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Apparent mineralocorticoid excess: A personal history
Apparent mineralocorticoid excess: A personal history Maria I. N e w , M . D . New York Hospital-Cornell University Medical Center, New York, N Y , USA
A personal memoir records the discovery of a new form of hypertension, apparent mineralocorticoid excess, which came about throuyh painstakin9 analysis of the symptoms of a Zu~i Indian 9irl. (Steroids 59:66-68, 1994)
Keywords: apparent mineralocorticoid excess; hypertension; cortisol
In 1973 Dr. Ed Biglieri of San Francisco asked me to consult on the unusual case of a child with hypertension and severe hypokalemia but only barely detectable levels of urinary steroids. Fred Katz, an endocrinologist who had been asked to analyze the child's urine, thought that water had been sent by mistake, since the urine contained virtually no steroids. The patient was a 3-year-old Zufii Indian girl, L.K. I stopped over in Gallup, New Mexico to examine her in a health clinic at the Indian Service Hospital. Because of her very low urinary aldosterone and cortisol levels, my first idea was that she must have 17-hydroxylase deficiency. I learned that without the administration of cortisol she had survived both salmonella sepsis and a cardiac catheterization at the Denver Children's Hospital, ordered because it was mistakenly assumed that her hypertension was due to congenital heart disease. The fact that stress did not produce signs of adrenal insufficiency argued against a cortisol deficiency. I decided that I must bring L.K. to New York for intensive evaluation because I realized I had never seen a case like her. I insisted that the mother accompany her to New York. Her mother was willing but said that I must present this plan to the tribe. So I went to the Zufii reservation, where a powwow had been arranged. The men came out of the "kiva," a ceremonial hut, dressed entirely in black, with their skin painted black as well. They sat in a circle, within which the women formed a second circle that included a very old woman, the matriarch of the Zufii tribe. There was
Address reprint requests to Maria I. New, M.D., New York Hospital Cornell University Medical College, 525 E. 68th Street, Room N-236, New York, NY 10021 USA.
66
Steroids, 1994, vol. 59, February
much singing--the words incomprehensible to me ---and cornflake boxes were tossed into the air. The matriarch explained that this ritual was taking place because L.K.'s illness was the result of a form of incest: her parents, both members of the Turkey Clan, had broken a tabu
Dr. Maria I. New
© 1994 Butterworth-Heinemann
Apparent Mineralocorticoid Excess: New in marrying each other, for marriage within a clan was forbidden. Members of the Turkey Clan were meant to marry into the Parrot Clan. At the end of the powwow it was decided that for L.K. to be cured, a deer must be killed while she watched. I indicated that I did not want to see this, and I don't know if the sacrifice took place, but I was fortunately able to arrange to take L.K. and her mother to New York the following day for clinical studies. I was worried that far from home--never having seen a river or a bridge--that the K.s might experience culture shock. I asked my husband, a psychiatrist, to meet us at the airport. But my efforts were not needed; whatever their thoughts, L.K. and her mother showed no signs of shock or surprise. The Zufii are a rather silent people and usually make no fuss at all, but I think that Mrs. K, though she spent most of her time with her hospitalized child, genuinely enjoyed her visit, especially a day at the circus. Now began an exhaustive study of L.K.'s mysterious disease. I first gave her dexamethasone to suppress the adrenal zona fasciculata, persisting in the hypothesis that L.K. had a 17-hydroxylase defect. But this only aggravated her hypertension. When I replaced dexamethasone with hydrocortisone, her hypertension worsened. While she was receiving steroid treatment and had very high blood pressure, I lowered the sodium in her diet. Her blood pressure fell sharply, despite the administration of glucocorticoid. The next step was to try to give