Arch Dis Child: first published as 10.1136/adc.55.6.427 on 1 June 1980. Downloaded from Archives of Disease in Childhood, 1980, 55, 427-434 Pseudohypoaldosteronism M J DILLON, J V LEONARD, J M BUCKLER, D OGILVIE, D LILLYSTONE, J W HONOUR, AND C H L SHACKLETON The Hospitalfor Sick Children and Queen Elizabeth Hospital for Children, London, Department of Paediatrics and Child Health, University ofLeeds, and Division of Clinical Chemistry, Clinical Research Centre, Harrow, Middlesex SUMMARY 10 infants are described with pseudohypoaldosteronism, 5 in detail and a further 5 briefly. They all presented with hyperkalaemia, urinary salt-wasting disease, and ostensibly normal renal and adrenocortical function. Diagnosis was established by demonstrating the greatly increased values of plasma renin activity and plasma aldosterone concentration, plus the increased excretion of aldosterone and its metabolites on gas chromatographic and mass spectrometric analyses of urine. The children were treated with sodium chloride supplements, up to 60 mmol/day, but by the time most ofthe infants were about a year old these could be stopped. Exogenous mineralocorticoids were without effect in those to whom they were administered. The precise aetiology of the condition remains conjectural; lack of renal tubular response to aldosterone seems probable. Pseudohypo- aldosteronism may be more common than has been thought and new techniques for investigating salt-wasting disorders may show its true incidence. Salt loss in infancy is often due to gastrointestinal This paper describes in detail 5 more children with disease and in such cases there is renal conservation PHA, and briefly refers to a further 5 cases in whom of sodium. In contrast, urinary salt loss occurs in diagnostic investigations were undertaken in our certain renal tubular disorders and in adrenal laboratories. The diagnosis was established in all 10 insufifciency. Severe salt loss in infancy has been children by the characteristic increase in plasma described despite ostensibly normal renal and renin and aldosterone levels, and in most children http://adc.bmj.com/ adrenocortical function, and has been attributed by the typical urinary corticosteroid findings. to lack of response of the renal tubule to endo- genous mineralocorticoids. This syndrome has been Methods called pseudohypoaldosteronism and since 1958, when it was first described by Cheek and Perry,' PRA and PAldo concentration were measured using 30 cases have been described.2-19 In one report20 the methods of Dillon,22 and Dillon and Ryness.23 7 additional but atypical cases were described and on October 1, 2021 by guest. Protected copyright. these patients were shown subsequently to have a defect of aldosterone biosynthesis.2' Abbreviations: The Hospital for Sick Children, London PHA: pseudohypoaldosteronism M J DILLON, consultant paediatrician PRA: plasma renin activity Institute of Child Health, London PAldo: plasma aldosterone J V LEONARD, senior lecturer in child health D OGILVIE, research fellow GC: gas chromatography Department of Paediatrics and Child Health, GC/MS: gas chromatographic and mass University of Leeds spectrometric J M BUCKLER, senior lecturer in paediatrics 17-OS: 17-oxosteroids Hornsby and District Hospital, Hornsby, Sydney, Australia 11-01: 11-oxygenation index D LILLYSTONE, consultant paediatrician 17-OHP: 17-hydroxyprogesterone Division of Clinical Chemistry, Clinical Research Centre, ACTH: adrenocorticotropic hormone Harrow, Middlesex 9FC: 9oc-fludrocortisone J W HONOUR, senior research officer Biomedical Mass Spectrometry Resource, Space Sciences DOCA: desoxycorticosterone Laboratory, University of California, Berkeley, USA ATP: adenosine triphosphate C H L SHACKLETON, deputy director 427 Arch Dis Child: first published as 10.1136/adc.55.6.427 on 1 June 1980. Downloaded from 428 Dillon, Leonard, Buckler, Ogilvie, Lillystone, Honour, and Shackleton Urinary metabolites of cortisol and corticosterone but extremely high excretions of allo-tetrahydro- were analysed by capillary GC.24 Tetrahydroaldo- corticosterone, tetrahydroaldosterone, and 18- sterone and 18-hydroxytetrahydroCompound A hydroxytetrahydroCompound A were noted (Table). were analysed simultaneously by a GC/MS analysis It was possible gradually to reduce the treatment selected ion monitoring method.2526 Plasma and with corticosteroids without relapse, and later the urine electrolytes were measured simultaneously salt supplements were tailed off. By age one year our by flame photometry in a 5-channel autoanalyser. patient was well and was receiving no treatment. He Standard methods were used to estimate urine 17- is now 5 years and is catching up in growth; he has a hydroxycorticoids,27 17JS,28 pregnanetriol,29 and normal blood pressure, and can tolerate salt the 11-OI.30 Competitive protein-binding methods deprivation even when stressed by illness. were used to determine