ࡱ> dfcW @bjbjyy ^<l<0d^40606060606060$1 3Z0Z0*o0***Z40*40**//0X T)_P&000000Y4*^Y40*t\T Congenital Adrenal Hyperplasia 21-Hydroxylase Deficiency Faith Beverly 26 April 2002 In congenital adrenal hyperplasia the deficiency of 21-hydroxylase accounts for more than 90% of CAH cases (4). This missing enzyme reduces the production of cortisol and salt-retaining hormone by the adrenal glands. In a normal system, the cholesterol that is produced by the body (or ingested through diet) is converted to cortisol, salt-retaining hormone and androgen when needed. Cortisol protects the body from illness or injury. If a CAH person receives a broken leg they could suffer a severe shock accompanied by dangerously low blood pressure. The salt-retaining hormone governs the amount of salt lost in urine via the kidneys. In the absence of this hormone, salt is lost uncontrollably. Androgens, in both men and women, provide such things as childhood growth spurts and genital hair. When the pituitary senses that not enough cortisol is being produced, more cholesterol is delivered for use. However, since there are no enzymes to produce the needed cortisol and salt-retaining hormone from the cholesterol all of the surplus is converted into androgens. Two main categories o f CAH exist. Classic results from complete or near complete block of enzyme activity and is clinically present at birth. Classic is found in about 1:12,000 to 1:15,000 births (4). The milder Nonclassic (late onset) form involves only partial blockage of enzyme activity. The non-classic form has been shown to have a frequency of 1 per 27 in Ashkenazi Jews, 1 per 53 in Hispanics, 1 in 63 in Yugoslavs, and 1 per 333 in Italians (1). Those having the Classic form of congenital adrenal hyperplasia are further categorized as either 'non-salt losers' (20% of CAH) or 'salt-losers' (80% of CAH) due to mutational variability in the 21-hydroxylase gene with the surrounding region. In girls, 'non-salt losers' are recognizable at birth from the enlarged clitoris and partially fused labia. This genital ambiguity ranges from mild clitoris enlargement to a fully masculinized penile urethra. (Non-classic onset does not form genital ambiguity in female infants). In cases where it is not diagnosed at birth, the excess production of androgens causes growth of the clitoris into a small 'penis.' In boys, 'non-salt losers' produce nothing that can be detected at birth. Diagnosis is usually made when premature growth of the penis occurs and/or pubic hair, or he becomes unusually tall. X-rays show advanced maturity of the patient's bones consequently shorting the average adult height of the male and female patient. 'Salt-losers', if not controlled, can suffer acute dehydration, very low blood pressure, nausea and vomiting. The levels of salt and sugar in the blood fall, and the potassium level rises. Undiagnosed males often die during the newborn period of shock from salt wasting. Non-salt losers hardly ever experience 'adrenal crisis' because they are able to produce more cortisol and more of the salt-retaining hormone than the salt-losers. An autosomal recessive disorder, 21-hydroxylase deficiency has been linked to genes mutated on the short arm of chromosome 6 at a unit distance of 21.3 from the centromere. An HLA complex closely linked to the 21-hydroxylase deficiency. Within this complex their is evidence of two genes that encode for the steroid 21-hydroxylase in the C4 region, however only the C4B (CYP21) section of the C4 region is functional in humans. When mutations arise within this complex and the gene that functionally codes for 21-hydroxylase, a deficiency results. The severity of the deficiency has been shown dependent on the extent of mutation generated by recombinations between CYP21 (functional gene) and CYP21P (pseudogene). Complete deletion of the CYP21B gene accounts for about 20% of cases of the classic form of congenital adrenal hyperplasia; Complete deletion of the