PRIMARY HYPEROXALURIA

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PRIMARY. HYPEROXALURIA

It.

Genetic Studies in a Family

Thomas H. Shepard, II, M.D., Lou-sein W. Lee, M.S. and Edwin G. Krebs, M.D. Departments of Pediatrics (T.H.S.) and Biochemistry (L.W.L., E.G.K.),

School of Medicine, Unitiersity of Washington

P

XIAIARY hyperoxaluria can be defined as a condition in which the daily excretion of oxalate in the urine is above 50 mg. In another paper,' the medical literature was reviewed and it was indicated that the re- sult of this biochemical alteration is pro- gressive nephrocalcinosis due to calcium oxalate. Primary hyperoxaluria is known to occur as a familial d i s e a ~ e , ~ - ~ and Archer et ale7 have published detailed studies suggesting that- primary hyperoxaluria is inherited as a Mendelian autosomal recessive. The purpose of this paper is to report a pedigree of a family with hyperoxaluria in which the disease appears to be trans- mitted as an autosomal Mendelian dominant.

MATERIALS AND METHODS

Determinations of oxalate in urine were carried out calorimetrically using the ferric complex of 8-hydroxy-7-iodo-5-quinoline sul- f ~ n a t e . ~ Most of the inorganic phosphate and other interfering anions were first removed using Dowex 3 in the acetate form.' In a study of 13 normal adults the average 24-hour urinary excretion of oxalic acid was found to be 34 mg. Eighty-five percent of the values were be- tween 15 and 50 mg. None of the normal values were over 55 mg. The uric acid was measured by the method of B r ~ w n . ~ The 24- hour urines were collected in glass containers and frozen until time of analysis.

RESULTS

The findings are recorded in Table I. Transmission of hyperoxaluria from parent to offspring is shown in three successive

generations (Fig. 1). Except for the propositus (111-7) there was no history of renal stones or renal disease in any other member. There was no person with a history suggesting gout, and in two of the other family members with hyperoxaluria, in whom determinations were performed, the uric acid in the serum was within normal limits; that of the propositus was elevated. There was no consanguinity.

DISCUSSION

A review of the literature1 revealed 24 cases of primary hyperoxaluria. In three reports the family history was not men- tioned and in six families the presence of other healthy siblings was not detailed. In 4 of the 19 families reported in which the family history was discussed, there was an additional sibling who was most likely also affected. The data from three families reported in detail by Archer et

aL7

were com- patible with recessive transmission of this characteristic. Only one sibship in each family was involved and although urinary excretion of oxalate was determined in 49 relatives, none showed elevated concentrations. In four other

report^,^,^,^^^

one member of the next older generation was known to have had renal stones. In none of these cases, however, was the stone shown to be composed of oxalate. Gramlo has documented the occurrence of urinary cal- culi composed of oxalate as a dominant trait, but the urinary excretion of oxalate was not measured and the clinical course of the affected members was not similar to that of

--

O The details of this method will be ~ublished a patient with primary hyperoxaluria. The

in a separate communication. authors have been unable to find any re-

-

(Accepted September 15, 1959; submitted May 18.)

This study was supported by the U.S.S. Bremerton Fund, Bremerton, Washington.

ADDRESS: (T.H.S.) Seattle 5, Washington.

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870 HYPEROXALURIA

I

I1

1 2 6

0

7

n3TA

8 9 1 0

m

d t h P T .

5 6 7

-

Mole

-

Female

A

Urine Oxolate Unknown

a

0

Urine Oxalate Normal

O

0

1 2 Urine Oxalote Elevated

.

