Gene Mutation Analysis And Treatment Observation Of Familial Glucocorticoid Deficiency Associated With Growth Hormone Deficiency

Background:Familial glucocorticoid deficiency (FGD) also named heredity isolated glucocorticoid deficiency(HIGD) or isolated glucocorticoid deficiency(IGD), is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. It was first described by Shepard et al.[2] in 1959. Glucocorticoid deficiency as a result of adrenal zona fasciculate resistive to ACTH leads to profound high level of ACTH, which results in excessive skin pigmentation. The onset age of patients varies from birth to adolescence. Convincing evidence indicates that glucocorticoids can modulate the secretion of growth hormone (GH). McEachera et al[4] in 2011 described the clinical cases of two full-term infants with congenital severe hypocortisolism, one with ACTH resistance and the other with isolated ACTH deficiency that was associated with GH deficiency.After given the glucocoryicoid replacement, both patients’growth hormone became normal, which indicate that there may have some relationship between FGD and growth hormone secretion through the molecular genetic mechanism is still unknown.Objective:To have a study on molecular genetics of FGD associated with GHD and explore the influence of glucocorticoid deficiency on growth hormone secretion.Methods:1.After obtaining the informed content, we collect peripheral blood and clinical data of from patient and his parents.The blood then was restored in -80℃.2.According to the disease genes (MC2R、MRAP、StAR、MCM4、NNT and TXNRD2 gene) have been reported, we used primer3 to design primers and primers were synthesized by shanghai huanrong biology technology company. Target genes were amplified by PCR which conducted by ABI PCR machine. Then 1% agarose gel electrophoresis was used for PCR product detection. After that we sent PCR product to huanrong company for purification, rubber cutting and sequencing. Compared chromas atlas results with NCBI gene sequence.3.Hydrocortisone 20mg 8am and 10mg 4pm, thyroid hormone 12.5μg qd, growth hormone 5U ih was administrated.4. Regular following-up, follow-up interval is 3 months, patients measuring height and gonad development condition, monitoring plasma cortisol, ACTH, gonadal hormone and GH levels, and take left hand X-ray once a year to estimate bone age. If necessary we’ll take growth hormone provocative test again.Results:1. Mutations in MC2R, MRAP,STAR, MCM4 and NNT genes all associated with FGD were not detected in patient.2. But in the third exon of TXNRD2 gene of patient and his parent we found C and G base respectively in 5 and 24 site are replaced by T base. The former one have no sense but the latter one is a homozygous missense mutation changing coding amino acid from alanine to serine (p.A 66 s), which may affect the function of TXNRD2 protein.3. During the follow-up peroid, patient has growed rapidly and increased about 17cm. Testis developed normally. There still has excessive ACTH and low cortisol level in plasma. Sex hormones level are normal and no water-electrolyte disturbances or hypoglycemic episodes were observed.Conclusions:1. G�'T was found in the third exon of TXNRD2 gene, but it needs further research to confirm whether this mutation affect the function of TXNRD2 protein or just because of gene polymorphism.2. For the patient of FGD associated with growth hormone deficiency, if GH secretory capacity can return to normal after appropriate glucocorticoid replacement and he growed rapidly after GH replacement, we think that GHD is unlikely caused by gene mutation.3. Since FGD and Addison’disease have similar clinical manifestations, we think that in patients who were diagnosed with Addison’s disease, if during the long-term follow-up patients still have too excessive ACTH, normal blood pressure and no water-electrolyte disturbances or hypoglycemic episodes were observed, FGD should be considered.