HEREDITARY RENAL DYSFUNCTION AND DEAFNESS

(1)

George Cassady, M.D., Kenneth Brown, M.D., Maimon Cohen, Ph.D.,

and William DeMaria, M.D.

I)iike Uniuersitij Sc/tool of ?ttedicine, Department of Pediatrics, Dmi rliam . North Carolina (171(1 \(ltionai Iim.stitutt’ of Dental Research, II,, man Genetics Section,

National InStitUtes of Health, Bethesda, Ztlaryland

(Submitted September 28; revision accepted for publication December 27, 1964.)

PRESENT ADDRESS: (CC.), Department of Pediatrics; University of Alabama Medical College,

Birming-ham 3, Alabania; (KB.), Human Genetics Branch. National Institute of Dental Research, National

Institutes of Health, Bethesda 14, Maryland; (MC.), Department of Hum:mn Genetics, University of

Michigan School of Medicine, Ann Arbor, Michigan; (W.D.M.), Department of Preventive Medicine,

Duke University School of Medicine, Durham, North Carolina.

This was presented, ill part, at the 31st annual meeting of the Society for Pediatric Research

on May 4, 1961, in Atlantic City, New Jersey.

PEDIATRICS, June 1965

HEREDITARY

RENAL

DYSFUNCTION

AND

DEAFNESS

967

D

UR1NG the past decade increasing

re-ports have reached the medical litera-ture describing a remarkable familial illness characterized by chronic renal disease and defective hearing. We have had the

oppor-tunity to follow more than twenty families

with this syndrome for periods of time

rang-ing from a few months to six years. Four hundred seventy-six members of seven of these families have been studied in

suffici-ent detail to permit analysis of the clinical findings. In our experience this disorder rep-resents a considerable portion of childhood “chronic nephritis,” and the apparent

in-frequency of the syndrome appears to

rep-resent not an absolute rarity of the disorder bitt rather a general ignorance concerning

its widely variable clinical picture. \Ve pre-sent our six years experience with this

dis-ease as an attempt to define these clinical parameters more clearly.

REVIEW OF THE LITERATURE

lleritable renal disease was frequently

discussed in the medical literature of the

Past century.1 In the early 1900’s, Cuthrie

and others24 reported a family with

hema-tuna similar to those already in the

litera-ture. The distinctive feature of this family

was discovered twenty-five years after the

original report when Alport5 first noted

deafness. The earliest contemporary reports of the syndrome were by Perkoff, et al.,e,

who studied 217 members of a single fam-ily; 205 of these were personally examined

by the Salt Lake group. The final clinical

picture that evolved from this remarkable

study#{176} was quite similar to that of the

Guy’s Hospital family.2u Two important

ad-ditions were the observations of pyuria as

a significant urinary finding and the de-scription of the “forme fruste” (termed by Perkoff the “carrier state”) using the

audio-gram as a diagnostic tool.

The eye defects occasionally reported as part of this syndrome have usually been

lens l 1 but nystagmus,

strabis-mus, myopia, and retinal detachment have

also been 15 Most reported

fami-lies, however, have not been noted to have ocular defects, and the importance of eye anomalies as primary components of the

syndrome has not been confirmed. An im-portant finding, the frequent occurrence of a severe form of otitis media, was reported

by Poli1#{176}and has been noted by other

aim-thors’5 1-S

Laboratory investigations of the syn-drome have been rather sparse and

unpro-ductive. Increase in the alpha-2 globulins

in affected family members was initially suggested by the work of Chappell, et al.,hl

and apparently confirming observations have been recorded.1 21) Absence of amino-aciduria in several reported famihiesl5,17, 20.31

(2)

FAMILY I - D KINDRED

:I

T

LFUUO I

t t t t

III

,, t “I

t

PROPOSITUS DIED

+

,;1 0 D .

