FABRY'S DISEASE Canad. Med. Ass. J.206 HENRY AND RALLY: Aug. 3, 1963, vol. 89

The difficulty in identifying the site for puncturein obese subjects has already been mentioned.

It must also be remembered that the iliac crestis covered by 0.5 cm. to 1 cm. of cartilage (Fig. 4)until centres of ossification appear at puberty, con-verting it to bone which may be occasionally verysclerotic. We obtained from children several biop-sies consisting entirely of hyaline cartilage beforewe realized how difficult it was to penetrate thismaterial in such subjects.

ComplicationsThe only complication of Silverman biopsy of the

iliac crest that we have encountered has been mildlocal discomfort, which has usually subsided within

24 hours. The danger of breaking the biopsy bladeshas been mentioned, but we are not aware that anysuch case has been described in the literature.

REFERENCES

1. MCFARLAND, W. AND DAMESHEK, W.: J. A. M. A., 166:1464, 1958.

2. PEARSON, H. A., MCFARLAND, W. AND CONE, T. E., JR.:Pediatrics, 26: 310, 1960.

3. CONRAD, M. E., JR. AND CROSBY, W. H.: J. Lab. Olin.Med., 57: 642, 1961.

4. BRODY, J. I. AND FINCH, S. C.: Amer. J. Med. 8ci., 238:140, 1959.

5. BIERMAN, H. R. AND KELLY, K. H.: Blood, 11: 370, 1956.6. LEY, A. B., PRENDERGAST, R. A. AND HARTMANN, W. H.:

Med. Olin. N. Amer., 45: 553, 1961.7. RUBINSFEIN, M. A.: J. A. M. A., 134: 55, 1947 (abstract).8. SIFFERT, R. S. AND ARKIN. A. M.: J. Bone Joint Surg.

[Amer.], 31.A: 146. 1949.9. TURKEL, H. AND BETHELL, F. H.: J. Lab. Olin. Med., 28:

1246, 1943.10. RHEINGOLD. J. J., WEISFUSE, L. AND DAMESHEK, W.:

New Engi. .1. Med., 240: 54, 1949.

The Renal Lesion in Angiokeratoma Corporis Diffusum(Fabry's Disease)

E. W. HENRY, M.D., F.R.C.P.[C], and C. R. RALLY, M.D., F.R.C.P.[C],Vancouver, B.C.

.RIGINALLY considered to be only a derma-'Jtologic curiosity, angiokeratoma corporis dif-fusum is being increasingly recognized as ageneralized disease which may cause prolongeddisability and premature death. Its characteristicfeatures are: (1) a more or less specific skin rashand (2) cardiovascular, renal and nervous systemabnormalities associated with the accumulation ofphospholipid material in ganglion cells, vascularendothelium and smooth muscle of arterial walls,heart muscle cells, and renal glomerular and tubularepithelial cells.The disease is hereditary and, in the most recent

and extensive study of 21 cases in eight families byWise, Wallace and Jellinek,1 is considered to de-pend on a sex-linked gene with occasional pene-trance in the heterozygous female and constantpenetrance in the homozygous male subject. Theclinical features are considered in detail and theliterature on the subject is exhaustively reviewedin the report by Wise and his colleagues.Fabry is credited with first describing the skin

lesion in 1898 and was responsible for the some-what cumbersome name of the disease (alterna-tively it is known as Fabry's disease). Ruiter,2 whohas written extensively about the condition, hascriticized this diagnostic term 'because "the lesionsare probably not angiomata; the hyperkeratosis isprobably only of subordinate importance and thespread cannot be considered diffuse".

From the Department of Medicine. University of BritishColumbia, and the Vancouver General Hospital.

