Familial Glucocorticoid Deficiency with a Point Mutation in the ACTH Receptor: A Case Report

Abstract

INTRODUCTIONFamilial glucocorticoid deficiency (FGD), also known as isolated glucocorticoid deficiency or hereditary unresponsiveness to ACTH, is an autosomal recessive disorder (1-4). Patients suffer from recurrent hypoglycemia, convulsions, hyperpigmentation, recurrent infections and failure to thrive (3). Investigation shows severe cortisol deficiency despite a high plasma ACTH levels, which leading to increased skin pigmentation as a result of activation of α -melanocyte stimulating hormone receptors (melanocortin-1 receptors) on cutaneous melanocytes (3, 4). There is no mineralocorticoid deficiency and the renin-angiotensin system is not affected. The molecular basis of this condition was first described in 1992 (5), and approximately 20 different ACTH receptor (MC2R) mutations have been reported in individuals or families with FGD (4, 6). Here, we report a boy with clinical and biochemical features of FGD who is homozygous for a mutation (D103N) in the MC2R gene. This is the first Korean report of FGD associated with a mutation of the MC2R gene. CASE REPORTThe patient was born to nonconsanguineous Korean parents at 40 weeks of gestation by Caesarean section for induction failure, with a birth weight of 3.7 kg. He was the only baby and there was no neonatal or infant death on family history. At first week after birth, he showed jaundice and treated with phototherapy for 3 days at local hospital. At 2 months of age, the patient was referred to our hospital for generalized hyperpigmentation. His weight was 7.1 kg (75th percentile) and length was 62.7 cm (75th percentile). Physical examination showed diffuse pigmentation of body including, oral mucosa, gum, hands, nails and scrotum. The external genitalia showed normal development. Routine laboratory tests including CBC, Na, K, Cl, Bun, Cr and glucose were normal, but AST (139 IU/L, normal range 15-55 IU/L), ALT (60 IU/L, normal range 5-45 IU/L), total bilirubin (6.7 mg/ dL, normal range 0.2-1.2 mg/dL) and direct bilirublin (2.6 mg/dL, normal range 0-0.4 mg/dL) levels were elevated. A 99mTc-DISIDA (Diisopropyl Iminodiacetic Acid) hepatobiliary scan was done and revealed neonatal hepatitis. Endocrinological evaluation showed very low serum cortisol level (0.3 μ g/dL, normal range 5-23 μ g/dL, 8:00 A.M.), with very high plasma ACTH level (18,000 pg/mL, normal range 10-60 pg/mL, 8:00 A.M.) at 09:00 hours. In response to a rapid ACTH stimulation test (15 μ g/kg bolus i.v.), his cortisol rose minimally from 1.0 to 2.6 μ g/dL. Plasma renin activity, aldosterone, 17-hydroxyprogesterone and very long-chain fatty acids were all normal. Abdominal ultrasonography showed normal adrenal glands. On the basis of the above findings, he was diagnosed with FGD, and was treated with oral hydrocortisone (15 mg/m 2 /day). Six months later, hyperpigmentation was markedly reduced, and the plasma ACTH level was reduced to 195.7 pg/mL. The patient has done well, but the Korean Med Sci 2009; 24: 979-81 ISSN 1011-8934 DOI: 10.3346/jkms.2009 Copyright � The Korean Academy of Medical ...

One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids

“…GR modulates the activation of both T H1 and T H2 cells, and limits the severity of the inflammatory process by regulating T-cell expression of pro-inflammatory molecules [79]. In humans, glucocorticoid deficiency is commonly associated with a defective immune response and recurrent infections [80]. In addition, studies on adrenalectomized rats showed that complete removal of glucocorticoids leads to an increase in susceptibility to LPS-induced inflammation [81].…”

Early diagnosis in familial glucocorticoid deficiency

“…FGD is classified into 2 types: type 1 and type 2 3,5,6,7 . Type 1 is characterized by mutation in ACTH Receptor [melanocortin 2 receptor (MC2R)] gene 3,5,6,7,8 .…”

“…5,7 As a compensatory feedback of low cortisol, high ACTH level will be noticed and those patients become pigmented as a result of excessive ACTH stimulation of melanocyte stimulating hormone receptors (melanocortin-1 receptor) on cutaneous melanocytes leads to increase melanin production and generalized hyperpigmentation. 3,4,5,7 …”

“…FGD is classified into 2 types: type 1 and type 2. 3,5,6,7 Type 1 is characterized by mutation in ACTH Receptor [melanocortin 2 receptor (MC2R)] gene. 3,5,6,7,8 Type 2 is characterized by a mutation in ACTH accessory protein [melanocortin 2 receptor accessory protein (MRAP)].…”

“… 3,5,6,7 Type 1 is characterized by mutation in ACTH Receptor [melanocortin 2 receptor (MC2R)] gene. 3,5,6,7,8 Type 2 is characterized by a mutation in ACTH accessory protein [melanocortin 2 receptor accessory protein (MRAP)]. 5,7 25% of FGD cases have mutation in MC2R while only 15 to 20% of FGD cases have mutations in MRAP.…”