Genotype-phenotype correlation in patients with 21-hydroxylase deficiency

Abstract

Introduction21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations.MethodsA total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands.ResultsDramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively.ConclusionBoth gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients.

Landscape of Adrenal Tumours in Patients with Congenital Adrenal Hyperplasia

“…The second section, Section 3.2, includes larger original studies (not case reports or series) where the prevalence of the adrenal tumours in CAH or of CAH in adrenal tumours was reported amid different clinical, genetic, or imaging characteristics (prevalence studies) (Figure 1). [53][54][55][56][57][58][60][61][62][63][64][65][66][67] and 7 phenotypically females [50,51,58], were identified according to our strategy (n = 18 case reports and series). Two male subjects had 46,XX karyotype [57,62].…”

“…The median age at tumour diagnosis in these CAH individuals was 46. Most of these mentioned patients with pathogenic variants of CYP21A2 were diagnosed with CAH after the discovery of an adrenal tumour (N = 20) [51][52][53][54][55][56][57][58][59][60][61][62][63][64]66,67]. Only five persons were previously known with CAH [50,54,64,65] (two more cases' data were not available).…”

“…Only five persons were previously known with CAH [50,54,64,65] (two more cases' data were not available). In terms of CAH form, most patients presented with SV-CAH (N = 13) [50,51,[55][56][57][58][61][62][63][64]66], followed by NC-CAH (N = 11) [51][52][53][54]59,60,66,67]; only two patients had SW-CAH [64,65], while another subject had a carrier status [51] (Table 1).…”

“…Table 1. Case reports (n = 13)/series (n = 5) with data regarding the clinical features of the patients diagnosed with CAH (CYP21A2 deficiency) and adrenal tumours/masses according to our strategy; the display starts with the earliest publication date within the decade of analysis [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. [51,53,55,59,64,66].…”

“…[51,53,55,59,64,66]. Two adrenal incidentalomas were classified as adrenocortical adenoma following the post-adrenalectomy pathological report [59,64]; two adrenal masses were classified as hyperplasia, one being an adenomatous hyperplasia [67] and the other "hyperplasia with mild atypia" according to the original terms [57]. Adrenocortical carcinoma was also identified in one patient (1/26) [52].…”