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FAMILIAL

INTRAHEPATIC

CHOLESTASIS

WITH

MENTAL

AND

GROWTH

RETARDATION

Richard C. Juberg, M.D., Roxie M. Holland-Moritz, M.D., Keith S. Henley, M.D.,

and Carlos F. Gonzalez, M.D.

-Departments of Human Genetics, Pediatrics, and Internal Medicine (Section of Gastroenterology),

The University of Michigan Medical School, Ann Arbor, and

The St. Clair Clink, St. Clair, Michigan

(Received March 2; accepted for publication June 2, 1966.)

Supported in part by the Children’s Bureau, Department of Health, Education and Welfare (R.C.J.),

by an Institutional Grant to the University of Michigan from the U. S. Public Health Service, by Public Health Service Research Grant 5-MO1-Fr-42-05 from the Division of Research Facilities and Resources to the Clinical Research Unit, University of Michigan, and by a Research Career Development Award of the National Institutes of Health to one of us (K.S.H.).

ADDRESS: (R.C.J.). Department of Pediatrics, West Virginia University, Morgantown, West Virginia

26506-PEDIATRICS, Vol. 38, No. 5, November 1966

819

T

HE purjose of this communication is to

describe a severe form of cholestasis beginning in infancy, apparenfly progres-sive in nature, and resulting in significant impairment of growth and development in four siblings. The evidence which suggests a genetic basis for this disorder is present-ed.

Case 1

CASE REPORTS

The proposita (IV-37 in Fig. 1) was born at

term on March 28, 1956, and weighed 3.3 kg

(7/io lb). During pregnancy the mother did not

receive tranquilizers, antibiotics, or blood

trans-fusions. The mother had never been jaundiced.

Hospital records show no indication of jaundice in the baby in the neonatal period, and when she was

discharged at 3 days of age, normal brown stools

were noted. Urinary color was considered to be normal. The baby was well until between 3 and

4 months of age when the mother noted a large

abdomen, a change in stool color from yellow to light gray, darkening of the urine, and scratching so that excoriations resulted. Although the mother

had not noticed any change in skin color, an

ex-amining physician said the baby was jaundiced. She had had an upper respiratory tract infection for 1 month prior to an episode of vomiting, which

prompted her first hospitalization at 53i months

of age. At admission she was very irritable, there was mucopurulent nasal discharge, and coarse rhonchi were heard bilaterally. The abdomen was

very distended, and, during the examination, a large, foul smelling stool was observed. She ap-peared malnourished and there was evidence of weight loss. Neither liver nor spleen was found to be enlarged. The groin and buttocks were red, and it was evident that the baby was in severe

discomfort with prunitus, particularly in the groin

but also over the entire body. In addition to the values in Table I, the red blood cells (rbc) were

noted to be hypochromic, there was no

eosino-philia, and the urinalysis showed no abnormality. Vhile in the hospital, she developed numerous, dime-sized hemorrhages on her back. A diagnosis of food allergy was made following elimination of some foods, and she was discharged when fin-proved on a soy bean milk formula plus vitamins

C and D.

At 6% months epistaxes and further bruising de-veloped with another upper respiratory infection. This led to admission to another hospital. She ap-peared acutely ill with fever, pallor, epistaxis,

scat-tered bruises, grunting respirations, and marked

abdominal distention. Her weight was slightly

be-low the 3rd percentile ( > 2 SD below the mean).

She was mildly jaundiced and the spleen was felt

1 cm below the left costal margin, but the liver

was not felt at the time of admission (Table II). At

the time the blood was typed as ABO group B and

Rh type C positive, D positive (the Rh typing

was later shown to be incorrect). The direct

Coombs test was negative. The clotting time was 180 minutes; the bleeding time was 1.5 minutes; the prothrombin time was prolonged; and she

was anemic. There was moderate anisocytosis, and

a few target cells were noted on two different

specimens. The bleeding stopped within 24 hours

after transfusion of 200 ml B positive blood and administration of vitamin K1 oxide. Prothrombin time was then normal. A diagnosis of pneumonia

was made, and she was treated with penicillin,

oxytetracycline, and streptomycin.

Mild jaundice continued with frequent scratch-ing. The red blood cell fragility test was normal. Following a subsequent rise in the white blood cell count (WBC) and a fall in the hemoglobin con-centration, she was treated with penicillin, tetra-cycline, and chloramphenicol. Bacillus proteus was

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DMale OFemale

O Sex unknown

U Intrahepatic cholestasis with mental

and physical retardation Cholangiolitis and cholangitis

B Normal liver function studies

Miscarriage

t Deceased

KINDRED 9000 HEREDITY CLINIC UNIVERSITY OF MICHIGAN

FIG. 1. Pedigree of the B. family. Dotted line indicates illegitimacy.

Ill

IV

TABLE I

HEMATOLOGICAL, CALCIUM, AND PHOSPHORUS VALUES OF THE FOUR AFFECTED SIBLINGS AND

THEIR MATERNAL AUNT

.

Patient Age gin/1 Hb WBC/mm3

Plateleti 1mm3

Prothrombin Time Sec

Ca ing/100 ml

P ing/100 ml

IV 37

mo

6-84 mo

81--lO4mo

21 mo

3yr

Syr

8yr

9yr

10.8

8.0_1.8*

10.7_13.5*

7.8

10.0

7.0

9.4

8.7

14,400

1,000_9,50*

9,600_19,000*

28,700

8,000

3,750

adequate

496,930

adequate

288,0O0

108 (is)f

11.7(1.8)t

78%

15.4 (13.0)t

11.2 5.6

8.6 7.5

IV-38

7mo 64yr

7yr

74yr

12.4

12.2

12.5

13.4

9,500

adequate

12.4 (13.0)t

13.8(12.0)t 10.5 8.2

IV-41

3 yr

34yr

4yr

13.5

14.0

7,850 adequate 13.1 (13.0)t

13.0(11.5)t 11.8 5.5

IV-42

lSmo

21 mo 2yr

11.5

9.2 10.7

9,850 adequate 15.1(13.0)t

14.2(11.5)t 10.7 7.4

111-27 28 yr 14.7 74%

* Range during hospitalization.

t Control.

(3)

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0-* Dr. Jean H. Webster, Petoskey, Michigan, personal communication.

