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Environmental deprivation and transient elevation of sweat electrolytes
Environmental deprivation and transient elevation of sweat electrolytes We report five children who had transient elevations in sweat electrolyte values in association with environmental deprivation. The high electrolyte values were not always associated with malnutrition, and normalized more rapidly than weight. The reason for these abnormalities is unknown. Inasmuch as elevated sweat electrolytes are rarely associated with environmental deprivation, repeat studies are recommended before diagnosing cystic fibrosis in such children. (J PEDIATR ] 985;107:231-234)
Katherine S. Christoffel, M.D., M.P.H., John D. Lloyd-Still, M.D., Gall Brown, M.D., and Harry Shwaehman, M.D. Chicago, Illinois, and Boston, Massachusetts
ENVIRONMENTAL DEPRIVATION a n d cystic fibrosis are two diagnoses c o m m o n l y considered in the evaluation of children with failure to thrive. W e report five children in whom it was difficult to differentiate these conditions because of transient elevation in sweat electrolyte concentrations. METHODS
Sweat tests were performed by t h e Gibson and Cooke iontophoresis method. 13 A m i n i m u m of 100 mg sweat weight was obtained in four patients and in three of five m e a s u r e m e n t s in the fifth patient ( > 6 9 mg in the other two measurements). Sweat electrolyte m e a s u r e m e n t s were routinely done in duplicate (two arms). A l t h o u g h sodium, potassium, a n d chloride were usually measured, only chloride values are reported because the sodium and chloride values correlated closely. CASE
I00
0."
95 9O
75-
,o ~
~,
50
", r:
\
g45
~ 40
35
' \
3O 25 20
Iol5~5 o
24
--' a5
ze
z7 z8
AGE,MONTHS
a9
z
3
4
5
6
~
8
9
AGE,YEARS
Figure. Sequential sweat chloride concentrations (mEq/L) in five neglected children ( I , A, e, A, O, patients 1 through 5, respectively). Values plotted represent mean of duplicate tests except those starred (*), which are values from single tests.
REPORT
Patient 1 was referred at 2 years of age for failure to thrive. He was the second of three children, born to a 20-year-old woman From the Department o f Pediatrics, Children's Memorial Hospital Northwestern University, Chicago; and the Department o f Medicine, Children's Hospital Medical Center, Harvard Medical School, Boston. Submitted for publication Nov. 8, 1984; accepted Jan. 16, 1985. Reprint requests: John D. Lloyd-Still, M.D., Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614.
whose husband was unemployed. He had abdominal distention, two or three bowel movements a day, and failure to gain weight even though he ate more than his two siblings did. On physical examination, both height and weight were well below the 3rd percentile. He had dry skin, a distended abdomen, and wasted buttocks; the rest of the examination yielded normal results. Sweat chloride values were 78 and 73 mEq/L. One-hour xylose absorption (after 5 gm orally) was normal at 32.2 mg/dl. The patient was hospitalized for further evaluation. Sweat chloride values during hospitalization steadily and rapidly decreased (Figure). Values of 40 and 45 mEq/L and then 16 and
The dournal of P E D I A T R I C S
231
232
Christoffel et al.