00

0

C

EXAMINED

FEMALE - APPARENTLY NORMAL

MALE -APPARENTLY NORMAL

AFFECTED - RENAL DISEASE

DEAF

INFANT/NEONATAL DEATHS

MISCARRIAGE - UNKNOWN SEX

RENAL DISEASE AND DEAFNESS

PROBABLY AFFECTED-RENAL DISEASE

Fic. 1. Family 1-D.

V

IV

III

I’

II

40

30

t

FIG. 2. Family 2-NI kindred.

968 RENAL DYSFUNCTION AND DEAFNESS

and the defect in amino acid metabolism in Schafer’s family1 represent a coincidental, unrelated metabolic error in a family with

the renal disease and deafness syndrome.

Knowledge of the pathology of this

dis-t

4-k’

c

p ease appears to be equally unsettled;

path-ologic studies on younger individuals dying with the disorder have generally been

in-terpreted as showing glomerulonephritis,

while in older individuals the interpretation has been pyelonephritis. Although “foam

cells” have been demonstrated at autopsy in some patients with the disease,6’ 12 their

non-specific nature has been conclusively demonstrated by Whalen, et

FAM ILIES

The first family was seen six years ago at

Duke Hospital (Fig. 1). This small kindred,

(3)

IV

III

II

Ftc. 3. Family 3-H kindred.

ARTICLES

V

Renal Clinic in less than one year, are of Anglo-Saxon descent, and are located in

North Carolina. The fifth family (Fig. 5), of German heritage, was found when the

ProPositits was hospitalized at the National

Institutes of Health for study of apparently unrelated gout.0 Most members of this family have resided in western Virginia for the past six generations. Family 6

(

Fig. 6)

is also Anglo-Saxon and is located in

south-em Florida. Family 7 (Fig. 7) was originally reported by Sturtz and Burke;17 IS through their co-operation and interest, we were able to considerably extend their clinical observations.

0 Our thanks to Drs. J. E. Seegmiller and R. R.

howell, National Institute of Arthritis and

Meta-holic Diseases, National Institutes of Health, for the

opportunity of studying this patient and his family.

All but a few instances of this syndrome

in the literature have been presented as

single family reports. In the majority of

these families, investigation did not extend past the immediate sibship of the

proposi-tus. An initial, major goal of our study was to investigate as many members of each

generation as possible. Minimal geographic migration enabled us to largely achieve our goal with these seven families.

METHODS

The first portion of the study was carried

out by repeated field trips. Family history was taken in detail by one of the authors

(M. C.); medical history was obtained by questionnaire with investigation and

(4)

V

III

II

I,

FIG. 4. Fanmily 4-C kindred.

included blood pressure, otoscopic and

funduscopic inspection; in the great

ma-jority a more complete examination was

performed. Blood was obtained on 90% of examined family members, the sera sepa-rated and stored at - 30#{176}Cuntil analyzed.

Urine was collected in wax containers, spec-imens centrifuged l)y standard methods,3 and sediment examined microscopically by

one of the authors (C. C. or K. B.) no later than 90 minutes after passage. Audiograms

were obtained in a quiet bitt not

sound-proof room in family members over 3 years

of age.#{176}Although background noise may produce specious hearing loss at low

fre-quencies, it does not mask significant

hear-ing loss at higher frequencies.

Electrophoresis of serum proteins and

lipoproteins was performed in our

labora-0 Maico Portable Audiometer, Model MA 2B.

tories with standard methods.’ 20 All other laboratory studies were performed by the Clinical Pathology Department of the Na-tional Institutes of Health, employing meth-ods standard in that department.

A detailed in-hospital evaluation of renal

function was 1)erfOrmed on 14 family

mem-bers.

DEFIN ITIONS

RENAL I)YSFUNCTION-freslily collected,

centrifuged urine containing more than

three red cells per HPF and/or more than

five white cells per HPF. Abnormal Addis count or pathologic evidence of renal

dis-ease was accepted as evidence of renal

dys-function. Isolated proteinuria or

uncon-firmed history of renal disease were not

considered diagnostic of renal dysfunction.