ABSTRACT

Electron microscopic details of theglomerular and tubular lesions in a 26-year-old man with angiokeratoma corporis dif-fusum are presented. Though unable toconcentrate urine above a specific gravityof 1.012, this patient showed preservationof the ability to acidify and alkalinize theurine following oral loads of ammoniumchloride (150 mEq./day) and sodium bi-carbonate (158 mEq./day) for several days.This observation is in contrast to previouslyreported findings and suggests that theregularly observed hyposthenuria in thisdisease does not depend on defects in iontransfer in the distal tubule system.

The purpose of this report is to present a caseand to discuss briefly the clinical manifestationsand, in more detail, the alterations in renal histo-logy and function.

CAsE HISToRY

The patient, V.F., was a 26-year-old fisherman at thetime of this investigation. Between the ages of 6 and 9years he had 'several attacks consisting of a severeburning sensation over the soles of both feet, associatedwith aching of the legs, malaise, nausea and vomiting.At the age of 11 and again at 13 he had attacks of

Canad. Med. Ass. J.Aug. 3, 1963, vol. 89 HENRY AND RALLY: FABRY'S DISEASE 207

Family history.-His mother and father were bothalive and well at 55 years of age. Both were normal onphysical examination and had normal urinalyses. Fourbrothers and three sisters were alive and well. Onematernal aunt had multiple sclerosis.

Physical examination revealed a muscular, intel-ligent young man with slightly puffy eyelids and staringeyes. The conjunctival veins showed areas of con-striction and bulb-like dilatation. Very superficial, fine,greyish-white radiating corneal opacities were visiblewith the slit lamp. His blood pressure varied from100 70 to 120/80 mm. Hg. A soft pulmonary systolicmurmur was audible only in the supine position.Moderate ankle edema was noted. Angiokeratomatawere present on the buttocks, thighs, scrotum andlower half of the trunk. They were 1 to 2 mm. indiameter, deep red to black, elevated, and occasionallyscaly, and did not fade on pressure. Some of the skinof the thighs and scrotum had a roseate appearancedue to a more diffuse telangiectasia. On the skin of theright lower extremity there were large circumscribedbrown patches several inches in diameter with super-imposed angiokeratomata, and on the vermilion borderof the lower lip numerous, 0.5 to 1 mm., red, flat,petechia-like lesions.

Laboratory data on admission.-The hemoglobinlevel was 13.8 g. %; microcytes were observed in theperipheral blood smear; the white blood cell count was4100k c.mm.; ESR 14 mm. in 1 hr. and platelet count321,000 c.mm. Bone marrow examination was un-remarkable. His blood urea nitrogen was 10 mg. %;serum uric acid, 4.0 and 6.2 mg. % on two estimations;and the serum cholesterol level, 186 mg. %. Electro-phoresis of plasma proteins showed no abnormality.The urine showed 1+ to .± protein, a maximum spe-cific gravity of 1.012; white cells, red cells and granularcasts in the urinary deposit; and no fat droplets onmultiple examinations. Various organisms were culturedfrom the urine, including Staphylococcus aureus,Streptococcus fecalis, coliform organisms and Proteusmirabilis. The intravenous pyelogram showed poor con-centration of dye but no other abnormality. The retro-grade pyelogram was normal. His chest radiographshowed a cardiothoracic ratio of 14.5/31.0 cm. andprominence of the left ventricle. His electrocardiogram(EGG) was abnormal, and probably indicative of leftventricular hypertrophy. The electromyogram showeda "tendency to polyphasic motor unit action potentials"but was otherwise normal. Normal mineralization ofspine was apparent radiologically. His electroencephalo-gram was normal.

During a febrile episode the urine was examined forhemoglobin, myohemoglobin, porphyrins and 5-hydroxyindoleacetic acid with negative results. Duringtwo attacks, T-wave inversion in the EGG was notedin Leads II, III, AVF and V5 and V6. The serumpotassium estimated on one of these occasions was3.5 mEq. 1. Seven days later the T-waves were againupright in the above leads, but the serum potassiumlevel had not changed significantly (3.6 mEq./l.).

