Adrenomedullary Function May Predict Phenotype and Genotype in Classic 21-Hydroxylase Deficiency

Phyllis W. Speiser

Schneider Children’s Hospital North Shore-Long Island Jewish Health System New York University School of Medicine New Hyde Park, New York 11042

Address all correspondence and requests for reprints to: Phyllis W. Speiser, M.D., Schneider Children’s Hospital, North Shore-Long Island Jewish Health System, New York University School of Medicine, 269-01 76th Avenue, New Hyde Park, New York 11042. E-mail: . pspeiser{at}LIJ.edu

Charmandari et al. (1) present intriguing data examining the relationship between CYP21 genotype, phenotype, and plasma catechols among patients with congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency. The authors conclude that disease severity (i.e. salt-wasting vs. simple virilizing classic CAH) can be equally well predicted by genotype and a single early morning plasma free metanephrine measured by liquid chromatography. The level of this O-methylated metabolite of epinephrine reflecting adrenal medullary stores of epinephrine is significantly lower among salt-wasters compared with simple virilizers. Plasma free metanephrine, like genotype, is a predictive test independent of exogenous steroid treatment or degree of adrenal cortical hormone control. Moreover, there is no circadian or ultradian variation, nor do stress or physical activity perturb ambient levels of plasma free metanephrine. One would like to know whether there is any use in continued monitoring of plasma metanephrine. For example, will such measurements serve as a marker for inadequate adrenal cortical hormone control, or for incipient adrenal crisis?

The cost of plasma metanephrine measurements and turn-around time are likely less than those for genotyping CYP21 (2). Thus, a cost-benefit analysis of routinely performing plasma metanephrines in all CAH patients at diagnosis would be of interest. To date, compromised adrenal medullary structure and function have been associated with only one inborn error of steroid metabolism, 21-hydroxylase deficiency. Deficiencies of other critical factors in steroid hormone synthesis or adrenal development could similarly disrupt the adrenal medulla, and it will be interesting to compare catechol profiles among different patient groups and determine the value of such measurements in various diseases. Would this test efficiently detect all forms of adrenal cortical insufficiency?

The positive predictive value of about 88–93% for patients classified as having null or group A (severe) mutations, and less deleterious mutations in group B, usually the most difficult to classify by phenotype, had a positive predictive value of 75%. These data are comparable to reports from various other centers (3, 4, 5, 6). The positive predictive value of plasma free metanephrine measurement in this study was 80.6%. Interestingly, clinical judgement yields a similar correct classification rate (3), and thus the worth of the experienced clinician should not be lost in the process of fine-tuning diagnosis and prognosis.

The authors suggest that plasma free metanephrine might be useful as a screening test to identify candidates for adrenalectomy (7). At present, adrenalectomy is not standard care for patients with CAH and can only be recommended in carefully selected individuals for whom conventional treatment modalities have been unsuccessful. The main rationale for considering adrenalectomy is to prevent excessive virilization of girls or women, and secondarily to avoid iatrogenic Cushing’s syndrome induced by large glucocorticoid doses. A counter-balancing consideration, however, is the fact that the adrenalectomized patient could be at greater risk for sudden death if deprived of essential medications. Moreover, although plasma free metanephrines and other catechols are low in severely affected CAH patients, these hormones are not absent and may still contribute to the stress response. Additionally, as noted by the authors, there is a bi-directional effect of catechols and glucocorticoids on the adrenal cortex and medulla, thus low levels of catechols may still enhance cortisol and/or aldosterone synthesis when 21-hydroxylase is partially impaired. These in vivo interactions remain to be elucidated.

This report involves a small number of children, and it will be important to confirm these findings in a larger group of patients. Clearly, the time at which one would want to predict disease severity and long-term outcome is in the newborn period. One limitation of this study is that no newborn subjects were included. Reference standards and appropriate cut-points for plasma free metanephrine will have to be determined for infants as well as older children and adolescents, if this test is to become clinically relevant.

Footnotes

Abbreviations: CAH, Congenital adrenal hyperplasia.

Received April 29, 2002.

Accepted April 30, 2002.

References

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