(5)

synony-VI

V

IV

III

II

dri

-

--Jj iji iii ji Jill

It t t t

Fie. 6. Family 6-B kindred.

FIG. 5. Family 5-K kindred.

mous with renal dysfunction; affected fam-ily members were so classified on the basis

of urine findings.7 Exceptions to this rule included a few family members diagnosed

as affected when renal dysfunction was

dis-covered in both a parent and a child of the

subject in (luestion.

Difficulties inherent in diagnosing the

IV

V

syndrome on a single clinical finding were

considerably increased by the vagaries of random urinalysis ; these prevented defini-tive initial diagnosis in many patients. On

repeat urinalysis it was striking that almost

all borderline cases were eventually

diag-nosed as affected. In a number of

(6)

VI

FIG. 7. Family 7-E kindred.

not l)Ossil)le. Classification of this suspicious group as affected is uncertain and arbitrary; their contrary inclusion into the normal

group is equally incorrect, and this dilemma prompted formation of a probably affected

group. Exclusion of this group from our

calculations probably results in some bias

toward underdiagnosis.

OTITIs MEDIA-a severe, refractory form

of the disorder often associated with

per-foration, frequently persisting into adult life and resulting in severely scarred, opaque

drums.

REFRACTIVE ERRORS were nearly all

myo-pie and our use of the term refers to myopic

refractive error of greater than two diopters

as determined l)y funduscopic examination.

We use the term deaf in preference to

hearing impairment only for convenience;

the clumsiness of the latter and the

prece-dent established in previous literature re-ports of this syndrome has caused us to

re-tam the term. Objectively, we mean by “deaf” either clinical impairment of hearing

or documented audiometric deficit of 20 decibels or greater at 4,000 cycles per

see-ond or more.

RESULTS

Clinical Findings (Table I)

HEARING: More than half of our males

and one-third of our females with the

(7)

af-TABLE I

CosIeAmt.TIvE FREQUENCY OF CERTAIN CLINICAL FINDINGS IN AFFECFED VERSUS NON-AFFECTED

INDIVID-UAL.S (PROBABLY AFFECTED PATIENTS ALSO SHOwN). SIGNIFICANCE LEVELS RF:FER TO X2 RKsumrs BETWEEN AFFECTED AND UNAFFECTED GROUPS WIThIN SEXES

(‘linical Finding

Mak8 Females

-1. 3()Probably 74

.4ffeeled .1ffec1ed Unaffected

85 .lffected Probably Affected 111 Unaffected l)eaf Cataracts Refractive error Otitis Illedia 47 (55%) 4 (5%) 28* (33%) 22 (26%) 24 (69%) 0(0%) 14 (40%) 13 (37%) 5 (5%) 0 (0%) 20 (18%) 17 (15%) 55 (39%) 11 (8%) 55t (39%) 54t (38%) 13 (43%) 0 (0%) 11 (37%) 10(33%) 5 (7%) 0 ((1%) 16 (22%) 14(18%) ARTICLES

* p= <.05. t p= <.01. p= <.001.

fected patients (otitis in 38% of affected with

normal audiograms and 48% of affected with

abnormal audiograms). Although conduc-tive (low-tone) deficit was seen on a number

of audiograms, the nerve (high-tone) deficit always constituted the major impairment.

Important differences between affected

individuals with hearing impairment and those with apparently normal hearing are

shown in

Table

II. The

older

mean

age

of

the deaf affecteds appears to be explained in Figure 8 which shows the progressive

in-crease with age of the proportion of affect-eds who manifest deafness. We suspect the

less linear progression with age of male as compared to female deafness is a result of the earlier onset of severe disease in the males and rather larger number of male deaths early in life.