Sweat test.-Moderately heavy sweating occurred onraising the body temperature to 99.60F. with hot waterbottles and blankets. Sweating commenced after 15minutes and was generalized. Several hundred sweatglands were seen under a standard coverslip placed onthe chest or quadriceps, after the dry skin had beencoated with starch and iodine powder. Administrationof 0.375 mg. carbachol subcutaneously was followed

208 HENRY AND RALLY: FABRY'S DISEASE

within five minutes by a great increase in salivationand sweating.Kidney function tests.-Phenosulfonphthalein (PSP)

excretion at 30 minutes was 51% (normal). The endo-genous creatinine clearance was 105 ml./min./1.73 in2; inulin clearance (GIN) was 112 ml./min./1.73in2 and para-aminohippuric acid clearance (CPAH)was 804 ml./min./1.73 in2.

Methods and TechniquesNeedle biopsy of the kidney was carried out using

the Franklin-Silverman needle with the patient in theprone position, after the method of Kark andMuehrckeY Tissue obtained was fixed for one hour at40'C. in buffered osmic acid, pH 7.4. The material wasthen embedded in methacrylate after alcohol dehydra-tion. A few blocks were embedded in Araldite epoxyresin. Sections were cut at it'. for the light microscopeand stained with a modified hematoxylin and eosin stainor with periodic-acid Schiff (PAS). Thin sections wereexamined unstained in the electron microscope.The urine specific gravity determinations .vere made

graviinetrically using the Westphal balance, while theurinary ammonia determinations were performed usingVan Slyke and Cullen's aeration technique fo1lo.ved bynesslerization.

Chloride determinations were carried out accordingto Asper's modified mercuric nitrate-diphenylcarbazoneprocedure,4 and the titratable acidity at pH 7.4 by amodified method, after Peters and Van Slyke.5

DISCUSSION

General Features of Angiokeratoma CorporisDiffusumThe foregoing case history illustrates most of the

important features of this disease. The diagnosis isusually made from the characteristic skin rash.Ruiter's description of the rash is as follows2: "Thelesions are purple red or dark blue to black, some-times leaden-hued spots or small papules hardlyraised above the surface, which are spread in vary-ing density over large parts of the skin, particularlythe skin of the trunk. In some cases lesions havealso been seen on the oral mucosa. The eruption isstrikingly monomorphous and the lesions tend tooccur in local crops. Sites of predilection are: thelumbosacral region; the umbilical region; the in-guinal folds; the buttocks, thighs and genitals; thelatter are often the site of the first lesions" (i.e. thedistribution is 'between navel and knees') (Fig. 1).Microscopicially the skin lesions are not trueangiomas but telangiectatic vessels in the papillarydermis lined by a single layer of endothelium.Keratosis is variable (Fig. 2).The diagnosis is confirmed by demonstration of

lipid material in the walls of blood vessels. Thismay be possible in the dermis (Fig. 3), though notregularly, since the amount of tissue in the ordinaryskin biopsy is small. Lipid material has also beendemonstrated in the smooth muscle cells of thearterial media, for example, in intercostal and othermedium-sized arteries; in heart muscle; in ganglioncells of the central nervous system and peripheral

Canad. Med. Ass. J.Aug. 3, 1963, vol. 89

Fig. 1.-The left buttock (subject V.F.) showing typicaldark red to black, pinhead-sized angiokeratomata, groupedaround the lateral end of the gluteal fold.

plexuses; and in epithelial cells of the renalglomeruli and tubules, especially Henle's loop andthe distal convoluted tubules. Analyses which havebeen carried out indicate that the material is aphospholipid related to, but differing in certainrespects from, sphingomyelin.The clinical picture produced by visceral involve-

ment has been described by many authors.' Somemanifestations may be due to the lipid infiltrationof epithelial cells and others to reduction in arterialblood supply associated with the vascular changes,but much of the symptomatology is poorly under-

Fig. 2.-Photomicrograph of an angiokeratomatous skinlesion (stained with hematoxylin and eosin (H & E) andmagnified X 100). The lesion consists of a vascular spacelined by a single layer of endothelium. There is a minordegree of hyperkeratinization of the overlying epidermis.