her ACTH while she was on the low-salt diet and normotensive to see if her blood pressure would be affected. ACTH administration over 5 days made her blood pressure rise again. After ACTH stimulation ended, we increased the sodium content of her diet, and she became hypertensive again. We then gave chlorothiazide, a diuretic, and her blood pressure fell. Spironolactone, a potassium-sparing diuretic that acts by competitively blocking the mineralocorticoid receptor, brought about remission of her hypertension. We concluded that she had an ACTH-stimulable form of hypertension and that there must be an undetected mineralocorticoid in her blood. ~-s We and others attempted to find such a mineralocorticoid in the biological fluids, including urine, blood, and saliva, s Dr. Diana Marver performed a toad bladder assay with L.K.'s serum, and Dr. John P. Coghlan infused Australian sheep with her extracted urine--both of these tests are exquisitely sensitive mineralocorticoid assays-- to no avail. Dr. Paul F. Palmberg conducted a lymphocyte stimulation test looking for mineralocorticoid effect and again found nothing. By this time we had established that this child secreted very little steroid and almost no known mineralocorticoid. Thus, there was neither biological nor biochemical evidence for the presence of a mineralocorticoid that could produce Lisa's hypertension and hypokalemia. We were puzzled until we demonstrated that the ratio of active to inactive metabolites of cortisol, T H E : T H F , in Lisa's urine was abnormal. Collaborating with Dr. Stanley Ulick we were able to show that though she secreted very little cortisol, the percent free cortisol was
increased. The results of these studies indicated that although L.K. had a very low secretion rate of cortisol, aldosterone, corticosterone, desoxycorticosterone, and all the other steroids that could be measured, the half-life of cortisol in her blood was prolonged, and the serum level was normal. 6 With Dr. William Rosner's help, we investigated the possibility that an abnormality of cortisol binding globulin would provide an explanation. However, we found that L.K.'s cortisol binding globulin was normal. 6 We proposed at this juncture that cortisol must be the bioactive steroid because it aggravated her hypertension. We confirmed this as a possibility through studies of the potential difference between her skin and her rectal mucosa, which, starting at an extremely high level, was made still worse by the administration of hydrocortisone. These studies were published in conjunction with Dr. Robert Carey of the University of Virginia. 7"8 In order to develop the hypothesis of the cortisol metabolic defect, we consulted with Leon Bradlow, Ph.D., who had developed with David Fukushima, Ph.D., a method of administering cortisol tritiated at position 11~ and then measuring the release of tritiated water as evidence of the conversion of the ll-hydroxy group to the keto group. We reasoned that if ll/Ydehydrogenation were defective in L.K., no [ 3 H ] H / O would be released, and this would signify that cortisol could not be converted to cortisone. Indeed, we found that Lisa did not release any [3H]HzO, while her mother released a normal amount. 6 We later studied other patients with this syndrome who showed the same abnormal pattern of low [3H]HzO excretion following infusion of [1 lc(-3H]cortisol. 9 We then enunciated a theory as to the cause of this disease, called "apparent mineralocorticoid excess," which we presented in 1982 at a Serono symposium organized by Dr. Mantero in Padua. T We hypothesized that there was no unusual mineralocorticoid in this disease, but that the hypertension and hypokalemia were caused by cortisol, which somehow interacted with a mineralocorticoid receptor in an abnormal way owing to an 11-dehydrogenase deficiency. Of great interest was the fact that though Dr. Carl Monder reported that there existed only one enzyme for the interconversion of cortisol to cortisone and cortisone to cortisol, 9 Lisa's defect was only in the conversion of cortisol to cortisone. She readily converted cortisone to cortisol. This suggested that the genetic regulation for the enzyme that converted cortisone to cortisol was different from that for the conversion of cortisol to cortisone as was corroborated in an animal study) ° Because we though the disorder might be genetic, we tested the rest of the Turkey Clan and members of the Zufii tribe but found that no one else was hypertensive and hypokalemic. We were later able to study in depth another patient, J.K., an Iranian. 