Differential Diagnosis Index Of Congenital Adrenal Hyperplasia And Adrenal Hypoplasia Congenita

BackgroundAdrenal insufficiency in children is associated with genetic factors, such as congenital adrenal hyperplasia (CAH), X-linked adrenal hypoplasia congenita (AHC), and adrenoleukodystrophy, etc. Secondly, the factors related to immunity, infection and bleeding. The disease is mainly expressed in the absence of glucocorticoid and mineralocorticoid, but the clinical manifestations of different individuals are different. Symptom onset age and performance according to the cause are various, most of the patients have a chronic progressive disease, but sometimes adrenal crisis occurs and endanger their lives.At present, the most common cause of adrenal insufficiency in children is congenital adrenal hyperplasia(The disease for more than 90% is 21 hydroxylase deficiency, associated with CYP21A2 gene mutation), X-linked adrenal hypoplasia congenita is rare (The disease is associated with mutations in the DAX1 gene), Because they are very similar in clinical manifestations, so often leads to misdiagnosis or delayed diagnosis, and thus delayed treatment. How to early identify AHC, the clinical manifestations of the disease, how to distinguish these two diseases, Those are all the problems that we need to face.Therefore, a retrospective control analysis was performed to compare the differences between these two diseases, such as the cause of the disease, the clinical manifestation, the auxiliary examination and the results of gene detection. So as to provide help for early diagnosis and early treatment of the disease.Objectives1. Clinical manifestation, treatment causes, blood biochemistry results, bone age, hormone levels, adrenal imaging (B ultrasound or CT) findings and other indicators were statistically compared between CAH and AHC, At the same time, compared with the normal control group. CYP21A2 gene was detected in girls, CYP21A2 gene and DAX1 gene was detected in boys. So as to provide guidance for clinical differential diagnosis of these two diseases, improve the understanding of AHC.2. The clinical manifestations were compared with the type of gene mutation of CAH and AHC, in order to understand the relationship between the type of Gene mutation and the clinical manifestations. So as to provide guidance for clinical treatment and prognosis.MethodsResearch object:1.CAH Group:comprised 49 patients who fulfilled the criteria of CAH diagnosed in the Department of pediatric from October 2010 to October 2014,30 were boys and 19 were girls.2.AHC Group:comprised 7 patients who fulfilled the criteria of AHC diagnosed in the Department of pediatric from October 2010 to October 2014, all of them were boys.3. Control Group:enrolled 30 children for health examination, Of these,17 were boys,13 were girls. There were no significant differences between the Observation group for age.Research method:1. To analyze the cause of the first visit of the CAH and AHC groups.The diagnosis and treatment of CAH and AHC groups were recorded, as well as the history of children, the age of initial treatment, reasons for visiting and the positive results of physical examination, and the results were statistically analyzed to compare the differences between the two.2. To Compare the difference between CAH and AHC groups in laboratory examination:Related hormone test results and electrolyte levels of the CAH and AHC groups Were recorded in detail. The results were statistically analyzed to compare the differences between the two. And the related hormone levels in the two groups were compared with the control group.3. To Compare The differences of imaging findings in CAH and AHC groups:The two groups were examined by Adrenal CT or B ultrasound, The left hand metacarpophalangeal joint radiography was taken in Children over 3 years old in order to understand the situation of bone age, and the results of the two groups were compared.4. To analyze the Correlation between phenotype and genotype of CAH and AHC group:Results of gene detection of the two groups were recorded, and analyzed the relationship between the clinical severity and the type of gene mutation. To understand whether there is a correlation between the two, and provide some guidance for clinical treatment and prognosis.Results1. Analysis of the cause of the first visit of CAH and AHC groups:Of the 49 children with CAH, The first reason for the visit was Symptoms of digestive system (21 cases). The second is abnormal neonatal screening (14 cases), then abnormal external genital organs (7 cases), Skin pigmentation (5 cases), Fast growth and growth retardation (2 cases), Among them,39 cases were salt wasting type and 10 cases were simple virilizing type. Of the Children with CAH confirmed within 6 months, The median age of 14 children diagnosed with 17-OHP was 31 days. It was earlier than the 22 cases of non screening diagnosis of the median age of 51 days, The difference was statistically significant (P< 0.01). Median age of diagnosis of 15 girls with CAH in 6 months was 42 days, and that of 21 boys was 41 days, The difference was not statistically significant (P> 0.05). All of the 7 cases diagnosed with AHC went to see a doctor because of digestive tract symptoms.They all had salt wasting and Skin pigmentation,but no external genital malformations.2. Analysis of laboratory examination results of CAH and AHC children:In 49 cases