Unsuspected mutation in a family with congenital adrenal hyperplasia
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Letter to the Editor Unsuspected Mutation in a Family With Congenital Adrenal Hyperplasia To the Editor: Congenital adrenal hyperplasia (CAH) due to 21- hydroxylase deficiency is an autosomal-recessive disor- der. Several common mutations are well characterized [White and New, 1992; Miller, 1994] and strong phe- notype/genotype correlations are described, although with many exceptions in individual patients [Wilson et al., 1995]. When both mutations are identified in an affected individual, one searches for the same muta- tions in the rest of the family. Furthermore, if the mu- tations found in the propositi are in agreement with the expected phenotype, one will assume that no other mutations are present in relatives. Consequently, obli- gate carriers are unlikely to be screened. Recently, unsuspected mutations were reported by Witchel et al. [1996] in two families affected by CAH. In the first one, the authors detected the G 656 mutation in both alleles in the propositus, and in the other family, the propositus had the G 656 mutation in one allele and a deletion/conversion in the other. Neither of them car- ried the Q318X mutation, which, surprisingly, was found in healthy relatives. We report on a similar case. A girl (Fig. 1, II-3) age 6 years, presented premature pubarche. Her height and bone maturation were above the normal limits and 17- hydroxyprogesterone response to ACTH stimulus was 51 nmol/L (normal reference 9 nmol/L). She presented a nonclassical phenotype. DNA analysis was estab- lished by means of the polymerase chain reaction and dot blot hybridization analysis [Speiser et al., 1992]. She was found to be a homozygous carrier for the V281L mutation. Her brother (II-2) was homozygous for the same mutation and showed the same phenotype (no other common mutations were present in either of them). The parents (I-3 and I-4) were heterozygous car- riers for the V281L mutation. Thereafter, a healthy cousin of the proposita (II-1) was referred for testing. At first we searched for the V281L mutation, but it was not present. When other known 21-hydroxylase muta- tions were tested, the analysis showed that this subject was a heterozygous carrier of the Q318X mutation. It is well known that if this mutation is present in both alleles, it will cause classic salt-losing CAH with 0% enzyme activity [Higashi et al., 1991]. Therefore, this finding is of great importance for correct genetic coun- seling. Unfortunately, samples from parents (I-1 and I-2) were not available. Mutation frequencies have been studied in some eth- nic groups and in ‘‘general caucasian populations’’ [Speiser et al., 1985; Owerbach et al., 1992], but it is not known whether in control caucasian populations, mutation frequencies are uniformly distributed or not. Further studies in general populations should be done to determine the exact risk in different areas. Mean- while, we suggest that all the relatives of patients with CAH should be tested at least for the most common 21-hydroxylase mutations. REFERENCES Higashi Y, Hiromasa T, Tanae A, Miki T, Nakura J, Kondo T, Ohura T, Ogawa E, Nakayama K, Fujii-Kurayama Y (1991): Effects of individual mutations in the P-450c21 pseudogene on P-450c21 activity and their distribution in patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem 109:638–644. Miller WL (1994): Genetic, diagnosis and management of 21-hydroxylase deficiency. J Clin Endocrinol Metab 78:241–246. Owerbach D, Sherman L, Ballard A-L, Azziz R (1992): Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21- hydroxylase deficiency. Mol Endocrinol 6:1211–1215. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI *Correspondence to: Josep Oriola, Servei d’Hormonologia, Hos- pital Clı ´nic i Provincial, C/Villarroel 170, 08036 Barcelona, Spain. E-mail:[email protected] Received 26 August 1996; Accepted 6 January 1997 Fig. 1. Mutational analysis. (-,-), non-carrier; (+,-), heterozygous; (+,+), homozygous for specified mutations. American Journal of Medical Genetics 71:249–250 (1997) © 1997 Wiley-Liss, Inc.
Transcript of Unsuspected mutation in a family with congenital adrenal hyperplasia
Letter to the Editor
Unsuspected Mutation in a Family With CongenitalAdrenal Hyperplasia
To the Editor:
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal-recessive disor-der. Several common mutations are well characterized[White and New, 1992; Miller, 1994] and strong phe-notype/genotype correlations are described, althoughwith many exceptions in individual patients [Wilson etal., 1995]. When both mutations are identified in anaffected individual, one searches for the same muta-tions in the rest of the family. Furthermore, if the mu-tations found in the propositi are in agreement withthe expected phenotype, one will assume that no othermutations are present in relatives. Consequently, obli-gate carriers are unlikely to be screened.
