Clinicopathologic conference: A three-month-old infant with failure to thrive, hepatomegaly, and...

American Journal of Medical Genetics 7:171-186 (1980)

Clinicopathologic Conference: A Three-Month-Old Infant With Failure to Thrive, Hepatomegaly, and Neurological lmpai rment

Aaron Friedman, James Bethzhold, Richard Hong, Enid F. Gilbert, Chirane Viseskul, and John M. Opitt

Departments of Pediatrics, Pathology, and Medical Genetics, The University of Wisconsin Center for Health Sciences and Medical School, Madison

CLINICAL PRESENTATION

Dr. Aaron Friedman, Dr. James Betzhold, Department of Pediatrics

evaluated for liver disease.

trimester she had had a flu-like illness followed by administration of influenza vaccine. The only drugs known to have been taken were Actifed@* and Dimetappa* for allergic or vasomotor rhinitis. Once, she was also briefly exposed to an insectide spray containing malathion and Fumarin. Delivery was by cesarian section. Birth weight was 3,000 gm; occipito-frontal head circumference (OFC) was 36-37 cm. At birth he had a heart murmur, undescended testes, and increased muscle tone.

breast milk or commercial formula. At that time he had a “trigonocephalic” skull with a flat top, prominent occiput, with bridging of the lambdoid and posterior sagittal sutures. The anterior fontanelle measured 3 X 3 cm. He had decreased range of motion of shoulders, 20” flexion contracture of the elbows, and bilateral cryptorchidism. His weight was 2.9 kg. During hospitalization he failed to gain weight on adequate caloric intake and he developed hepatomegaly. An intravenous pyelogram suggested presence of a horseshoe kidney. Re- sults of laboratory tests were: TORCH studies negative; total serum proteins 4.6 mg%; albumin 2.9 mg%; protein electrophoresis normal; bilirubin total 1 .O, indirect 0.1 ; alkaline

A 3%-months-old white male was admitted to Madison General Hosptial to be

He was born at term to a 24-year-old, gravida 2, para 1 woman. During the first

At six weeks he was admitted to another hospital because he fed poorly, either on

*Actifed@ : triprolidine HC1, pseudoephedrine HCI. Snimetappe: brompheniramine maleate, phenylephrine HCl, phenylpropanolamine HCI.

Received for publication February 14, 1980; revision received March 21, 1980.

Address reprint requests to Aaron Friedman, M.D., University of Wisconsin Center for Health Sciences and Medical School, Madison, WI 53792.

0148-7299/80/0702-0171$02.90@1980 Alan R. Liss, Inc.

172 Friedman et a1

phosphatase 468 IU; LDH 460 IU; SCOT 92 IU; CPK 35mU; gamma glutamyl transpep- tidase 10 IU; alpha-1-antitrypsin 280 mg%; HAA negative twice; serum copper 68 pg%; a fetoprotein 4-8 pg/ml; ceruloplasmin 15.2 mg%; 24-hour-urine copper 18 pg; D-xylose < 10% excretion; 24-hour-urine amino acids and mucopolysaccharide screen negative; sweat test normal twice; normal stool pH and reducing substances. Barium swallow and small bowel follow-through-enema were normal. A smill bowel biopsy was normal. A liver biopsy showed fatty changes, pseudoductular and ductular proliferation, portal and periportal fibrosis, and nodular regeneration. An EEG was done because of questionable seizure activity and was interpreted as normal. He developed massive ascites, was begun on total parenteral nutrition (TPN), and transferred to Madison General Hospital.

On admission to Madison General Hospital he weighed 3.3 kg, OFC was 37 cm. He was also found to have clinodactyly of 5th fingers, accentuation of the upper transverse helices with a cartilage tubercle at the right apex. He had moderate myopia and sub- albinotic fundi. Massive ascites with tachypnea persisted. Laboratory data included: hematocrit 20.9; WBC 15,900 per mm3 (70% polys, 8% bands, 19% lymphs, 3% monos); decreased number of platelets; reticulocyte count 1 1.3% (259,000/mm3 absolute); pro- thrombin time 10.5 seconds (10.6 control), partial thromboplastin time 33 seconds; urinalysis unremarkable; arterial pH 7.48; POz 49; pCOz 34; H2C03 25 mEq/liter; Na 137 mEq/liter; CI 88 mEq/liter; BUN 17 mg%; Ca 9.2 mg/dl; Pi 3.7 mg/dl; Mg 1.9 mg/dl; SGPT 21 IU; albumin 3.5 gm/liter; total serum protein 4.3 gm/liter; IgM 295 (normal 20-1 19); urine amino acid screen - slightly increased amounts of serine, threonine, and glycine. Ascites fluid showed a cell count of 89 cells/mm3 (26 lymphocytes, 12 poly- morphonuclear leukocytes, 62 other) and a protein of 1.5 gm%. One hour D-xylose was 6.3 mg/, increasing to 30 mg% 6 days later. A glactose-1-phosphate uridyl transferase level was normal. Chest fdm showed elevated diaphragms. An ECG was normal. A urine specimen did not contain organophosphates.

ical status and then begun on slow nasogastric feeding of commercial formula. Several days after the institution of oral feedings, he abruptly developed respiratory distress with cardiomegaly and pulmonary infiltration and died shortly thereafter.