CYP21B region and an 8-bp deletion in the third exon is associated with the salt-wasting form; A G-to-T transversion in the seventh exon is associated with the late-onset form; and approximately 70% of mutations in the CYP21B gene causing classic and nonclassic CAH are point mutations (1). The most frequent mutations where I2 splice, 42% in salt wasting; I172N, 33% in simple virilizing; and V281L, 40% in the late onset form of CAH (1). The 21-hydroxylase pseudogene, CYP21P or CYP21A, is situated closely to the functional gene CYP21. The pseudogene has 3 main defects : an 8-bp deletion in exon 3, a T insertion in exon 7, and a stop codon in exon 8 (1). The DNA corresponding to 21-hydroxylase is 2kb long . This gene contains 10 exons, however, the non functional C4B region contains an 8-base deletion in codons 110-112, resulting in a frame shift that brings a stop codon into the reading frame at codon 130; a second frameshift and a nonsense mutation occurs further down stream (1). The protein produced by the C4B gene approximately contains 494 amino acids. The enzyme is at most 28% homologous to other cytochrome P450 enzymes that have been studied (1) such as CYP21A2, P450C21, CYP21A1P, CYP21P and CYP21A - all part of the subfamily XXIA (of the family steroids) on chromosome 6. The irregular "gene conversions" (unequal meiotic crossing over), recombinations, and point mutations in this region account for the 21-hydroxylase deficiency. Approximately 20 states include screening for CAH as a part of their newborn screening profiles. CAH is a lifelong disorder with no available cure. Medication, taken daily, in the form of tablets and/or shots, replace the missing hormones. Medical treatment of CAH also includes gender assignment in newborns with genital ambiguity. It is suggested that in ambiguity cases the infant should be reared in the gender of the chromosomal sex. However some suggest that XX individuals with CAH with extensively fused labia and a penile clitoris should be raised as a male (3). While those XX individuals with a hypertrophied clitoris should be reared as female (3). XY individuals with CAH are raised as males (3). Another argument involves the decision of sex by the patient, not the surgeon, when the age of the patient reaches at least 15 years. The Federal Prohibition of Female Genital Mutilation Act of 1995 states that "whoever knowingly circumcises, excises, or infibulates the whole or any part of the labia majora or labia minora or clitoris of another person who has not attained the age of 18 years shall be fined under this title" unless the operation was "necessary to the health of the person" or to the "person in labor for medical purposes connected with that labor" by those licensed to do so (5). There is a current move to present a bill that is re-written in gender-neutral language thereby protecting all children male, female or intersexed. Proponents of gender assigning discretion, such as Phillip Gruppuso, M.D., states that "predicting the future gender identity of an infant with ambiguous genitalia is uncertain at best." Those who hear the understanding of early intervention such as Peter Lee, M.D. suggests "that many, if not most, of the people who have had {genital reconstruction} as infants are pleased with the choice." However, there have been many cases when early genital assignment has not seemed to match the biochemistry of the developed "male" or "female" brain that recognizes an incompatibility and subsequent gender confusion for themselves in later years (4). Studies of girls and women with congenital adrenal hyperplasia involve a finding of increased rough-and-tumble play, preference for masculine toys and other tomboyish behavior. Studies have also found elevated rates of homosexual feelings among adult women with CAH compared to control women. Though, at the same time, only a minority of women with a history of CAH admit to homosexual feelings. "An advantage for finding