6 The results were similar to those in L.K. Additional reports came from Dr. Jeremy Winter, who had one case in a Canadian Algonquin Indian family and another in an unrelated part-Indian family.~ It is probable that Werder, a general practitioner in
Steroids, 1994, vol. 59, February
67
Personal History Switzerland, was the first to report a case of apparent mineralocorticoid excess. ~2,13 Puzzling and still unexplained aspects of the cases of L.K. and J.K. and others with apparent mineralocorticoid excess are: 1. The hypotension and shock-like syndrome that results from administration of triamterene. 2. The variable course of hypertension in different patients. In L.K., the hypertension began at an early age and required diuretics and/or low-sodium diet in addition to spironolactone to control. She had no detectable cardiomyopathy or cardiac hypertrophy and no other evidence of end-organ disease. Nonetheless, she died suddenly at the age of 15 years. J.K.'s hypertension was also of early childhood onset but was apparently well controlled by spironolactone. He suffered a stroke and had hemiparesis at age 12, yet is still alive in his late teens. Dr. Edwards' patient was diagnosed at the age of 21 years following a 2-week period of altered vision; in addition to his hypertension he had other problems (polydipsia, nocturia; 3 recent episodes of tonsillitis associated with carpopedal spasms and perioral paresthesia) but had never been treated for them. 14 Unlike L.K. and J.K., Dr. Edwards' patient demonstrated a lowering of blood pressure with dexamethasone. What is the basis for the clinical variability of the hypertension and its complications in these patients? 3. The basis of restriction of the defect to the adrenal. L.K. underwent full puberty, indicating her capability of ovarian steroid secretion of C19 and C18 steroids outside of the ACTH axis. She did seem to have a relatively sluggish adrenarche, with Tanner I pubic hair and Tanner II breasts at the age of 14. 4. Administration of aldosterone up to 1 mg/day did not induce exacerbation of the hypertension, simulating "aldosterone escape." How is it that aldosterone cannot displace cortisol from the mineralocorticoid receptor? 5. Finally, why are the patients not Cushingoid if 1 l/3hydroxysteroid dehydrogenase causes cortisol half-life to be prolonged and the Type II (glucocorticoid) receptors as well as the Type I (mineralocorticoid) receptors are replete with cortisol? 6. Administration of RU 486 to block the cortisol Type II receptors did not alleviate the symptoms. Indeed, the hypertension and hypokalemia were aggravated. ~5 By now approximately 25 patients with AME have been identified, and this rare and complicated disease has provided us with new insights into the pathophysiology of steroid-induced hypertension and mechanisms of receptor specificity. Beyond the scientific challenges presented by the disease, I became extremely attached to my patients. I learned a great deal from my dealings with L.K., Mrs. K., and the Zufii tribe. I was enormously grieved at her untimely death and frustrated that she did not live longer, so that we could better explain her disease and offer her a cure. Mrs. K. told me that she thought her
68
Steroids, 1994, vol. 59, February
daughter's death was caused by her grief over the sudden, violent death of a close friend. She thought Lisa had died of a broken heart. The cultural differences were still too great to bridge. After 12 years of consultations, explanation, and counselling about the management of her hypertension, I think her family still believed that evil spirits, not hormones or genes, were the cause. White people's medicine has its limits, even in the age of molecular medicine.
References 1.
2.
3. 4. 5. 6.
7.
8.
9.
10.
11.
12.
13. 14. 15.