plasma cortisol,3' 17-OHP,32 and 11-deoxycortisol.33 Plasma ACTH was deter- Case 2. This girl was the fifth child of unrelated mined by radioimmunoassay.34 English parents. Her birth was normal and she weighed 3 04 kg. At 7 days she had been found in a Case reports collapsed state and on admission to hospital was moribund. She was resuscitated with intravenous fluids, antibiotics, and hydrocortisone as the pre- Case 1. This boy was the second child of unrelated sumptive diagnosis was septicaemia. The initial English parents. He was born normally at term response was satisfactory, but the next day her weighing 2 75 kg and since birth he had had re- condition deteriorated with pronounced electrolyte current episodes of vomiting. At 9 weeks he was imbalance despite intravenous fluids (plasma Na admitted to hospital because of a severe episode of 125 mmol/l, K 8-4 mmol/l). Congenital adrenal vomiting associated with dehydration. Plasmasodium hyperplasia was suspected although her genitalia (Na) was 118 mmol/l and potassium (K) 5 0 mmol/l. were normal; she was treated with DOCA, hydro- A presumptive diagnosis of salt-losing congenital cortisone, salt supplements, and an ion-exchange adrenal hyperplasia was made and he was treated resin. Several days later her condition again deterior- with intravenous fluids and intramuscular hydro- ated, plasma Na falling to 125 mmol/l and K rising cortisone. After more vomiting associated with to 8 2 mmol/l. At this stage PRA was 107 300 ng hyponatraemia, 9FC was given orally but his Al/I per hour and PAldo concentration much symptoms persisted. greater than 3000 pmol/l (Table). Plasma electro- Despite the treatment with mineralocorticoids the lytes failed to improve until she was given 60 mmol/ salt-losing state persisted; therefore 9FC was day NaCl in addition to hydrocortisone and DOCA. stopped and sodium chloride (NaCl) supplements She developed pneumonia, superimposed cardiac http://adc.bmj.com/ (50 mmol/day) were started. He became hyper- failure, and generalised convulsions. With intensive tensive (140/110 mmHg) and remained so when the treatment she recovered and was finally stabilised on NaCl supplements were withdrawn, although he 50 mmol/day NaCl. went into negative Na balance and plasma Na Standard tests of renal function, including intra- fell to 125 mmol/l. Plasma Na values were venous pyelography, gave results that were within eventually stabilised above 130 mmol/l with Na normal limits. Adrenal function tests including supplements of 60 and the mmol/day, blood pressure plasma 17-OHP, plasma cortisol, plasma 11- on October 1, 2021 by guest. Protected copyright. slowly returned to normal. Because of the persistent deoxycortisol, urine 17-oxogenic steroids, urine hypertension, PRA, and PAldo concentration were 17-OS, and urine pregnanetriol were essentially measured. PRA was 81 000 ng Al/I per hour normal before and after ACTH stimulation. (reference range for age, 472-3130 ng Al /1 per hour), She has maintained satisfactory progress. Her and PAldo concentration was considerably greater blood pressure remained normal on treatment. She than 3000 pmol/l (reference range for age, 160-3000 was discharged from hospital at 2 months on corti- pmol/l) (Table). sone 10 mg twice daily, 9FC 0 1 mg daily, and 25 Standard tests of renal function (including intra- mmol/day of added NaCl. The 9FC was stopped at venous pyelography) all gave results that were age 10 months and the cortisone withdrawn by 13 within normal limits. Adrenal function tests in- months. Aged 41 years, although small, she has cluding plasma 17-OHP, plasma cortisol, plasma grown normally with height and weight following 11-deoxycortisol, urine 17-OS, and urine 11-OI, the 3rd centile. GS/MS analysis of urinary cortico- before and after ACTH stimulation were essentially steroids at 21 years showed only moderately raised normal. GC/MS analyses of urinary corticosteroids tetrahydroaldosterone and 18.hydroxytetrahydro- were carried out on day 5 of the ACTH stimulation Compound A. Secretion of cortisol metabolites was test. Cortisol metabolites were moderately raised normal for age. Arch Dis Child: first published as 10.1136/adc.55.6.427 on 1 June 1980. Downloaded from Pseudohypoaldosteronism 429 80 °| za 0 Z |0 2 z 00 o 0%al 0o 0O] I) A aO a 110 Cli _-I .09 in - 00 E ~00 _lC C4 L.C 88 .0l en |0 A o V 0% 0 l 00 E - %O 00 R E% 0008° A 00oo tn> .04 01 88§ in Z O 9 C 0 Cl 00 O 0_ cl_ 0 00 Cq o w0 o I- 0 .. 0ZI E0 Cq) 01 Cl 0 E0 VE _ C.-000 oocoo 3 0 00%O -00 00 Cl V t Xl X 0. 88u 0.. enE %iD tn http://adc.bmj.com/ 00 0% enA a a %0O 0. oo 2 ZO Z 'ogo 004 0> %O t.- oo en C.) 00 ChN 0r- A0 0 Cl4 A 00 .-4 0 on October 1, 2021 by guest. Protected copyright. QW U 9 co a. t-00 en A z ~z C.) o E 11 2: Arch Dis Child: first published as 10.1136/adc.55.6.427 on 1 June 1980. Downloaded from 430 Dillon, Leonard, Buckler, Ogilvie, Lillystone, Honour, and Shackleton Case 3.