a genetic link to sexual orientation lies mostly in obtaining civil rights under the current law. This information may also abolish society's tendency to seek and establish blame for a person's divergent sexuality " (6). Sequence for the gene encoding 21-hydroxylase (exons italicized and bold) 4042 BP; 779 A; 1261 C; 1154 G; 848 T; 0 other; tcgacagcta gatttccagg ctggaatcct gccctccaca acatgcgaac aatacccgtg 60 ttgcatatag agcatggctg tgaagagttg agtgagtgcc cacaaagcac ttagagcagt 120 gtctggtaca tgctattact ccgcagcggg aaaccacttc ctcctttgtc ttctgggcac 180 ttttgtgagt gaaaggaggc actaataaca atcacactgg gatacctgta tatactggaa 240 tgccccaggc aaaccaggct taaactgtat tactctatct gtagcttaaa ctaacaaaca 300 acccacacaa atcacatttt gttcttcagg cgattcagga aggcctatta ggcagggact 360 gccattttct ctctgagaca aacatcatgc cagtaaactg gcccacggtg gggtggcaga 420 gggagagggc ccaggtgggg gcggacacta ttgcctgcac aggtgatgtg gaaccagaaa 480 gctgactctg gatgcaggaa aaaggtcagg gttgcatttc ccttccttgc ttcttgatgg 540 gtgatcaatt tttttgaaat acggacgtcc caaggccaat gagactggtg tcattccaga 600 aaagggccac tctgtgggcg ggtcggtggg agggtacctg aaggtggggt caagggaggc 660 cccaaaacag tctacacagc aggagggatg gctggggctc ttgagctata agtggcacct 720 cagggccctg acgggcgtct cgccatgctg ctcctgggcc tgctgctgct gctgcccctg 780 ctggctggcg cccgcctgct gtggaactgg tggaagctcc ggagcctcca cctcccgcct 840 cttgccccgg gcttcttgca cttgctgcag cccgacctcc caatctatct gcttggcctg 900 actcagaaat tcgggcccat ctacaggctc caccttgggc tgcaaggtga gaggctgatc 960 tcgctctggc cctcaccata ggagggggcg gaggtgacgg agagggtcct ctctccgctg 1020 acgctgcttt ggctgtctcc cagatgtggt ggtgctgaac tccaagagga ccattgagga 1080 agccatggtc aaaaagtggg cagactttgc tggcagacct gagccactta cctgtaaggg 1140 ctgggggcat tttttctttc ttaaaaaaat ttttttttaa gagatgggtt cttgctatgc 1200 tgcccaggct ggtcttaaat tcctagtctc aaatgatcct cccacctcag cctcaagtgt 1260 gagccacctt tggggcatcc ccaatccagg tccctggaag ctcttggggg ggcatatctg 1320 gtggggagaa agcaggggtt ggggaggccg aagaaggtca ggccctcagc tgccttcatc 1380 agttcccacc ctccagcccc cacctcctcc tgcagacaag ctggtgtcta ggaactaccc 1440 ggacctgtcc ttgggagact actccctgct ctggaaagcc cacaagaagc tcacccgctc 1500 agccctgctg ctgggcatcc gtgactccat ggagccagtg gtggagcagc tgacccagga 1560 gttctgtgag gtaaggctgg gctcctgagg ccacctcggg tcagccttgc ctctcacagt 1620 agcccccgcc ctgcccgctg cacagcggcc tgctgaactc acactgtttc tccacagcgc 1680 atgagagccc agcccggcac ccctgtggcc attgaggagg aattctctct cctcacctgc 1740 agcatcatct gttacctcac cttcggagac aagatcaagg tgcctcacag cccctcaggc 1800 ccacccccag cccctccctg agcctctcct tgtcctgaac tgaaagtact ccctcctttt 1860 ctggcaggac gacaacttaa tgcctgccta ttacaaatgt atccaggagg tgttaaaaac 1920 ctggagccac tggtccatcc aaattgtgga cgtgattccc tttctcaggg tgaggacctg 1980 gagcctagac acccctgggt tgtaggggag aggctggggt ggagggagag gctccttccc 2040 acagctgcat tctcatgctt cctgccgcag ttcttcccca atccaggtct ccggaggctg 2100 aagcaggcca tagagaagag ggatcacatc gtggagatgc agctgaggca gcacaaggtg 2160 gggactgtac gtggacggcc tcccctcggc ccacagccag tgatgctacc ggcctcagca 2220 ttgctatgag gcgggttctt ttgcataccc cagttatggg cctgttgcca ctctgtactc 2280 ctctccccag gccagccgct cagcccgctc ctttcaccct ctgcaggaga gcctcgtggc 2340 aggccagtgg agggacatga tggactacat gctccaaggg gtggcgcagc cgagcatgga 2400 agagggctct ggacagctcc tggaagggca cgtgcacatg gctgcagtgg acctcctgat 2460 cggtggcact gagaccacag caaacaccct ctcctgggcc gtggtttttt tgcttcacca 2520 ccctgaggtg cgtcctgggg acaagcaaaa ggctccttcc cagcaacctg gccagggcgg 2580 tgggcaccct cactcagctc tgagcactgt gcggctgggg ctgtgcttgc ctcaccggca 2640 ctcaggctca ctgggttgct gagggagcgg ctggaggctg ggcagctgtg ggctgctggg 2700 gcaggactcc acccgatcat tccccagatt cagcagcgac tgcaggagga gctagaccac 2760 gaactgggcc ctggtgcctc cagctcccgg gtcccctaca aggaccgtgc acggctgccc 2820 ttgctcaatg ccaccatcgc cgaggtgctg cgcctgcggc ccgttgtgcc cttagccttg 2880 ccccaccgca ccacacggcc cagcaggtga ctcccgaggg ttggggatga gtgaggaaag 2940 cccgagccca gggaggtcct ggccagcctc taactccagc ccccttcagc atctccggct 3000 acgacatccc tgagggcaca gtcatcattc cgaacctcca aggcgcccac ctggatgaga 3060 cggtctggga gaggccacat gagttctggc