, Pery M, Weiss RE, Refetoff S, Hochberg Z: The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor. Thyroid 1999;9:887–894.
22.
Clark AJL, Metherell LA, Cheetham ME, Huebner A: Inherited ACTH insensitivity illuminates the mechanisms of ACTH action. Trends Endocrinol Metab 2006;16:451–457.
© 2008 S. Karger AG, Basel
2008
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