Recently, unsuspected mutations were reported byWitchel et al. [1996] in two families affected by CAH. Inthe first one, the authors detected the G656 mutation inboth alleles in the propositus, and in the other family,the propositus had the G656 mutation in one allele anda deletion/conversion in the other. Neither of them car-ried the Q318X mutation, which, surprisingly, wasfound in healthy relatives.
We report on a similar case. A girl (Fig. 1, II-3) age 6years, presented premature pubarche. Her height andbone maturation were above the normal limits and 17-hydroxyprogesterone response to ACTH stimulus was51 nmol/L (normal reference 9 nmol/L). She presenteda nonclassical phenotype. DNA analysis was estab-lished by means of the polymerase chain reaction anddot blot hybridization analysis [Speiser et al., 1992].She was found to be a homozygous carrier for theV281L mutation. Her brother (II-2) was homozygousfor the same mutation and showed the same phenotype(no other common mutations were present in either ofthem). The parents (I-3 and I-4) were heterozygous car-riers for the V281L mutation. Thereafter, a healthycousin of the proposita (II-1) was referred for testing.At first we searched for the V281L mutation, but it wasnot present. When other known 21-hydroxylase muta-tions were tested, the analysis showed that this subjectwas a heterozygous carrier of the Q318X mutation. It is
well known that if this mutation is present in bothalleles, it will cause classic salt-losing CAH with 0%enzyme activity [Higashi et al., 1991]. Therefore, thisfinding is of great importance for correct genetic coun-seling. Unfortunately, samples from parents (I-1 andI-2) were not available.
Mutation frequencies have been studied in some eth-nic groups and in ‘‘general caucasian populations’’[Speiser et al., 1985; Owerbach et al., 1992], but it isnot known whether in control caucasian populations,mutation frequencies are uniformly distributed or not.Further studies in general populations should be doneto determine the exact risk in different areas. Mean-while, we suggest that all the relatives of patients withCAH should be tested at least for the most common21-hydroxylase mutations.
REFERENCES
Higashi Y, Hiromasa T, Tanae A, Miki T, Nakura J, Kondo T, Ohura T,Ogawa E, Nakayama K, Fujii-Kurayama Y (1991): Effects of individualmutations in the P-450c21 pseudogene on P-450c21 activity and theirdistribution in patient genomes of congenital steroid 21-hydroxylasedeficiency. J Biochem 109:638–644.
Miller WL (1994): Genetic, diagnosis and management of 21-hydroxylasedeficiency. J Clin Endocrinol Metab 78:241–246.
Owerbach D, Sherman L, Ballard A-L, Azziz R (1992): Pro-453 to Sermutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency. Mol Endocrinol 6:1211–1215.
Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI
*Correspondence to: Josep Oriola, Servei d’Hormonologia, Hos-pital Clınic i Provincial, C/Villarroel 170, 08036 Barcelona, Spain.E-mail:[email protected]
Received 26 August 1996; Accepted 6 January 1997
Fig. 1. Mutational analysis. (−,−), non-carrier; (+,−), heterozygous;(+,+), homozygous for specified mutations.
American Journal of Medical Genetics 71:249–250 (1997)
© 1997 Wiley-Liss, Inc.
(1985): High frequency of nonclassical steroid 21-hydroxylase defi-ciency. Am J Hum Genet 37:650–667.
Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT,Lesser M, New MI, White P (1992): Disease expression and moleculargenotype in congenital adrenal hyperplasia due to 21-hydroxylase de-ficiency. J Clin Invest 90:584–595.
White PC, New MI (1992): Genetic basis of endocrine disease 2: Congenitaladrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocri-nol Metab 74:6–11.
Wilson RC, Mercado AB, Cheng KC, New MI (1995): Steroid 21-hydroxylase deficiency: Genotype may not predict phenotype. J ClinEndocrinol Metab 80:2322–2329.
Witchel SS, Lee PA, Trucco M (1996): Who is a carrier? Detection of un-
suspected mutations in 21-hydroxylase deficiency. Am J Med Genet61:2–9.
Josep Oriola*Servei d’HormonologiaHospital Clınic i Provincial de Barcelona
Carles PaviaSeccio d’EndocrinologiaHospital Universitari de Sant Joan de DeuBarcelona, Spain
250 Letter to the Editor