EYE DEFECTS: A significant increase in

myopic refractive errors was present in af-fected family members. Cataracts were found in only four affected males; in two

instances they were first noted during a

terminal episode of uremia. The other two

males with lens opacities were elderly (ages 62 and 76). Excepting a 23-year-old girl with a unilateral cataract, the mean age of

affected females with cataract was 68 years

(range 48 to 94 years).

OTITIS MEDIA: An increased incidence of

otitis media in affected family members was suggestive in affected males and statistically significant in affected females.

OTHER FINDINGS: Growth retardation of

moderate degree and retarded eruption of

permanent teeth* were inconsistently

pres-ent in a few children with severe renal

im-pairment. External ear malformations were

not unusually frequent. Hypertension (dia-stolic > 100) was noted in about one-third of affected males (28/85) and one-fourth of affected females (37/141). Half of all af-fected individuals enjoyed according to

their knowledge excellent health at the time

of our study (“asymptomatic,” Table II).

In-hospital Evaluation

Table

III presents findings in fourteen affected members representing four families.

0 Dental exams performed by the courtesy of

Drs. Carl Witkop and Robert Wolf, National

In-stitute of Dental Research, National Institutes of

Health.

TABLE II

COMPARATI yE FREQUENCY OF CERTA IN CimNI(AL

FIND-1NGS iN DEAF AFFECTED VEIIsI’s NON-DEAF AFFECTED

INDIVIDUALS Clinical . . Finding .Ifalea Ermalea 47 Deaf Affected , 38 ?Son-Deaf Affected Deaf A.ffcted , 86 ZSop,-Deaf Affected

Mean age (yr)

(8)

100

-80

60

40

20

FEMAL ES

MALES

p::;

64#{176}/a

0- I9 20-39 40-59 60 & over

AGE

33#{176}/c

I0O/4

0-19 20-39 40-59 6O over

AGE

MALES FEMALES

974 RENAL I)YSFUNCTION AND DEAFNESS

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Ftc. 8. Proportion of affected population deaf-by generation (per cent).

These I)atients represent the clinical

spec-trum of hereditary renal dysfunction from

the asmptomatic ‘oman with persistently

normal random urinalyses and audiograms

(B. K.) to a young father studied during his terminal uremic episode

(

0. H.).

The most sensitive early index of renal impairment in this disease appears to be

the Addis count, but degree of renal

impair-ment seemed to be most accurately

pre-dicted l)y inability to conserve water in the

face of dehydration. Using the standard

12-hour dehydrating period and employing

urine specific gravity as an index of urine

osmolarity, the maximum urine concentra-tion tended to reflect the general degree of

clinical impairment. Retention or impaired clearance of urea nitrogen and creatinine

were not sensitive parameters of renal

func-tion in this syndrome. No alterations in total

serum protein or cholesterol were noted, and serum electrolytes, calcium, and

phos-phorus were abnormal only with marked

renal impairment (not in Table III).

In the course of the in-hospital studies,

we consistently observed steady improve-ment in several parameters of renal func-tion; most striking was the decrease in cells

Fat;. 9. Characteristics of abnormal urinalysis in affected family menlbers.

Key : RBC, iSOlItte(l hematuria; \VBC, isolated 1)Yuri1; \VBC and RBC, both henlaturia and l)vuria;

prottill, isolated 1)roteilluria; cells and 1)rotein, red and/or white cells in ad(lition to prot(in increased

(9)

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BUN. ( reatinine

Ine acid ( Iiolesterol

tOtal protein (g”’)

Itch, (;an)ma .Ipla’ Alpha’ Albumin l’ercentage a I.ih)iprotein

Affected No. t7laffeeled No. Affected No. Unaffected

Females No. .54 .57 61 63 60 60 61) .59 .59 .59 16.0 (±0.6)

0.9l (± 0.03)

.5.36 (±0lI) 148.0 (±3.0)