He was maintained on TPN for several weeks with some improvement in biochem-

DI SCUSSl ON

Dr. Richard Hong, Department of Pediatrics

deductions from the protocol data. In so doing, he demonstrates techniques of problem solving and discusses the clinical manifestations of a number of possible diagnoses. This is to make the exercise a learning experience for the audience. In addition to the printed clinical history, however, a discussant must always ask, “Why me?” This is an especially relevant question when there are obviously more capable individuals in the audience to discuss this case, eg, Dr. Odell or Dr. Opitz. My perception of the answer to that question will indeed markedly influence my final diagnoses, as you will see.

to which one or, at most two, manifestations are of prime importance and must draw the focus of the investigation. Manifestations which are unique or rare are often worthy of initial attack as they narrow the search considerably. All other symptoms, signs, and clues are relegated to more secondary roles. In this case, I shall asume that the liver problem is the key disturbance and that its understanding will allow the other pieces of the puzzle to easily fall into place.

As I understand it, the discussant in a CPC is to arrive at a diagnosis by making

I have been taught to approach diagnostic problems by first making a judgment as

CPC: 3-Month-Old With FTT, Liver, CNS Disease 173

What is the nature of this liver problem? I am struck by the rapid, overwhelming, relentlessly downhill course seen here. For example, massive ascites developing so early in the course of infantile liver disease is really qute unusual. Cirrhosis due to biliary atresia is one of the most severe forms seen, but usually requires years for the appearance of massive ascites. Certain forms of severe liver disease were looked for, namely galac- tosemia, tyrosinemia, and methoninemia, and excluded by enzyme analysis and urinary amino acid screening. Wilson’s disease and alpha-1 antitrypsin deficiency must always be considered in chronic liver disease of childhood, but the rapidly progressive course is against those disorders. Alpha-1 antitrypsin deficiency presents as a cholestatic syndrome, and Wilson’s disease is seldom seen before age 6-7 years. I think that the normal SGPT and lack of icterus speak against a severe form of neonatal hepatitis [Roy et al, 1975; Schubert, 19751.

Thus, of the likely forms of hepatodestructive mechanisms, none really fits the bill quite well. I must now look elsewhere.

At this juncture, one can ask if there is another aspect in this case which is unique and may redirect our focus. Here, my selection as the discussant must be considered. I am not known for my expertise in the liver; if I am identified with an organ it must be the thymus. There is nothing in the history to suggest a major thymic defect; however, it is not unusual to have serveral months of apparent well-being even with marked thymic deficiency. I think this is primarily a matter of luck and depends on whether the patient has been exposed by chance or not to a given pathogen. There is a liver disorder which is associated with a thymus disorder, namely the cerebral-hepato-renal (CHR) syndrome of Zellweger. It is of interest that the association of these two entities was first publicized by Drs. Gilchrist, Opitz, Gilbert, and co-workers of the University of Wisconsin [Gilchrist et al, 19741. The fact might disqualify Dr. Opitz from discussion of this case. Although I have not seen a case of the Zellweger syndrome, the description of the facial abnormalities, especially those of the ears is not inconsistent with what is usually found in the CHR syndrome.

I now turn to another aspect of this case which may provide insight into the com- mon thread which we have been seeking, namely, the arthrogryposis. Arthrogryposis is a symptom of disturbed intrauterine limb movements. The patient must have had an under- lying muscle or neurological disorder which resulted in infrequent intrauterine motion with consequent fixation of the joints. This is analogous to contractures which develop in children as a result of inadequate movement in juvenile rheumatoid arthritis. How then to connect neuromuscular disease to liver disease?

usually be ascribed to infection, autoimmunity, or toxin. In the absence of other evidence for intrauterine infection, eg, manifestations of the rubella syndrome, retinitis, or microcephaly, I shall dismiss infection. However, the elevated IgM is somewhat suggestive of an infection. There is no known autoimmune disorder which would produce this picture and the age of onset for autoimmune disease would be most unusual.

We know that the mother was exposed to malathion during early pregnancy. What might be the consequence of that exposure? It has been recorded that an exposure to as little as 3 parts per million of malathion can cause abnormal locomotion in minnows so that they acquire a skeletal abnormality similar to scoliosis [Weis and Weis, 19761 . It is also known that environmental toxins can affect the lymphoid system of fetal monkeys. I am not aware of hepatotoxicity from these types of exposure, but the great susceptibility of developing organ systems to various insults makes it easy for me to accept the fact that multiple organ systems in this unfortunate child could have been affected by the malathion.

We are now in the realm of multisystem disease. Causation of multisystem disease can

174 Friedman et a1

I shall therefore state that I believe the clinical picture seen here was due to malathion toxicity. Inasmuch as a malformation syndrome due to this cause has not been described, I shall take the liberty of naming this entity the Malathion Associated Fetal Induced Anomaly or the MAFIA syndrome.

REFERENCES

Gilchrist KW, Opitz JM, Gilbert EF, Tsang W, Miller P: Immunodeficiency in the cerebro-hepato-

Roy CC, Silverman A, Cozzetto FJ: “Pediatric Clinical Gastroenterology,” St. Louis: C.V. Mosby,

Schubert WK: Liver disease in infants and children. In Schiff L (ed): “Diseases of the Liver,” Phila-

Weis P, Weis JS: Abnormal locomotion associated with skeletal malformation in the Sheepshead Min-

renal syndrome of Zellweger (Letter). Lancet 1: 164-165, 1974.

