Kershnar AK, Roe TF, Kogut MD. Adrenocorticotropic hormone unresponsiveness: report of a girl with excessive growth and review of 16 reported cases. J Pediatr 1972;80:610-9.In 1972, Kershnar et al described a 4-year 9-month-old girl with adrenal crisis in the setting of pneumonia, hypoglycemia, hyperpigmentation, and tall stature. She had multiple prior admissions for fever, seizure, or coma that began at age 11 months. Endocrine testing identified elevated adrenocorticotropic hormone (ACTH) levels and cortisol deficiency, with normal secretory rates and function of aldosterone, deoxycorticosterone, and corticosterone. These laboratory studies ruled out classic forms of congenital adrenal hyperplasia and primary adrenal insufficiency. Family history included a sibling with hyperpigmentation and hypoglycemia who died at age 2 1/2 years. The authors reviewed 16 similar cases with presentations between 2 months and 9 years. Predominant symptoms included seizures, hyperpigmentation, and gastrointestinal complaints. Three had familial involvement.Kershnar et al identified that the patient's presentation and laboratory studies reflected end-organ unresponsiveness to ACTH, inherited in an autosomal-recessive pattern. More than 20 years later in 1993, an inactivating mutation in the ACTH receptor, the melanocortin 2 receptor (MC2R), was recognized as the cause of familial glucocorticoid deficiency (FGD) type 1. Mutations in the MC2R accessory protein, MRAP, were later identified as the cause of FGD type 2.Diagnosis of FGD should be considered when children present with symptoms of cortisol deficiency, including hypoglycemia, hyperpigmentation, and adrenal crisis, along with elevated ACTH and intact mineralocorticoid function. FGD type 1 accounts for 25% of cases and is associated with tall stature and median symptom onset at 2 years.1Teng-Teng L.L. Chung L.F. Chan L.A.M. Adrian J.L.C. Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2.Clin Endocrinol (Oxf). 2010; 72: 589-594Crossref PubMed Scopus (53) Google Scholar FGD type 2 accounts for 20% of cases and is associated with normal stature and median symptom onset at 1 month.1Teng-Teng L.L. Chung L.F. Chan L.A.M. Adrian J.L.C. Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2.Clin Endocrinol (Oxf). 2010; 72: 589-594Crossref PubMed Scopus (53) Google Scholar Genetic testing can identify mutations in the genes for MC2R or MRAP; other etiologies include nonclassical lipoid congenital adrenal hyperplasia (FGD type 3), less-common mutations related to oxidative stress or DNA replication, syndromic forms of ACTH resistance, and still-unknown genetic defects. The patient in this case presumably had FGD type 1 based on her tall stature; treatment was with hydrocortisone, which remains the standard treatment of FGD today. Kershnar AK, Roe TF, Kogut MD. Adrenocorticotropic hormone unresponsiveness: report of a girl with excessive growth and review of 16 reported cases. J Pediatr 1972;80:610-9. In 1972, Kershnar et al described a 4-year 9-month-old girl with adrenal crisis in the setting of pneumonia, hypoglycemia, hyperpigmentation, and tall stature. She had multiple prior admissions for fever, seizure, or coma that began at age 11 months. Endocrine testing identified elevated adrenocorticotropic hormone (ACTH) levels and cortisol deficiency, with normal secretory rates and function of aldosterone, deoxycorticosterone, and corticosterone. These laboratory studies ruled out classic forms of congenital adrenal hyperplasia and primary adrenal insufficiency. Family history included a sibling with hyperpigmentation and hypoglycemia who died at age 2 1/2 years. The authors reviewed 16 similar cases with presentations between 2 months and 9 years. Predominant symptoms included seizures, hyperpigmentation, and gastrointestinal complaints. Three had familial involvement. Kershnar et al identified that the patient's presentation and laboratory studies reflected end-organ unresponsiveness to ACTH, inherited in an autosomal-recessive pattern. More than 20 years later in 1993, an inactivating mutation in the ACTH receptor, the melanocortin 2 receptor (MC2R), was recognized as the cause of familial glucocorticoid deficiency (FGD) type 1. Mutations in the MC2R accessory protein, MRAP, were later identified as the cause of FGD type 2. Diagnosis of FGD should be considered when children present with symptoms of cortisol deficiency, including hypoglycemia, hyperpigmentation, and adrenal crisis, along with elevated ACTH and intact mineralocorticoid function. FGD type 1 accounts for 25% of cases and is associated with tall stature and median symptom onset at 2 years.1Teng-Teng L.L. Chung L.F. Chan L.A.M. Adrian J.L.C. Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2.Clin Endocrinol (Oxf). 2010; 72: 589-594Crossref PubMed Scopus (53) Google Scholar FGD type 2 accounts for 20% of cases and is associated with normal stature and median symptom onset at 1 month.1Teng-Teng L.L. Chung L.F. Chan L.A.M. Adrian J.L.C. Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2.Clin Endocrinol (Oxf). 2010; 72: 589-594Crossref PubMed Scopus (53) Google Scholar Genetic testing can identify mutations in the genes for MC2R or MRAP; other etiologies include nonclassical lipoid congenital adrenal hyperplasia (FGD type 3), less-common mutations related to oxidative stress or DNA replication, syndromic forms of ACTH resistance, and still-unknown genetic defects. The patient in this case presumably had FGD type 1 based on her tall stature; treatment was with hydrocortisone, which remains the standard treatment of FGD today.