Phenotype and genotype characteristics of Indonesian 21-hydroxylase deficient patients
Keywords:
congenital adrenal hyperplasia (CAH), phenotype, genotype, 21-hydroxylase deficiency
Abstract
Background Congenital adrenal hyperplasia (CAH) is the mostcommon cause of ambiguous genitalia in children and 90-95%
cases show 21-hydroxylase deficiency. More than 100 mutations
have been described and of these, four mutations have been
frequently reported in Asia. Those mutations are deletion/large
gene conversion (LGC), intron2 splice mutation (I2 splice), point
mutations at codon 172 (I172N) and codon 356 (R356W).
Genotyping is very valuable since close correlation observed
between genotype and phenotype.
Objective To identify phenotype and genotype characteristics of
CAH due to 21-hydroxylase deficiency (CAH-21OH) and
correlation between them.
Methods From June to November 2006 we analyzed 37 confirmed
CAH-21OH patients treated at the Department of Child Health,
Cipto Mangunkusumo Hospital during the period of 1990-2006.
Polymerase chain reaction (PCR) followed by restriction fragment
length polymorphism (RFLP) analysis or amplification-created
restriction site (ACRS) were performed. We first identified deletion/
LGC and I172N mutation that had been mostly reported in salt
wasting (SW) and simple virilizing (SV) form patients respectively.
Results There were 37 patients, consisted of 6 males and 31
females with the ratio 1:5.2. Of those, 25, 10, 2 patients were
SW, SV and non-classic (NC) form, respectively. PCR-RFLP or
ACRS was performed to detect two mutations in 32 patients (64
alleles). Deletion/LGC was found in 6 alleles while I172N
mutations in two. All deletion alleles showed SW phenotype but
I172 mutated alleles showed SW and SV phenotype.
Conclusion There is a consistent close association between
genotype and phenotype in our CAH-21OH patients.
References
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of congenital adrenal hyperplasia due to 21-hydroxylase
deficiency. Hum Reprod 2004;10:469-85.
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Phenotype-genotype correlation in 56 woman with nonclassical
congenital adrenal hyperplasia due to 21-hydroxilase deficiency.
J Clin Endocrinol Metab 2001;86:207-13.
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newborn period. Urol Clin North Am 2004;31:435-43.
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hydroxylase deficiency diagnosed after the introduction of a
newborn screening program in Japan. Clin Pediatr Endocrinol
2003;12:19-23.
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Carrier analysis and prenatal diagnosis of congenital adrenal
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without demonstrable mutation within the structural gene
for CYP21. J Clin Endocrinol Metab 2002;87:2668-73.
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countries. J Clin Endocrinol Metab 2001;86:2958-64.
21. Loke KY, Tan IT, Lee WR, Lee YS. Epidemiology of 21-
hydroxylase deficiency in Singapore [abstr]. J Pediatr
Endocrinol Metab 2002;15:397-403.
22. Joint LWPES/ESPE CAH Working Group. Consensus
statement on 21-hydroxylase deficiency from the Lawson
Wilkin Pediatric Endocrinology Society and the European
Society for Paediatric Endocrinology. J Clin Endocrinol Metab
2002;87:4048-53.
23. Grumbach MM, Conte FA. Disorder of sex differentiation.
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editors. William textbook of endocrinology. 9th ed.
Philadephia: WB Saunders;1998. p. 1361-8.
24. Carrol MC, Campbel D, Porter RR. Mapping of steroid 21-
hydroxylase genes adjacent to complement component C4
genes in HLA the major histocompatibility complex in man.
Proc Natl Acad Sci 1985; 82: 521-5.
25. Hochbergt Z, Gardos M, Bernderly A. Psychosocial outcome
of assigned females and males with 46,XX virilizing congenital
adrenal hyperplasia. Eur J Pediatrics 1987;146:497-9.
26. Delague V, Souraty N, Khallouf E, Tardy V, Chouery E,
Halaby G, et al. Mutational analysis in Lebanese patient with
congenital adrenal hyperplasia due a deficit in 21-hydroxylase
[abstr]. Horm Res 2000;5:77-82.