New MI, Sa~nger P, Novogroder M, Levine LS, Ulick S (1976). Low-renin hypertension and hypokalemia in a 3-year-old girl with deficiency of all known steroids. Presentation before the Annual Meeting of the Society for Pediatric Research, St. Louis, April 1976. Pediatr Res 10:341/342, 1976. New MI, Levine LS, Biglieri EG, Pareira J, Ulick S (1977). Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J Clin Endocrinol Metab 44: 924-933. New MI, Levine LS {1977). An unidentified ACTH-stimulable adrenal steroid in childhood hypertension. In: New MI, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, p. 143. Ulick S, Ramirez LC, New MI (1977). An abnormality in steroid reductive metabolism in a hypertensive syndrome. J Clin Endocrinol Metab 44: 799. Ulick S, Ramirez LC (1977). Steroid patterns in a juvenile hypertensive syndrome. In: New MI, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, pp. 165-170. Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosier A, Bradlow HL, New MI (1979). A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endoerinol Metab 49:757 764. New MI, Oberfield SE, Carey R, Greig F, Ulick S, Levine LS (1982). A genetic defect in cortisol metabolism as the basis for the syndrome of apparent mineralocorticoid excess. In: Mantero F, Biglieri EG, Edwards CRW (eds.): Endocrinology of Hypertension (Proceedinos of the Serono Symposia, Vol. 50). Academic Press, New York, pp. 85-101. Oberfield SE, Levine LS, Carey RM, Greig F, Ulick S, New MI {1983). Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess. J Clin Endocrinol Metab 56:332 339. Monder C, Shackleton CHL, Bradlow HL, New MI, Stoner E, Iohan F, Lakshmi V (1986). The syndrome of apparent mineralocorticoid excess: its association with 1 l/J-dehydrogenase and 5/]-reductase deficiency and some consequences for corticosteroid metabolism. J Clin Endocrinol Metab 63:55(~557. Lakshmi, V, Monger C. Evidence for independent ll-oxidase and l l-reductase activities of l l//-hydroxysteroid dehydrogenase:Enzyme latency, phase transitions and lipid requirements. Endocrinology 116:552 560, 1985. Winter JSD, McKenzie JK (1977). A syndrome of low-renin hypertension in children. In: New M1, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, pp. 123-133. Werder E, Zachmann M, Vollman JA, Veyrat R, Prader A (1973). Unusual steroid excretion in a child with low-renin hypertension. International Study Group for Steroid Hormones, Rome, Italy, December (abstract). Werder E, Zachmann M, Vollmin JA, Veyrat R, Prader A (1974). Unusual steroid excretion in a child with low renin hypertension. Res. Steroids 6:385-389. Stewart PM, Corrie JET, Shackleton CHL, Edwards CRW (1988). Syndrome of apparent mineralocorticoid excess. J Clin Invest 82:340-349. Speiser PW, Riddick LM, Martin K, New MI (1993). Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. Metabolism 42:843-845.
A personal memoir records the discovery of a new form of hypertension, apparent mineralocorticoid excess, which came about throuyh painstakin9 analysis of the symptoms of a Zu~i Indian 9irl. (Steroids 59:66-68, 1994)
Keywords: apparent mineralocorticoid excess; hypertension; cortisol
In 1973 Dr. Ed Biglieri of San Francisco asked me to consult on the unusual case of a child with hypertension and severe hypokalemia but only barely detectable levels of urinary steroids. Fred Katz, an endocrinologist who had been asked to analyze the child's urine, thought that water had been sent by mistake, since the urine contained virtually no steroids. The patient was a 3-year-old Zufii Indian girl, L.K. I stopped over in Gallup, New Mexico to examine her in a health clinic at the Indian Service Hospital. Because of her very low urinary aldosterone and cortisol levels, my first idea was that she must have 17-hydroxylase deficiency. I learned that without the administration of cortisol she had survived both salmonella sepsis and a cardiac catheterization at the Denver Children's Hospital, ordered because it was mistakenly assumed that her hypertension was due to congenital heart disease. The fact that stress did not produce signs of adrenal insufficiency argued against a cortisol deficiency. I decided that I must bring L.K. to New York for intensive evaluation because I realized I had never seen a case like her. I insisted that the mother accompany her to New York. Her mother was willing but said that I must present this plan to the tribe. So I went to the Zufii reservation, where a powwow had been arranged. The men came out of the "kiva," a ceremonial hut, dressed entirely in black, with their skin painted black as well. They sat in a circle, within which the women formed a second circle that included a very old woman, the matriarch of the Zufii tribe. There was
Address reprint requests to Maria I. New, M.D., New York Hospital Cornell University Medical College, 525 E. 68th Street, Room N-236, New York, NY 10021 USA.
