The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency: a case series

CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. DESIGN: Case series. PATIENTS AND RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. CONCLUSION: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity. SIGNIFICANCE STATEMENT: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency

The broad phenotypic spectrum of 17α-hydroxylase/17,20-lyase (CYP17A1) deficiency : a case series

Context 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. Objective To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. Design Case series. Patients and results We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. Conclusion Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity

Itch in Children with Type 1 Diabetes: A Cross-Sectional Study

Abstract Introduction Type 1 diabetes (T1D) is reported to be one of the most common medical conditions in school-age youth and is ranked third in the prevalence of pediatric conditions. Only a few studies have investigated the occurrence of itch in diabetes mellitus, reporting conflicting data. The purpose of this study was to investigate the prevalence of itch in T1D to provide itch characteristics and to explore the potential underlying causes. Methods This prospective study evaluated itch among 100 children with T1D. Itch intensity was assessed with the Numerical Rating Scale (NRS) and the 4-Item Itch Questionnaire (4IIQ). The Children's Dermatology Life Quality Index (CDLQI) was implemented to assess the quality of life issues. Various clinical features and factors influencing itch were also examined. Skin dryness was evaluated clinically by non-invasive assessment of epidermis moisturizing. Results Itch occurred in 22% of children with T1D with the mean maximal intensity of 5.9 ± 3.0 points in NRS and 6.7 ± 3.5 points in 4IIQ (median, 5.5 points). In the majority of patients, the itch was limited to a few regions of the body; usually, the upper limbs (68.2%) were affected, followed by the lower limbs (50%) and the trunk (31.8%). Clinically examined skin xerosis was significantly more advanced in children with itch compared with those without itch (p < 0.01). The mean CDLQI score in the itchy group was 4.0 ± 4.7 points (median, 2.5 points), indicating a small impairment of quality of life. The intensity of itch (both NRS last 3 days and NRS last 24 h) correlated positively with life quality impairment (R = 0.7; p = 0.015 and R = 0.8, p = 0.002, respectively). Conclusions Our study found itch as a moderately frequent symptom in children with T1D; however, itch presence and intensity may relevantly debilitate quality of life among subjects. We suggest that dryness of the skin may play a role in the pathogenesis of itch in this population