Canad. Med. Ass. J.Aug. 3, 1963, vol. 89 HENRY AND RALLY: FABRY'S DIsl..sE 209

Fig. 3.-Photomicrograph of a small blood vessel in thedermis (stained with PAS, magnified x 1000). PAS positivegranular material is present in the cytoplasm of the endo-thelial cells.

stood. Pain is a prominent feature in the majorityof cases and may be very severe. It is commonlyreferred to the limbs and its distribution bears norelationship to the skin rash. The nature of the painwas discussed in detail by Wise et al., who con-cluded that it probably arises at the peripheralnerve endings. Premature cerebral vascular diseasewith strokes occurring at an early age, even innormotensive persons, has been described. Super-ficial corneal opacities demonstrable with the slitlamp have been found regularly when sought.Beading of the conjunctival and retinal veins alsooccurs; later, hypertensive changes in the fundi maybe superimposed. Diarrhea and bleeding hemor-rhoids occur with increased frequency. Strangely,though the telangiectases have been described inthe bowel mucosa at autopsy, significant bleedingfrom sources other than hemorrhoids has not beendescribed. Arthropathy of the terminal inter-phalangeal joints of the fingers is not uncommonand avascular necrosis of the head of the femur hasoccurred, presumably owing to ischemia from thevascular lesion.Moderate normocytic or hypochromic anemia is

not uncommon. Lipid-filled cells may be seen onbone marrow biopsy. Vacuolated reticuloendothelialcells have also been seen in lymph nodes, liver andspleen at autopsy. Pyrexial episodes, often asso-ciated with exacerbations of pain, are common andsome defect of the heat-regulating mechanism isvery often present. There may be hypohidrosis orexcessive sweating. General malaise and attacks ofgiddiness, headaches and weakness with little ob-jective evidence of disease may lead to the patient'sbeing given a "psychoneurotic" classification.Chronic leg edema without hypoproteinemia is acommon manifestation; occasionally edema may bemore widespread. Varicose veins occur in about aquarter of patients. Cardiac involvement may besecondary to hypertension, or due to lipid depositsin the myocardium, or secondary to "premature"coronary artery disease. The incidence of asthmaand emphysema is apparently increased in patientswith this disease.

The Renal LesionAngiokeratoma corporis diffusum shortens life

expectancy. The average age of 19 patients atdeath was 42 years, with a range of 30 to 54 years.'The most frequent cause of death is uremia due

to renal injury, with or without hypertension. Pro-teinuria probably occurs sooner or later in the greatmajority of patients.. The usual sequence of thedisease in males is: first decade-development ofthe skin rash; second decade-onset of proteinuria;fourth or fifth decade-uremia. The protein leak isvariable, ranging from a trace to 3 g. or more perlitre, but sustained heavy losses do not occur andthere is no hypoalbuminemia. The urine sedimentmay contain an excess of red blood cells, white cellsand hyaline or granular casts. Lipid globules, whichmay be extracellular or intracellular ("fat cells"),may be found and are more characteristic than theother cellular elements, but these may also occurin other conditions associated with lipid accumula-tion in tubule cells, e.g. the nephrotic syndrome.Loss of concentrating ability with resultant polyuriaand possibly nocturia is a fairly early feature of therenal lesion and may constitute the most definiteevidence of chronic renal disease, along with per-sistent abnormalities in the urinary sediment andperhaps only a trace of proteinuria.