Dead

+

FIG. 1. Pedigree of family with primary hyperoxaluria. Propositus is 111-7.

ports where hyperoxaluria was expressed dence that the trait is due to a dominant

as a dominant gene. gene. Of the four matings involving an af-

In the present study the presence of fected individual, three yielded affected hyperoxaluria in three generations is evi- offspring (nothing is known about the

TABLE I

- - -- - -- - _-.-

Jlem ber 4 .rle Serum

17car Crine

Male at Cause of Death U r i c

Generation of

Deuth Oxalate

or

Birth or Comme~rts .I r id

Feniale ( Y ? ) ( m g / 1 0 0 n d ) (mg1'4 h r )

I 1. hi 1887 7 1 Coronary occlusion - 6 1 . 4

2. F 1890 33 Childbirth - -

3. h i 1884 55 Heart attack - -

-

Scarlet fever

-

3 offspring, all well

4 offspring, all well N o offspring N o offspring

111 1 . F 1934 - - - -

2. 31 1947 - - -- -

3. P 1929 - - -

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ARTICLES

871

fourth). If the trait were due to a recessive allele, this would require that all three mates of the a£fected individuals b e car- riers of a rare allele, which is highly im- probable. Therefore, inheritance of the dis- order in this family is probably not due to a recessive gene.

If the inheritance of two clinically similar diseases can be shown to differ it might follow that the etiology is different. In comparing the cases studied in detail, and said to b e inherited as a recessive by Archer et al.,' with the present case, the authors are unable to detect any clear-cut clinical differences. However, the laboratory finding of elevated uric acid in the blood in the propositus differed from the findings in Archer's cases.

Of interest, and slightly suggestive of a different mode of inheritance, is the rela- tively high number of affected siblings in the two other families in which elevation of uric acid in the serum has been observed. E d w a r d ~ , ~ in a sibship of six, probably had four affected. In the family of Aponte and Fetter4 three of six siblings had the disease. None of the other generations in these two families has yet been reported to be affected. In the family here reported, the uric acid levels in the serum in the parents and one half-brother of the propositus were normal. Aponte and Fetter observed an elevated level in the healthy father of their patients. The urinary excretion of oxalate, however, was not measured in the parents.

SUMMARY

Hyperoxaluria has been studied in a family and found to b e inherited as a probable autosomal dominant. Only one member of the family developed nephrocalcinosis. The possible existence of a sec-

ond form of hyperoxaluria with elevated concentrations of uric acid in the blood is discussed.

Acknowledgment

The authors wish to thank Dr. Stanley Gartler for his editorial help. Drs. Jerald Hol- man and Lawson Wilkins, who suggested this study, were the first to observe that the urinary excretion of oxalate in the patient's mother was increased.

REFERENCES

1. Shepard, T. H., Creighten, S. A., Krebs, E. G., Lee, L. W., and Thuline, H. C.: Primary hyperoxaluria. Clinical and pathologic findings in a patient with calcium oxalate nephrocalcinosis. PEDI- ATRICS, 25:582, 1960.

2. Chou, L. Y., and Donohue, W. L.: Oxalo- sis: possible inborn error of metabolism with nephrolithiasis and nephrocalcinosis due to calcium oxalate as predomi- nating features. PEDIATRICS, 10:660, 1952.

3. Newns, G. H., and Black, J. A.: Case of calcium oxalate nephrocalcinosis. Great Ormand St. J., June, 1953, p. 40. 4. Aponte, G. E., and Fetter, T. R.: Famil-

ial idiopathic oxalate nephrocalcinosis. Am. J. Clin. Path., 24:1363, 1954. 5. Edwards, D. L.: Idiopathic familial oxalo-

sis. Arch. Path., 64:546, 1957. 6. Godwin, J. T., Fowler, M. F., Dempsey,

E. F., and Henneman, P. H.: Primary hyperoxaluria and oxalosis. New England J.

Med., 259: 1099, 1958.

7. Archer, H. E., Dormer, A. E., Scowen, E. F., and Watts, R. W. E.: Observa- tions on the possible genetic basis of primary hyperoxaluria. Ann. Human Genet., 22: 373, 1958.

8. Burrows, S.: A colorimetric method for determination of oxalate. Analyst, 75: 80, 1950.

9. Brown, H.: The determination of uric acid in human blood. J. Biol. Chem., 158: 601, 1945.

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1960;25;869

Pediatrics

Thomas H. Shepard II, Lou-sein W. Lee and Edwin G. Krebs