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V281L CYP21A2 genotype associated with congenital adrenal hyperplasia form. A case report from South Italy
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Clinical Biochemistry 40 (2007) 1435 – 1436
First case of V281+I172N/V281L CYP21A2 genotype associated with congenital adrenal hyperplasia form. A case report from South Italy Paola Concolino a,b , Salvatore Corsello c , Cinzia Carrozza a , Angelo Minucci a , Concetta Santonocito a , Rosa Maria Lovicu c , Stefano Angelo Santini b , Franco Ameglio a , Cecilia Zuppi a , Ettore Capoluongo a,⁎ a
Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, Largo F. Vito, 1-00168, Rome, Italy b Laboratory of Clinical Pathology - IRCCS Casa Sollievo della Sofferenza - San Giovanni Rotondo, Foggia, Italy c Institute Medical Pathology, Catholic University, Rome, Italy Received 21 April 2007; received in revised form 18 June 2007; accepted 10 September 2007 Available online 26 September 2007
Abstract Objectives: To report a first case of 21-hydroxylase deficiency associated with a new genotype determined by V281+I172N/V281L mutations of the CYP21A2 gene. Design and methods: Direct genetic sequencing of CYP21A2 gene was performed. Results: Both siblings had the same genotype, namely V281+I172N/V281L, while their parents resulted as V281L and V281+I172N carriers, respectively. Conclusions: V281+I172N/V281L genotype should be included in the panel of mutations associated with the non-classical forms of 21hydroxylase deficiency. © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: CYP21A2; V281L; I172N
Objective The aim of this study is to report a case of two siblings presenting a new genotype, described here for the first time, including two mutations of the CYP21A2 gene associated with the 21-hydroxylase deficiency. The two siblings came from the “Campania” Region of the Southern Italy. The above mentioned patients (one male and one female) were affected by the nonclassical form of congenital adrenal hyperplasia (NC-CAH) [1]. Results Clinical examination The 31-year-old female patient [160 cm of height and 50 kg of weight (BMI = 19.5)] presented with oligo-amenorrea dating ⁎ Corresponding author. Fax: +39 6 30156706. E-mail address: [email protected] (E. Capoluongo).
from the menarche age (12-year-old), hirsutism (Ferriman index = 12), mild acneic skin, and mild hyperinsulinism evaluated by 75 g oral glucose load. External genitalia were female with unambiguous feature. Pelvic ultrasonography showed a typical polycystic ovary picture. The 28-year-old male [170 cm of height and 68 kg of weight (BMI = 23.5)] was fenotipically male (Tanner G5 P5, testicular volume 20 mL bilaterally) only presenting with androgenic alopecia. Testicular ultrasonography documented a normal pattern without any evidence of adrenal rests. Seminal fluid examination showed a oligo-therato-zoospermia (8 millions sperms/mL; 56% mobile 2 h; 26% typical). At present, the two patients, following the international literature suggestions [1], are successfully treated with dexamethasone and their compliance is good. In fact, based on laboratory results (see later), both patients were treated with dexamethasone 250 μg (the female) and 375 μg (the male) to the late evening, every day, with clinical improvement.
0009-9120/$ - see front matter © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2007.09.002
1436
P. Concolino et al. / Clinical Biochemistry 40 (2007) 1435–1436
Laboratory examinations 1) Female patient: the laboratory tests showed the following results: basal 17-OH progesterone = 39 nmol/L, dehydroepiandrosterone sulfate (DHEA-S) = 7.0 μmol/L, ACTH = 5.94 pmol/L, testosterone = 2.07 nmol/L; Δ4androstenedione = 18.8 nmol/L, cortisol = 662.4 nmol/L; estradiol = 136 pmol/L; estrone = 100 fmol/L. In addition, GnRH test showed hyperresponsiveness of LH (LH basal 3.8, peak 89; FSH basal 4, peak 9 UI/L). After ACTH stimulation (250 μg 1–24 ACTH i.m. time 0′) an increase of 17-OH progesterone (204 nmol/L value peak at 30′) was observed. 2) Male patient: presented higher basal 17-OH progesterone and ACTH levels: 204 nmol/L and 19.4 pmol/L, respectively. In addition, serum basal levels of testosterone were 21.6 nmol/L, DHEA-S 9.4 μmol/L and cortisol 654.1 nmol/ L. Because of the high diagnostic 17-OH progesterone basal values, ACTH stimulation was obviously not performed. Furthermore, the genetic screening, by direct sequencing of CYP21A2 gene [2], furnished the following results: both siblings had the same genotype, namely V281+I172N/V281L. We highlight that I172N mutation is usually associated with simple virilizing form of congenital adrenal hyperplasia, while V281L is associated with NC-CAH [3]. Both siblings presented a NC-CAH phenotype. A segregation analysis obtained by screening the parents showed that the father was a V281L + I172N bearer while the mother presented only the V281L mutation, indicating that the two mutations were in trans condition in both siblings. Conclusions We underline that a) to our knowledge, the present genotype (V281+I172N/ V281L) has not been previously described, not only in the general population, but also in affected subjects.