1975.

delphia: J.P. Lippincott, 1975.

now, Cyprinodon variegatus, exposed to Malathion. Environ Res 12: 196-200, 1976.

AUTOPSY FIND1 NGS

Dr. Enid F. Gilbert, Departments of Pathology and Pediatrics

“lie infant weighed 4,000 gm and measured 52 cm (crown-heel length). There was a peculiar facial appearance and the ears were dysplastic. A small amount of hemorrhagic fluid was present in the pleural and pericardial cavities. No evidence of a thymus gland was present. Approximately 200 ml of clear, yellow ascitic fluid was present in the peritoneal cavity. The heart and lungs showed no significant pathological changes. The liver was enlarged, weighed 280 gm (normal 100 gin), and was yellowish-brown and uniformly nodular. Microscopic sections showed evidence of cirrhosis with periportal fibrosis and biliary dysgenesis (Fig. 1). There was a moderate degree of fatty metamor- phosis and evidence of some giant cell transformation and cholestasis within the hepato- cytes (Fig. 2). A small amount of iron-positive pigment was present within the liver cells (Fig. 3). Electron microscopic examination of the liver showed absence of peroxisomes. These changes were all consistent with the liver changes of the cerebro-hepato-renal (CHR) syndrome of Zellweger. Additional abnormalities included a horseshoe kidney (Fig. 4) with small g1omcr:ilar and tubular cysts (Fig. 5). Esophageal varices indicated portal hypertension.

Neuropathological Findings (Dr. Chirane Viseskul)

microgyria in the frontal and occipital lobes and pachygyria of temporal lobes (Fig. 6). The cerebellum, pons, and medulla were atrophic, and the corpus callosum was hypo- plastic. Microscopic sections showed cortical dysgenesis with irregular neuronal stratifica- tion in the layers of the cerebral cortex (Fig. 7). Focal areas of neuroglial tissue were present in the pia-arachnoid and fibrillary astrocytosis, and Alzheimer type 2 glial cells were seen in the cerebral cortex. Sections of midbrain, pons, and medulla showed atrophic changes with fibrillary astrogliosis. In the cerebellum the folia were severely atrophic with areas of astroghosis. Atrophy with astroghosis was present in sections of the spinal cord.

The brain weighed 500 gm (normal 600 gm) and was symmetrical. There was


Fig. 1. Gross appearance of the liver showing a diffuse, finely nodular cirrhosis.

Fig. 2. Microscopic section of the liver showing uniform nodules marginated by fibrous tissue (Tri- chrome X 100).

176 Friedman et a1

Fig. 3. Microscopic section of liver showing deposit of iron pigment, particularly within Kupfer cells (Prussian Blue stain X 250).

Fig. 4. Gross appearance of the horse-shoe kidney.


Fig. 5. Microscopic appearance of kidney showing variably sized cortical cysts.

Fig. 6 . Gross appearance of brain showing pachygyria of temporal lobes and microgyria of frontal and occipital lobes.

178 Friedman et a1

Fig. 7. Microscopic section of cerebral cortex showing disarray of neurons (cortical dysgenesis) (H & E X 250).

PATHOLOGICAL DIAGNOSIS:

Dr. Enid F. Gilbert

varices; horseshow kidney; cerebral dysgenesis; thymic agenesis. Because of the history of insecticide exposure and possible viral infection during pregnancy, extensive toxico- logical and viral isolation studies were performed at the Wisconsin State Laboratory of Hygiene. No such agents were identified in multiple samples. The pathological changes in the liver and brain are compatible with the Zellweger Syndrome. This was confirmed by the absence of peroxisomes in the liver observed by ultrastructural studies. We have observed thymic agenesis in the Zellweger syndrome [Gilchrist et al, 19741, and this has now been observed by others.

Cerebro-hepato-renal syndrome of Zellweger with cirrhosis of liver and esophageal

DISCUSSION

Dr. Enid F. Gilbert

The syndrome under discussion seems to have been reported for the first time in 1964 in the 2 M. sibs included by Zellweger in a paper by Bowen el a1 [1969] , which also included a description of another syndrome seen in 2 sibs studied at John Hopkins Hospital by


Bowen, Lee, and Lindenberg. The first affected M. sib was born with profound hypotonia, bilateral congenital glaucoma, hypospadias, short fingers, and simian creases; he died at 2 weeks and no autopsy was done. The subsequent affected sib was reported in detail by Zellweger and had congenital hypotonia and glaucoma with corneal opacities, epicanthic folds, abnormally large ears, a highly arched palate, enlarged liver and clitoris, flexion contractures of fingers, subsequent failure to thrive, severe retardation of psychomotor development, severe hypotonia requiring nasogastric tube feedings, calcific stippling of skeleton, severely abnormal EEG, and signs of liver involvement with intestinal bleeding and hypoprothrombinemia. The infant died at 4% weeks of pneumonia and was additional- ly found to have multiple subcapsular cysts of both kidneys, patent ductus arteriosus, a communication between the left subclavian vein and the left atrium, hypoplasia of the cerebellar hemispheres and tonsils, and flattened temporal lobes with depressed gyri. The liver was not mentioned. Thus, all the elements of today’s case were present in this proto- type report.

