Endocrine Abstracts

CYP17A1 is a key enzyme of human steroidogenesis, which is unique in that it catalyses two reactions, 17-hydroxylase activity and 17,20 lyase activity. 17-hydroxylase deficiency, a variant of congenital adrenal hyperplasia, results in hypertension and mild glucocorticoid deficiency. Loss of 17,20 lyase activity results in sex steroid deficiency, presenting with undervirilisation in boys (46, XY DSD) and lack of pubertal development in girls. Here we present the cases of two sisters with 17-hydroxylase deficiency presenting with severe glucocorticoid deficiency.

Case 1

A 4-week-old infant (46, XX) was assessed for prolonged jaundice and failure to thrive. A random serum cortisol was <25 nmol/l. A Synacthen test (with peak cortisol <25 nmol/l), normal 17-OHP and raised ACTH confirmed severe primary adrenal insufficiency. Gas chromatography/mass spectrometry (GC/MS) analysis of the urinary steroid pattern revealed predominant excretion of pregnenolone metabolites suggestive of combined and complete absence of CYP17A1 activities. Genetic test confirmed novel homozygous mutation of the CYP17A1 gene yielding an early truncation of the CYP17A1 protein.

Case 2

A 6-week-old infant (46XX) and younger sibling of case 1 also presented with failure to thrive. Investigations confirmed primary adrenal insufficiency and genetic tests confirmed identical mutation as that of case 1. Their mother was identified to be a heterozygous carrier of the mutation.

Both girls are currently on Hydrocortisone supplements and doing well.

Conclusion: In 17-hydroxylase deficiency, relative increase of corticosterone with its glucocorticoid effect compensates for the lack of cortisol and hence rarely manifests with overt glucocorticoid deficiency. However in these two cases, very early truncation of the CYP17A1 protein explains the near total loss of activity with residual corticosterone secretion not sufficient to compensate for the loss of glucocorticoid synthesis in the early neonatal period. These cases further highlight the value of urinary steroid secretion analysis by the GC/MS in the differential diagnosis of adrenal insufficiency.