HISTOLOGICAL OBSERVATIONS OF LIVER Biosiics OF THE Fouit AFFECTED SIBLINGS AND THEm MATEIINAL AUNT

Patient Age Type of

Bzop.y findings

IV-37

10 mo

9 yr

Surgical

Needle

Hepatic cells show coarse granulations on a clear backgroun(1. There are mmri-able degrees of pericanalicular brownish green pigmentation and some

caitali-cular plugging. Stains for hemosiderin, lipofuscins, melanin, and ceroi(l are

negative. liOn, fibrous strands, confirmed by Massoifs trichrome stain, ex-tend out from the portal areas and central veins. Focal close approximation of

several triads. Occasional focus of mononuclear infiltrate and fibrosis suggest

repair of necrotic focus. Indistinct interlobular bile ducts, often with

incon-spicuously collapsed lumina and irregularly flattened epithelia.

Diagnosis: Suggestive of congenital hypoplasia in asmall amount of material

Fragmented tissue without representation of portal areas. Bile pigment and

canalicular plugging more prominent than previously. “Feathery

degenera-tion,” multinucleation and cytomnegaly more prominent than previously.

Diagnosis: “Intrahepatic cholestasis.”

IV-38 74 yr Needle

Very adequate biopsy specimen. Normal radial parencilymal architecture of the liver lobule is not present and while central veins are easily found and

dilated, the triads are inconspicuous, and only rare interlohular bile ducts are

found. Intracanalicular bile stasis is accompanied by pigmentation of par-enchymal cells. Cellular unrest and multinucleatiomi of liver cord cells with

occasional megalocytic cells. Focal necrosis in the lobules. Prominent

glyco-gen in the nuclei.

Diagnosis :“Intrahepatic cholestasis.”

IV-41 4 yr Needle

Compared with the three siblings, this patient has the least stasis alid cell

pigmentation. Portal areas less well defined than would be expected for this age. Dearth of bile ducts.

Diagnosis: “Intrahepatic cholestasis.”

IV-42 2 yr Needle

Mild but evident bile stasis in canaliculi. Like the other three siblings, portal spaces are small and compressed with a paucity of interlohular bile ducts.

Pigmentation of parenchymal cells and “cellular unrest.” Absence of normal

radiating lobular architecture and many cord cells assume a pseudoductular

arrangement. Thin fibrous bands traverse and accentuate lobules. Focal

cellular necrosis. Prominent glycogen in nuclei.

Diagnosis: “Intrahepatic cholestasis.”

Summary: Similar changes with variable degrees in all four siblings. Bile stasis in canaliculi seen in all, most evident in IV-37, least in I\’-41. Pigment (bile and lipofuscin) is also seen in all four, least evident in 1\’-41. Cellular unrest with multinucleated (up to 4 and 5 nuclei) cells and some megalocytic parenchymal cells in all, least evident in IV-41. Normal lobular radiation is not seen and interlobular bile ducts are rare to absent.

111-27

I

28 yr

“In the liver biopsy specimen the liver cord cells are markedly swollen with

cytoplasmic granules and the sinusoids are compressed. In several irregular areas there are collections of lymphocytes and these appear to be arranged

Needle around small bile ducts. There are three areas where there is some reactive

fibrosis around bile ducts. Lipid vacuolization of liver cords is seen in

approxi-mately 10% of the cells.

(5)

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The WBC continued between 12,000 and

22,000/cu mm, the latter associated with

eosino-philia of 14. Examination of the stools for trypsin activity was positive. Escherichia coli was cultured from the pharynx on two occasions. Cytological

examinations of two different urine specimens for

cytomegalic inclusion bodies were negative, but

cultures were not attempted. Acholic stools were never seen, but the urine was consistently

posi-live for bile. The reticulocyte count did not

ex-ceed 3sf. Radiological survey of the long bones was negative. The nonprotein nitrogen was

re-ported between 31 and 40 mg/ 100 ml.

During the 2 months of hospitalization, her

liver size fluctuated from 13i cm to 5 cm below

the right costal margin. Pruritus persisted. She

was also treated with erythromycin and mycosta-tin. Developmentally, she was not able to sit alone at 8 months, but she could roll over and reach for objects. She remained below the 3rd percentile in

weight.

The child was transferred to the University of Michigan Hospital for a liver biopsy, which was

performed on January 15, 1957 (Table III and Fig.

2 and 3). At operation the liver edge was sharp

and located 2 cm below the right costal margin.

The gallbladder contained a small amount of light brown bile. The extrahepatic biliary ducts were found to be normal, and the operative

Fic. 2. IV-37. Masson’s trichrome stain of liver.

Well developed bile duct from surgical biopsy

at 10 months.

Fic. 3. IV-37. H. and E. stain of liver. Chronic inflammatory cell infiltrate in Parc11ckY1a from

surgical biopsy at 10 months.

cholangiogram demonstrated a normal extrahepatic

system with ready spill of contrast material from

the gallbladder into the duodenum. A small lymph node was removed and showed chronic

hvper-plastic lymphadenitis without evidence of a spe-cific chronic infective granuloma. Postoperatively

her course was uneventful, except that she

ap-peared more jaundiced and was febrile for several

days, although the wound did not heal com-pletely for 9 months. Urinalyses were repeatedly

normal except for the presence of bile. Stools

were now clay colored. Bromsulphalein (BSP) in-jected intravenously did not appear in the feces.

Her pruritus (lid not improve with antihistaminic and cholagogic drugs. She was discharged without

a definitive diagnosis.

In the 7 years between the first and second ad-missions to the University Hospital, there were nine hospitalizations for either pneumonia, otitis

media, or furunculosis. On each occasion jaundice

was more evident with the associated infection. In December 1957, at the age of 21 months,

anemia was treated with 250 ml of blood. Sodium concentration of sweat was 22 meq/l. Bleeding from the ear in March 1959 was treated with 5

(6)

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Fic. 5. IV-42. II. and E. stain of liver. Periportal fibrosis froln I)erc11t1neous biopsy at 23 ears. the right costal margin. The spleen was just

pal-pable. The fingers and hands were short and stubby vith thick, coarse wrinkled skin (Fig. 6).

Nail development of the toes was poor.

Tuberculin and histoplasmin skin tests were negative. Examinations of urine for phenlpsTuvic

acid and acid mucopolvsaccharide were negative.

Hvpochromic anemia with depression of granu-locytes but not of platelets WaS noted. The reti-culocyte count was 2.2i. The radiological bone

age was 3 to 33& s-ears. Ceruloplasmin

concen-tration in the serum was “noniial.” The intelli-gence quotient was 67 by the verbal (Stanford-Binet Form L-M) and the nonverbal (Leiter In-ternational Perforlllance Scale) tests.

