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A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy.

Alqahtani MA, Shati AA, Zou M, Alsuheel AM, Alhayani AA, Al-Qahtani SM, Gilban HM, Meyer BF, Shi Y - Int J Endocrinol (2015)

Bottom Line: A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients.The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity.In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Aseer Central Hospital, Abha 62523, Saudi Arabia.

ABSTRACT
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260 (∗) ) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

No MeSH data available.


Related in: MedlinePlus

Clinical presentations of a patient with classic steroid 11β-hydroxylase deficiency. (a) Forehead showing facial acne indicated by a black arrow. (b) Macropenis. Penile is enlarged (8.7 cm in length) with scrotum hyperpigmentation. Testes volume is prepubertal and no pubic hair. (c) Age to penile length graph. The graph shows the penile length and growth (8.7 cm) and penile length is more than 90th percentiles. (d) Left hand X-ray shows advanced bone age between 5 to 6 years of age. (e) Chest X-Ray indicates mild to moderate cardiomegaly.
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fig1: Clinical presentations of a patient with classic steroid 11β-hydroxylase deficiency. (a) Forehead showing facial acne indicated by a black arrow. (b) Macropenis. Penile is enlarged (8.7 cm in length) with scrotum hyperpigmentation. Testes volume is prepubertal and no pubic hair. (c) Age to penile length graph. The graph shows the penile length and growth (8.7 cm) and penile length is more than 90th percentiles. (d) Left hand X-ray shows advanced bone age between 5 to 6 years of age. (e) Chest X-Ray indicates mild to moderate cardiomegaly.

Mentions: A 21-month-old boy was admitted to the emergency department with respiratory symptoms. He had history of progressive penile enlargement and darkness of skin for the last 10 months. His elder brother died 13 years ago with similar clinical presentations (Case 1). His weight was 13 kg (Z-score: 1.1, 85.3th percentile), height 92 cm (Z-score: 2.4, 99.2th percentile), and blood pressure 139/90 mmHg (Z-score for age-based pediatric blood pressure for systolic/diastolic pressure: 4.3/3.9, 100th percentile. Z-score equal to or greater than 95th percentile indicates hypertension). Physical examination showed gum, skin, and scrotal hyperpigmentation, facial acne, and penile enlargement of 8.7 cm (above 90th percentile). Testicular size was prepubertal (less than 2 mL) and no pubic hair (Figures 1(a), 1(b), and 1(c)). Laboratory tests showed serum ACTH: 507 pg/mL (normal: 5–60 pg/mL), cortisol: 44 μg/dL (normal: 55–248 μg/dL), 17α-hydroxyprogesterone (17-OHP): 67 nmol/L (normal: 0.3–2.5 nmol/L), DOC: 319 ng/dL (normal: 4–49 ng/dL), and androstenedione: 11 ng/mL (normal: 0.4–4.1 ng/mL). His bone age was at 5-6 years of age (Figure 1(d)). Chest X-ray showed mild to moderate cardiomegaly (Figure 1(e)). Echocardiography showed mild left ventricular dilatation with mild impairment of function with ejection fraction of 44% (normal 55–70%). The patient was diagnosed as congenital adrenal hyperplasia steroid 11β-hydroxylase deficiency based on his clinical presentations and lab tests. The patient was given hydrocortisone 50 mg (80 mg/kg/m2) intravenous bolus as a stress dose then followed by maintenance dose of 12.5 mg/kg/m2 (5 mg am, 2.5 mg noon, and 2.5 mg pm) with antihypertensive medication (captopril 6.25 mg orally three times a day). Six months later following treatment, echocardiography showed normal left ventricular systolic function. Blood pressure became normal at 88/44 mmHg (50 percentile according to his age). Hydrocortisone decreased to 2.5 mg orally three times a day as a maintenance dose to be continued for life. Gradual reduction of captopril was initiated from 6.25 mg once daily to complete cessation after 3 months. The skin color was improving and acne disappeared.


A Novel Mutation in the CYP11B1 Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy.