7.14 (±0.11) 1.10( ± 0.0-1)

0.65 (±0.(fl)

0.39 (±0.0)

0t7 (± 0.01)

4.38 (± 0. 09)

72 76 81 8 82 82 82 Si 81 13.7 (±0.1) 0.71 (±0.02)

4.02 (± 0.17)

216.0 (± 5.0)

7.25 (±0.03)

1.01 (± 0.03) 0. 66 (± 0. 02) 0. 38 (± 0. 02)

0.27 (± 0.01)

4.74(±0. 08) 102 92 95 109 110 105 105 105 104 104 14.5 (±0.4)

0.76 (± 0.02)

4 .27 (±0. 16)

244.0 (±6.0)

7.12 (± 0.05) 1.11 (± 0.04) 0.64 (± 0.02)

0.57 (± 0.02)

0.26 (± 0.01)

4.5 (± 0.01) 47 41 38 44 45 43 43 43 43 43 16.9± 1.5 12.1 (±0.3)

0.66 (± 0.02)

3.70 (± 0.17)

209.0 (±7.9)

7. 14 (± 0. 13)

1.06 (± 0.05) 0.67( ±0.03)

0.58 (± 0.03)

0.27 (± 0.01)

4.52 (± 0.09)

26. 8 ± I .6 107 20.4± 1.2 44 26.8±2.8

TABLE IV

MEAN VALUES OF LABORATORY RESULTS (STANDARD Etotoas)

Significtnt difterence hetvecr iffecIed md utiafleeted males at 0.05 level of prohability.

and prtei11 in the urine. OIl the other hand,

110 significant changes were observed in

renal concentrating ability. No bed rest or

active limitation of activity was imposed on

any patient, and no dietary restrictions were

initiated during the period of

hospitaliza-tion.

Laboratory

URINE: The predominance of the red

cell as the major abnormal element of af-fected male urine and the similar position of the white cell in the affected female urine

is shown in Figure 9. These white cells may have been due to contamination as “mid-stream” specimens were not collected; that they did not represent infection is shown by the results of 58 urine cultures obtained

on 24 affected patients. Ten males had 19

negative cultures. Fourteen females

had

34

cultures; 3 of these females had 7 postive

cultures; in one of these women positive

cultures followed urinary tract

instrumenta-tion. No unusual bacteria were isolated; all

cultures for tubercle bacillus and fungi

were negative.

All l)ut one of 26 intravenous pyelograms ol)tained on affected family members were classified as normal.

BLooD: The inability of usual laboratory tests of renal function to separate affected

family members from their normal peers is

striking. (Table IV). A statistically

signifi-cant (p < .05) decrease in serum lipoprotein migrating in the alpha fraction was

ob-served in affected individuals. Anti-human kidney antibodies were tested for using the

method of Kramer, et None were

de-tected in any of 92 affected family members

whose sera was examined.0

Deafness

COMMENT

A characteristic bilateral high-frequency nerve deafness is an integral component of the syndrome. Presence of hearing deficit is

of great diagnostic

aid

in the isolated case,

but its absence must not rule out

considera-tion of the syndrome; normal hearing in al-most half our patients with renal disease

emphasizes this fact. In our experience the

audiogram has been most useful as a diag-nostic tool in affected females in whom the

renal disease may be mild in nature and the

high-tone hearing impairment subclinicalt and of delayed onset. Extensive use of the audiometer has demonstrated a higher

pro-0 Performed through the courtesy of Dr. N.

Kramer, Department of Medicine, George

Wash-ington University School of Medicine, Washington,

D.C.

I

A high-tone hearing deficit involving

fre-quencies well above conversational range may he

(11)

ARTICLES

portion of affected females with hearing deficit than has previously been appreciated.