Culture of the peripheral blood revealed that the chromosome nulliber was 46 in 26 cells

cx-aniined. Five cells ere selected for detailed an-alvsis and studs-. Each of these cells contained 16 chromosomes in Group C (6-12-X) and 4

chromosomes in Group G (21-22-Y), which is

nor-ma! for a female. There was no evidence of structural abnormality (such as, translocation or

deletion). No structural variation, which might

be considered a marker and thus followed in the family, was found.

In September 1964 she s-as admitted to a local

FIG. 4. IV-37. II. and E. stain of liver. Bile throm- hospital because of a urinary tract infection. The bus and accumulation of bile pigment from per- stools were positive to guaiac, but

roentgenologi-cutaneous biopsy at 9 years.

The stools, which had been bulks’ and loose, im-1roved in consistency on a low fat diet.

At 4 years when admitted to another hospital,

she was just recovering from “3-day measles” and had signs of an upper respiratory tract infection.

She was jaundiced, and her skin was excoriated

from scratching. The liver was palpated 5 cm

be-low the right costal margin, and the spleen was

again felt just below the left costal margin. Warty

growths were present on the vulva and in the perianal region, which were large enough to inter-fere with defecation. Examinations of the urine

for bile remained positive.

At 5 years, she was operated upon for an

in-cisional hernia and an abscess at the site of the original biopsy.

\Vhen readmitted to the University hospital in

May 1964, her weight and height were both

mark-edly less than the 3rd percelltile. The head

circurn-ference was 48.5 cm (19.1 in.) and the chest cir-cumfercnce was 60 cm (23.6 in.). She presented an unusual facial appearance because of a small,

round head, round face, prominent bulging eyes,

and slightly bulging cheeks. She could only walk

slowly, often needing support, and she could not

run. Iler gait was widely based, and she showed

genu recurvaturn. Her hair was -er fine and light

(7)

FIG. 6. IV-37. Hands at 9 years showing short, stubby appearance with thickened skin and convex

nails.

I

ARTICLES

cal examination of the esophagus for varices was reported to be negative.

In May 1965 she was admitted to the Clinical Research Unit of the University Hospital. She was

just over 9 ears of age, and recently six per-manent incisor teeth had erupted. The heart was questionably enlarged by percussion, and a systolic

murmur (grade 1 of 4) was heard along the lower

left sternal border and considered to be func-tional. The liver was palpated 63i cm below the

right costal margin and the spleen was palpated 23i cm below the left costal margin. The gallblad-der did not visualize following ingestion of Tele-paque. BSP retention increased from 13.5 at 45

minutes to 25% at 120 minutes. This raises the

possibility that sonic conjugated BSP was released

from the liver into the blood stream rather than

being excreted in the biliary system. A percutan-eous liver biopsy was performed (Fig. 4). The

child was discharged on a regime of oral iron,

water soluble vitamins, and cholestvramine (% teaspoonful three times per day which was

in-creased to 3i and then 1 teaspoonful three times per day). The latter drug was stopped after 1 month because the mother noted no diminution

ilL scratching. Subsequent experience with other children suggests that the starting dose aS too small. Response to the iron therapy was nOt

evalu-ated.

\Vhen last seen at the age of 9I2 years, she could not stand without support, although she was attending school in an ungraded class. The

liver was palpable 5 Clii below the right costal margin and the sl)leen was palpable 4 cm below

the left costal margin. The photographs of Figures 7 and 8 were taken at this age and show the proposita and her three affected siblings, to be described, compared with their three normal siblings.

Case 2

IV-38 (Fig. 1), a sister of the proposita, was born on October 13, 1957, after 63 months of

-

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FIG. 7. B. sibship. From the left, the proposita (IV-37) at 91#{176}jvr, affected sister (IV-38) at 8 yr,

nor-mal brother (IV-39) at 73 yr, normal sister (IV-43) at vr, normal brother (IV-40) at 6h yr, affected

(8)

Fic. 8. B. sibship. Same order as in Figure 7. Note leaning stance of the proposita.

gestation and weighed 1.36 kg (3 ib). The mother had ingested no drugs. Icterus was noted at age

48 hours, at which time she was having normal

meconium stools. On this same date, a papular

rash was noted over her trunk which disappeared

within 48 hours. She received penicillin for 4 days and ox-gen for 7 days. When 9 days old, because

of increased jaundice, increased lethargy, and

reddened umbilicus, she was given oxytetracycine.

The total bilirubin was 11 mg/100 ml, and blood

culture showed hemolytic staphylococcus, coagu-lase positive. There was no major blood group incompatibility, and the direct Coombs test was negative. She received a total of 70 ml blood after

the hemoglobin concentration decreased to 6.7 gm/100 ml at 5 weeks of age. There was no

nota-tion of jaundice after 11 days of age, normal

brown stools were noted, and urine color was normal.

The history of her illness is similar to her older

sister’s. Pruritus appeared at 4 months, and she

also scratched until she bled. Her urine had been

noted to be unusually deep yellow, but the stools were not light colored. Her abdomen was noted to

be large. The parents became concerned when she failed to gain weight, and an intravenous

pyelo-gram (IVP) at age 7 months was normal. She did

not appear jaundiced (Tables I and II). Four

urinalyses were examined specifically for inclusion bodies, but none were seen. She had rubella at 18 months.

She was hospitalized elsewhere at 21 months to investigate the severe growth retardation. She weighed 4.8 kg (1019i6 lb). She had sat unsup-ported at 14 months, and by 21 months she was

able to pull herself up to stand but could not walk. There was Inarked wasting of the face, ex-tremities, and buttocks with a distended abdomen

and prominent superficial abdominal veins. There was no intra-abdominal fluid and no

hepato-splenomegaly.

There was no retardation in bone age. Hilar calcifications were seen in the roentgenogram of

the chest, but tuberculin and histoplasmin skin

tests were negative. Sodium concentration of sweat was 36.4 meq/l. Blood urea nitrogen (BUN) was 13 mg/100 ml. A trace of bile was reported in

the urine on one occasion. An oral glucose

toler-ance test showed a maximum increase of 40 mgI

100 ml above the fasting level at 2 hours. A

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827

found to be low and she was treated with a

modified celiac diet, vitamins, and pancreatin. By 2% years she weighed 6.8 kg (15 lb) The

color of her skin was sallow with scattered ex-coriations. The abdomen was protuberant, the

liver was palpable 3 cm below the right costal

margin, but the spleen was not felt. Warty growths were noted in the perineum and, especially, in the perianal region. By this time she walked with

support but did not talk. She learned to walk

Un-aided at 3li years. At this time she was reported to have loose stools, which were light in color, and

her urine was darker than normal.