Renal BiopsyThe typical renal biopsy findings are illustrated

by material obtained from our patient. Allglomeruli showed a fine vacuolation of the epi-thelial cells in alcohol-fixed sections which gavethem a "foamy" appearance (Figs. 4 and 5). Therewas no basement membrane thickening in PAS-stained sections (Fig. 6). This finding was alsoconfirmed by electron microscopy. Many cells inthe distal convoluted tubules and loops of Henleshowed a similar change, whereas cells in theproximal tubule showed no significant abnormality.

Fig. 4.-Photomicrograph of renal biopsy specimen (stainedwith H and E, magnified X 200). The glomeruli fill Bow-man's capsule and there is a loss of the normal "tufted"appearance. Endothelial cells are swollen and appear "foamy"or vacuolated. The capillaries contain red blood cells innormal numbers.

210 Henry and Rally: Fabry's Disease Canad. Med. Ass. J.Aug. 3,1963, vol. 89

Fig. 5..Photomicrograph of renal biopsy specimen (stainedwith H and E, magnified X 600). Enlargement of a segmentof glomerulus showing more clearly the foamy appearanceof the endothelial cells.

Though no sizable vessels were present in thesesections, the interlobular arteries have been de¬scribed as showing intimal thickening with edemaand degenerative changes in the medial musclewhich contained foam cells.4 These changes havebeen held responsible for wedge-shaped scars in

Fig. 7..Photomicrograph of renal biopsy specimen (con-voluted tubule, stained with PAS, magnified X 1200). Thereis no thickening of the basement membrane of the tubule.PAS-positive granular material is present in the cytoplasmof the tubular epithelial cells. The appearance of disruptionof individual cells is probably due to artefact.

vealed further resolution of these bodies, whichhave an interesting "lamellar" pattern after prepara-tion for this examination (Figs. 8-10). Thesecharacteristics are compatible with a phospholipidcomposition.

Fig. 6..Photomicrograph of renal biopsy specimen (glo-merulus, stained with PAS, magnified X 1200). There isno thickening of the capillary basement membrane (con-voluted line). PAS-positive material is present in finelygranular and in larger spherical aggregations in this fairlyseverely damaged glomerulus.

the renal parenchyma which have been noted inestablished cases and are presumed to be ischemic.The pathology, in patients dying in uremia, is com-

plicated by extensive scarring and superimposedhypertensive changes.The lipid infiltrate described is more or less

specific for Fabry's disease. Very occasionally amilder degree of lipidosis with a few foam cells inthe glomeruli may be seen in subjects with a severe

nephrotic syndrome or the xanthomatoses. Thelipid material has been shown in several instancesto be doubly refractile and to have the stainingcharacteristics of phospholipid.2' 6

Staining of biopsy material from the patient de¬scribed in this report showed that the material intubular epithelial cells was both osmophilic andPAS-positive (Figs. 6-10). Electron microscopy re-

Fig. 8..Electron photomicrograph of renal biopsy specimen(glomerulus, magnified X 12,000). Absence of thickening ofthe basement membrane of the glomerular capillaries isconfirmed. A lamellar structure apparently corresponding tothe PAS-positive material in Fig. 6 is seen toward the lowerleft corner.

Renal Function

Apart from general observations of the degreeof protein leak, the presence of impaired con-

centrating ability and the extent of azotemia, thereappear to be only three cases in the literature onwhich fairly detailed renal function studies werecarried out. One of these was studied by Fessas,Wintrobe and Cartwright7 and two by Colley et al?As would be expected, the usual indices of renalfunction, such as endogenous creatinine, inulin andPAH clearances, seem to agree fairly well with thedegree of destruction of the renal parenchyma,when this can be assessed from bicrpsy or autopsy.However, de Wardener's group,6 noting the regularearly loss of concentrating ability, suggested that

HtNI.Y AND RALLY: FABRY'S DISEASE 211

'1

Fig. 9.-Electron photomicrograph of renal biopsy specimen(convoluted tubule, magnified X 27,000). A portion of anucleus is present at the top. Two small granules are seenconsisting of laminated osmiophilic material, enclosed by asingle membrane. Numerous mitochondria are present andsome show swelling. No transitions between mitochondriaand laminated bodies can be seen.

this might be due specifically to the distal tubulepathology. They also found that their first casefailed significantly to increase urine titratable

Fig. 10.-Electron photomicrograph of renal biopsy speci-men (detail from convoluted tubule, magnified x 40,000).Further detail of structure of granules in convoluted tubularepithelial-cell cytoplasm showing the lamellated appearance.

acidity or NH4+ excretion following oral ingestionof 150 mEq. of ammonium chloride daily for fivedays and suggested that this too might indicateimpaired distal tubule function.