The Journal of Pediatrics August 1985
Table. Clinical details in five children with transient elevation of sweat chloride values a n d neglect
Patient
Age at presentation (yr)
Expected weight for age (~)
Height (%)
19
21/2
73
<5
2A
35A2
80
39
6
52
4 9
1%2
91
5 o
2~12
64
50
<5
30 --
Weight (%) <5
10
<5
10 <5
Stool trypsin
Secretin test
Jejunal biopsy
Pulmonary status
1:5
--
Normal
Normal
Normal
Normal
Normal
Normal
Negative
Normal
Normal
Normal
Normal
--
--
Normal
Negative
--
Normal
Perihilar infiltrate
13 mEq/L were obtained 2 days apart. Stool trypsin was positive at only 1:5 dilution on three occasions. Serum trypsinogen was 26 (normal, 10 to 70 ~tg/ml). He gained 0.8 kg in 7 days in the hospital. Findings on intestinal biopsy, to rule out celiac disease, were normal. After discharge, sweat chloride values were 17 and 17 mEq/L, and later 32 and 39 mEq/L. Skeletal survey revealed split cranial sutures and growth arrest lines compatible with psychosocial deprivation. On further questioning, a history was obtained of drinking water from the toilet bowel and eating garbage. Weight gain ceased after discharge to home. He was subsequently placed in foster care, where he grew 7.6 cm taller and gained 1.5 kg in 3 months. The clinical details for four other children with elevated sweat electrolytes and evidene of psychosocial deprivation and neglect are shown in the Table and Figure. DISCUSSION Sweat tests are c o m m o n l y performed incorrectly. Rosenstein et al? reviewed 234 patients referred for sweat testing, of whom 62 h a d undergone previous testing; results
Evidence of neglect History of repeated injuries caused by child abuse or neglect; split coronal sutures and multiple growth arrest lines in hospital; drank from toilet, ate garbage; good growth in hospital and foster care Custody battle including interstate abductions; dramatic weight gain when situation stabilized (to 40th percentile) Delayed bone age; hospitalized twice for drug ingestions; immersion burns at age 3 years; school and behavior problems Mother with "self-inflicted hepatitis" Rapid psychomotor development during hospitalization; symptoms resolved and growth and development normalized in foster care
of 29 tests had been reported as negative, and of 33 tests, positive. Results of quantitative pilocarpine iontophoresis sweat tests led to a c h a n g e of diagnosis in 27 (43.5%) of these 62 patients, and most of these errors were false positive. P a l m e r et al? found a false positive rate of 0.6% in 5828 tests when chloride values >61 m E q / L were regarded as positive. S h w a c h m a n et al. 3 stated t h a t in 99% of patients with cystic fibrosis, sodium values will be >73.7 m E q / L and chloride values >77.4 m E q / L , and t h a t the probability of this s t a t e m e n t being true is 99%. Similarly, the upper limits for controls was interpreted to show t h a t at least 99% of individuals without cystic fibrosis will have sodium values <47.1 m E q / L and chloride values <46.9 mEq/L. Conditions other t h a n cystic fibrosis have been associated with elevated sweat electrolyte values, including ectodermal dysplasia, glycogen storage disease type 1, adrenal insufficiency, familial hypoparathyroidism syndrome, malnutrition, fucosidosis, nephrosis with edema,
Volume 107 Number 2
pitressin-resistant diabetes insipidus, mucopolysaccharidosis, hypothyroidism, Mauriac syndrome, and familial cholestatic syndromes. 6 More recently, 5 acute respiratory disorders (croup, epiglottitis, viral pneumonia) and chronic respiratory disorders including tracheal compression, retained foreign body, bronchopulmonary dysplasia, and a~-antitrypsin deficiency have also been noted to produce false positive values. Transitory elevation of sweat electrolytes and partial pancreatic insufficiency have been reported in patients with protein calorie malnutrition7,8 and in anorexia nervosa? The Mauriac syndrome, seen in diabetic children given inadequate insulin and diet therapy, has also been reported with false positive sweat electrolyte values, ~~ and has somatomedin activity in the hypopituitary range. ~ In patient 1, the normalization of sweat electrolytes occurred prior to substantial weight gain, making it unlikely that malnutrition alone explained his elevated sweat electrolyte concentrations. The history and radiographic findings confirmed a diagnosis of deprivation dwarfism, 1z,/3 in which a number of alterations in hypothalamic hormones have been described. Patients 2 and 4 had minimal evidence of malnutrition (Table), and rapid normalization of sweat chloride concentrations. By far the commonest cause of difficulty in interpreting sweat electrolyte values is in patients with "borderline" sweat electrolyte concentrations. In our experience, the number of such patients is fewer than 5% in any large cystic fibrosis center. One of us (H.S.) has identified at least 100 of these patients, of whom 25 have a disorder indistinguishable from cystic fibrosis. 14In most of the other 75 patients, pancreatic function is normal, and major pulmonary symptoms have been related to wheezing. A familial cholestatic syndrome ~5.~6 has been described in which initial sweat electrolyte values are in the normal range but subsequently become persistently elevated to the range seen in cystic fibrosis. Autopsies on two of these patients showed marked malnutrition but no evidence of cystic fibrosis. False negative sweat tests are well recognized in infants with cystic fibrosis with edema ~7,~8 and when the weight of sweat is insuff• (<100 mg). 19 In our experience, environmental deprivation is an extremely rare cause of transient sweat electrolyte elevation. However, because this entity exists, any child who does not pursue a normal course for cystic fibrosis should undergo repeat sweat electrolyte determination. Neglect can also occur in association with cystic fibrosis. Currently, 2.8% of our (JL-S) patients with cystic fibrosis have been referred for protective services. In all of these children, repeat sweat electrolyte values have remained in the cystic fibrosis range.