Alqahtani MA, Shati AA, Zou M, Alsuheel AM, Alhayani AA, Al-Qahtani SM, Gilban HM, Meyer BF, Shi Y - Int J Endocrinol (2015)

Clinical presentations of a patient with classic steroid 11β-hydroxylase deficiency. (a) Forehead showing facial acne indicated by a black arrow. (b) Macropenis. Penile is enlarged (8.7 cm in length) with scrotum hyperpigmentation. Testes volume is prepubertal and no pubic hair. (c) Age to penile length graph. The graph shows the penile length and growth (8.7 cm) and penile length is more than 90th percentiles. (d) Left hand X-ray shows advanced bone age between 5 to 6 years of age. (e) Chest X-Ray indicates mild to moderate cardiomegaly.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig1: Clinical presentations of a patient with classic steroid 11β-hydroxylase deficiency. (a) Forehead showing facial acne indicated by a black arrow. (b) Macropenis. Penile is enlarged (8.7 cm in length) with scrotum hyperpigmentation. Testes volume is prepubertal and no pubic hair. (c) Age to penile length graph. The graph shows the penile length and growth (8.7 cm) and penile length is more than 90th percentiles. (d) Left hand X-ray shows advanced bone age between 5 to 6 years of age. (e) Chest X-Ray indicates mild to moderate cardiomegaly.
Mentions: A 21-month-old boy was admitted to the emergency department with respiratory symptoms. He had history of progressive penile enlargement and darkness of skin for the last 10 months. His elder brother died 13 years ago with similar clinical presentations (Case 1). His weight was 13 kg (Z-score: 1.1, 85.3th percentile), height 92 cm (Z-score: 2.4, 99.2th percentile), and blood pressure 139/90 mmHg (Z-score for age-based pediatric blood pressure for systolic/diastolic pressure: 4.3/3.9, 100th percentile. Z-score equal to or greater than 95th percentile indicates hypertension). Physical examination showed gum, skin, and scrotal hyperpigmentation, facial acne, and penile enlargement of 8.7 cm (above 90th percentile). Testicular size was prepubertal (less than 2 mL) and no pubic hair (Figures 1(a), 1(b), and 1(c)). Laboratory tests showed serum ACTH: 507 pg/mL (normal: 5–60 pg/mL), cortisol: 44 μg/dL (normal: 55–248 μg/dL), 17α-hydroxyprogesterone (17-OHP): 67 nmol/L (normal: 0.3–2.5 nmol/L), DOC: 319 ng/dL (normal: 4–49 ng/dL), and androstenedione: 11 ng/mL (normal: 0.4–4.1 ng/mL). His bone age was at 5-6 years of age (Figure 1(d)). Chest X-ray showed mild to moderate cardiomegaly (Figure 1(e)). Echocardiography showed mild left ventricular dilatation with mild impairment of function with ejection fraction of 44% (normal 55–70%). The patient was diagnosed as congenital adrenal hyperplasia steroid 11β-hydroxylase deficiency based on his clinical presentations and lab tests. The patient was given hydrocortisone 50 mg (80 mg/kg/m2) intravenous bolus as a stress dose then followed by maintenance dose of 12.5 mg/kg/m2 (5 mg am, 2.5 mg noon, and 2.5 mg pm) with antihypertensive medication (captopril 6.25 mg orally three times a day). Six months later following treatment, echocardiography showed normal left ventricular systolic function. Blood pressure became normal at 88/44 mmHg (50 percentile according to his age). Hydrocortisone decreased to 2.5 mg orally three times a day as a maintenance dose to be continued for life. Gradual reduction of captopril was initiated from 6.25 mg once daily to complete cessation after 3 months. The skin color was improving and acne disappeared.

Bottom Line: A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients.The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity.In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Aseer Central Hospital, Abha 62523, Saudi Arabia.

ABSTRACT
Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260 (∗) ), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260 (∗) ) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

No MeSH data available.


Related in: MedlinePlus