The same condition was independently studied by Dr. Opitz in the Y. sibs from Wisconsin and reported by Smith et a1 [1965]. The third paper on the subject by Passarge and McAdams [1967] suggested the name cerebro-hepato-renal syndrome. In view of Dr. Zellweger’s earlier contribution, Dr. Opitz called the syndrome the Zellweger syndrome ; since several other conditions are cerebro-hepato-renal syndromes (eg, Wilson Disease), Dr. McKusick suggested the condition be called the cerebrohepatorenal syndrome of Zellweger, the term used by Dr. Hong today.

The paper by Smith et a1 on the two severely hypotonic Y. sibs gave a detailed description of the external phenotype, documented the liver involvement as intrahepatic biliary dysgenesis, lack of normal lobular architecture and diffuse fibrosis, polycystic kidneys, VSD, incomplete descent of gonads, and hypertrophied pylorus. They suggested autosomal recessive inheritance as the most likely cause.

Passarge and McAdams [ 19671 first spoke precisely of micronodular cirrhosis, polycystic kidneys potter type 111), the presence of cataracts and severely deficient myelination of brain, possible sudanophilic leukodystrophy, and cerebral sclerosis.

in the Y family and 2 affected brothers in the H family. The presence of the renal cysts in these patients prompted Drs. Opitz and David Smith to make contact with Dr. Edith Potter, then still at the Chicago Lying-in Hospital (University of Chicago), who noted a golden-yellow pigment in the liver of their patients and suggested that this might be iron. On the basis of the characteristic histological changes and the yellow pigment, she identified another affected infant from an inbred Dutch family from Holland, Michigan.

The hint of excessive iron storage was followed up by Drs. Shahidi and Vitale of our Department of Pediatrics in the H. sibs. The golden-yellow pigment did indeed stain deeply with Russian Blue, and when it became possible to transfer R.H. from Minneapolis to Madison for further study, his serum iron was 270 pg/100 ml, and the total iron binding capacity was 284 pg/lOO ml without any hematologcal abnormality, excessive iron intake, or prior transfusion. Heavy deposits of iron were found in liver and bone marrow macrophages. EDTA treatment increased iron and zinc excretion 4- and %fold respectively; both fell to normal values by the third day. At autopsy these investigators determined a minimum of 99 mg iron/kg of body weight, compared to a normal of 75 mg. Since bone marrow and muscle iron determinations were not carried out, it can be estimated that the infant may have contained as much as twice the normal amount of iron. The hemoside- rin-ferritin ratio was also increased; serum proteins and transferrins were electrophoretical- ly normal.

Over the ensuing 4 years Dr. Opitz and co-workers studied another affected sib

180 Friedman et a1

In March of 1968, Dr. Opitz presented his comprehensive review of the syndrome and 4 new cases at the first Conference on the Clinical Delineation of Birth Defects. The iron defect was called “congenital hemosiderosis.” Dr. ZuRhein’s extensive neuropathol- ogic studies showed increased brain weight (due to extra water content), olfactory hypoplasia, polymicrogyria and pachygyria, and leukoencephalomyelopathic changes (not sudanophilic luekodystrophy).

turned out to be another affected sib in the Iowa M. family previously studied by Zell- weger. The Taylor et a1 [1969] paper should be consulted to correct the several genealogi- cal inaccuracies of the original Bowen et a1 [ 19641 report.

Our subsequent studies of the pathological changes in the Zellweger Syndrome were published by Gilchrist et al [1974, 1975,19761.

One of the most important discoveries made in the Zellweger syndrome is that of Goldfischer et a1 El9731 , who documented in liver biopsy distorted shape of mitochondria, sparse smooth endoplasmic reticulum, and total absence of reactive peroxisomes, findings which have since become the sine qua non of the diagnosis.

Goldfischer et a1 prepared mitochondrial fractions from the brain biopsy of one of their patients and from the liver biopsy of the other patient and showed that with NAD- reducing substrates (succinate, glutamate, malate) the rate of respiration in the patients’ tissue was diminished by 70% compared to control tissue. Addition of adenosine diphos- phate failed to stimulate respiration. Oxygen consumption was normal with ascorbate and tetramethylphenylene diamine, which transfers electrons directly to the cytochrome chain. These data, together with the cytochemical staining of the mitochondria in the diamino-benzidine medium suggested to these workers that the cytochrome portion of the electron transport chain was intact, but that there was a defect in electron transport prior to the cytochromes. Similar mitochondrial oxidative defects were present in brain, liver, and muscle. Succinate-tetrazolium reductase activity with menadione present to serve as an intermediate electron acceptor was virtually absent in brain and muscle and was markedly reduced in liver. It was more nearly like that of controls when phenazine metho- sulfate was substituted for menadione. This led to the conclusion that the basic biochemical defect in the Zellweger syndrome was between the flavoprotein and coenzyme Q, possibly in the region of nodieme iron protein, but the authors were unable to relate this postulated defect to the variably increased storage of iron in this disease.