Environmental deprivation and sweat electrolytes
233
In patients with problems in categorizing sweat electrolyte abnormalities, several laboratory tests can augment clinical examination, including the secretin test to detect impaired bicarbonate secretion, 2~ measurement of serum immunoreactive trypsinogen, 2~ and measurement of nasal mucosal electrolyte potential differences? 2 When newborn screening for cystic fibrosis becomes routine practice, we will likely see an increasing number of patients with problems in categorizing sweat abnormalities. We thank Ramona Russell and Sophie Podyma for secretarial assistance.
REFERENCES
1. Gibson LE, Cooke RE: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 23:545, 1959. 2. Shwachman H, Mahmoodian A: Pilocarpine iontophoresis sweat testing results of seven years' experience. Mod Probl Pediatr 10:158, 1967. 3. Shwaehman H, Mahmoodian A, Neff RK: The sweat test: Sodium and chloride values. J PEDIATR98:576, 1981. 4. Rosenstein BJ, Langbaum TS, Gordes E, et al: Cystic fibrosis: Problems encountered with sweat testing. JAMA 240:1987, 1978. 5. Palmer J, Huang NN, Schidlow D, et al: What is the true incidence and significance of false-positive and false-negative sweat tests in cystic fibrosis? 12 years experience with almost 6000 tests. Cystic Fibrosis Club Abstracts 25:43, 1984. 6. Gibson LE: The sweat abnormality in cystic fibrosis. In Lloyd-Still JD, editor: Textbook of cystic fibrosis. Boston, 1983, John Wright-PSG, pp 33-42. 7. Senecal J, Dan V: The sweat test in children with malnutrition. Turk J Pediatr 5:31, 1963. 8. Mace JW, Schanberger JE: Elevated sweat chlorides in a child with malnutrition. Clin Pediatr 10:285, 1971. 9. Luthi M, Zurbrugg RP: A puzzling triad: Anorexia nervosa, high sweat electrolytes and indication to partial exocrine pancreatic insufficiency. Helv Paediat Acta 38:149, 1983. 10. Rosenfeld R, Spigelblatt L, Chicoine R: False positive sweat test, malnutrition, and the Mauriac syndrome. J PEDIATR 94:240, 1979. 11. Winter R J, Phillips LS, Green OC, et al: Somatomedin activity in the Mauriac syndrome. J PEDIATR97:598, 1980. 12. Globel H J, Capitano MA, Kirkpatrick JA: Radiographic findings in children with psychosocial dwarfism. Pediatr Radiol 4:83, 1976. 13. Powell GF, Brasel JA, Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. N Engl J Med 276:1271, 1967. 14. Shwachman H, Mahmoodian A: Interpretation of the sweat test in the diagnosis of cystic Fibrosis. In Lawson D, editor: Cystic fibrosis: Horizons. Proceedings of the Ninth International Cystic Fibrosis Congress. New York, 1984, John Wiley & Sons, p 203. 15. Lloyd-Still JD: Familial cholestasis with elevated sweat electrolyte concentrations. J PEDIATR99:580, 1981. 16. Hillemeier AC, Hen J, Riely CA, et al: Meconium peritonitis
234
Christoffel et al.
and increasing sweat chloride determinations in a case of familial progressive intrahepatic cholestasis. Pediatrics 69:325, 1982. 17. MacLean WC, Tripp RW: Cystic fibrosis with edema and falsely negative sweat test. J PED1AT~ 83:86, 1973. 18. Gunn T, Belmonte MM, Colle E, et al: Edema as the presenting symptom of cystic fibrosis: Difficulties in diagnosis. Am J Dis Child 132:317, 1978. 19. Barnes GL, McNaught S: False negative sweat tests with apparently adequate sweat collections. Aust Paediatr J 14:78, 1978.