Before her admission to the University of

Michi-gan Hospital for the first time in May 1964,

treat-ment with bile salts was reported to have in-creased the color of her stools. The urine was said

to be brown intermittently. For the first time,

she was noted to be jaundiced by the parents.

At 63i years she was noted to be constantly scratching, and the skin showed many

excoria-tions (Table I). Her weight and height were less

than the 3rd percentile. The abdomen was en-larged, and the liver was palpable 3 cm below the right costal margin. Slight clubbing was present.

Her posture was lordotic.

Tuberculin and histoplasmin skin tests were negative. There was no defect of urinary concen-trating ability and no albuminuria. Urine tests

for phenylpyruvic acid and acid

mucopolysac-charide were negative. The bone age was less than 2 years. Bone marrow morphology was normal. By

the verbal and nonverbal tests, her I.Q. was 62.

At 73 years her eyes were less prominent. A

cardiac murmur was considered to be functional. The spleen was not palpable, and the liver was

difficult to define. Her stool, the darkest in color of the four affected children, was negative to

Fouchet’s reagent for bile pigments. There was faint visualization of the gallbladder by oral

chole-cystography. Following ingestion of fat, the

shadow was denser but still faint. The BSP

re-tention was 15.5% at 45 minutes and 16.% at 120 minutes. Percutaneous liver biopsy was per-formed. She was discharged on a regime of choles-tyramine (li teaspoonful three times per day which

was increased to 3i and then 1 teaspoonful three

times per day) and water soluble vitamins. The former was discontinued after 1 month, and the mother reported no diminution in scratching.

When last seen at the age of 8% years, the liver

margin was indistinct, and the spleen was not

palpated. She did not have the ambulatory diffi-culties of her sister. She had not been experienc-ing much pruritus, but she has not been as con-sistently jaundiced as her older sister. She has not been frequently ill like her sister, and she has not required hospitalization for other than investigational purposes. She was attending school

in a special education class.

Case 3

The only affected male (IV-41, Fig. 1) was born on April 26, 1961, at term and weighed 3.24 kg

(731s Ib). The mother had received an injection

of an unknown material for threatened abortion at 2 months’ gestation. She took approximately 12 red and grey capsules for relief of headache throughout the pregnancy. Throughout this and

the subsequent tsvo pregnancies she also took

vitamins. He was not noted to be jaundiced in

the neonatal period; the hospital record stated that

the stools changed from meconium to brown to

yellow prior to discharge, and no note was made

about color of urine. This boy had operations for bilateral inguinal hernias at 6 and 10 weeks of age.

He developed pruritus at about 4 months but

the stools were not acholic and the urine was not

dark. He bled readily from scratching, especially

around the ears. He gained weight satisfactorily

until he was about 2 years old. He was at that

time noted to have a large abdomen and frequent

stools which were loose and sometimes floated.

They were improved on a gluten-free diet with

added skimmed milk. He was never thought to

be jaundiced. His appetite was good.

His development was considered about the same

as that of his male siblings except that he did

not walk alone until 19 months. He sat unsup-ported at 8 months, said simple sentences at 18

months, and was toilet trained at 2% years. On admission to University Hospital in May 1964 his weight was found to be at the 10th percentile (within 2 SD of the mean) while his

height was less than the 3rd percentile. The skin was excoriated with multiple patches of erythe-matous, scaly lesions over the trunk and extensor

surfaces of the extremities. The heart was

ques-tionably enlarged; a cardiac murmur ( grade 1 of

4) was considered to be functional. The liver was questionably felt 1% cm below the right costal

margin, but the spleen could not be felt. His

hands were short and stubby with broad fingers

and presented the appearance of clubbing. His

bone age was 2% years. The peripheral eosinophil count was 6%. There was no albuminuria,

galac-tosuria, or glycosuria, and urine specific gravity was 1.025. Tests on the urine for phenylpyruvic acid and acid mucopolysaccharide were negative.

Old tuberculin and histoplasmin skin tests were

negative (Tables I and II).

During the next year he appeared quite well;

but, he was noted to have rhinorrhea most of the time, he developed epistaxis occasionally, and he occasionally complained of abdominal pain.

He was admitted for percutaneous liver biopsy

to the Clinical Research Unit of University Hos-pital in May 1965 at the age of 4 years. The

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828

the chest circumference was 59.5 cm (23.5 in.).

He was a chubby boy who did not appear jaun-diced. His facial outline was square rather than

round like that of the affected sisters. The liver

was palpable Ui cm below the right costa! mar-gin. The spleen was not enlarged to palpation or

percussion. The skin was rough, thick and

ex-coriated. The nails of the fingers were convex while those of the toes were flat.

At this time his eosinophilia had risen to 18%,

which could not be accounted for on the basis of

pica. Further inquiries revealed that the family kept a dog. An oral cholecystogram showed nor-ma! opacification of the gallbladder. He showed

11% BSP retention at 45 minutes and 13% at 120 minutes. A percutaneous liver biopsy was

per-formed. He too was discharged on a regime of cholestyramine (3i teaspoonful three times per day which was increased to ii and then 1

tea-spoonful three times per day) and water soluble

vitamins. The cholestyramine was discontinued by

the mother after 1 month.

When he was last examined in January 1966 at the age of 4% years, he was not jaundiced and his

skin did not show evidence of recent scratching. The liver was palpable 5 cm below the right

costal margin, and the tip of the spleen could be

felt. He has always appeared less severely and less

frequently jaundiced and more robust than the two older affected sisters, even though he is small

in comparison with other children his age. His urine has never been very dark. His most

trouble-some smptom has been pruritus, and his abdomen

has always been unusually large.

Case 4

IV-42 (Fig. 1), a full-term, infant girl was born

on February 2, 1963. Birth weight was 3.24 kg

(7%’i Ib) and she was a breech presentation. On

the third clay she was noted to be slightly

jaun-diced, but she was discharged the following day.

Her stools were recorded as meconium in the

newborn nursery, and there was no note about

urine color. A right inguinal hernia was repaired at the age of 6 weeks. Pruritus was noted at 5

months, and the mother noted intermittent dark urine, light stools, and jaundice. The child was

hospitalized at 11 months for diarrhea and an enlarged liver was found. She was treated with intravenous fluids but did not receive blood. She was considered to have the same disease as her

three siblings.

She crawled at 12 months but did not sit un-supported until she was 13 months. She was said to speak clearly in sentences at 18 months but did

not walk until 26 months.

When admitted to the University Hospital in

Mw 1964, the anterior fontanelle had remained open. She had received vitamin supplementation for many months. Both her height and weight

were in the 10th percentile. The skin showed

many small excoriated lesions widely scattered

over the body with evidence of bleeding. The

liver was palpable 6% cm below the right costa! margin, and their was an umbilical hernia. Her

hands were noted to be stubby.