Diisseldorf [Versmold et al, 1975, 19771 further clarified the situation. In their patient these workers also found absence of peroxisomes from hepatocysts, but contrary to the findings of Goldfischer et al, they documented the presence of smooth endoplasmic reticulum. No catalase was found by histochemistry or spectroscopy. Mitochondria showed normal succinate and glutamate respiration and normal coupling of respiration to the phosphorylation potential. The cytochrome (cyt) content was diminished to one-third with an abnormally inversed redox pattern of the respiratory chain in the controlled state, cyt b being SO%, cyt c 23% reduced. The oxygen affinity of cyt a3 was normal. These findings excluded a defect in the nonheme iron protein region of the respiratory chain as postulated by Goldfischer et al [1973] but pointed to a functional abnormality of cyt b in their patient.

This strand of thinking was pursued most ingeniously by Dr. Sharp’s group of gastroenterologists at the University of Minnesota [Hanson et al, 19791. Proceeding from results of in vitro studies (which had suggested that the formation of CZ4 bile

At that meeting Taylor et a1 presented a new case of the Zellweger syndrome. This

The collaborative studies of investigators from the Universities of Munich and


acids - chenodeoxylic acid and cholic acid - from C2, cholesterol requires mitochondrial oxidative cleavage of the terminal 3 carbons of the side chain) these investigators studied 3 Zellweger syndrome patients for the presence of mitochondrial defects in bile acid synthesis. All 3 excreted excessive amounts of 3a, 7a-dihydroxy-5 0-cholestan-26-oic acid, 301, 7a, 12a-trihydroxy-5 0-cholestan-26-oic acid, and 3a, 7a, 12a, 240-tetrahydroxy-5 0-cholestan-26-oic acid (varanic acid), precursors of chenodeoxylic acid and cholic acid that had undergone only partial side chain oxidation. These findings strongly supported the role of mitochondrial oxidative side chain cleavage in the overall scheme of bile acid synthesis and the hypothesis of defective mitochondrial oxidation in the Zellweger syndrome. It also suggests a diagnostic test in doubtful or suspected cases.

Thus, the clinico-pathological changes in the Zellweger syndrome include: Craniofacial. Characteristic appearance with pear or light-bulb shaped head, full

upper lids, slight mongoloid slant of palpebral fissures, epicanthic folds, minor anomalies of formation of auricles, micrognathia, fullness of “jowls” and of nape of neck, initially normal OFC, late microcephaly, normocephaly, or megaloencephaly.

Eyes. Corneal clouding, cataracts, congenital glaucoma, occasional microphthalmia, nystagmus retinal holes without detachment, retinal degeneration with extinguished ERG.

CNS. Severe to profound congential hypotonia, virtual absenc of psychomotor development and failure of development of visual, auditory or other sensory discrimina- tions, seizures, highly abnormal EEG and reduced DTR’s. Megalencephaly: increased brain water content. CNS dysgenesis affecting cerebral hemispheres, cerebellum, and the inferior olivary complex. Neocortical malformation associated with neuronal heterotopia, pachygyria, micropolygyria or focal lissencephaly. Impeded neuronal migration affecting only part of the cortical neurons (most neurons of cortical layers I1 and I11 are in their normal laminar positions, while others lie in heterotopic intra- and subcortical positions). In the cerebellum, large Purkinje cell hetereotopias lie subjacent to intact Purkinje and granule cell cortical laminae. Striking laminar discontinuities in the principal nucleus of the inferior olivary complex. Accumulation of lipid within histiocytes or free in gray and white matter, marked proliferation of protoplasmic astrocytes in gray matter. Clus- ters of lipid-filled macrophages and occasional cholesterol crystals may be seen in the molecular layer of the cerebellum. Occasional widespread diffuse degeneration of medul- lated nerve fibers in the cerebral white matter with phagocytosis of sudanophilic material by histocytes and microghal cells.

Skeletal. More or less extensive chondrodysplasia ,calcificans congenita-like stippling of cartilage epiphyses, occipital bone, patellae, hips, and greater trochanters. Later porosis, reduction in bone age, hypotonic bell-shaped thoracic cage; rare metaphyseal lucencies due to intraosseous vascular abnormalities.

Limbs. Camptodacytly of fingers, limitation of motion at large-small joints, club- foot, metatarsus adductus, or rocker-bottom feet, simian creases - mostly indications of prenatal movement disorder (reduction).

Reticuloendothelial system. Excessive accumulation of iron in spleen, bone marrow, liver, lungs, etc. Extramedullary hematopoiesis, hypoplasia or absence of thymus.

Lungs. Pulmonary hypoplasia, pneumonia as fatal event, rare pneumocystis carini infection.

182 Friedman et a1

Heart. Patent ductus arteriosus, patent foramen ovale, marked focal internal fibrosis of the aorta, anomalous venous return, double outlet right ventricle, ventricular septal defect, anomalies of aortic arch (interrruption, dextroposition, origin of left com- mon carotid artery from the proximal innominate artery).

pancreatic islets, sometimes with hypoglycemia.

of multiple cortical cysts, congenital glomerulosclerosis, albuminuria, excessive excretion of several amino acids, ureteral duplication.

Genital system. Maldescent of gonads in both sexes, clitoral hypertrophy, rarely hypospadias.

Liver. Hepatomegaly with invariable lobular disarray and apparently progressive fibrosis, less commonly micronodular cirrhosis, intrahepatic biliary dysgenesis and bile stasis, ultrastructural defects of mitochondria and absence of peroxisomes, symptomatic liver disease (jaundice, hypoprothrombinemia).