The Journal of Pediatrics August 1985
20. Gaskin K J, Durie PR, Corey M, et al: Evidence for a primary defect of pancreatic HCO3 secretion in cystic fibrosis. Pediatr Res 16:544, 1982. 21. Burlina A, Rizzotti P, Tonon M, et al: Serum immunoreactive trypsin in cystic fibrosis. Scand J Gastroenterol 15:35, 1980. 22. Knowles M, Gatzy J, Boucher R: Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 305:1489, 1981.
Katherine S. Christoffel, M.D., M.P.H., John D. Lloyd-Still, M.D., Gall Brown, M.D., and Harry Shwaehman, M.D. Chicago, Illinois, and Boston, Massachusetts
ENVIRONMENTAL DEPRIVATION a n d cystic fibrosis are two diagnoses c o m m o n l y considered in the evaluation of children with failure to thrive. W e report five children in whom it was difficult to differentiate these conditions because of transient elevation in sweat electrolyte concentrations. METHODS
Sweat tests were performed by t h e Gibson and Cooke iontophoresis method. 13 A m i n i m u m of 100 mg sweat weight was obtained in four patients and in three of five m e a s u r e m e n t s in the fifth patient ( > 6 9 mg in the other two measurements). Sweat electrolyte m e a s u r e m e n t s were routinely done in duplicate (two arms). A l t h o u g h sodium, potassium, a n d chloride were usually measured, only chloride values are reported because the sodium and chloride values correlated closely. CASE
I00
0."
95 9O
75-
,o ~
~,
50
", r:
\
g45
~ 40
35
' \
3O 25 20
Iol5~5 o
24
--' a5
ze
z7 z8
AGE,MONTHS
a9
z
3
4
5
6
~
8
9
AGE,YEARS
Figure. Sequential sweat chloride concentrations (mEq/L) in five neglected children ( I , A, e, A, O, patients 1 through 5, respectively). Values plotted represent mean of duplicate tests except those starred (*), which are values from single tests.
REPORT
Patient 1 was referred at 2 years of age for failure to thrive. He was the second of three children, born to a 20-year-old woman From the Department o f Pediatrics, Children's Memorial Hospital Northwestern University, Chicago; and the Department o f Medicine, Children's Hospital Medical Center, Harvard Medical School, Boston. Submitted for publication Nov. 8, 1984; accepted Jan. 16, 1985. Reprint requests: John D. Lloyd-Still, M.D., Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614.
whose husband was unemployed. He had abdominal distention, two or three bowel movements a day, and failure to gain weight even though he ate more than his two siblings did. On physical examination, both height and weight were well below the 3rd percentile. He had dry skin, a distended abdomen, and wasted buttocks; the rest of the examination yielded normal results. Sweat chloride values were 78 and 73 mEq/L. One-hour xylose absorption (after 5 gm orally) was normal at 32.2 mg/dl. The patient was hospitalized for further evaluation. Sweat chloride values during hospitalization steadily and rapidly decreased (Figure). Values of 40 and 45 mEq/L and then 16 and
The dournal of P E D I A T R I C S
231
232
Christoffel et al.
The Journal of Pediatrics August 1985
Table. Clinical details in five children with transient elevation of sweat chloride values a n d neglect
Patient
Age at presentation (yr)
Expected weight for age (~)
Height (%)
19
21/2
73
<5
2A
35A2
80
39
6
52
4 9
1%2
91
5 o
2~12
64
50
<5
30 --
Weight (%) <5
10
<5
10 <5
Stool trypsin
Secretin test
Jejunal biopsy
Pulmonary status
1:5
--
Normal
Normal
Normal
Normal
Normal
Normal
Negative
Normal
Normal
Normal
Normal
--
--
Normal
Negative
--
Normal
Perihilar infiltrate
13 mEq/L were obtained 2 days apart. Stool trypsin was positive at only 1:5 dilution on three occasions. Serum trypsinogen was 26 (normal, 10 to 70 ~tg/ml). He gained 0.8 kg in 7 days in the hospital. Findings on intestinal biopsy, to rule out celiac disease, were normal. After discharge, sweat chloride values were 17 and 17 mEq/L, and later 32 and 39 mEq/L. Skeletal survey revealed split cranial sutures and growth arrest lines compatible with psychosocial deprivation. On further questioning, a history was obtained of drinking water from the toilet bowel and eating garbage. Weight gain ceased after discharge to home. He was subsequently placed in foster care, where he grew 7.6 cm taller and gained 1.5 kg in 3 months. The clinical details for four other children with elevated sweat electrolytes and evidene of psychosocial deprivation and neglect are shown in the Table and Figure. DISCUSSION Sweat tests are c o m m o n l y performed incorrectly. Rosenstein et al? reviewed 234 patients referred for sweat testing, of whom 62 h a d undergone previous testing; results
