E 373 1

OBSERVATIONS ON THE POSSIBLE GENETIC BASIS O F PRIMARY HYPEROXALURIA

BY H. E. ARCHER, A. E. DORMER, E. F. SCOWEN AND R. W. E. WATTS The Medical Unit, St Bartholomew’s Hospital, London, E.C. 1

Primary hyperoxaluria (Archer, Dormer, Scowen & Watts, 1957 a) is characterized clinically by progressive calcium oxalate urolithiasis beginning in early childhood, and biochemically by the occurrence of a continuous high urinary oxalate excretion. Recurrent urinary tract infections, nephrocalcinosis, and renal hypertension ensue, and death occurs in childhood or early adult life. It is necessary to distinguish cases of primary hyperoxaluria from the more common cases of juvenile urolithiasis which are not associated with an elevated urinary oxalate excretion and which do not necessarily carry this bad prognosis. It has been suggested previously that primary hyperoxaluria may result from an inborn metabolic error (Archer et al. 1 9 5 7 ~ ) . If this were so, the condition would be analogous to cystinuria (see for example Harris & Robson, 1957); and to xanthinuria (Dent & Philpott, 1954), in both of which conditions, a biochemical abnormality results in the excretion of large amounts of a relatively insoluble substance in the urine with consequent urolithiasis.

In the present work, evidence of an elevated urinary oxalate excretion has been sought among the relatives of three proven cases of primary hyperoxaluria, in an attempt to establish whether an hereditary pattern is demonstrable in this condition.

METHODS The clinical data pertaining to the propositi of Families 1 and 2 have been reported elsewhere as Case 1 and Case 2, respectively (Archer et aE. 1 9 5 7 ~ ) . The proposita of Family 3 was described by Newns & Black (1953).

Twenty-four-hour urine collections vere analysed wherever possible ; a few individuals de- clined to supply a complete specimen and an early morning urine sample was analysed instead. The urinary oxalate content was determined as described previously (Archer et al. 19576); and the urinary creatinine was determined by a standard procedure (Hawk, Oser & Summerson, 1949). I n an investigation using normal adult subjects (Archer et al. 1957b) the urinary oxalate excretion values did not exceed 40 mg. (COOH), .2H,O per 24 hr., or 0.020 mg. (COOH), .2H,O per mg. urinary creatinine. Higher values for the oxalate/creatinine ratio (up to 0.04) are encountered in normal children (Archer et al. unpublished data).

Information was also sought concerning the cause of death of the deceased members of the families, and of any morbidity which might be ascribed to urolithiasis.

RESULTS Except for the propositi, no abnormally high levels of urinary oxalate have been encountered in the present study (Figs. 1-3, and Tables 1-3). There is no history of consanguinity in any of the families, and among the relatives a history compatible with a diagnosis of primary hyper- oxaluria was obtained only in the brother of the propositus in Family 3 (see also Newns & Black, 1953).

2 5 Vol. 22

374 POSSIBLE GENETIC BASIS O F PRIMARY HYPEROXALURIA

Fig. 1. Pedigree of Family 1.

lkQd I

KEY

Hyperoxrlurla b o p o s i t u s , proposita Stillborn or died In Infancy

d Dead

Figure under is urinary oxalate excretion mg./dry

Fig. 2. Pedigree of Family 2.

I

I -l- I 9kAl 0 9 10 11 12 13 14

1s 21 ~ 10 17 21

Fig. 3. Pedigree of Family 3. The sib of the proposita haa been recorded aa a case of primary hyperoxaluria on the basis of retrospective clinical appraisal only.

H. E. ARCHER AND OTHERS 375

Table 1. Urinary oxalate excretion values together with mortality and morbidity data concerning the members of Family 1 (Fig. 1)

I

I1

History of urinary

tract abnor- mality

I M.

2 F. 3 M. 4 F.

I M. 2 M. 3 M. 4 F. 5 M* 6 F. 7 M. 8 M. 9 M. 10 M. 1 1 M. 12 M. 13 M. 14 F. 15 M. 16 F. 17 M. 18 M.

Urine oxalate

Member, male or female

Year of

birth

Oxdate/ creatinine

ratio (mg./mg.)

Genera- tion Cause of death

I I M. 2 F. 3 M. 4 F.

64 59 75 77

Rheumatic heart disease Bronchitis Carcinoma of prostate ' Senile decay '

None None None None

I877 I 876 I879 I 876

1897 1899 I903 J 903 I905

I933 1941 1935

I1 I F. 2 F. 3 M. 4 M. 5 F.

Alive Alive Alive Alive Alive

13

< 5 28 6

21

0'01 I 0.015

0.0 I 9 0.003

0'001

None None None None None

Yes None None

I11 I M.* 2 M. 3 M.

Alive Alive Alive

I 80-290 35 20

o.oyg---o. 149 OT I 8 0'012

18.29 10.28

0.0113 0.0064

* Proposit,us.