Unfortunately their 38-year-old male patient was

FEB. 3/61 FEB. 4 FEB. 5 FEB. 6

I I

CL _______

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60 MEQ/DAY 62 MEQ 76 MEQ 94 MEQ 05 MEQA _______________

URINE VOLUMEML/HR

212 HENRY AND RALLY: FABRY'S DISEASE

URINE VOLUMEML/HR

I .CURINE S.G.RANGE I.C

I .C

URINE pHRANGE

SERUM NaMEQ/L

SERUM KMEQ/L

SERUM CIMEQ/L

150 [

1401-

120 I-

110

100 I-

URINE NaMEQ /DAY

URINE KMEQ/DAY

URINE CIMEQ/DAY

Canad. Med. Ass. 3.Aug. 3, 1968. vol. 89

URINARY AMMONIUM . -TITRATABLE ACIDITY U 100

MEQ/DAY

WHOLE BLOOD pH 7.4 ____

41HEMATOCRIT .38 ____ ____

35

77WEIGHT 74

KG 71

NH4CI NaHCO3150 MEQ/D 158 MEQ/D

Fig. 12.-Diagram showing day-to-day variation in the indices noted on the left hand sideduring: (a) 7-day period on demand diet only, (b) 6-day period ammonium chloride 150 mEq./day added. (c) 4-day period on diet only, (d) 6-day period sodium bicarbonate 158 mEq./dayadded, and (e) demand diet only. The total period of study occupied 33 days. Where severalvalues were obtained during 24 hours, as in the case of urine specific gravity and urine pH,they are expressed as a range with a vertical line joining the minimum and maximum values.

in the late stages of renal disease with moderateazotemia and malignant hypertension at the time

of the study, and autopsy not long thereafter re-vealed the expected extensive renal damage.

Canad. Med. Ass. J. HENRY AND RALLY: FABRY'S DISEASE 213Aug. 3, 1963, vol. 89

Therefore one might more reasonably attributethese deficiencies to advanced renal disease. Never-theless it was considered worth while to checkthese findings in our patient with his less severedegree of renal damage; the results of these in-vestigations are presented in Figs. 11 and 12. Thediurnal pattern in the rate of urine formation wasrather variable, the maximum rates of excretiontending to occur in the afternoon and evening. Thisis similar to patterns recorded in many individualswithout renal disease who have been studied bysimilar methods in this hospital.The urine specific gravity, accurately recorded

by a gravimetric method, fell as low as 1.003 duringperiods of peak urine flow. However, it is of con-siderable interest that at no time during the 33-daystudy did the specific gravity rise above 1.012.Unfortunately, methods of determining the urineosmolality were not available at the time of thisinvestigation.

Diuresis occurred .vith administration of bothammonium chloride and sodium bicarbonate,though to a greater degree with the former. Apredominant chloruresis was observed coinci-dentally with the ammonium chloride administra-tion, and predominant natriuresis with sodiumbicarbonate. Presumably an increase in urinarybicarbonate excretion occurred with the latter, butit is not recorded.The urine PH, which varied between 5.3 and 6.1

during the four days preceding acidification withammonium chloride, fell as low as 4.8 on the thirdday of ingestion and remained around 5.0 to 5.4for the remainder of this period.The urinary ammonium excretion rose steadily

from a mean level of 70-80 mEq./24 hours duringthe four days preceding NH4C1 loading to aplateau at around 200 mEq./24 hours on the fifthand sixth days of administration. Urinary titratableacidity increased following ammonium chlorideadministration, but to a much lesser degree. The in-crease in H + ion excretion during this period failedto account quantitatively for the amount ingested,but during the four days succeeding termination ofthe period of acidification the ammonium excretionremained above resting levels.