Evidence of neglect History of repeated injuries caused by child abuse or neglect; split coronal sutures and multiple growth arrest lines in hospital; drank from toilet, ate garbage; good growth in hospital and foster care Custody battle including interstate abductions; dramatic weight gain when situation stabilized (to 40th percentile) Delayed bone age; hospitalized twice for drug ingestions; immersion burns at age 3 years; school and behavior problems Mother with "self-inflicted hepatitis" Rapid psychomotor development during hospitalization; symptoms resolved and growth and development normalized in foster care
of 29 tests had been reported as negative, and of 33 tests, positive. Results of quantitative pilocarpine iontophoresis sweat tests led to a c h a n g e of diagnosis in 27 (43.5%) of these 62 patients, and most of these errors were false positive. P a l m e r et al? found a false positive rate of 0.6% in 5828 tests when chloride values >61 m E q / L were regarded as positive. S h w a c h m a n et al. 3 stated t h a t in 99% of patients with cystic fibrosis, sodium values will be >73.7 m E q / L and chloride values >77.4 m E q / L , and t h a t the probability of this s t a t e m e n t being true is 99%. Similarly, the upper limits for controls was interpreted to show t h a t at least 99% of individuals without cystic fibrosis will have sodium values <47.1 m E q / L and chloride values <46.9 mEq/L. Conditions other t h a n cystic fibrosis have been associated with elevated sweat electrolyte values, including ectodermal dysplasia, glycogen storage disease type 1, adrenal insufficiency, familial hypoparathyroidism syndrome, malnutrition, fucosidosis, nephrosis with edema,
Volume 107 Number 2
pitressin-resistant diabetes insipidus, mucopolysaccharidosis, hypothyroidism, Mauriac syndrome, and familial cholestatic syndromes. 6 More recently, 5 acute respiratory disorders (croup, epiglottitis, viral pneumonia) and chronic respiratory disorders including tracheal compression, retained foreign body, bronchopulmonary dysplasia, and a~-antitrypsin deficiency have also been noted to produce false positive values. Transitory elevation of sweat electrolytes and partial pancreatic insufficiency have been reported in patients with protein calorie malnutrition7,8 and in anorexia nervosa? The Mauriac syndrome, seen in diabetic children given inadequate insulin and diet therapy, has also been reported with false positive sweat electrolyte values, ~~ and has somatomedin activity in the hypopituitary range. ~ In patient 1, the normalization of sweat electrolytes occurred prior to substantial weight gain, making it unlikely that malnutrition alone explained his elevated sweat electrolyte concentrations. The history and radiographic findings confirmed a diagnosis of deprivation dwarfism, 1z,/3 in which a number of alterations in hypothalamic hormones have been described. Patients 2 and 4 had minimal evidence of malnutrition (Table), and rapid normalization of sweat chloride concentrations. By far the commonest cause of difficulty in interpreting sweat electrolyte values is in patients with "borderline" sweat electrolyte concentrations. In our experience, the number of such patients is fewer than 5% in any large cystic fibrosis center. One of us (H.S.) has identified at least 100 of these patients, of whom 25 have a disorder indistinguishable from cystic fibrosis. 14In most of the other 75 patients, pancreatic function is normal, and major pulmonary symptoms have been related to wheezing. A familial cholestatic syndrome ~5.~6 has been described in which initial sweat electrolyte values are in the normal range but subsequently become persistently elevated to the range seen in cystic fibrosis. Autopsies on two of these patients showed marked malnutrition but no evidence of cystic fibrosis. False negative sweat tests are well recognized in infants with cystic fibrosis with edema ~7,~8 and when the weight of sweat is insuff• (<100 mg). 19 In our experience, environmental deprivation is an extremely rare cause of transient sweat electrolyte elevation. However, because this entity exists, any child who does not pursue a normal course for cystic fibrosis should undergo repeat sweat electrolyte determination. Neglect can also occur in association with cystic fibrosis. Currently, 2.8% of our (JL-S) patients with cystic fibrosis have been referred for protective services. In all of these children, repeat sweat electrolyte values have remained in the cystic fibrosis range.