27. Tukel T, Uyguner O, Wei JQ, Yuksel-apak M, Saka N, Song
DX, et al. A novel semiquantitative polymerase chain
reaction/enzyme digestion-based methode for detection of
large scale deletion/conversion of the CYP21 gene and
mutation screening in Turkish families with 21-hydroxylase
deficiency. J Clin Endocrinol Metab 2003;88:5893-7.
28. White PC, New MI. Genetic basis of endocrine disease 2:
congenital adrenal hyperplasia due to 21-hydroksilase
deficiency. J Clin Endocrinol Metab 1992;74:6-11.
29. Jaaskelainen J, Levo A, Outilainen R, Partanen J. Population-
wide evaluation of disease manifestation in relation to
molecular genotype in steroid 21-hydroxylase deficiency:
good correlation in well defined population. J Clin Endocrinol
Metab 1997;82:3293-7.
30. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-
hydroxylase deficiency : genotip may not predict phenotype.
J Clin Endocrinol Metab 1995;80:2322-9.
hyperplasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D,
editors. The metabolic and molecular bases of inherited
disease. 3rd ed. New York: McGraw-Hill; 2001. p. 4077-115.
2. New MI, Ghizzoni L, Speiser PW. Update on congenital adrenal
hyperplasia. In: Lifshitz F, editor. Pediatric endocrinology. 3rd
ed. New York: Marcel Dekker Inc; 1996. p. 305-20.
3. New MI. An update of congenital adrenal hyperplasia. Ann
NY Acad Sci 2004;1038:14-43.
4. Speiser PW, White PC. Congenital adrenal hyperplasia. N
Engl J Med 2003;349:776-88.
5. Forest MG. Recent advances in the diagnosis and management
of congenital adrenal hyperplasia due to 21-hydroxylase
deficiency. Hum Reprod 2004;10:469-85.
6. Levine LS. Congenital adrenal hyperplasia. Pediatr Rev
2000;5:159-70.
7. Speiser PW. Congenital adrenal hyperplasia owing to 21-
hydroxylase deficiency. Endocrinol Metab Clin North Am
2001;30:31-59.
8. White PC, Speiser PW. Congenital adrenal hyperplasia due
to 21-hydroxylase deficiency. Endocr Rev 2000;21:245-91.
9. Deneux C, Tardy V, Dib A, Mornet E, Billaud L, Charron D, et al.
Phenotype-genotype correlation in 56 woman with nonclassical
congenital adrenal hyperplasia due to 21-hydroxilase deficiency.
J Clin Endocrinol Metab 2001;86:207-13.
10. Hyun G, Kolon T. A practical approach to intersex in the
newborn period. Urol Clin North Am 2004;31:435-43.
11. Ogawa E, Fujieda K, Tachibana K, Inomata H, Kinoshita E,
Kusuda S, et al. Mortality in patient with congenital 21-
hydroxylase deficiency diagnosed after the introduction of a
newborn screening program in Japan. Clin Pediatr Endocrinol
2003;12:19-23.
12. Colletti JE, Homme JL, Woodridge DP. Unsuspected neonatal
killers in emergency medicine. Emerg Clin North Am
2004;22:926-60.
13. Loke KY, Lee YS, Lee WW, Poh LK. Molecular analysis of
CYP-21 mutation for congenital adrenal hyperplasia in
Singapore [abstr]. Horm Res 2001;55:179-84.
14. Lee HH, Kuo J, Chao HT, Lee YJ, Chang JG, Tsai CH, et al.
Carrier analysis and prenatal diagnosis of congenital adrenal
hyperplasia caused by 21-hydroxylase deficiency in Chinnese.
J Clin Endocrinol Metab 2000;85:597-600.
15. Mathur R, Menon PS, Kabra M, Goyal RK, Verma IC.
Molecular genetic studies in Indian patient with 21-
hydroxylase deficiency [abstr]. J Pediatr Endocrinol Metab
2001;14: 27-35.
16. Koyama S, Toyoura T, Saisho S, Shomozawa K, Yata J. Genetic
analysis of Japanese patient with 21-hydroxylase deficiency:
identification of a patient with a new mutation of a
homozygous deletion of adenine at codon 246 and patient
without demonstrable mutation within the structural gene
for CYP21. J Clin Endocrinol Metab 2002;87:2668-73.
