Objective To explore the diagnosis and treatment of familial glucocorticoid deficiency and the prevention strategy of adrenal crisis through clinical and genetic analysis. Methods Five children diagnosed with familial glucocorticoid deficiency treated from October 2017 to October 2023 were retrospectively analyzed. Their medical history, endocrine, metabolic, genetic variations, treatment and outcomes were summarized. Results Among the 5 children, 4 were male and 1 was female. They were diagnosed aged 1 month 23 days to 1 year and 11 months. All patients presented with mucocutaneous pigmentation and hypoglycemia, along with elevated plasma adrenocorticotropic hormone (ACTH) and decreased cortisol. Two cases (40%) had convulsions. Three (60%) showed slow weight gain. Four (80%) required hospitalization immediately after birth. Two cases had elevated plasma testosterone, while 3 had normal plasma testosterone (<0.025 ng/ml). One case (20%) had decreased blood potassium. Four had elevated plasma renin. Two (40%) had elevated aldosterone. Three types of genetic defects were found in the 5 sick children. One case was MRAP c.106+1G>C homozygous mutation. Two cases were NNT compound heterozygous mutations: c.385C>T (p.Arg129Ter)/c.383T>G (p.Val128Gly) and c.1455del (p.Ile486Tyrfs?11)/c.972_973delinsC (p.Lys324Asnfs?10), respectively. Two cases were MC2R compound heterozygous mutations: c.433C>T (p.Arg145Cys)/c.710T>C (p.Leu237Pro) and c.145delG (p.Val49Cysfs?35)/c.307G>A (p.Asp103Asn), respectively. All children received oral hydrocortisone acetate tablets. One took oral 9α-fluorohydrocortisone at the same time. One patient with transiently elevated blood TSH took oral levothyroxine tablets for 6 months. One case had severe brain injury and died of multiple organ failure caused by pulmonary infection at the age of 2 years and 2 months. Two children experienced adrenal crisis due to infection. The 4 surviving children are 10 months to 7 years and 1 month old at the last follow-up. One has delayed language development. Three cases have normal physical and intellectual development, with alleviated mucocutaneous pigmentation and no recurrence of hypoglycemia. Conclusions Children with familial glucocorticoid deficiency exhibit significant clinical heterogeneity. All present with mucocutaneous pigmentation, elevated plasma ACTH, and decreased cortisol. Hypoglycemic convulsions and growth retardation are also essential manifestations. Lifelong glucocorticoid supplementation is essential for the treatment. Mineralocorticoid supplement is needed for patients with mineralocorticoid deficiency. Close monitoring is necessary to prevent and treat adrenal crisis.