Endocrine glands. Frequently reduced weight of adrenals, marked hyperplasia of

Urinary system. Fetal lobulation, occasional horseshoe kidney, frequent presence

Gastrointestinal tract. Malrotation of colon, Meckel’s diverticulum.

Others. In one case an unusual granulomatous process was seen in parapsoatic fatty tissue with the occurrence of giant cells, calcifications and empty crystal spaces.

In summation: the Zellweger syndrome is a lethal, autosomal recessive disorder affecting virtually every organ and tissue in the body and including anomalies of incomplete differentiation, aplasias, hypoplasias, hyperplasias, dysplasias, structural and functional immaturities, deformities and other manifestations of congenitally severely disturbed CNS function, and disease manifestations due to complications of hypotonia and liver involvement. Basic problem seems to be defect of mitochondrial oxidative function in every tissue tested so far. Particulate catalase has been found to be deficient in liver.

DISCUSSION

Dr. John Opitz, Departments of Medical Genetics and Pediatrics

I make a few final remarks about this case with high respect for the elegant and scholarly expositions of Drs. Hong and Gilbert and with some frustration and sadness about subsequent events in this family.

When the child was at Madison General Hospital, both clinical geneticist-faculty members were out of town, consulting clinicians were puzzled by the combination of unusually severe liver disease, joint involvement, and minor cranio-facial development anomalies. The infant’s appearance was not as typical as in the usual Zellweger syndrome case and he had hypertonia rather than hypotonia. The possibility of congenital infection and/or poisoning was a “red herring” which misled clinicians and side tracked pathol- ogists until the typical CNS findings were correctly interpreted by Dr. Viseskul, and ultrastructural studies of the liver confirmed absence of peroxisomes.

By the time a year had elapsed since the infant’s death. During this interval the parents could not be given a definite diagnosis or correct genetic counseling. And while the University stayed in contact with the parents by correspondence, the parents moved to Iowa and the terminal care of the mother’s subsequent pregnancy was assumed by the State University of Iowa Hospitals. Recently Dr. James W. Hanson called from Iowa City to tell me that the mother had had another affected infant boy.


What are the lessons to be learned from this case to prevent recurrence of similar events in the future? First we must go back to the clinical presentation of Dr. Hong’s discussion. I strongly suspect that Dr. Hong’s final diagnosis was made tongue-in-cheek to spoof the clinical geneticists and their acronymic naming propensities. Also, Dr. Hong may have needed a diverting ploy to slight the ease with which he made the correct diagnosis. Or was it the right diagnosis? I was told by Dr. Hanson that when Dr. Zellweger saw the recently born affected brother he seriously questioned the diagnosis.

The clinician’s “multisystem disease” is the epistemological equivalent of the geneticist’s “pleiotropy,” which means that all manifestations are a consequence of one cause whether mendelian or chromosomal mutation, teratogen, or multifactorial genetic/ environmental interaction. The presence of minor anomalies and arthrogryposis-like contractures in this child implies a congenital onset; economy of hypotheses demands that all of his development defects, deformities, and disease manifestations be viewed as components of a single syndrome, whatever its cause or pathogenesis.

A MEDLINE search for a syndrome of profound psychomotor retardation, congenital contractures, and liver disease will yield among others, references on the Zellweger syndrome. It may have missed the crucial paper by Versmold et al [I9771 because the eponym was not among the key words coded by those authors. However, the term “cerebro-hepato-renal syndrome” was. The biochemical findings reported in that paper were discussed above by Dr. Gilbert. Here we are only interested in the child’s clinical manifestations.

That boy’s intrauterine growth had been normal; postnatal growth was severely impaired. The infant was hypertonic, lacked the typical Zellweger syndrome appearance and epiphyseal cartilage stippling; several EEG’s were normal. The fundi were peripherally hypopigmented in a manner suggesting retinitis pigmentosa, and there was hypochromic anemia. However, the infant did have increased serum iron, saturated iron binding capacity and transferrin levels. The infant lived longer than most Zellweger syndrome patients do, dying suddenly at 15 months. Profound psychomotor retardation, apparent blindness and deafness, and liver disease were present before death. The clinical picture was suf- ficiently atypical so that the authors spoke of a “metabolic disorder similar to Zellweger syndrome . . .,” but autopsy findings were exactly like those in classic Zellweger syndrome.

Our patient apparently had the hypertonic “Zellweger syndrome-like’’ disorder reported by Versmold et al [ 19771 . considering the extraordinary spectrum of CNS abnormalities known in the Zellweger syndrome, I am not too surprised at hypertonia in a syndrome ordinarily expected to present with hypotonia; however, there is sufficient difference in clinical manifestations to concede the point that our patient and that of Versmold et a1 may have had a disorder different from the Zellweger syndrome.

Does that mean that the “pseudo-Zellweger” syndrome is not a genetic disorder and that the mother of our patient therefore had a neghgibly small recurrence risk? The older sib of the Versmold et a1 patient was also affected - thus, both mothers have a 25% recurrence risk. Due to the above mentioned circumstances this risks was not conveyed to the mother of our patient in time.