The prognostic importance of deafness in predicting more severe and rapidly

progres-sive renal impairment is real and appears to be equally significant in both sexes. Serial

audiograms in three of our patients (7-V-53, 7-IV-110, 1-IV-1) demonstrated the progres-sive course of hearing impairment com-patible with historical evidences from other

family members and data from the

litera-ture.

Otitis Media

The demonstrated association of severe, recurrent otitis media with hereditary renal

disease is puzzling. Because of the lack of similarity between this renal disorder and poststreptococcal acute glomerulonephritis, we doubt the otitis represents a primary

streptococcal infection leading to

subse-quent glomerulonephritis. We have no

in-formation concerning middle ear or eusta-chian tube malformations in these patients. The absence of increased susceptibility to infection in our patients with hereditary

renal disease and normal gamma-globulins in their electrophoretic patterns makes

un-likely the possibility of decreased immuno-logic protection in this group.

Eye

The small proportion of our affected pa-tients with cataracts, the advanced age of most members of the cataract group, and the presence of uremia in most of the few

young members of this group have led us to

suspect that any increase in cataract

mci-dence above that found in a general popula-tion is secondary to changes brought about

by renal failure. Although refractive error

was significantly associated with renal

dys-function, our means of diagnosing this pa-rameter were rather crude and we encour-age scepticism concerning a real

relation-ship. Suggestions that frequent renal

mal-718 mental retardation/i or “lop

ears”#{176}may be components of this syndrome have not been confirmed by our work.

Laboratory Results

We have conclusively demonstrated

nor-mal total protein and cholesterol in this disease and protein electrophoretic studies in more than 140 patients have failed to confirm alterations in the alpha-2 fraction,

as suggested by Chappll, et a!.

The percentage of total lipoprotein

mi-grating as the “alpha” fraction is

signifi-cantly less in affected than in normal family

members. This difference may be more

ap-parent than real for several reasons: (1) The

normal family member group was

signifi-cantly younger than the affected group. An

apparently decreased proportion of alpha

lipoprotein is normal with increasing age,

largely as a result of an absolute rise of

those lipids migrating in the beta fraction.

(

2) Electrophoresis results are expressed as

a proportion of total, and our data do not

allow calculation of absolute lipoprotein

values. A substantial absolute decrease of

the alpha lipoprotein fraction should result

in a significant change in the total

choles-terol. Absence of a lowered cholesterol in our affected individuals, in spite of a

(Ic-crease in alpha lipoprotein by

electrophore-sis, suggests alteration in the B/ ratio,

which, in view of the age difference

he-tween the affected and normal groups,

is most likely due to increasing B lipopro-teins with age. Further investigations of the

lipoprotein fractions in hereditary renal

dis-ease and deafness by ultra-centrifugal

tech-niques appear to be necessary in order to

clearly resolve these questions.

Laboratory evaluation of the individual

patient has been unrewarding as a

diaglios-tic tool. Most important in diagnosis of the

syndrome is a careful search of fresh,

con-centrated urine and painstaking, detailed

family history. Our experience with this

disease has demonstrated the major

impor-tance of the following diagnostic criteria:

(

1) evidences of renal dysfunction (repeated urinalyses and determination of concentrat-ing ability are of particular value), (2)

high-tone hearing deficit (the audiogram may be

(12)

otitis media, (4) positive family history

(

members of each generation with

combina-tions of these findings). \Ve have come to

suspect the presence of this disease in any

patient with a positive family history who manifests one or more of the other crite-na.

Our data permit no postulation as to the

origin or pathophysiology of this disorder. Our speculations have centered about

simi-larities of this syndrome to two changes commonly observed in those who do not have this familiar affliction:

1. Worsening of urinary sediment

abnor-malities with body stress due to infection

or strenuous exercise in patients with this

syndrome max’ merely represent an

exag-geration of the same phenomena

docu-mentedo in individuals from unaffected

families. The origin of this finding in those individuals is unknown.

