Endocrinology and Metabolism

Original Articles

Molecular Genetic Studies on the Human CYP21A2 Gene (1).: Byung Kiu Park, Hyang Ok Woo, Han Wook Woo; J Korean Endocr Soc. 1994;9(3):219-227. Published online November 6, 2019

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Abstract PDF: Congenital adrenal hyperplasia, especially due to steroid-12-hydroxylase(P450c21) deficiency, is one of the most common autosomal recessive inborn errors at adrenal steroidogenesis in Korean. Molecular genetic analysis has demonstrated that there are two steroid 21-hydroxylase genes, CYP21A1P and CYP21A2. The CYP21A2 gene encodes P450c21, whereas the CYP21A1P gene is a pseudogene. Since there is 98 percent homology between the CYP21A1P and CYP21A2 gene in nucleotide sequences, it has hampered the characterization of molecular defects in the CYP21A2 gene.In this study, efforts have been made to selectively PCR amplify the CYP21A2 gene and test feasibility of DNA microextraction from Guthrie card for prospective use of molecular screening. This study was also aimed at investigating deletion mutations in P450c21 deficient patients, as well as allele frequencies and average heterozygosity of exon 1 A/C polymorphism in Korean newborns. Genomic DNAs were obtained from Guthrie cards of 50 Korean newborns by microextraction method and these DNAs were analyzed by PCR-allele specific oligonucleotide(ASO) hybridization. First part of the CYP21A2 gene has been successfully amplified and digested by restriction enzyme using Taq I or Kpn I, subsequently run on 1.5% agarose gel to confirm its specificity. The anterior 1141 bp PCR product was utilized to examine the frequency and average heterozygosity of exon 1 A/C polymorphism in 100 alleles by ASO dot blot hybridization. Amplified genomic DNAs from four P450c21 deficient patients out of three families were screened by PCR to see if any one has complete deletion of the CYP21A2 gene.The results were as follows;1) The average 1230ng of genomic DNA was obtained form single semi-circled Guthrie card of 1/2 inch diameter by microextraction method, which has been successfully used for DNA analysis.2) The PCR amplified anterior 1141 bp product from the CYP21A2 gene was digested by Kpn I, generating 309 bp, 832 bp fragments, not by Taq I, indicating its specificity.3) The frequencies of exon 1 nucleotide 138 A/C polymorphism in Korean population were 0.81, 0.91 respectively, and average heterozygosity was 0.31.4) None of four P450c21 deficient patients turned out to carry complete deletion of the CYP21A2 gene based on selective PCR amplification of the CYP21A2 gene.In conclusion, dried blood spots from Guthrie card can be sued for DNA analysis because of easy sample collection, bandling, shipment, and DNA extraction feasibility. The selective PCR amplification of the CYP 21A2 gene will pave the way for molecular characterization in P450c21 deficient patients. The exon 1 A/C polymorphism can by efficiently used for molecular diagnosis of P450c21 deficiency in informative families, though it has a drawback of handling radioactive material.

Six Cases of Congenital Adrenal Hyperplasia That Were Due to 17alpha-hydroxylase/17,20-lyase Deficiency.: Dong Hoon Shin, Sung Hoon Yu, Young Min Choi, Jung Gu Kim, Sang Wan Kim, Chan Soo Shin, Kyong Soo Park, Seong Yeon Kim; J Korean Endocr Soc. 2009;24(2):109-115. Published online June 1, 2009; DOI: https://doi.org/10.3803/jkes.2009.24.2.109

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17alpha-hydroxylase/17,20-lyase deficiency is a rare phenotype of congenital adrenal hyperplasia (CAH), and this is characterized by hyporeninemic hypertension, primary amenorrhea and abnormality of the secondary sexual characteristics (pseudohermaphroditism in men). This type of CAH is usually misdiagnosed at first as mineralocorticoid induced hypertension with primary aldosteronism, but primary amenorrhea with deficient sex hormone is a clue for making the correct diagnosis. The authors experienced 6 cases of 17alpha-hydroxylase/17,20-lyase deficiency in patients who ranged from 15 to 42 years of age. 4 cases were diagnosed according to the investigation of their mineralocorticoid-induced hypertension and 2 cases their primary amenorrhea and sexual infantilism. All of them had hypokalemia, hyporeninemic hypertension and an atrophied uterus and ovaries. In the genotypic male (46 XY), the testicles were atrophied in the abdominal cavity. The levels of cortisol, estrogen and dehydroepiandrosterone sulfate (DHEAS) were low, but the levels of progesterone and 11-deoxycorticosterone were high. Therefore, the diagnosis of 17alpha-hydroxylase/17,20-lyase deficiency should be considered in female patients who present with both sexual infantilism and mineralocorticoid hypertension. We report on these cases with a brief review of the literature.