Table 2. Urinary oxalate excretion values together with mortality and morbidity data concerning the members of Family 2 (Fig. 2)

History of urinary

tract abnormality

Urine oxalate

Year of

birth Age death at ! Cause of death

Member, male or female

:enera- I Oxalatel

I 1871

I 870 __ -

66 Chronic bronchitis, diabetes mellitus

Acute pancreatitis Cancer Cancer (throat)

None

None None None

80 81

?

- Alive Alive Alive Alive Alive Alive

Alive Alive Alive Alive Alive

? 30

Alive Alive As a

38

baby

Stillborn - - - - - -

Wounds - - - - -

Pernicious anaemia Staph. pyaemia

- - -

- None None None None None None

None None None None None None None None None

-

-

25. Val. 22

376 POSSIBLE GENETIC BASIS OF PRIMARY HYPEROXALURIA

3;enera- t ion

111

IV

Member, male or female

I M. 2 M. 3 M. 4 If. 5 M. 6 M. 7 F. 8 M. 9 M.

10 M. 1 1 F. 1 2 F. 13 F. 14 M. I S M. 16 M. 17 F. 18 F. 19 M. 20 F. 21 111. 22 F. 23 F. 24 M.

I M. 2 M. 3 M. 4 F. 5 F.

8 F. 9 M.

10 M.

I I M. I 2 F.*

13 M.

{; 5:

14 M. 1 5 M. 16 F. 17 M.

Year of

birth

- - - __ -- __ - 1923 1926 - - 1928 I938 ‘934 1942 I936 I 920 I923

I925

I 898 1902 I993 190.5 1912

I946

-

- 1949 I955 I952 I955 1950 1950 I952

I953

I945

I947

I949

I954

I957 1931 I935

I948

I_

-

Table 2 (cod.)

Age a t death (Year)

Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive

Alive

Alive Alive Alive 14

Alive

Alive

Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive

Alive

Alive

Alive

Alive

Alive Alive Alive

Cause of death

____

History of urinary

traat ibnormalit y

_- Xone None None None None None None None None None None None None None None None None

None

None None None None None

None

None None None None None None None None None None

None

Y 0s

None

None

None None None

Mmn (22) S.D.

Urine oxalate

* Proposita.

H. E. ARCHER AND OTHERS

Table 3. Urinary oxalate excretion values together with mortality and morbidity concerning the members of Family 3 (Fig. 3 )

377

Urine oxalate

Mem-ber , male or female

Year of

birth

Age a t death (Year)

History of urinary tract abnorrnali t,y

>enera- tion

Oxdate/ creatinine

ratio (mg./mg.) _ _ _ _ _ - -

Cause of death

I I M. z F.

Accident Carcinoma of stomitcl:

54 63

38 -

Alive 9 P 34

? Alive

I1 Asthma Heart failure

‘Chest trouble’ ‘Chest trouble’ Osteomyelitis ‘ Chest trouble ’

-

-

None None None None None None None Passed ‘gravel’ I933

I M. 2 M. 3 F. 4 M. 5 M. 6 M. 7 M. 8 M.

I M. 2 P. 3 F. 4M. 5 F. 6 M. 7 M- 8 F. 9 M. 10 F. 1 1 M. 12 F. 13 M.

111 Alive Alive Alive 9

Alive Alive Alive

Alive Alive Alive Alive Alive

I

0’012 0.017 0‘01 1 - 0.005

0.006 0.0 I 3 - - 0.013 0.009 0’0 I2 - -

None None None None None None None None None Recurrent cystitis None Recurrent cystitis 4 History renal colic

Recurrent oxalate

Recurrent oxalate stones

stones -

None None None None None None None None None None None

~~

-

-

- 0‘010 0.007

0.009 0.0 14 0.032 0.009 0.033 0’0 I 0

0.037 0.008

-

(20 ) 0.0140 0.0089

IV

-

I M.

2 F.*

3 M. 4 F. 5 M. 6 M. 7 M. 8 M. 9 M- 10 F. I I M. 12 M. 13 M. 14 M.

1939

I947

I949 1936 I939

I 948 I945 I949 I952 I954 I955 I950 19.55

-

Ursemia -

95-182

- I 3 I 1 - 8

I 5

3 21

I 0 - ‘7 21

8

8

I day Alive Alive 4

Alive Alive Alive Alive Alive Alive Alive Alive

Uraemia

Prematurity - -

Pneumonia - - - - - - - -

Mean S.D.

* Proposite.