of CAH,39 patients were diagnosed as salt wasting type. All the 7 patients diagnosed with AHC had salt wasting changes at first visit. There was no significant difference in the incidence of salt wasting (P> 0.05). And the comparison of the serum potassium, sodium, and carbon dioxide in the children with CAH and AHC had no statistical significance (P> 0.05). COR、ACTH、17-OHP、P、T、FSH、LH and E2 were detected in all patients with CAH and AHC, Compared wi th the control group, the T, P,17-OHP, E2 and ACTH in CAH group were higher than those in the control group (P< 0.01), COR was lower than that of the control group (P< 0.05), There was no significant difference in FSH and LH between the two groups(P> 0.05). Compared with the AHC group, there was no significant difference between the two groups (P> 0.05) in COR, ACTH was significantly lower than that of AHC group(P< 0.05),17-OHP, P, T, LH, FSH, E2 were significantly higher than those in AHC group, the difference was statistically significant (P< 0.01). The 17-OHP, COR, P, FSH, LH, T, E2 in AHC group were lower than those in the control group, ACTH was higher than that of the control group, The difference was statistically significant (P< 0.01)3. Analysis of imaging findings in children with CAH and AHC 40 cases of children with CAH underwent adrenal imaging examination(28 cases had adrenal B ultrasound examination,12 cases had adrenal CT examination), adrenal volume of 19 cases was found to increase, The abnormal rate of adrenal imaging in children with CAH was 47.5%. Most showed bilateral adrenal enlargement, A few of them showed unilateral adrenal enlargement. Among the 32 cases of the type of salt wasting, there were 18 cases of adrenal enlargement, accounted for 56.3%. Among the 8 cases of simple virilizing type, There were 1 cases of adrenal enlargement, accounted for 12.5%. The proportion of the adrenal enlargement in the salt wasting type was higher than that of the simple virilizing. The difference was statistically significant (P< 0.05). 6 of the 7 cases of AHC were examined with adrenal imaging(3 cases underwent CT examination,3 cases underwent B ultrasound examination). In 2 cases of these, the volume of the double adrenal gland was decreased, and the rest of the patients showed no abnormality. The abnormal rate of adrenal imaging examination in children with AHC was 33.3%, The main performance was double adrenal volume reduction. Children older than 3 years underwent bone age radiography test,8 cases showed bone age significantly ahead of actual age, bone age of another 2 cases are consistent with actual age. Of patients older than 3 years old, bone age of 3 cases with AHC was detected, including 2 cases whose bone age and chronological age were consistent, bone age of 1 cases was delayed.4. Gene mutation detection of CAH and AHCCYP21A2 gene mutation was detected in 25 of 49 cases with CAH, 22 cases of those were found Pathogenic mutation, there was no pathogenic mutations detected in the CYP21A2 gene exon encoding region in 3 cases, multiple variants are known to have polymorphic loci,most likely not pathogenic. In 22 patients with mutation, a total of 8 types of mutation were detected. The percentage of the mutations involved in allele gene was I2G (22.7%), I172N (20.5%,), Del(13.6%), Q318X(13.6%), R356WC9.1%), ClusterE6 (6.8%), G110fs (6.8%), L307fs (4.5%). Among them the compound heterozygous mutation accounted for 54.5%, homozygous mutations accounted for 45.5%. Genotype of 16 cases with salt wasting was homozygous or compound heterozygous consisted of Del, Q318X, R356W, Cluster E6, G110fs, L307fs and I2G,which could Cause complete loss of enzyme activity or almost total loss. And the genotype of 6 cases with simple virilizing was homozygous or compound heterozygous consisted of I172N and other mutations mentioned above that cause the enzyme activity to complete loss(or nearly complete loss). DAX1 gene mutation was found in 7 children diagnosed as AHC, all was Half-mutation. Including c.656-665del GCACAAATCA p. ser219fs; c.548delG, p. Gly183Valfs; c.1343T>C, p. Phe448ser; c.1134-1137delCGCC p. Ala379fs; c.978-979delGG, p. Glu327Aspfs. The other 2 cases had large fragment deletion mutation in NR0B1 geneConclusions1. Digestive tract symptoms and skin pigmentation were the common clinical manifestations of CAH and AHC. In addition, the common cause of CAH also included the screening abnormal increasing of 17-OHP, external genital malformations, etc,but AHC does not have this kind of performance.17-OHP screening is very important, so that CAH can be found in early.2.17-OHP, P, T and E2 were increased in CAH children, while these indicators and LH,FSH were decreased in AHC chiIdren. Both have obvious differences, which can be used as the differential diagnosis index of them.3. The Imaging performance of CAH was increased adrenal volume and advanced bone age, While AHC showed decreased adrenal volume and delayed bone age, and this can be used as one of the differential diagnosis index of them, too.4. Gene detection can be used to identify CAH and AHC in patients with atypical clinical or supplementary examination, and can clearly diagnose timely. The clinical type and genotype of CAH were highly consistent, so that It can predict the severity of the disease and provide guidance for the treatment.5. In this study,4 new mutations of DAX1 gene were found.which had not been reported in previous literature.