66
Steroids, 1994, vol. 59, February
much singing--the words incomprehensible to me ---and cornflake boxes were tossed into the air. The matriarch explained that this ritual was taking place because L.K.'s illness was the result of a form of incest: her parents, both members of the Turkey Clan, had broken a tabu
Dr. Maria I. New
© 1994 Butterworth-Heinemann
Apparent Mineralocorticoid Excess: New in marrying each other, for marriage within a clan was forbidden. Members of the Turkey Clan were meant to marry into the Parrot Clan. At the end of the powwow it was decided that for L.K. to be cured, a deer must be killed while she watched. I indicated that I did not want to see this, and I don't know if the sacrifice took place, but I was fortunately able to arrange to take L.K. and her mother to New York the following day for clinical studies. I was worried that far from home--never having seen a river or a bridge--that the K.s might experience culture shock. I asked my husband, a psychiatrist, to meet us at the airport. But my efforts were not needed; whatever their thoughts, L.K. and her mother showed no signs of shock or surprise. The Zufii are a rather silent people and usually make no fuss at all, but I think that Mrs. K, though she spent most of her time with her hospitalized child, genuinely enjoyed her visit, especially a day at the circus. Now began an exhaustive study of L.K.'s mysterious disease. I first gave her dexamethasone to suppress the adrenal zona fasciculata, persisting in the hypothesis that L.K. had a 17-hydroxylase defect. But this only aggravated her hypertension. When I replaced dexamethasone with hydrocortisone, her hypertension worsened. While she was receiving steroid treatment and had very high blood pressure, I lowered the sodium in her diet. Her blood pressure fell sharply, despite the administration of glucocorticoid. The next step was to try to give her ACTH while she was on the low-salt diet and normotensive to see if her blood pressure would be affected. ACTH administration over 5 days made her blood pressure rise again. After ACTH stimulation ended, we increased the sodium content of her diet, and she became hypertensive again. We then gave chlorothiazide, a diuretic, and her blood pressure fell. Spironolactone, a potassium-sparing diuretic that acts by competitively blocking the mineralocorticoid receptor, brought about remission of her hypertension. We concluded that she had an ACTH-stimulable form of hypertension and that there must be an undetected mineralocorticoid in her blood. ~-s We and others attempted to find such a mineralocorticoid in the biological fluids, including urine, blood, and saliva, s Dr. Diana Marver performed a toad bladder assay with L.K.'s serum, and Dr. John P. Coghlan infused Australian sheep with her extracted urine--both of these tests are exquisitely sensitive mineralocorticoid assays-- to no avail. Dr. Paul F. Palmberg conducted a lymphocyte stimulation test looking for mineralocorticoid effect and again found nothing. By this time we had established that this child secreted very little steroid and almost no known mineralocorticoid. Thus, there was neither biological nor biochemical evidence for the presence of a mineralocorticoid that could produce Lisa's hypertension and hypokalemia. We were puzzled until we demonstrated that the ratio of active to inactive metabolites of cortisol, T H E : T H F , in Lisa's urine was abnormal. Collaborating with Dr. Stanley Ulick we were able to show that though she secreted very little cortisol, the percent free cortisol was
increased. The results of these studies indicated that although L.K. had a very low secretion rate of cortisol, aldosterone, corticosterone, desoxycorticosterone, and all the other steroids that could be measured, the half-life of cortisol in her blood was prolonged, and the serum level was normal. 6 With Dr. William Rosner's help, we investigated the possibility that an abnormality of cortisol binding globulin would provide an explanation. However, we found that L.K.'s cortisol binding globulin was normal. 6 We proposed at this juncture that cortisol must be the bioactive steroid because it aggravated her hypertension. We confirmed this as a possibility through studies of the potential difference between her skin and her rectal mucosa, which, starting at an extremely high level, was made still worse by the administration of hydrocortisone. These studies were published in conjunction with Dr. Robert Carey of the University of Virginia. 7"8 In order to develop the hypothesis of the cortisol metabolic defect, we consulted with Leon Bradlow, Ph.D., who had developed with David Fukushima, Ph.D., a method of administering cortisol tritiated at position 11~ and then measuring the release of tritiated water as evidence of the conversion of the ll-hydroxy group to the keto group. We reasoned that if ll/Ydehydrogenation were defective in L.K., no [ 3 H ] H / O would be released, and this would signify that cortisol could not be converted to cortisone. Indeed, we found that Lisa did not release any [3H]HzO, while her mother released a normal amount. 