Clinical characteristics and genetic analysis of two children with Familial glucocorticoid deficiency type 1 due to variants of MC2R gene / 中华医学遗传学杂志

OBJECTIVE@#To improve the recognition of Familial glucocorticoid deficiency type 1 (FGD1) due to variants of melanocortin 2 receptor (MC2R) gene.@*METHODS@#Two children with FGD1 diagnosed at the Henan Children's Hospital respectively in 2019 and 2021 were selected as the study subjects. Clinical data, treatment, follow-up and results of genetic testing were collected and retrospectively analyzed.@*RESULTS@#Whole exome sequencing revealed that both children had harbored compound heterozygous variants of the MC2R gene, including c.433C>T (p.R145C) and c.710T>C (p.L237P) in child 1, and c.145delG (p.V49Cfs*35) and c.307G>A (p.D103N) in child 2, among which c.710T>C (p.L237P) and c.145delG (p.V49Cfs*35) were unreported previously.@*CONCLUSION@#FGD1 is clinically rare, and genetic sequencing is crucial for the definite diagnosis. Discovery of the and novel variants has enriched the mutational spectrum of the FGD1 gene.

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

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralocorticoid deficiency. We report a 2 month-old boy of nonconsanguineous parents, presented with hyperpigmentation. Physical examination showed diffuse dark skin of body including, oral mucosa, gum, hands, nails and scrotum. Laboratory evaluation revealed low serum cortisol (0.3 microgram/dL), with very high plasma ACTH level (18,000 pg/mL), and serum cortisol level did not increase after ACTH stimulation test. Serum sodium, potassium, plasma renin activity, aldosterone and 17-hydroxyprogesterone were normal. Sequence analysis of the ACTH receptor (MC2R) gene showed a homozygous mutation of D103N. Diagnosis of FGD was made and treatment started with oral hydrocortisone.

Genetic polymorphisms of MC2R gene associated with responsiveness to adrenocorticotropic hormone therapy in infantile spasms / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms.</p><p><b>METHODS</b>We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed.</p><p><b>RESULTS</b>Four single nucleotide polymorphisms (SNPs) were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T > C. Three SNPs (rs1893220, rs2186944 and -2T > C) showed a significant difference between the cases and controls (P < 0.05 for all). The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases (39%) than in the controls (60%) (P = 0.00003). The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers (RR = 0.42, 95% CI 0.26-0.70, P = 0.0001). ACTH responsiveness was strongly associated with the TCCT haplotype (P = 0.000082). Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy (P = 0.0002; P = 0.0003, respectively).</p><p><b>CONCLUSIONS</b>Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.</p>