Her maximum urine concentration was 1.020, there was no albuminuria or glycosuria, and tests

for phenylpyruvic acid and acid mucopolysac-charide were negative. Old tuberculin and histo-plasmin skin tests were negative. Her bone age was 12 months (Tables I and II).

When admitted to the Clinical Research Unit

at 2% years for liver biopsy, her height was at the

3rd percentile, while her weight was still at the

10th percentile. The head circumference was 47

cm (18.5 inches) and the chest circumference 52 cm (20.5 inches). Her face appeared round with bulging cheeks, a depressed nasal bridge, and bilateral inner epicanthal folds. The heart was

questionably enlarged to percussion, and a mur (grade 1 of 4) was considered to be

func-tional. The abdomen was protuberant, the liver was palpable 33i cm below the right costa! mar-gin, and the spleen could not be felt. The skin

color was bronze, and it was thick and rough.

There was excoriation and bleeding. Nails of the

fingers were more convex than normal. Her fin-gers appeared short and stubby.

The gallbladder did not visualize with a total of 3 gm of Telepaque. Her BSP retention was 16% at 45 minutes and 27% at 120 minutes. A per-cutaneous biopsy of the liver was performed (Fig. 5). She received the same medications as did IV-38 and IV-41 at the time of discharge.

Eight months later, at the age of 3 years, she appeared more jaundiced than her siblings. She was constantly scratching. The liver was palpable 6 cm below the right costal margin, and the tip

of the spleen could be felt. Her jaundice has fre-quently appeared as intense and sometimes more intense than that of her oldest sister.

In summary, similar symptoms first ap-peared at approximately the same age in each of the four siblings. The male has ap-peared to be the least affected. The

pre-senting manifestation has been pruritus at 3 to 5 months and, in the females, enlarge-ment of the abdomen, pallor of the stools, darkening of the urine, and jaundice have

occurred. The most prominent manifesta-tions in the male have been pruritus and abdominal enlargement. Their development

has been slow, and their growth has been

marked by relatively more retardation in

(11)

GiRL ‘S PHYSICAL OEVELOPMENT - I TO 18 YEARS

AGE IN YEARS

829

FIG. 9. Growth of the three affected females of the B. sibship.

Physically, they have each consistently had a moderately enlarged liver, an

incon-sistently enlarged spleen, protuberant ab-domen, short fingers and toes, prominent

eyes, and rough, thickened skin.

Figures 9 and 10 reveal their growth re-tardation. In contrast, the older normal brother is in the 50 to 75th percentile

(with-in 1 SD from the mean) for height and on

the 90th percentile for weight (within 2 SD

from the mean); the younger normal

broth-er is in the 10 to 25th percentile (within

2 SD from the mean) for height, and the 50

to 75th percentile for weight. The younger, unaffected sister at 10 months of age is 80

cm (31.5 in.) in length and 10.4 kg (23 ib) in weight.

A 28-year-old married female ( 111-27, Fig. 1),

maternal aunt of the proposita, is the only relative on eIther side of the family who is known to have had any form of liver disease. She was admitted to the Burns Clinic, Petoskey, Michigan, on January

29, 1965, because of right lower quadrant pain. She had been under observation because of obesity

but had not responded to dietary restrictions. Past history revealed that in May 1956 she had undergone an exploratory abdominal operation

elsewhere, performed because of recurrent, crampy,

right upper quadrant pain and suspected ectopic

pregnancy. Adhesions were found in the right lower quadrant in the region of a previous ap-pendectomy, but the liver appeared normal. The

0

0

C 2

(12)

AGE IN YEARS

830 FAMILIAL CHOLESTASIS

U) I 4-) 2

BOY ‘S PHYSICAL DEVELOPMENT - I TO 18 YEARS

FIG. 10. Growth of the affected male of the B. sibship.

gallbladder emptied easily with pressure and

con-tamed several faceted stones. Then in August 1959 she underwent a cholecystectomy. A small fibrotic gallbladder with thickened wall and one ovoid stone measuring almost 2.5 cm in diameter was found, but there were no signs of acute infiamma-tion. The liver again was reported to be normal. There was no preoperative jaundice.

The physical examination was within normal

limits, except for obesity.

Laboratory sttIdies during the 1965 admission,

in addition to those in Tables I and II, included: complete blood cell count, veneral disease re-search laboratories test for syphilis, catheterized

urine, pregnancy test, and urine for porphyrins

were all within normal limits, as were the BUN,

creatinine, calcium, phosphorous, fasting blood sugar, and uric acid determinations. The serum

gamma globulin was slightly elevated at 1.73 gm/ 100 ml. An IVP showed blending of the right midrenal calyx, and there was non-filling of the

left lower pole calyces. A retrograde pyelogram

showed evidence of extrinsic pressure on the

dome of the urinary bladder. Barium enema ex-amination showed a normal large bowel and ter-minal ileum. Upper gastrointestinal examination showed abnormal motility. A roentgenogram of the chest was normal. The abnormal BSP reten-tion was interpreted to be secondary to

overadmin-istration of the dye as a result of the patient’s

marked obesity.

(13)

ARTICLES 831

Bio-Science Laboratories, Los Angeles. California 91403.

data are recorded in Table III. Subsequenfly, she is reported to have remained in good health and

to have lost weight.

Biochemical Characterization

In all the siblings studied elevation of total bilirubin has usually been moderate, the highest recorded value in any of the

four siblings was 12.8 mg/100 ml in the youngest affected, and two normal values have been obtained-one in IV-38 and one in IV-41. The proportion of the total as con-jugated has generally been three fourths. The oldest sibling has been more

consis-tently hyperbilirubinemic as well as clini-cally jaundiced than the three younger sib-lings, but she has not shown progression in the total level nor in the proportion of con-jugated bilirubin. The maternal aunt has not been hyperbilirubinemic.

Alkaline phosphatase levels in serum have been elevated, the higher values have been obtained in the younger siblings and at younger ages. One normal value has been recorded for the eldest. Alkaline

phos-phatase activities in the serum of the

mater-nal aunt have been normal.

Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)

activities in serum have been moderately

elevated in the four siblings, but the values

for the aunt were markedly increased.

Cholesterol values in serum for the four

siblings have been slightly elevated.

While total serum protein values have been either normal or slightly low, the dis-tribution of components has generally been

altered because of diminution in the

albu-men portion with increases in the alpha-i, alpha-2, and beta globulin portions. The percent of total proteins recorded as gamma globulin has been normal. While this is true for the four siblings, in contrast, the maternal aunt showed a slight elevation in the gamma globulin portion as the only

abnormality.