Coincident with sodium bicarbonate ingestionthere was a marked increase in urine pH whichreached the range of 7 to 8 for the last three daysof this five-day period. Urinary ammonium excre-tion, which, as has been noted, had not yet returnedto normal, was rapidly and dramatically reduced toa negligible amount within two days. Titratableacidity fell to 0, and on the third to fifth days freeOH- ion was present, presumably associated withbicarbonate excretion.The 24-hour K+ elimination parallelled the urine

volume excretion except in period (d) where the

low daily excretion in the face of a moderatediuresis and large natriuresis could be interpretedas indirect evidence of decreased aldosteronesecretion in response to a large Na+ intake.Changes in the serum levels of Na+, K+ and

C1 during the study were recorded. Balancestudies were not carried out. The blood pH showedsome alteration in the expected directions. Thehematocrit was of approximately the same value atthe end as at the begining of the study.There was a slight steady weight loss throughout

the 33-day period.

CoNcLusIoNsIt is concluded that the lack of concentrating

ability in angiokeratoma corporis diffusum is notrelated to any obvious disability in electrolytetransfer in the distal tubule system. In particular itis not necessarily associated with a defect in abilityto acidify or alkalinize the urine (in interesting con-trast to the findings in primary hyperaldosteron-ism).

Failure of the patient to develop a more con-centrated urine than that indicated by a specificgravity of 1.012 might be taken to indicate either(1) that the distal tubule and collecting ductepithelium had become relatively insensitive toantidiuretic hormone (ADH) or (2) that waterreabsorption was occurring under adequate ADHstimulation but in the absence of an osmoticgradient in the medullary interstitium.

Unfortunately no direct or indirect evidence ofthe level of ADH secretion is available.

SUMMARY

Angiokeratoma corporis diffusum (Fabry's disease)is a sex-linked hereditary disorder occurring princi-pally in males. The disease is manifested by a character-istic skin rash and by serious, progressive, systemic dis-ease usually leading to a fatal outcome in the fourth orfifth decade of life, the course being singularly uninflu-enced by treatment to date. Impairment of renal func-tion is the commonest cause of death. A case has beenpresented and the nature of the renal lesion in this andin other reported cases has been discussed.

The laboratory data were determined and the two graphsproduced by the G. F. Strong Laboratory for MedicalResearch under the direction of Professor K. A. Evelyn.The authors are indebted to the Pathology Department,

Vancouver General Hospital, and Dr. W. H. Chase for thephotomicrographs and electron photomicrographs.

REFERENCES

1. WIsE, D., WALLACE, H. J. AND JELLINEK, E. H.: Quart.J. Med.. 31: 177, 1962.

2. RUITER, M.: Milestones in Dermatology. Excerpta Med.(Amst.) 1959. Sect. xiii, 2: 61.

3. KARK, R. M. AND MUEHRCKE, R. C.: Lancet, 1: 1047, 1954.4. ASPER, S. P.. JR., SCHALES, 0. AND SCHALES, S. S.: J. Biol.

Chem., 168: 779, 1947.5. PETERS, J. P. AND VAN SLYKE, D. D.: Quantitative clinical

chemistry, Vol. 2, Methods, Williams & Wilkins Com-pany, Baltimore, 1932, p. 827

6. COLLEY, J. R. et al.: Brit. Med. J., 1: 1266, 1958.7. FEssAs, P., WINTROBE, M. M. AND CARTWRIGHT, G. E.:

A.M.A. Arch. Intern. Med., 95: 469, 1955.