21-Hydroxylase deficiency: Mutational spectrum and Genotype–Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification

Turan, İhsan; Taştan, Mehmet; Boga, Duygu D.; Gürbüz, Fatih; Kotan, Leman Damla; Tuli, Abdullah; Yüksel, Bilgin

doi:10.1016/j.ejmg.2019.103782

Cited by 14 publications

(12 citation statements)

References 23 publications

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“…In CYP21A2 , a T-to-A change at nucleotide 518 was predicted to be a substitution of the isoleucine at residue 173 for asparagine, p.Ile173Asn. This pathogenic variant has been widely reported in 21-OHD, and functional analysis has been performed ( 3 , 4 ). The p.Arg672His was located at a hot-spot region in SCN4A .…”

Section: Discussionmentioning

confidence: 99%

“…The presence of homozygous p.Ile173Asn genotype, classified in group c, predicts simple virilising 21-OHD. However, these patients tend to have hyperkalemia ( 3 , 4 ). Fludrocortisone treatment is initiated before the definite diagnosis, as suggested in CAH guidelines because of its life-threatening nature, causing 25% of patients to receive unnecessary fludrocortisone treatment ( 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, genetic analysis is guiding in these patients ( 3 , 7 ). Prior to deciding on such treatment, it is vital to review all possibilities, take a careful medical history and family history and perform a physical examination.…”

Section: Discussionmentioning

confidence: 99%

“…Prior to deciding on such treatment, it is vital to review all possibilities, take a careful medical history and family history and perform a physical examination. Here, CYP21A2 genetic analysis is also highly useful in deciding upon fludrocortisone treatment ( 3 ). It was unusual to detect hypokalemia with a sign of hyperaldosteronism in a case where we expected a possible lack of aldosterone production.…”

Section: Discussionmentioning

confidence: 99%

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Co-existence of Congenital Adrenal Hyperplasia and Familial Hypokalemic Periodic Paralysis due to CYP21A2 and SCN4A Pathogenic Variants

Çetin¹,

Turan²

2021

Jcrpe

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Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH), usually due to biallelic variants in CYP21A2 . Classical 21-hydroxylase deficiency is characterised by virilisation of the external genitalia in females and hypocortisolism. Hyponatremia and hyperkalemia are among the common biochemical findings. Familial hypokalemic periodic paralysis (FHPP) is a rare disorder in which affected individuals may experience paralytic episodes associated with hypokalemia, caused by pathogenic variants in SCN4A or CACNA1S. A 14-year-old female, who had been diagnosed with classical 21-hydroxylase deficiency and treated with hydrocortisone and fludrocortisone since early infancy, presented with acute onset weakness. The laboratory results revealed a remarkably low serum potassium level. The family history revealed that both her father and uncle had the same hypokalemic symptoms, which suggested an FHPP diagnosis. We found two previously reported homozygous variants in the CYP21A2 (p.Ile173Asn) and SCN4A (p.Arg672His) genes in the patient. Therefore, diagnoses of simple virilising 21-hydroxylase deficiency and FHPP were genetically confirmed. Here, FPHH and chronic overtreatment with fludrocortisone may explain the presentation of our patient with severe hypokalemia. The family’s medical history, which is always a valuable clue, should be investigated in detail since rare inherited conditions may co-occur in geographies where consanguineous marriages are common and the genetic pool is diverse. In patients with CAH, care should be taken to avoid overtreatment with fludrocortisone. Androgens may have triggered the hypokalemic attack in FHPP, as supported in a previous study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Co-existence of Congenital Adrenal Hyperplasia and Familial Hypokalemic Periodic Paralysis due to CYP21A2 and SCN4A Pathogenic Variants

Çetin¹,

Turan²

2021

Jcrpe

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“…21‐OHD can be divided into classic (salt wasting [SW] and simple virilizing [SV]) and non‐classic (NC) subtypes based on clinical manifestation 2 . There is a strong correlation between CYP21A2 genotype and clinical phenotype 3,4 . The three phenotypes mentioned above are caused by different mutations in the CYP21A2 gene and correspond to residual 21‐hydroxylase activities of lower than 1%, 1%–5%, and 20%–50% 5 .…”

Section: Introductionmentioning

confidence: 99%

Bone mineral density and trabecular bone score in patients with 21‐hydroxylase deficiency after glucocorticoid treatment

Gao

Wang

Guan

et al. 2021

Clinical Endocrinology

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Objective Patients with 21‐hydroxylase deficiency (21‐OHD) are at risk of reduced bone mineral density (BMD) and fracture due to long‐term glucocorticoid treatment. Trabecular bone score (TBS) is complementary to conventional BMD as a marker for bone quality in patients with glucocorticoid‐induced osteoporosis. The purpose of this study is to evaluate the BMD and TBS in a cohort of patients with 21‐OHD and analyse factors related to TBS. Design An observational study. Patients A total of 46 21‐OHD adult patients treated with glucocorticoid for over 10 years who visited Peking Union Medical College Hospital between 2015 and 2019 were recruited. Eight male patients included in this study were all under 50 years old, and 38 female patients were all premenopausal. Measurements Diagnosis was confirmed by multiplex ligation‐dependent probe amplification combined with sequencing. Data were collected on physical characteristics, serum hormones and glucocorticoid treatment. Skeletal quality was evaluated by BMD and TBS, and factors related to TBS were analysed. Results Among the 46 patients, 2 (4.3%) had low BMD (Z‐score ≤ −2), while 11 (23.9%) patients had low TBS (degraded or partially degraded microarchitecture). The proportion of bone abnormality evaluated by TBS was higher than that by BMD (p < .001). Patients with lower TBS had significantly higher daily hydrocortisone dosage (p = .009 for males; p = .019 for females). TBS value was negatively correlated with daily hydrocortisone dosage (r = −.317, p = .026), and positively correlated with BMI in female patients (r = .345, p = .034). And there was a negative correlation between TBS value and the current age in male patients (r = −.741, p = .036). The distribution of genotypes (p = 1.000 for male; p = .567 for female) or phenotypes (p = .486 for male; p = .075 for female) had no statistical difference in patients with normal or abnormal TBS. Conclusions Approximately 24% of patients with 21‐OHD had abnormal microarchitecture of their bone in our study, and TBS score was negatively correlated with daily glucocorticoid dosage in patients. TBS may be used alongside conventional BMD as a complementary marker for bone evaluation in 21‐OHD patients.

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Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns

Concolino

Paragliola

2021

Mol Diagn Ther

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21-Hydroxylase deficiency: Mutational spectrum and Genotype–Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification

Cited by 14 publications

References 23 publications

Co-existence of Congenital Adrenal Hyperplasia and Familial Hypokalemic Periodic Paralysis due to CYP21A2 and SCN4A Pathogenic Variants

Co-existence of Congenital Adrenal Hyperplasia and Familial Hypokalemic Periodic Paralysis due to CYP21A2 and SCN4A Pathogenic Variants

Bone mineral density and trabecular bone score in patients with 21‐hydroxylase deficiency after glucocorticoid treatment

Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns

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