Retention of BSP at 45 minutes has

been elevated, and 2-hour determinations

showed the same or slightly more retention

in the four siblings. The maternal aunt

showed marked retention. It is apparent, then, that the maternal aunt has not shown

the same biochemical abnormalities as the

four affected siblings.

As the metabolism of bilirubin in the liver involves, successively, uptake, conju-gallon, and excretion, and as most of the

bilirubin in the serum was conjugated, this

suggests that the final step of excretion is impaired in these children. This is support-ed by the grossly elevated levels of bile acids in the serum in all four affected sib-lings and the uniformly increased ratio of the trihydroxy to dihydroxy acids (Table IV). This suggests a defect in the excretory mechanism located between the sites of conjugation and the lumen of the bile duc-tule, rather than severe parenchymatous, hepatocellular failure. The mechanism of excretory failure may be functional, me-chanical, or both. The histological evidence does not support the presence of a mechan-ical defect, as bile ducts were identified both at operation in the proposita and in the liver biopsy specimens (Fig. 2 and 5). Par-enchymatous hepatocellular damage was further suggested by the presence of slight, but persistent, elevations of the

transami-nases of the serum of the affected children. This is more striking because the commonly accepted upper limits of normal for these estimations are regarded by some as too high.5 The changes in the alkaline phospha-tase are those frequenfly seen in cholestasis.

On the other hand, the concentrations of

the serum proteins were less strikingly

ab-TABLE IV

SERUM BILE ACIDS OF THE FOUR AFFECTED SIBLINGS

Patient

Dihyd cozy

Bile Acids

5g/m.l

Trihydrozy

Bile Acids

pg/mt

Trihydrozy

-Dihydrozy

AdultNorrntI

IV-37

IV-38

IV-41 IV-42

0-I .9 as

chenodesoxy-cholic acid

27

16

23 20

0-3.5 as

cholic acid

54

66

66

79

<I .0

2.0

4.12 2.87

(14)

normal and characterized by an elevation

in the concentrations of and globulins in the serum. This differentiates this condition biochemically from cirrhosis of uncertain origin (postnecrotic cirrhosis, multilobular cirrhosis, etc.) in which increases in the gamma-globulin concentration in serum are usually found.

FAMILY INVESTIGATION

The pedigree of the family is illustrated

in Figure 1. There is no consanguinity,

al-though both families come from the same

area in the northern part of Michigan’s lower peninsula. Including the sibship of the father, his family has lived in the same

area for four generations and is thought to have originated from France and Germany. Including the sibship of the mother, her family has lived in the same area for three

generations, but their origin is not known.

Aside from the maternal aunt there was no

one with a history of jaundice or liver dis-ease. The father is a cement worker and has always been healthy. The mother has been a housewife since her marriage at age 17 and has never been employed outside the

home. The maternal grandfather was killed in World War II.

One paternal uncle and one of his Sons

have diabetes mellitus. Several members of both families apparently consume moderate quantities of alcohol. Both families tend to

shortness; the father’s height is 168 cm (66

in.), the paternal grandfather’s is 173 cm (68

in.), and the paternal grandmother’s is 157

cm (62 in.). The mother’s height is 152 cm (60 in.), the maternal grandfather’s was 183

cm (72 in.), and the maternal grandmother’s

is 165 cm (65 in.).

Blood was obtained from the only four living great-grandparents, three living grandparents, parents, normal siblings, and all 15 living uncles, half-uncles and aunts,

except for one paternal aunt who was in a mental institution. (The results of these studies are summarized in Table V, which appears in the reprints only.) The only ab-normalities discovered were those for the maternal aunt (111-27) who had developed

symptoms and was hospitalized shortly

af-terwards (see Case Report).

COMMENT

Although presenting with jaundice, the children described by us have none of the clinical and biochemical features of the un-conjugated hyperbilirubinemias discussed and elucidated by Arias.6 The presence of severe and apparently progressive histolog-ical abnormalities shown in the liver

biop-sies as well as the preponderance of conju-gated bilirubin distinguish these cases from the group of conditions sometimes referred to as “Gilbert’s disease” and from the

Cri-gler-Najjar syndrome, both of which are characterized by increased levels of circu-lating unconjugated bilirubin.

Because of the nature of the histological abnormalities, our patients are distin-guished from the syndrome described by

Rotor, Manahan, and Florentin,7 the case of Schiff, Bffling, and Oikawa,8 the siblings presented by Davis and Young,9 the syndrome reported by Haverback and Wirtschafter,1#{176} and the case of Vest, Kauf-mann, and Fritz. Our patients are also

different from those reported by Dubin and

J

ohnson who have shown infiltration of the liver with an incompletely identified

pig-ment as the sole histological abnormality.12

There are, however, some apparent simi-larities between the patients reported here

and various forms of familial or apparently familial recurrent jaundice manifesting an “obstructive” pattern. Summerskill and

(15)

abnor-malities during remissions, and there were no irreversible sequelae.

Tygstrup in 1960 described two cases of

intermittent jaundice which first appeared at ages 1 and 2.16 Though not

demon-strated, the patients “were probably re-lated.” Liver biopsy indicated intrahepatic cholestasis. Serum bilirubin levels were higher and both GOT and GPT activities in serum were lower than in the cases of the present report. Although symptoms were severe during periods of jaundice, the con-dition seemed to be completely reversible. There is no evidence of reversibility in our

cases, indeed progression is apparent,

pos-sibly to hepatic cirrhosis.

Kuhn in 1963 reported intrahepatic cho-lestasis in two brothers.17 The elder brother had experienced recurrent attacks of jaun-dice from the age of 14 years, the serum

bi-lirubin reaching 22 mg/100 ml. Alkaline

phosphatase activity in serum never

ex-ceeded 28.5 King-Armstrong units, and other “liver function tests” were normal. It

was thought that this represented

progres-sion to primary biliary cirrhosis. The younger brother’s illness began at the age of 17 s-ears and was similar. Liver biopsy

showed intracellular and intercellular bile

thrombi, and there was no evidence of he-patitis nor of any other pigment. The au-thor suggested that the new syndrome be called “familial jaundice due to intrahepatic cholestasis.” However, the onset was much later than in the present cases, and the manifestations were considerably milder.