In this connection the following is of interest. One of the co-authors of the Versmold et a1 paper (Prof. H.J. Bremer, Dusseldorf) wrote to me on 11 March, 1976 that “. . . our Munich-Dusseldorf group has examined 2 additional children, both with the “classic” [Zellweger syndrome] manifestations. In these children we also found the defect of particulate catalase (no defect of the non-particulate catalase of cells such as erythrocytes) and the same redox changes of cytochrome b and c as in the clinically some-

184 Friedman et a1

what atypical case. In addition it was possible to demonstrate conclusively that, contrary to Goldfischer’s results, electron transport in the nonheme-iron region is normal. His contrary results are probably due to postmortem changes. . . . At the moment it remains an open question whether the defect of particulate catalase is the primary defect or whether - like the changes in the cytochrome b and c region - it is a secondary defect (perhaps involving enzyme protein structure).” In that letter Professor Bremer alludes to my previous suggestion that the 2 entities might be the same, but rather variable disorder; since in his family and the one under discussion, 2 sets of brothers are affected (no living sisters), X-linked inheritance of the “pseudo-Zellweger syndrome’’ should also be considered.

collaborate with clinicians in appropriate studies to determine feasibility of prenatal diagnosis in both disorders and of carrier detection in the “pseudo-Zellweger” syndrome should it turn out to be an X-linked disorder. Because of the complexity of the biochemical reactions in question, I would not be surprised about genetic heterogeneity.

Pathogenetically, what kind of syndrome is this condition? Initially we viewed it as a true multiple congenital anomalies (MCA), ie, malformation syndrome. In this case it is marvelous to see how hindsight can improve the clinician’s understanding of the pathogenetic nature of a given syndrome. For in view of the severe generalized mitochondrial oxidative defect, the development manifestations of the Zellweger syndrome can only be regarded as results of a prenatal metabolic dysplasia which mostly results in anomalies of incomplete development.

But at the end it must be stated clearly that regardless of the scientific aspects of the subject, which may be studied and argued for another few decades, the birth of the second affected child in the family under discussion was preventable and, so far as I am able to determine, this failure represents too many “cooks for the pie” with none taking sole responsibility, or a breakdown of communications within the complex and far-flung web of University Hospital staff and faculty. Most likely, it is a combination of both and at the same time a sharp reminder that a University setting ought not to preclude the best of primary care skills.

I shall leave it to the somatic cell geneticists and metabolic disease specialists to

REFERENCES

Agamanolis DP, Robinson HB Jr, Timmons GD: Cerebro-hepato-renal syndrome. Report of a case with histochemical and ultrastructural observations. J Neuropath Exp Neurol 35:226-246, 1976.

Ariizumi M: Cerebro-hepato-renal syndrome. Nippon Rinsho Suppl 1480-1481, 1978. Bartoletti S, Armfield SL 111, Ledesma-Medina J: The cerebro-hepato-renal (Zellweger’s) syndrome:

Report of four cases. Radiology 127:741-745, 1978. Bernstein J, Brough AJ, McAdams AJ: The renal lesion in syndromes of multiple congenital malforma-

tions. Cerebrohepatorenal syndrome; Jeune asphyxiating thoracic dystrophy; tuberous sclerosis; Meckel syndrome. BDOAS X/4:35-43, 1973.

Bull Johns Hopkins Hosp 114:402-414, 1964.

neuropathology, and the demonstration of Penumocystis carinii pneumonitis in two siblings. Eur J Pediatr 127:229-245, 1978.

29: 2473-2478,1977.

renal de Zellweger. Rev Espaii Pediatr 29:455-470, 1973.

Bowen P, Lee CSN, Zellweger H, Lindenberg R: A familial syndrome of multiple congenital defects.

Brun A, Gilboa M, Meeuwisse GW, Nordgren H: The Zellweger syndrome: subcellular pathology,

Camera C, Centa A, Canepa M: A case of Zellweger’s cerebro-hepato-renal syndrome. Minerva Pediatr.

Cotero A, Prats JM, Bilbao F, Camarero C, Larrea F, Rodriguez Soriano J: Syndrome cerebro-hepato-


Danks DM, Tippett P, Adams C, Campbell P: Cerebro-heapto-renal syndrome of Zellweger. J Pediatr

Evrard P, Caviness VS Jr, Prats-Vinas J , Lyon G: The mechanism of arrest of neuronal migration in 86:382-387,1975.

the Zellweger malformation, an hypothesis based upon cytoarchitectonic analysis. Acta Neuro- pathol (Berl) 41:109-117, 1978.

Garzuly F, Szabo L, Kadas L: Neuronale Migrationsstorungen bei Cerebro-Hepato-Renalem Syndrom “Zellweger.” Neuropadiatrie 5: 318-328, 1974.

Gilchrist KW, Opitz JM, Gilbert EF, Tsang W, Miller P: Immunodeficiency in the cerebro-hepato-renal syndrome of Zellweger. Lancet 1:164-165, 1974.

Gilchrist KW, Gilbert EF, Shahidi NT, Opitz JM: The evaluation of infants with the Zellweger (cerebro- hepato-renal) syndrome. Clin Genet 7:413-416, 1975.

Gilchrist KW, Gilbert EF, Goldfarb S, Spranger JW, Opitz JM: Studies of malformation syndrome of man XIB. The cerebro-hepato-renal syndrome of Zellweger: comparative pathology. Eur J Pediatr 121:99-188, 1976.