378 POSSIBLE GENETIC BASIS O F PRIMARY HYPEROXALURIA

DISCUSSION Some evidence for the view that primary hyperoxaluria is a rare disease has been presented elsewhere (Archer et al. 1957a) and we are only aware of five reported cases in which the con- tention that calcium oxalate urolithiasis was attributable to an elevated urinary oxalate excretion was supported by chemical measurement of the oxalate content of the urine (Newns & Black, 1953; Aponte & Fetter, 1954; Archer et al. 1 9 5 7 ~ ) . Although such terms as familial idiopathic oxalate nephrocalcinosis (Aponte & Fetter, 1954) and familial oxaluria (Myers, 1957) have been used to describe the condition which we term primary hyperoxaluria there have been no previously reported detailed studies of the urinary oxalate excretion by members of the families in which cases have arisen, and in some of the published case reports the clinical data relating to the family history are not presented. Gram (1932) published an extensive pedigree of a family in which a number of cases of calcium oxalate urolithiasis had arisen, urinary oxalate determinations were not performed and as far as can be judged, from the clinical data the cases were not examples of primary hyperoxaluria, although some other possible genetically determined cause cannot be excluded on the basis of the available evidence. A previously unreported family which was grouped by Myers (1957) with the case of Newns & Black (1953) under the title familial oxaluria and in which three members of one generation suffered from renal calculi in childhood was recently investigated in our laboratory. The three affected sibs, their brother, both parents and a paternal uncle were all shown to excrete normal amounts of oxalate in the urine, and it appears, therefore, that these cases should not be regarded as examples of primary hyperoxaluria, a conclusion which is in accord with their clinical progress.

Although the available information is scanty, some preliminary generalizations, which may be relevant to a consideration of the possible hereditary basis of primary hyperoxaluria are permissible: (1) No certain relevant abnormality has been recorded in the parents of any case of primary hyperoxaluria except for the father of Dunn’s (1955) case who had passed a single urinary calculus. Dunn’s (1955) investigation did not, however, include urinary oxalate deter- minations on either the propositus or the relatives. (2) No cases have yet been reported to have arisen from consanguineous parents. (3) Reports of male cases predominate, but affected females seem to suffer from an equally severe disease. (4) Most of the cases have occurred as isolated examples within a family, but Newns & Black (1953) report two affected sibs, in only one of whom was the urinary oxalate measured (see Fig. 3 of the present paper also), Aponte & Fetter (1954) reported affected identical twins in both of whom the urinary oxalate was measured during life together with another presumably affected sib in whom the urinary oxalate was not measured.

These data are compatible with primary hyperoxaluria being due to the operation of a rare recessive character, but in the absence of more evidence for the occurrence of the condition among sibs they cannot be regarded as offering clear-cut support for such a hypothesis.

SUMMARY Primary hyperoxaluria has a characteristic natural history and is delineated biochemically by a continuous high urinary oxalate excretion. No abnormally high level of urinary oxalate has been discovered among the sibs, parents, first cousins, uncles and aunts, and more distant relatives of three proven cases of the condition. Among the deceased relatives a history sug-

H. E. ARCHER AND OTHERS 379

gesting primary hyperoxaluria was obtained only in the case of one sib of one of the propositi. There was no history of consanguinity in any of the families. The bearing of the findings and of the scanty relevant. data in the literature on the postulated hereditary basis of the condition is briefly discussed.

We are indebted to Dr G. H. Newns for his help in tracing Family 3, and to Prof. M. L. Rosenheim and Dr R. E. Bonham-Carter for their permission to study the family which was originally mentioned by Myers (1957). Dr H. Harris kindly read through our manuscript and made a number of valuable suggestions. We are also pleased to acknowledge the assistance of our Senior Technician, Mr. L. Rawlings.

REFERENCES APONTE, G . E. & FETTER, T. R. (1954) . Familial oxalate nephrocalcinosis. A m r . J. Clin. Path. 24, 1363. ARCHER, H. E., DORMER, A. E., SCOWEN, E. F. & WATTS, R. W. E. (1957a) . Primary hyperoxaluria.

ARCHER, H. E., DORMER, A. E., SCOWEN, E. F. & WATTS, R. W. E. (1957b). Studies on the excretion of

DENT, C. E. & PHILPOTT, G. R. (1954). Xanthinuria an inborn error (or deviation) of metabolism. Lancet,

DUNN, H. G. (1955) . Oxalosis. A m r . J . Dis. ChiZd. 90, 58. GRAM, H. C. (1932) . The heredity of oxalic urinary calculi. Acta med. scand. 78, 268. HARRIS, H. & ROBSON, E. B. (1957). Cystinuria. Amer. J . Med. 22, 774. HAWK, P. B., OSER, B. L. & SUMMERSON, W. H. (1949). Practicd Physiological Chemistry, p. 839, 12th ed.

MYERS, N. A. A. (1967). Urolithiasis in childhood. Arch. Dis. Child. 32, 48. NEWNS, G . H. & BLACK, J. A. (1953) . A case of calcium oxalate nephrocalcinosis. Great Ormond St. J .

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5, 40 .