b) the Bachega study et al. [4] presented a similar genotype, defined V281+I172N/conv, without V281L homozygosity, in association with a late onset form of CAH. c) the same genotype produces two different hormonal levels in the siblings regarding the serum 17-OH progesterone and ACTH basal concentrations. In particular, the higher DHEAS levels of the male proband may be a consequence of the higher serum ACTH levels, as also reported by C. Deneux et al. [5]. d) these findings may confirm [5] the presence of different in vivo mechanisms for the 21-hydroxylase deficiency compensation, due to the different level of penetrance of CYP21A2 mutations, as reported in the literature [5]. Further investigations should be planned to evaluate the prevalence of this specific genotype in different Italian areas, especially in the presence of mild or subclinical forms of CAH disease. Finally, this genotype should be included in the panel of those already listed for association with the non-classical forms of 21-hydroxylase deficiency. References [1] New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92(1):142. [2] Concolino P, Satta MA, Santonocito C, Carrozza C, Rocchetti S, Ameglio F, et al. Linkage between I172N mutation, a marker of 21-hydroxylase deficiency, and a single nucleotide polymorphism in Int6 of CYP21B gene: a genetic study of Sardinian family. Clin Chim Acta 2006;364:298–302. [3] Trakakis E, Laggas D, Salamalekis E, Creatsas G. 21-Hydroxylase deficiency: from molecular genetics to clinical presentation. J Endocrinol Invest 2005;28:187–92. [4] Bachega TA, Billerbeck AE, Madureira G, Marcondes JA, Longui CA, Leite MV, et al. Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency. J Clin Endocrinol Metab 1998;83:4416–9. [5] Deneux C, Tardy V, Dib A, Mornet E, Billaud L, Charron D, et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2001;86:207–13.
Clinical Biochemistry 40 (2007) 1435 – 1436
First case of V281+I172N/V281L CYP21A2 genotype associated with congenital adrenal hyperplasia form. A case report from South Italy Paola Concolino a,b , Salvatore Corsello c , Cinzia Carrozza a , Angelo Minucci a , Concetta Santonocito a , Rosa Maria Lovicu c , Stefano Angelo Santini b , Franco Ameglio a , Cecilia Zuppi a , Ettore Capoluongo a,⁎ a
Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University School of Medicine, Largo F. Vito, 1-00168, Rome, Italy b Laboratory of Clinical Pathology - IRCCS Casa Sollievo della Sofferenza - San Giovanni Rotondo, Foggia, Italy c Institute Medical Pathology, Catholic University, Rome, Italy Received 21 April 2007; received in revised form 18 June 2007; accepted 10 September 2007 Available online 26 September 2007
Abstract Objectives: To report a first case of 21-hydroxylase deficiency associated with a new genotype determined by V281+I172N/V281L mutations of the CYP21A2 gene. Design and methods: Direct genetic sequencing of CYP21A2 gene was performed. Results: Both siblings had the same genotype, namely V281+I172N/V281L, while their parents resulted as V281L and V281+I172N carriers, respectively. Conclusions: V281+I172N/V281L genotype should be included in the panel of mutations associated with the non-classical forms of 21hydroxylase deficiency. © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: CYP21A2; V281L; I172N
Objective The aim of this study is to report a case of two siblings presenting a new genotype, described here for the first time, including two mutations of the CYP21A2 gene associated with the 21-hydroxylase deficiency. The two siblings came from the “Campania” Region of the Southern Italy. The above mentioned patients (one male and one female) were affected by the nonclassical form of congenital adrenal hyperplasia (NC-CAH) [1]. Results Clinical examination The 31-year-old female patient [160 cm of height and 50 kg of weight (BMI = 19.5)] presented with oligo-amenorrea dating ⁎ Corresponding author. Fax: +39 6 30156706. E-mail address: [email protected] (E. Capoluongo).