ctggtatgtg gggggccggg ggcctgccgt 3120 gaaaatgtgg tggaggctgg tccccgctgc cgctgaacgc ctccccaccc acctgtccac 3180 ccgcccgcag atcgcttcct ggagccaggc aagaactcca gagctctggc cttcggctgc 3240 ggtgcccgcg tgtgcctggg cgagccgctg gcgcgcctgg agctcttcgt ggtgctgacc 3300 cgactgctgc aggccttcac gctgctgccc tccggggacg ccctgccctc cctgcagccc 3360 ctgccccact gcagtgtcat cctcaagatg cagcctttcc aagtgcggct gcagccccgg 3420 gggatggggg cccacagccc gggccagaac cagtgatggg gcaggaccga tgccagccgg 3480 gtacctcagt ttctccttta ttgctcctgt acgaacccct cccctccccc ctgtaaacac 3540 agtgctgcga gatcgctggc agagaaggct tcctccagcg gctgggtggt gaaggaccct 3600 ggctcttctc tcggggcgac ccctcagtgc tcggcagtca tactggggtg cgagagaggt 3660 gggcagcagc tcagcctccc cccgctgggg agcgaaagtt tcttggtctc agcttcattt 3720 ccgtgaaggg caccgagaac tcgaagccct tccagtggta ccagctcact ccctgggaaa 3780 ggggttgtca agagagagtc aaagccggat gtcccatctg ctcttcccgt tccccttaag 3840 gaggtagctc ccagcactca accaacctcc ccgcagagct cccttcctga ccctccgctg 3900 cagaggattg aggcttaatt ctgagctggc cctttccagc caataaatca actccagctc 3960 cctctgcgag gctggcatga ttgttccatt tcacccagcc actcagtccc ttgcctgtta 4020 cactgtgggg ctgaaaccta gg 4042 (7) Protein sequence for 21-hydroxylase (exons underlined) 1) MLLLGLLLLLPLLAGARLLWNWWKLRSLHLPPLAPGFLHLLQPDLFT PIYLLGLTQKFGPIYRLHLGLQD 2) VVVLNSKRTIEEAMVKKWADFAGRPEPLTY 3) KLVSRN FTYPDLSLGDYSLLWKAHKKLTRSALLLGIRDSMEPVVEQLTQEFCE 4) RMRAQPGTPVAIEEFTEFSLLTCSIICYLTFGDKIK 5) DDNLMPAYYKCIQEVLKTWSHWSIQIVDVIPFLR 6) FFPNPFTGLRRLKQAIEKRDHIVEMQLRQHK 7) SLVAGQWRDMMDYMLQGVAQPSMEEGSGQLLEGHFTVHMAAVDLLIGGTETTANTLSWAVVFLLHHPE 8) IQQRLQEELDHELGPGASSSRVPYKDRFTARLPLLNATIAEVLRLRPVVPLALPHRT TRPSS 9) ISGYDIPEGTVIIPNLQGAHLDETVWFTERPHEFWP D 10) RFLEPGKNSRALAFGCGARVCLGEPLARLELFVVLTRLLQAFTLLPSGDA FTLPSLQPLPHCSVILKMQPFQVRLQPRGMGAHSPGQNQ (7) References OMIM :  HYPERLINK http://www.ncbi.nlm.gov/htbin-post/Omim?dispmim?201910#DESCRIPTION http://www.ncbi.nlm.gov/htbin-post/Omim?dispmim?201910#DESCRIPTION SwissProt:  HYPERLINK http://www.expasy.org/sprot/ http://www.expasy.org/sprot/ Ambiguous Sex of Ambivalent Medicine? The Hastings Center Report. Hastings-on-Hudson. May/June 1998, Volume 28, Issue 3, Pages 24-35. "Welcome to CAH Our Voices and Our Stories" :  HYPERLINK http://www.cahourstories.net/ www.cahourstories.net/ NPR : "Letters on the Biological Basis of Homosexuality" :  HYPERLINK http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htm http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htm Homosexuality : It's In Your Genes :  HYPERLINK http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htm http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htm Gene sequencing/Protein sequencing : http://srs.ebi.ac.uk/srs6bin/cgi-bin/wgetz?-id+lFkS1IePN4+-e+[EMBL:'HSCP2113'] $>?w $T$o(((((?)B)z)*1*6*u*+,,h,m,,,,R-[-_-`-----_.....l/////0000'1+1,1x1|1}111112 333^3b3c33333?4Q4U44444Y5555556676;6<6666 56\]6]CJ>*CJCJ CJ(CJ$Z$>?M[\]^_`abcdefghijklmn$a$@nopqrstuvwx 6,~!#$$$ $S$T$$$dd`$a$$&%w%%&j&& ']'''P(((C)))6***)+z++,m,,-`--..S...F///9000,1}112p223c334V444I555<666/766::H:I:::::::F;G;f;j;;;<<~<<<<<<<<<A=B=C=N=O=w=x=y=====L>M>v>w>x>>>>>&?'?(?v?w?x???????H@I@J@jUjMU0JjnU 0JmHsHjUmHsH 0JmHsHjU jUmHsH>*6]OJPJQJ^J 56\]@/777"8s889f99: : ::::H:I:::!;G;j;;;;<< "( Px 4 #\'*.25@9<V<~<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<C==>>x?J@@@d^ & Fdd` J@n@@>*/ =!"#$%DyK Chttp://www.ncbi.nlm.gov/htbin-post/Omim?dispmim?201910#DESCRIPTIONyK nhttp://www.ncbi.nlm.gov/htbin-post/Omim?dispmim?201910 DESCRIPTIONDyK http://www.expasy.org/sprot/yK :http://www.expasy.org/sprot/DyK www.cahourstories.net/yK <http://www.cahourstories.net/DyK Ohttp://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htmyK http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htmDyK Ohttp://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htmyK http://cas.bellarmine.edu/tietjen/RootWeb/npr_letters_on_the_biological_ba.htm i0@0 Normal_HmH sH tH 2@2 Heading 1$@&6]<A@< Default Paragraph Font.U@. 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