Environmental deprivation and sweat electrolytes
233
In patients with problems in categorizing sweat electrolyte abnormalities, several laboratory tests can augment clinical examination, including the secretin test to detect impaired bicarbonate secretion, 2~ measurement of serum immunoreactive trypsinogen, 2~ and measurement of nasal mucosal electrolyte potential differences? 2 When newborn screening for cystic fibrosis becomes routine practice, we will likely see an increasing number of patients with problems in categorizing sweat abnormalities. We thank Ramona Russell and Sophie Podyma for secretarial assistance.
REFERENCES
1. Gibson LE, Cooke RE: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 23:545, 1959. 2. Shwachman H, Mahmoodian A: Pilocarpine iontophoresis sweat testing results of seven years' experience. Mod Probl Pediatr 10:158, 1967. 3. Shwaehman H, Mahmoodian A, Neff RK: The sweat test: Sodium and chloride values. J PEDIATR98:576, 1981. 4. Rosenstein BJ, Langbaum TS, Gordes E, et al: Cystic fibrosis: Problems encountered with sweat testing. JAMA 240:1987, 1978. 5. Palmer J, Huang NN, Schidlow D, et al: What is the true incidence and significance of false-positive and false-negative sweat tests in cystic fibrosis? 12 years experience with almost 6000 tests. Cystic Fibrosis Club Abstracts 25:43, 1984. 6. Gibson LE: The sweat abnormality in cystic fibrosis. In Lloyd-Still JD, editor: Textbook of cystic fibrosis. Boston, 1983, John Wright-PSG, pp 33-42. 7. Senecal J, Dan V: The sweat test in children with malnutrition. Turk J Pediatr 5:31, 1963. 8. Mace JW, Schanberger JE: Elevated sweat chlorides in a child with malnutrition. Clin Pediatr 10:285, 1971. 9. Luthi M, Zurbrugg RP: A puzzling triad: Anorexia nervosa, high sweat electrolytes and indication to partial exocrine pancreatic insufficiency. Helv Paediat Acta 38:149, 1983. 10. Rosenfeld R, Spigelblatt L, Chicoine R: False positive sweat test, malnutrition, and the Mauriac syndrome. J PEDIATR 94:240, 1979. 11. Winter R J, Phillips LS, Green OC, et al: Somatomedin activity in the Mauriac syndrome. J PEDIATR97:598, 1980. 12. Globel H J, Capitano MA, Kirkpatrick JA: Radiographic findings in children with psychosocial dwarfism. Pediatr Radiol 4:83, 1976. 13. Powell GF, Brasel JA, Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. N Engl J Med 276:1271, 1967. 14. Shwachman H, Mahmoodian A: Interpretation of the sweat test in the diagnosis of cystic Fibrosis. In Lawson D, editor: Cystic fibrosis: Horizons. Proceedings of the Ninth International Cystic Fibrosis Congress. New York, 1984, John Wiley & Sons, p 203. 15. Lloyd-Still JD: Familial cholestasis with elevated sweat electrolyte concentrations. J PEDIATR99:580, 1981. 16. Hillemeier AC, Hen J, Riely CA, et al: Meconium peritonitis
234
Christoffel et al.
and increasing sweat chloride determinations in a case of familial progressive intrahepatic cholestasis. Pediatrics 69:325, 1982. 17. MacLean WC, Tripp RW: Cystic fibrosis with edema and falsely negative sweat test. J PED1AT~ 83:86, 1973. 18. Gunn T, Belmonte MM, Colle E, et al: Edema as the presenting symptom of cystic fibrosis: Difficulties in diagnosis. Am J Dis Child 132:317, 1978. 19. Barnes GL, McNaught S: False negative sweat tests with apparently adequate sweat collections. Aust Paediatr J 14:78, 1978.
The Journal of Pediatrics August 1985
20. Gaskin K J, Durie PR, Corey M, et al: Evidence for a primary defect of pancreatic HCO3 secretion in cystic fibrosis. Pediatr Res 16:544, 1982. 21. Burlina A, Rizzotti P, Tonon M, et al: Serum immunoreactive trypsin in cystic fibrosis. Scand J Gastroenterol 15:35, 1980. 22. Knowles M, Gatzy J, Boucher R: Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 305:1489, 1981.