from the menarche age (12-year-old), hirsutism (Ferriman index = 12), mild acneic skin, and mild hyperinsulinism evaluated by 75 g oral glucose load. External genitalia were female with unambiguous feature. Pelvic ultrasonography showed a typical polycystic ovary picture. The 28-year-old male [170 cm of height and 68 kg of weight (BMI = 23.5)] was fenotipically male (Tanner G5 P5, testicular volume 20 mL bilaterally) only presenting with androgenic alopecia. Testicular ultrasonography documented a normal pattern without any evidence of adrenal rests. Seminal fluid examination showed a oligo-therato-zoospermia (8 millions sperms/mL; 56% mobile 2 h; 26% typical). At present, the two patients, following the international literature suggestions [1], are successfully treated with dexamethasone and their compliance is good. In fact, based on laboratory results (see later), both patients were treated with dexamethasone 250 μg (the female) and 375 μg (the male) to the late evening, every day, with clinical improvement.
0009-9120/$ - see front matter © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2007.09.002
1436
P. Concolino et al. / Clinical Biochemistry 40 (2007) 1435–1436
Laboratory examinations 1) Female patient: the laboratory tests showed the following results: basal 17-OH progesterone = 39 nmol/L, dehydroepiandrosterone sulfate (DHEA-S) = 7.0 μmol/L, ACTH = 5.94 pmol/L, testosterone = 2.07 nmol/L; Δ4androstenedione = 18.8 nmol/L, cortisol = 662.4 nmol/L; estradiol = 136 pmol/L; estrone = 100 fmol/L. In addition, GnRH test showed hyperresponsiveness of LH (LH basal 3.8, peak 89; FSH basal 4, peak 9 UI/L). After ACTH stimulation (250 μg 1–24 ACTH i.m. time 0′) an increase of 17-OH progesterone (204 nmol/L value peak at 30′) was observed. 2) Male patient: presented higher basal 17-OH progesterone and ACTH levels: 204 nmol/L and 19.4 pmol/L, respectively. In addition, serum basal levels of testosterone were 21.6 nmol/L, DHEA-S 9.4 μmol/L and cortisol 654.1 nmol/ L. Because of the high diagnostic 17-OH progesterone basal values, ACTH stimulation was obviously not performed. Furthermore, the genetic screening, by direct sequencing of CYP21A2 gene [2], furnished the following results: both siblings had the same genotype, namely V281+I172N/V281L. We highlight that I172N mutation is usually associated with simple virilizing form of congenital adrenal hyperplasia, while V281L is associated with NC-CAH [3]. Both siblings presented a NC-CAH phenotype. A segregation analysis obtained by screening the parents showed that the father was a V281L + I172N bearer while the mother presented only the V281L mutation, indicating that the two mutations were in trans condition in both siblings. Conclusions We underline that a) to our knowledge, the present genotype (V281+I172N/ V281L) has not been previously described, not only in the general population, but also in affected subjects.
b) the Bachega study et al. [4] presented a similar genotype, defined V281+I172N/conv, without V281L homozygosity, in association with a late onset form of CAH. c) the same genotype produces two different hormonal levels in the siblings regarding the serum 17-OH progesterone and ACTH basal concentrations. In particular, the higher DHEAS levels of the male proband may be a consequence of the higher serum ACTH levels, as also reported by C. Deneux et al. [5]. d) these findings may confirm [5] the presence of different in vivo mechanisms for the 21-hydroxylase deficiency compensation, due to the different level of penetrance of CYP21A2 mutations, as reported in the literature [5]. Further investigations should be planned to evaluate the prevalence of this specific genotype in different Italian areas, especially in the presence of mild or subclinical forms of CAH disease. Finally, this genotype should be included in the panel of those already listed for association with the non-classical forms of 21-hydroxylase deficiency. References [1] New MI. Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92(1):142. [2] Concolino P, Satta MA, Santonocito C, Carrozza C, Rocchetti S, Ameglio F, et al. Linkage between I172N mutation, a marker of 21-hydroxylase deficiency, and a single nucleotide polymorphism in Int6 of CYP21B gene: a genetic study of Sardinian family. Clin Chim Acta 2006;364:298–302. [3] Trakakis E, Laggas D, Salamalekis E, Creatsas G. 21-Hydroxylase deficiency: from molecular genetics to clinical presentation. J Endocrinol Invest 2005;28:187–92. [4] Bachega TA, Billerbeck AE, Madureira G, Marcondes JA, Longui CA, Leite MV, et al. Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency. J Clin Endocrinol Metab 1998;83:4416–9. [5] Deneux C, Tardy V, Dib A, Mornet E, Billaud L, Charron D, et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2001;86:207–13.