6 We later studied other patients with this syndrome who showed the same abnormal pattern of low [3H]HzO excretion following infusion of [1 lc(-3H]cortisol. 9 We then enunciated a theory as to the cause of this disease, called "apparent mineralocorticoid excess," which we presented in 1982 at a Serono symposium organized by Dr. Mantero in Padua. T We hypothesized that there was no unusual mineralocorticoid in this disease, but that the hypertension and hypokalemia were caused by cortisol, which somehow interacted with a mineralocorticoid receptor in an abnormal way owing to an 11-dehydrogenase deficiency. Of great interest was the fact that though Dr. Carl Monder reported that there existed only one enzyme for the interconversion of cortisol to cortisone and cortisone to cortisol, 9 Lisa's defect was only in the conversion of cortisol to cortisone. She readily converted cortisone to cortisol. This suggested that the genetic regulation for the enzyme that converted cortisone to cortisol was different from that for the conversion of cortisol to cortisone as was corroborated in an animal study) ° Because we though the disorder might be genetic, we tested the rest of the Turkey Clan and members of the Zufii tribe but found that no one else was hypertensive and hypokalemic. We were later able to study in depth another patient, J.K., an Iranian. 6 The results were similar to those in L.K. Additional reports came from Dr. Jeremy Winter, who had one case in a Canadian Algonquin Indian family and another in an unrelated part-Indian family.~ It is probable that Werder, a general practitioner in
Steroids, 1994, vol. 59, February
67
Personal History Switzerland, was the first to report a case of apparent mineralocorticoid excess. ~2,13 Puzzling and still unexplained aspects of the cases of L.K. and J.K. and others with apparent mineralocorticoid excess are: 1. The hypotension and shock-like syndrome that results from administration of triamterene. 2. The variable course of hypertension in different patients. In L.K., the hypertension began at an early age and required diuretics and/or low-sodium diet in addition to spironolactone to control. She had no detectable cardiomyopathy or cardiac hypertrophy and no other evidence of end-organ disease. Nonetheless, she died suddenly at the age of 15 years. J.K.'s hypertension was also of early childhood onset but was apparently well controlled by spironolactone. He suffered a stroke and had hemiparesis at age 12, yet is still alive in his late teens. Dr. Edwards' patient was diagnosed at the age of 21 years following a 2-week period of altered vision; in addition to his hypertension he had other problems (polydipsia, nocturia; 3 recent episodes of tonsillitis associated with carpopedal spasms and perioral paresthesia) but had never been treated for them. 14 Unlike L.K. and J.K., Dr. Edwards' patient demonstrated a lowering of blood pressure with dexamethasone. What is the basis for the clinical variability of the hypertension and its complications in these patients? 3. The basis of restriction of the defect to the adrenal. L.K. underwent full puberty, indicating her capability of ovarian steroid secretion of C19 and C18 steroids outside of the ACTH axis. She did seem to have a relatively sluggish adrenarche, with Tanner I pubic hair and Tanner II breasts at the age of 14. 4. Administration of aldosterone up to 1 mg/day did not induce exacerbation of the hypertension, simulating "aldosterone escape." How is it that aldosterone cannot displace cortisol from the mineralocorticoid receptor? 5. Finally, why are the patients not Cushingoid if 1 l/3hydroxysteroid dehydrogenase causes cortisol half-life to be prolonged and the Type II (glucocorticoid) receptors as well as the Type I (mineralocorticoid) receptors are replete with cortisol? 6. Administration of RU 486 to block the cortisol Type II receptors did not alleviate the symptoms. Indeed, the hypertension and hypokalemia were aggravated. ~5 By now approximately 25 patients with AME have been identified, and this rare and complicated disease has provided us with new insights into the pathophysiology of steroid-induced hypertension and mechanisms of receptor specificity. Beyond the scientific challenges presented by the disease, I became extremely attached to my patients. I learned a great deal from my dealings with L.K., Mrs. K., and the Zufii tribe. I was enormously grieved at her untimely death and frustrated that she did not live longer, so that we could better explain her disease and offer her a cure. Mrs. K. told me that she thought her
68
Steroids, 1994, vol. 59, February
daughter's death was caused by her grief over the sudden, violent death of a close friend. She thought Lisa had died of a broken heart. The cultural differences were still too great to bridge. After 12 years of consultations, explanation, and counselling about the management of her hypertension, I think her family still believed that evil spirits, not hormones or genes, were the cause. White people's medicine has its limits, even in the age of molecular medicine.