Citations

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Functional Identification of Compound Heterozygous Mutations in the CYP17A1 Gene Resulting in Combined 17α-Hydroxylase/17,20-Lyase Deficiency
Eun Yeong Mo, Ji-young Lee, Su Yeon Kim, Min Ji Kim, Eun Sook Kim, Seungok Lee, Je Ho Han, Sung-dae Moon
Endocrinology and Metabolism.2018; 33(3): 413. CrossRef
17α-hydroxylase Deficiency Mimicking Hyperaldosteronism by Aldosterone-producing Adrenal Adenoma
Yun Kyung Cho, Hyeseon Oh, Sun-myoung Kang, Sujong An, Jin-Young Huh, Ji-Hyang Lee, Woo Je Lee
The Korean Journal of Medicine.2016; 91(2): 191. CrossRef

Case Reports

A Case of Congenital Adrenal Hyperplasia Combined with a Testicular Adrenal Rest Tumor and Adrenal Incidentaloma.: Gyu Rang Cho, Hee Won Chueh, Jung Pyo Kim, Jin A Jung, Jae Ho Yoo, Sung Kook Yoon, Kyu Geun Hwang; J Korean Endocr Soc. 2007;22(5):365-370. Published online October 1, 2007; DOI: https://doi.org/10.3803/jkes.2007.22.5.365

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Abstract PDF

The fundamental defect among patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylse deficiency is the inability to synthesize cortisol and aldosterone adequately. Ineffective cortisol synthesis signals the hypothalamus and pituitary to increase the production of corticotropin releasing hormone and adrenocorticotropic hormone, respectively. Consequently, the adrenal glands become hyperplastic. It is well known that an adrenal adenoma can develop from hyperplastic tissue under increased corticotropin stimulation of the adrenal cortex in patients that are suffering with CAH. The etiologic mechanism of adrenal incidentaloma remains uncertain, but several hypotheses have been suggested. A testicular adrenal rest tumor has been reported to form in association with the excessive secretion of adrenal androgen by inadequate control after adolescence in CAH. We present a case of poorly controlled salt-losing CAH due to 21-hydroxylase deficiency combined with a testicular adrenal rest tumor and adrenal incidentaloma.

Citations

Citations to this article as recorded by

A new compound heterozygous mutation in a female with 17α-hydroxylase/17,20-lyase deficiency, slipped capital femoral epiphysis, and adrenal myelolipoma
Fan Yang, Yongting Zhao, Jie Lv, Xia Sheng, Lihong Wang
Gynecological Endocrinology.2019; 35(5): 385. CrossRef
A case of testicular adrenal rest tumor in a male child with congenital adrenal hyperplasia
Joo Hwa Kim, Kyong Ah Yun, Choong Ho Shin, Sei Won Yang
Korean Journal of Pediatrics.2008; 51(9): 1018. CrossRef

Two Cases of Simple Virilizing Congenital Adrenal Hyperplasia with Compound Heterozygous Mutations of CYP21 Gene.: Koon Soon Kim, Yun Sun Choi, Youn Sun Bai, So Young Rha, Young Suk Jo, Minho Shong; J Korean Endocr Soc. 2007;22(4):299-304. Published online August 1, 2007; DOI: https://doi.org/10.3803/jkes.2007.22.4.299

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Abstract PDF: Steroid 21-hydroxylase deficiency is the most frequent cause of congenital adrenal hyperplasia (CAH), which is an inherited inability to synthesize cortisol. Actually, CAH is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. In some cases, discordance has been observed between the genotype and the phenotype. We recently experienced two cases of simple virilizing congenital adrenal hyperplasia with compound heterozygous mutations of the CYP21 gene. The patients had primary amenorrhea and showed virilization. We have described these two cases along with a review of the literature.