Goldfischer S, Moore CL, Johnson AB, Spiro AG, Valsamis MP, Wisniewski HK, Ritch RH, Norton WT, Rapin I, Gartner LM: Peroxisomal and mitochondria1 defects in the cerebro-hepato-renal syndrome. Science 182:62-64, 1973.

Hanson RF, Szczepanik-Van Leeuwen P, Williams GC, Grabowski G, Sharp HL: Defects of bile acid synthesis in Zellweger’s syndrome. Science 203: 1107-1108, 1979.

Jan JE, Hardwick DF, Lowry RB, McCormick AQ: Cerebro-hepato-renal syndrome of Zellweger. Am J DisChild 119:274-277, 1970.

Kohn R, Mundel G : Cerebro-hepato-renal syndrome: report of a case. Helv Paediatr Acta 24:352-360, 1969.

Monnens L, Bakkeren J , Parmentier G, Janssen G, van Haelst U, Trijbels F , Eyssen H: Disturbances in bile acid metabolism of infants with the Zellweger (cerebro-hepato-renal) syndrome. Europ J Pediatr 133:31-35, 1980.

Gerritsen T: The Zellweger syndrome (cerebro-hepato-renal syndrome). BDOAS V/2: 144-158, 1969.

Opitz JM, ZuRhein GM, Vitale L, Shahidi NT, Howe JJ, Chou SM, Shanklin DR, Sybers HD, Dood AR,

Passarge E, McAdams AJ: Cerebro-hepato-renal syndrome. J Pediatr 71:691-702, 1967. Patton RH, Christie DL, Smith DW, Beckwith JB: Cerebro-hepato-renal syndrome of Zellweger: Two

patients with islet cell hyperplasia, hypoglycemia and thymic anomalies, and comments on iron metabolism. Am J Dis Child 124:840-844, 1972.

Roentgen01 Rad Ther Nucl Med 109:313-322, 1970.

failure to thrive. J Pediatr 73:602-606, 1968.

Poznanski AK, Nosanchuk JS, Baublis J, Holt JF: The cerebro-hepato-renal syndrome (CHRS). Am J

Punnett HH, Kirkpatrick JA: A syndrome of ocular abnormalities, calcification of cartilage, and

Schmid F: Padiatrische Radiologie, Vol 1. Berlin-Heidelberg-New York: Springer, 1973, pp 248-256. Simpson JL, German J: Developmental anomaly resembling the trisomy 18 syndrome. Ann G6nBt

12:107-110, 1969. Smith DW, Opitz JM, Inhorn SL: A syndrome of multiple developmental defects including polycystic

kidneys and intrahepatic biliary dysgenesis in two siblings. J Pediatr 67:617-624, 1965. Sommer A, Bradel EG, Hamoudi AB: The cerebro-hepato-renal syndrome (Zellweger’s syndrome).

Biol Neonat 25:219-229,1974. Stanescu B, Dralands L: Cerebro-hepato-renal (Zellweger’s syndrome). Ocular involvement. Arch

Ophthal 87:590-592, 1972. Taylor JC, Zellweger H, Hanson JW: Addendum: A new case of the Zellweger syndrome. BDOAS

V,’2:159-160,1969. Trijbels J, Monnens L, Bookelman H, Willems J, Raay-Selten A van, Corstiaensen J : Biochemical studies

in the cerebro-hepato-renal syndrome of Zellweger. J Inher Metab Dis 2:39-43, 1979. Versmold H, Brauser B, Herzog V, Bassewitz H von, Bremer HJ: Deficiency of peroxisomes, catalase

and cytochrome B : A genetic defect of oxygen metabolism? Pediatr Res (Abstract): 9:861, 1975 Versmold HT, Bremer HJ, Herzog V, Siege1 G, Bassewitz DB von, Irle U, Voss H von, Lombeck I,

Brauser B: A metabolic disorder similar to Zellweger syndrome with hepatic acatalasia and absence of peroxisomes, altered content and redox state of cytochromes, and infantile cirrhosis with hemosiderosis. Eur J Pediatr 124:261-275,1977.

Vincens A, Guillat J-C, Gatin G, Rodier J, Graveleau D: A propos d’un cas de syndrome de Zellweger

186 Friedman et al

(syndrome hCpato-cCr%bro-rdnal). Ann Pbdiatr 20:593-560, 1973.

1969.

migration. Actd Neuropathol (Berl) 20:175-198, 1972.

hepatorenal syndrome of Zellweger. Am J Roentgmol 115:607-610, 1972.

Vitale L, Opitz JM, Shahidi NT: Congenital and familial iron overload. N Lngl J Med 280:642 645,

Volpe J J , Adams KD: Cerebro-hepato-renal syndrome of Zellweger: An inherited disorder of neuronal

William JP, Secrist L, Fowtcr GW, Gwinn JL, Dumars KC: Roentgenographic features of cerebro-

Addendum: After completion of the CPC there was published the work by Monnens et al [ 19801, which confirmed the work by Hanson et a l [I9791 by demonstrating increased serum levels of di- and trhydroxycoprostanic acid.

Clinicopathologic conference: A three-month-old infant with failure to thrive, hepatomegaly, and...

Documents

Transcript of Clinicopathologic conference: A three-month-old infant with failure to thrive, hepatomegaly, and...