Ahrens, Harris, and MacMahon

de-scribed four non-related cases of atresia of

the intrahepatic interlobular bile ducts in

1951.15 Three of the four also had

abnor-malities of the extrahepatic bile ducts,

which may have been acquired. The course of the disease was characterized by a rela-tively long life span in comparison with the common situation in extrahepatic bile duct

atresia. The patients had extensive general-ized skin xanthomatosis associated with marked and characteristic elevation of serum lipids. The siblings of the present re-port have not had xanthomatosis and have

not had comparable serum cholesterol ele-vations. The presence of intrahepatic bile ducts in all four siblings studied by us dis-tinguishes our patients from those de-scribed by Ahrens, et al.8 The possibility that these bile ducts may disappear later in the course of the disease remains open.

“Byler’s Disease : Fatal Familial

Intra-hepatic Cholestasis in an Amish Kindred” was reported in six members of four

sib-ships by Clayton, et al. in 1965.19 The time

of onset, development of the disease, and biochemical characterization are similar to those in the family of the present report. However, in four of the six, death occurred

between 17 months and 8 years, and there

was no mention of mental retardation. The conclusion was that the syndrome was probably due to autosomal recessive inheri-tance and was the result of an error in bile salt metabolism. Apparently, clinically simi-lax cases have been observed by others but not in a family with as many affected off-spring as in the family we have investi-gated.1#{176}

With the possible exception of the report

by Clayton, et al.,19 we do not believe that the present cases are sufficiently like any previously described to be included with them at this time.

Before a genetic etiology can be seriously considered for a disease in an individual family, other possible causes must be elimi-nated as conclusively as possible. After ex-haustive questioning, we have been unable to find a drug, with or without known hepa-to-toxic properties, which all four affected children have ingested at a sufficiently early age to account for the early onset of symp-toms. There have been no unusual foods consumed prior to the onset of symptoms, and their diets have been the same as those of their healthy siblings and appeared ade-quate. The family has not travelled outside

the state of Michigan.

(16)

834

TABLE VI

BLOOD Gitoucs OF THE B. FAMILY

Position in

Pedigree

Relation ABO Rh MNSs P Kell Kji’ K1P Fr Jka a LeP

IlI-4 IIl-3 IV-37 IV-38 IV-39 IV-40 IV-41 IV-4Z IV-43 Mother Father Proposita Sister (affected) Brother Brother Brother (affected) Sister (atteeted) Sister B 0 B 0 0 B B B 0 cDE/cde eI)E/cde cde/cde cl)E/cde cDE/cde cDE/cDE cde/cde cDE/cDE cde/cde MNs MNSs MNSs MNs MSs Ns MNs MNs MNs + + + + + + + + + -+ + -+ -+ + + + + + + + + + + + + + + -+ + + + + + -+ + + + + + + -+ + -+ + -+ + + -+ -+

-A specific maternal influence is possible,

either by deficiency or by ingestion. The

course of the pregnancies was not unusual,

and the mother’s diet has apparently been

adequate. Drug ingestion, specifically of tranquilizers, has been repeatedly denied. She has not had any infections or severe fe-brile illnesses during the gestations.

The onset of the jaundice in the middle

third of the first year is unlike that due to blood group incompatibility. The blood groups of the four affected and three healthy siblings do not reveal blood group genes consistently characteristic of the four affected children (Table VI). The direct

Coombs test has been negative on several

occasions.

Genetic determination of neonatal

hepati-tis has been suggested, at least in some families. Analysis by the Weinberg sib

method showed the trait to be consistent

with an autosomal recessive mode of

inheri-tance in the analysis by Hsia, et al.2#{176} Cassa-dy, et a!. in 1964 reported a family with “giant-cell hepatitis” and suggested that genetic factors appeared to be significant in the causation of the syndrome.21 Two

dis-tinguishing factors indicate that the cases of the present family do not represent the cat-egory of “neonatal hepatitis:” (1) all four

affected children were normal during the

neonatal period and did not begin to be

symptomatic until the middle third of the first year; (2) the histological picture is

different, because even the early biopsies of the present family do not show the multinu-cleated giant cells which are typically seen in neonatal hepatitis.

Four criteria are commonly used for the assessment of the role of genetic factors in the etiology of a given trait.’#{176}These are customarily employed after the description of numerous cases whose identity is reason-ably well assured. They are generally map-plicable in the evaluation of an individual

family, but they may be supportive. The conclusion that genetic factors are responsi-ble for a trait in a single family is tentative and usually reached by the reasonable ex-clusion of all other possible causative fac-tors.

The first criterion is the occurrence of the disease in definite numerical proportions among individuals related by descent. Since there are no previous cases reported in the literature which are sufficienfly similar to those in the present family, even a limited analysis is not possible. In the present family, of the six children born after the proposita, three are affected.

The second criterion is the failure of the

disease to spread to nonrelated individuals. There is no evidence that the disease in this family has been communicated to anyone

in the area in which the family has lived. The two older affected siblings have had a limited school experience, without apparent

(17)

The third criterion is the onset of the dis-ease at a characteristic age without a known precipitating event. This has been observed four times in this family. The time of onset has been similar as well as the de-velopment of the clinical manifestations, especially in the affected females. No

pre-cipitating event has been identified even

after extensive questioning.

The fourth criterion is the greater concor-dance of the disease in monozygotic than in dizygotic twins. To our knowledge there are no reports of a similar disease picture in

twins.

If a disease is determined by genetic fac-tors, three questions arise. (1) Is a single locus responsible or is it polygenic or

possi-bly polyfactorial? (2) How is the mutant

gene related to its normal allele? (3) Is there an identifiable simple protein altera-tion?

In this family with intrahepatic

cholesta-sis the remarkable similarity of the process, particularly of the three females, suggests the role of a similar, perhaps single etio-logic factor.

The possibility of sex modifying the course of the disease exists because of the

slightly milder course of the male. In order

to be substantiated, this would require the identification and study of further families.

If two assumptions can be accepted, i.e., that all four siblings are similarly affected and that this is due to genetic factors, then the question of the mode of inheritance de-pends, first upon the state of health of the parents, and second, on that of all other rel-atives, since there is no consanguinity.

The parents are not clinically affected. This is equally true for all three living grandparents and presumably also for the fourth who was fit for military service at the time of death. The disease could be de-termined by a dominant gene if sporadic mutation occurred four times in one sib-ship. Since the rate of spontaneous muta-tion in man is of the order of i0, the likeli-hood of this event is (10#{176}),and, therefore, this possibility is highly unlikely. Alterna-tively, the disease could also be determined

by a dominant gene if one of the parents is

a gonosomal mosaic, a significant portion of a gonad having experienced a mutation at a very early stage in its development. This

argument can be employed for a disease which appears in families but which does not conform to the usual modes of inheri-tance. On the other hand, at the present

time it can neither be proven nor dispro-yen. A recessive mode of inheritance, auto-somal (since the father is unaffected) is the most acceptable explanation. Each parent is a carrier of the mutant gene, presumably derived from one grandparent, and some of the aunts and uncles should also be hetero-zygous at this locus.