References 1.
2.
3. 4. 5. 6.
7.
8.
9.
10.
11.
12.
13. 14. 15.
New MI, Sa~nger P, Novogroder M, Levine LS, Ulick S (1976). Low-renin hypertension and hypokalemia in a 3-year-old girl with deficiency of all known steroids. Presentation before the Annual Meeting of the Society for Pediatric Research, St. Louis, April 1976. Pediatr Res 10:341/342, 1976. New MI, Levine LS, Biglieri EG, Pareira J, Ulick S (1977). Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J Clin Endocrinol Metab 44: 924-933. New MI, Levine LS {1977). An unidentified ACTH-stimulable adrenal steroid in childhood hypertension. In: New MI, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, p. 143. Ulick S, Ramirez LC, New MI (1977). An abnormality in steroid reductive metabolism in a hypertensive syndrome. J Clin Endocrinol Metab 44: 799. Ulick S, Ramirez LC (1977). Steroid patterns in a juvenile hypertensive syndrome. In: New MI, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, pp. 165-170. Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosier A, Bradlow HL, New MI (1979). A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endoerinol Metab 49:757 764. New MI, Oberfield SE, Carey R, Greig F, Ulick S, Levine LS (1982). A genetic defect in cortisol metabolism as the basis for the syndrome of apparent mineralocorticoid excess. In: Mantero F, Biglieri EG, Edwards CRW (eds.): Endocrinology of Hypertension (Proceedinos of the Serono Symposia, Vol. 50). Academic Press, New York, pp. 85-101. Oberfield SE, Levine LS, Carey RM, Greig F, Ulick S, New MI {1983). Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess. J Clin Endocrinol Metab 56:332 339. Monder C, Shackleton CHL, Bradlow HL, New MI, Stoner E, Iohan F, Lakshmi V (1986). The syndrome of apparent mineralocorticoid excess: its association with 1 l/J-dehydrogenase and 5/]-reductase deficiency and some consequences for corticosteroid metabolism. J Clin Endocrinol Metab 63:55(~557. Lakshmi, V, Monger C. Evidence for independent ll-oxidase and l l-reductase activities of l l//-hydroxysteroid dehydrogenase:Enzyme latency, phase transitions and lipid requirements. Endocrinology 116:552 560, 1985. Winter JSD, McKenzie JK (1977). A syndrome of low-renin hypertension in children. In: New M1, Levine LS (eds.), Juvenile Hypertension. Raven Press, New York, pp. 123-133. Werder E, Zachmann M, Vollman JA, Veyrat R, Prader A (1973). Unusual steroid excretion in a child with low-renin hypertension. International Study Group for Steroid Hormones, Rome, Italy, December (abstract). Werder E, Zachmann M, Vollmin JA, Veyrat R, Prader A (1974). Unusual steroid excretion in a child with low renin hypertension. Res. Steroids 6:385-389. Stewart PM, Corrie JET, Shackleton CHL, Edwards CRW (1988). Syndrome of apparent mineralocorticoid excess. J Clin Invest 82:340-349. Speiser PW, Riddick LM, Martin K, New MI (1993). Investigation of the mechanism of hypertension in apparent mineralocorticoid excess. Metabolism 42:843-845.