A Case of Congenital Adrenal Hyperplasia due to 11beta-Hydroxylase Deficiency.: Ohk Hyun Ryu, Hye Jin Yoo, Soo Yeon Park, Soon Beom Kwon, Sang Soo Park, Hee Young Kim, Kye Won Lee, Ji A Seo, Jeong Heon Oh, Sin Gon Kim, Nan Hee Kim, Kyung Mook Choi, Sei Hyun Baik, Dong Seop Choi; J Korean Endocr Soc. 2004;19(1):58-63. Published online February 1, 2004

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Abstract PDF: Congenital adrenal hyperplasia refers to a group of autosomal recessive disorders that is defective in the synthesis of cortisol. The enzymes most often affected are 21-hydroxylase and 11beta hydroxylase. The low levels of cortisol stimulate the pituitary gland to release ACTH. Chronic elevation of the ACTH level causes bilateral adrenal hyperplasia and a secondary increase in androgen formation. We examined a 19 year-old woman presented with clitoral hypertrophy and vaginal spotting. The subjects basal level of serum cortisol was low, but the serum levels of ACTH, 17a-hydroxyprogesterone, deoxy-corticosterone were elevated. The urinary excretions of 17-ketosteroids and 17-hydroxycorticosteroids were also increased. The karyotyping study and transrectal ultrasonography showed normal findings. The patient underwent clitoris reduction surgery and received hydrocortisone. To the best of our knowledge, this is the first case of 11beta-Hydroxylase deficiency in Korea.

A Case of Primary Amenorrhea due to 17 -Hydroxylase Deficiency.: Hong Seub Rim, Seon Hwa Lee, Jung Min Hong, Jae Hyun Nam, Hee Back Park, Chul Woo An, Do Min Ki, Sung Kil Lim, Young Duk Song, Hyun Chul Lee, Kap Bum Huh, Inn Soo Kang; J Korean Endocr Soc. 2001;16(1):130-133. Published online February 1, 2001

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Abstract PDF: 17 -Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia that is characterized by primary amenorrhea, absence of secondary sex characteristics, hypertension, and a hypokalemic alkalosis that has resulted resulting from increased production of deoxycorticosterone and corticosterone by the adrenal. The diagnosis of this enzyme deficiency can be recognized by the increasing serum concentrations of steroid precursors, DOC and corticosterone and the decreasing concentrations of cortisol, and adrenal androgens. We diagnosed this in a 19 year old female who presented with primary amenorrhea. We report this case with a review of the literatures.

Original Article

A Study on the Relationship Between Genotype and Phenotype in Korean Patients with Congenital Adrenogenital Syndrome Caused by 21-hydroxylase Deficiency.: Dong Kyu Jin, Jung Sim Kim, Seung Mi Song, Sung Joon Park, He Zin Hwang, Hwa Young On, Phil Soo Oh, Si Whan Koh, Mee Ryung Uhm, Dong Hwan Lee, Jah Hoon Shin, Heon Seok Han, Hong Sik Kim, Cheol Woo Ko, Han Wook Yoo, Jin Sung Lee, Duk Hee Kim; J Korean Endocr Soc. 2000;15(2):237-247. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Congenital adrenal hyperplasia (CAH) results from an inherited defect in enzymatic steps required to synthesize cortisol from cholesterol. 21-hydroxylase deficiency accounts for 95% cases of CAH. It appears that the frequency and the type of the responsible mutations differ according to the ethnic background and the type of mutation can predict the clinical outcomes such as salt losing type (SL), simple virilizing type (SV) and non-classic type (NC). METHODS: We have analyzed CYP21 genes in 55 Korean cases (110 chromosomes) of CAH by Southern blotting, PCR-dot hybridization and PCR amplification-created restriction site method. The patients include 43 cases of SL and 12 of SV. None of the NC was found. RESULTS: We found the mutations in 94% (103/110) of the examined chromosomes. A total of 10 types of mutations were discovered. The mutations include aberrant splicing of intron 2 (i2, 35%), CYP21 gene deletion (32%) and I172N (11%) in order. When the relationship between the clinical types and genotypes were correlated, most of the SL patients have either i2 (42%) or CYP21 gene deletion (41%), while SV patients have I172N (33%) or P30L (21%). The parents' mutation was investigated in 20 cases. In 4 families, one of the parents was not the obligatory heterozygote carrier i.e. did not have a mutation. The results suggest the high incidence of de novo mutation. CONCLUSION: We have identified the frequency of mutations of the CYP21 in Korean AGS patients. Our results shows that the clinical type of AGS can be predicted from the genotypes of CYP21. Also the high incidence of de novo mutation of CYP21 confirmed the genetic instability of major histocompatibility III region where the CYP21 is located.

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