In this case the aunt with cholangiolitis and cholangitis could be considered as a manifest heterozygote for the gene which is then incompletely recessive. In the event that the aunt’s disease is unrelated to that of the four siblings, this hypothesis would be unnecessary. Her clinical presentation and biochemical characterization are con-siderably different from that of the four sib-lings, and we, therefore, conclude that her disease is probably not related.

For the disease in this sibship we suggest the term of familial intrahepatic cholestasis

with mental and growth retardation. In this family autosomal recessive inheritance ap-pears as the most likely etiology. The path-ogenetic mechanism, which may not be pri-manly hepatic, remains to be identified.

SUMMARY

Four siblings have been described with similar onset and progression of

intrahepat-ic cholestasis. Pruritus at 3 to 5 months was the presenting manifestation and was

ac-companied by jaundice, an enlarged

abdo-men, bilirubinuria, and occasional light stools. Liver enlargement, retarded growth, and mild mental retardation have been present in all.

(18)

836

pattern of the proteins, with elevation of the and globulin fractions.

Liver biopsies have been characterized by bile stasis in the presence of bile ducts. Two of the children show hepatic fibrosis which appears to be progressive and irre-versible.

Aside from one aunt with cholangitis and cholangiolitis, there are no family members with liver disease. Autosomal recessive in-heritance is suggested.

REFERENCES

1. Behrendt, H. J.: Diagnostic Tests In Infancy

and Childhood, ed. 2. Philadelphia: Lea

and Febiger, 1962.

2. Pearson, S., Stern, S., and McGavock, T. H.:

A rapid, accurate method for the deter-mination of total cholesterol in serum.

Anal. Chem., 25:813, 1953.

3. Carey, J. B., Jr. : The serum

trihydroxy-dihy-droxy bile acid ratio in liver and biliary

tract disease. J. Clin. Invest., 37:1494, 1958.

4. Osbom, E. C., Wootton, I. D. P., Da Silva, L. C., and Sherlock, S. : Serum-bile-acid

levels in liver disease. Lancet, 2:1049,

1959.

5. Henley, K. S., Schmidt, E., and Schmidt, F.

\V. : Enzymes In Serum. Their Use in

Di-agnosis. Springfield, Illinois: Charles C

Thomas, 1966.

6. Arias, I. M. : Chronic unconjugated

hyper-bilirubinemia without overt signs of

hemo-lysis in adolescents and adults. J. Clin. Invest., 41:2233, 1962.

7. Rotor, A. B., Manahan, L., and Florentin, A.: Familial non-hemolytic jaundice with di-rect van den Bergh reaction. Acta Med. Philipp., 5:37, 1948.

8. Schiff, L., Billing, B. H., and Oikawa, Y.:

Familial nonhemolytic jaundice with

con-jugated bilirubin in the serum. New Eng.

J.

Med., 260:1315, 1959.

9. Davis, \V. D., Jr., and Young, P. C.: An

unusual type of hyperbilirubinemia with

bromsulphalein retention and microscopic-ally normal liver. Gastroenterology, 37:206,

1959.

10. Haverback, B. J., and Wirtschafter, S. K.: Familial nonhemolytic jaundice with

nor-ma! liver histology and conjugated

biliru-bin. New Eng. J. Med., 262:113, 1960.

11. Vest, M. F., Kaufmann, H. J., and Fritz, E.: Chronic non-haemolytic jaundice with con-jugated bilirubin in the serum and normal

liver histology: a case study. Arch. Dis.

Child., 35:600, 1960.

12. Dubin, I. N. : Chronic idiopathic jaundice: a

review of fifty cases. Amer. J. Med., 24:

268, 1958.

13. Summerskill, W. H. J., and Waishe, J. M.: Benign recurrent intrahepatic “obstructive”

jaundice. Lancet, 2:686, 1959.

14. Summerskill, W. H. J.: The syndrome of be-nign recurrent cholestasis. Amer. J. Med., 38:298, 1965.

15. Neel, J. V., and Schull, W. J.: Human He-redity, Chicago: The University of Chi-cago Press, p. 285, 1954.

16. Tygstrup, N. : Intermittent possibly familial

intrahepatic cholestatic jaundice. Lancet, 1:1171, 1960.

17. Kuhn, H. A. : Intrahepatic cholestasis in two

brothers. German Med. Monthly, 8:185,

1963.

18. Ahrens, E. H., Jr., Harris, R. C., and

Mac-Mahon, H. E. : Atresia of the intrahepatic bile ducts. PEDIATRICS, 8:628, 1951.

19. Clayton, R. J., Iber, F. L., Ruebner, B. H., and McKusick, V. A. : Byler’s disease:

Fa-tal familial intrahepatic cholestasis in an Amish kindred. J. Pediat., 67:1025, 1965. 20. Hsia, D. Y.-Y., Boggs, J. D., Driscoll, S. G.,

and Gellis, S. S.: Prolonged obstructive

jaundice in infancy. V. The genetic

com-ponents in neonatal hepatitis. Amer. J.

Dis. Child., 95:485, 1958.

21. Cassady, C., Morrison, A. B., and Cohen, M. M. : Familial “giant-cell hepatitis” in infancy. Amer. J. Dis. Child., 107:456,

1964.

Acknowledgment

This study was made possible by the

coopera-tion of Dr. Joanne E. Mertz, who referred the

original patient and supplied detailed information

regarding the early course of the three older chil-dren, and that of Dr. Gustav A. Uhlich, both of the Burns Clinic, Petoskey, Michigan, who

pro-vided the information concerning the maternal

aunt. The blood group determinations were

(19)

1966;38;819

Pediatrics

Richard C. Juberg, Roxie M. Holland-Moritz, Keith S. Henley and Carlos F. Gonzalez

RETARDATION

FAMILIAL INTRAHEPATIC CHOLESTASIS WITH MENTAL AND GROWTH

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(20)

1966;38;819

Pediatrics

Richard C. Juberg, Roxie M. Holland-Moritz, Keith S. Henley and Carlos F. Gonzalez

RETARDATION

FAMILIAL INTRAHEPATIC CHOLESTASIS WITH MENTAL AND GROWTH

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Therefore, the present study demonstrated that the hybrid larvae of heteroclarias can be reared with formulated artificial diets for 21-days as with live feed of