2. The patient with renal disease and

deafness seems less strange when compared

with a normal peer who has received

strep-tomycin, polymyxin, or a similar polypep-tide antimicrobial. Mechanisms of renal and inner ear damage produced by these drugs are unknown, hut the temporary nature of their toxicity to the normal kidney,#{176} the role that duration of treatment plays in

their ill effects, and the prevention of nephrotoxicity in animals pretneated with

methyl-donor aminoacids2 suggest th at further work in this area might lead to bet-ten understanding of hereditary renal dis-ease and deafness.

SUMMARY AND CONCLUSIONS

For the past six years we have been

en-gaged in the study of 476 members of seven families with hereditary renal disease and deafness. \Ve have been profoundly im-pressed with the commonness of the syn-drome arid by the wide spectrum of clinical findings with which the disorder may

pre-sent. \Ve have often uncovered the

syn-drome successfully mimicking acute and

chronic nephritis and pyelonephnitis in

university hospitals and schools for the deaf,

and we suspect a much greater frequency than is generally recognized.

The

clinical features of families with this disorder are remarkedly similar in spite of

the broad clinical spectrum of the disease in individual patients. This had led us to con-sider the syndrome as a single disease state.

Males with deafness in the first two dee-ades of life have more severe renal

impair-ment, and risk of early death is mitch higher

in this group. A significant number of males

were found to have little hearing

impair-ment early in life and, although urinary

sediment abnormalities were present, to run a more chronic course. Late in life this

group has unequivocal evidences of renal disease and progressive hearing impairment, but a shortened life span does not seem to be characteristic. Urinary sediment in both

groups of males is characterized by red

cells; proteinuria and

(

less frequently)

pyunia are sometimes associated with the

hematuria, and on rare occasion isolated

pyuria may be present. Otitis media is

sug-gestively but not significantly increased in

our affected males; eye defects, particularly

myopic refractive errors, are significantly increased in the affected females.

No single, simple diagnostic test has been

found. The importance of a careful history and repeated urine examination and a high index of suspicion when these techniques reveal abnormality has been shown, and

certain clinical criteria for diagnosis which have proven of value have been offered.

REFERENCES

1. Pel, P. K. : Die Erhlichkeit der (hronischen

Nephritis. Ziet. KIm. Med., 38:127, 1899.

2. Guthrie, L. C. : “Ideopathic” or congenital

hereditary and family haematuria. Lancet,

1:1243, 1902.

3. Kendall, G., and Hertz, A. F. : Hereditary

fa-milial congenital haemorrhagic nephritis.

Guy’s Hosp. Rep., 66:137, 1912.

4. Hurst, A. F. : Hereditary familial congenital

haemorrhagic nephritis. Guy’s Hosp. Rep.,

73:368, 1923.

5. Alport, A. C. : Hereditary familial congenital

haemorrhagic nephritis. Brit. Med. J., 1:504.

(13)

ARTICLES

6. Perkoff, C. T., Stephens, F. E., Dolowitz, D.

A., and Tyler, F. H. : A clinical study of

hereditary interstitial pvelonephritis. Arch.

Intern. Med., 88:191, 1951.

7. Stephens, F. E., Perkoff, G. T., Dolowitz,

D. A., and Tyler, F. H. : Partially sex-linked

dominant inheritance of interstitial

pyelo-nephritis. Amer. J. Hum. Gen., 3:303, 1951.

8. Perkoff, G. T., Nugent, C. A., Dolowitz, D. A.,

Stephens, F. E., Cames, W. H., and Tyler,

F. H. : Folow-up study of hereditary chronic

nephritis. Arch. Intern. Med. 102:733, 1958.

9. Perkoff, G. T. : Biology of Pyelonephritis

(Henry Ford Hospital International

Sym-posium). Edited by E. L. Quinn and F. H.

Kass. Boston: Little, Brown, 1960, pp.

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Pediatrics

George Cassady, Kenneth Brown, Maimon Cohen and William DeMaria