A case of ‘non-classic’ Non-Classic Congenital Adrenal Hyperplasia
Nora Sawan1, Danielle Donoghue1, Jaskiran Gill1, Vassiliki Bravis1,2
1 Department of Metabolic Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, 2 Department of Endocrinology, Diabetes and Metabolism, Imperial College London
We present a case of a 28-year-old Portuguese lady, who presented with oligoamenorrhoea and hirsutism since menarche, at age 11. She had been treated with the oral contraceptive pill for 12 years, for a diagnosis of polycystic ovarian syndrome, despite a BMI of 21 kg/m2. She also complained of chronic fatigue.
Blood pressure was 101/66mmHg. Baseline electrolytes showed sodium 140mmol/L, potassium 3.6mmol/L. Short synacthen test (SST) confirmed the biochemical diagnosis of congenital adrenal hyperplasia (CAH) [17-hydroxyprogesterone of 32.5nmol/L (0min), 173.5nmol/L (30min), 201.2nmol/L (60min)]. Long synacthen test revealed cortisol of 356 nmol/L (0min), 389 nmol/L (30min), 488 nmol/L (60min), 534 nmol/L (240min), 586 nmol/L (360min), 815 nmol/L (440min), 279 nmol/L (2880min). Aldosterone activity was reduced at 60pmol/L. The cortisol aspect of the SST was: cortisol 275nmol/L (0min), 335nmol/L (30min), 371nmol/L (60min) and when repeated: 407/431/429nmol/L at respective times. Prolonged oral glucose tolerance test revealed hypoglycaemia at 3 hours post-glucose load (glucose 2.1mmol/L) with appropriate spontaneous recovery (glucose 4.1 mmol/L at 300min). Long synacthen test showed a baseline cortisol of 356nmol/l with a peak cortisol of 815nmol/L.
Genetic testing confirmed non-classical CAH due to 21-hydroxylase deficiency. She was heterozygous for CYP21A2 c89C>T p.P30L and c. 841G>T p.V281L mutations with normal CYP21A2 copy number. She started dexamethasone 0.25 mg daily and responded well. Androstenedione levels decreased to 11.4nmol/L. She is still complaining of fatigue but is menstruating regularly and has been counselled towards planning a pregnancy.
The 21-hydroxylase enzyme is encoded by the CYP21A2 gene and 12 mutations account for almost 95% of cases of the non-classic phenotype of CAH. p.V281L and p.P30L are both missense mutations that tend to confer a mild phenotype as they allow for 20-50% of normal enzyme activity. Despite general correlations, the CYP21A2 deficiency phenotype does not always correlate precisely with the genotype. This suggests that other genes influence the clinical manifestations. In this case where two of the commonest mutations co-exist, symptoms and signs would place this patient in a ‘phenotypical spectrum’ between CCAH and NCAH. Utilizing rigid criteria to distinguish among salt wasting, simple virilizing and NCAH can be problematic because impaired 21-hydroxylase function represents a continuum of decreased enzyme activity, as in this patient.