17. Liao XY, Zhang YF, Gu XF. CYP21 gene point mutation study
in 21-hydroxylase deficiency patient [abstr]. Zhonghua Er
Ke Za Zhi 2003;41:670-4.
18. Bajpai A, Kabra M, Menon PS. 21-hydroxylase deficiency:
clinical features, laboratory profile and pointers to diagnosis
in Indian children. Indian Pediatrics 2004;41:1226-32.
19. Kharrat M, Tardy V, M’rad R, Maazqui F, Jemaa LB, Refai M,
et al. Molecular genetic analysis of Tunisian patient with a
classic form of 21-hydroxylase deficiency: identification of
four novel mutations and high prevalence of Q318X
mutation. J Clin Endocrinol Metab 2004;89:368-74.
20. Kovacks J, Votava F, Heinze G, Solyom J, Lebl J, Pribilincova
Z. Lesson from 30 years of clinical diagnosis and treatment
of congenital adrenal hyperplasia in five middle European
countries. J Clin Endocrinol Metab 2001;86:2958-64.
21. Loke KY, Tan IT, Lee WR, Lee YS. Epidemiology of 21-
hydroxylase deficiency in Singapore [abstr]. J Pediatr
Endocrinol Metab 2002;15:397-403.
22. Joint LWPES/ESPE CAH Working Group. Consensus
statement on 21-hydroxylase deficiency from the Lawson
Wilkin Pediatric Endocrinology Society and the European
Society for Paediatric Endocrinology. J Clin Endocrinol Metab
2002;87:4048-53.
23. Grumbach MM, Conte FA. Disorder of sex differentiation.
In: Wilson JD, Foster DW, Kronenberg HM, Laresen PR,
editors. William textbook of endocrinology. 9th ed.
Philadephia: WB Saunders;1998. p. 1361-8.
24. Carrol MC, Campbel D, Porter RR. Mapping of steroid 21-
hydroxylase genes adjacent to complement component C4
genes in HLA the major histocompatibility complex in man.
Proc Natl Acad Sci 1985; 82: 521-5.
25. Hochbergt Z, Gardos M, Bernderly A. Psychosocial outcome
of assigned females and males with 46,XX virilizing congenital
adrenal hyperplasia. Eur J Pediatrics 1987;146:497-9.
26. Delague V, Souraty N, Khallouf E, Tardy V, Chouery E,
Halaby G, et al. Mutational analysis in Lebanese patient with
congenital adrenal hyperplasia due a deficit in 21-hydroxylase
[abstr]. Horm Res 2000;5:77-82.
27. Tukel T, Uyguner O, Wei JQ, Yuksel-apak M, Saka N, Song
DX, et al. A novel semiquantitative polymerase chain
reaction/enzyme digestion-based methode for detection of
large scale deletion/conversion of the CYP21 gene and
mutation screening in Turkish families with 21-hydroxylase
deficiency. J Clin Endocrinol Metab 2003;88:5893-7.
28. White PC, New MI. Genetic basis of endocrine disease 2:
congenital adrenal hyperplasia due to 21-hydroksilase
deficiency. J Clin Endocrinol Metab 1992;74:6-11.
29. Jaaskelainen J, Levo A, Outilainen R, Partanen J. Population-
wide evaluation of disease manifestation in relation to
molecular genotype in steroid 21-hydroxylase deficiency:
good correlation in well defined population. J Clin Endocrinol
Metab 1997;82:3293-7.
30. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-
hydroxylase deficiency : genotip may not predict phenotype.
J Clin Endocrinol Metab 1995;80:2322-9.
Published
2007-10-31
How to Cite
1.
Oswari A, Tridjaja B, Setianingsih I, Tambunan T, Pulungan A, Batubara J. Phenotype and genotype characteristics of Indonesian 21-hydroxylase deficient patients. PI [Internet]. 31Oct.2007 [cited 10Nov.2024];47(5):189-5. Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/412
Section
Pediatric Endocrinology
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Received 2016-08-31
Accepted 2016-08-31
Published 2007-10-31
Accepted 2016-08-31
Published 2007-10-31
