BRIEF REPORTCongenital Hepatoblastoma and Schizencephaly in an Infant With

Beckwith-Wiedemann Syndrome

Laura L. Worth, MD, PhD,1 John M. Slopis, MD,2 and Cynthia E. Herzog, MD1*

Key words: hepatoblastoma; schizencephaly; Beckwith-Wiedemann syndrome;seizures

Hepatoblastoma is the most common malignant tumorof the liver in infants and children, but has only rarelybeen reported in newborns [1–6]. Surgical resection isthe preferred treatment, but fewer than half of hepato-blastomas are resectable at diagnosis [6]. Preoperativechemotherapy has improved the outcome for patients byshrinking tumors, thereby increasing the proportion ofresectable lesions. Several chemotherapeutic combina-tions have been shown to be effective, cisplatin being thecore of most regimens [5,7,8]. However, a challenge oc-curs when treating neonates with chemotherapeuticagents that require renal or hepatic metabolism or excre-tion; neither of these organs is fully developed even in afull-term infant. Our experience with a newborn withBeckwith-Wiedemann syndrome (BWS) and hepatoblas-toma, who required preoperative chemotherapy, is there-fore instructive.

Our patient was a 4,100 g term male infant born to a37-year-old Hispanic female. The pregnancy and deliv-ery were uncomplicated. At birth his physical examina-tion was notable for an enlarged liver that extended to thelevel of the umbilicus, an umbilical hernia, a left-sidehydrocele, and asymmetry of the lower extremities. Theright thigh measured 14 cm and the left thigh 16.5 cm.The neonatal period was complicated by hypoglycemiathat responded to glucose administration. No chromo-somal anomalies in the peripheral blood monocytes weredetected.

Magnetic resonance imaging revealed a 9 × 7 × 7 cmheterogeneous mass involving the right lobe of the liverthat compressed the intrahepatic inferior vena cava.Chest CT was negative for metastases. A fine-needleaspirate of the mass confirmed the diagnosis of hepato-blastoma. No embryonal elements were present; the fetalpattern showed some differentiation.

Because the mass was unresectable, the infant wastreated with two courses of preoperative carboplatin (tar-get AUC of 5 ml/min/m2) and fluorouracil (20 mg/kg).There was an initial response with a fall in thea-feto-

protein (AFP) level, but the AFP rose prior to and fol-lowing the second course (Table I). He was taken tosurgery, where a gross total resection was achieved. Fol-lowing surgery he was treated with two cycles of doxo-rubicin (2.5 mg/kg), vincristine (1.5 mg/m2), and cisplat-in (3 mg/kg). For the second course, the vincristine wasaltered to 0.05 mg/kg secondary to possible gastric outletsyndrome (bilious emesis) following the first vincristine.He has been off therapy for 15 months and is withoutevidence of cancer.

The patient continued to grow and develop normally;however, at 12 months of age he had a seizure that wasassociated with a temperature to 101°F. It was atypicalfor a febrile seizure because it was associated with post-ictal paralysis. Two months later, the patient experienceda generalized seizure lasting 20–25 min. An EEG wasobtained and showed evidence of right hemispheric sharpwaves, with intermittent slowing. An MRI of the brain(Fig. 1) showed a signal pattern consistent with an ab-normal neural migration pattern, or schizencephaly. Hehas had no further seizure activity after the initiation ofdilantin therapy.

DISCUSSION

The Beckwith-Wiedemann syndrome (BWS) occursin 1:15,000 live births. This child had many physicalcharacteristics consistent with that diagnosis: hemihyper-

1Department of Pediatrics, University of Texas M.D. Anderson CancerCenter, Houston, Texas2Department of Neurology, University of Texas Medical School,Houston, Texas

*Correspondence to: Cynthia E. Herzog, M.D., Department of Pedi-atrics, University of Texas M.D. Anderson Cancer Center, 1515 Hol-combe Blvd., Box 87, Houston, TX 77030.E-mail: cherzog@mdanderson.org

Received 10 June 1999; Accepted 2 August 1999

Medical and Pediatric Oncology 33:591–593 (1999)

© 1999 Wiley-Liss, Inc.

tophy (Fig. 2), large size for gestational age, hypoglyce-mia in the newborn period, earlobe creases, an abdominalwall defect, and hepatoblastoma. Approximately 7.5% ofpatients with BWS develop tumors [9], Wilms tumorbeing the most common (>50%) and hepatoblastoma oc-curring less commonly.

Cancer in the first year of life is relatively rare [10,11].Administration of chemotherapy in the newborn period iscomplicated by the fact that the kidney and liver are not

yet fully functional, and mature organs are necessary forthe metabolism or excretion of many anticancer agents[12,13]. Chemotherapy for hepatoblastoma includes cis-platin given in combination with doxorubicin [5,7] or

TABLE I. Changes in Laboratory Values With Time*

AgeAFP

(ng/ml)GFR

(ml/min/m2)

Bilirubin(mg/100 ml)(total/direct) Comment

1 Day 129,5006 Days 226,029 41 20.1/9.4 Carbo/5FU21 Days 46,71527 Days 52,928 50 9.0/5.5 Carbo/5FU48 Days 176,83760 Days 165,610 Surgical resection62 Days 685,00074 Days 13,947 70 1.6 CDDP/Adr/VCR83 Days 7,427 0.4 CDDP/Adr/VCR4 Months 3234.5 Months 90.46.5 Months 35.97.5 Months 14.410 Months 4.6 0.3

*Carbo, carboplatin; 5FU, fluorouracil; CDDP, cisplatin; Adr, doxo-rubicin; VCR, vincristine.

Fig. 1. MRI scan of the brain showing abnormal signal pattern con-sistent with schizencephaly (arrow).

Fig. 2. Hemihypertrophy of left lower extremity.

592 Worth et al.

fluorouracil and vincristine [8]. In our patient, treatmentwas further complicated by ABO incompatibility andmarked hyperbilirubinemia (Table I), so vincristine anddoxorubicin were contraindicated. The low renal func-tion, although appropriate for age, made us reluctant touse cisplatin. Carboplatin was chosen as an initialtherapy because doses could be calculated based on cur-rent renal function, and it has a response profile similar tothat of cisplatin in most cases [14]. The infant was there-fore initially treated with carboplatin and fluorouracil.The AFP level decreased after the first course of therapy,but rose prior to the second course and continued to riseeven thereafter (Table I). Because of the rising AFP andlimitations on our ability to give other chemotherapeuticagents safely, the patient was taken to surgery and thetumor was removed. Postoperatively, the bilirubin levelnormalized and his renal function improved. He was thentreated with two courses of cisplatin, doxorubicin, andvincristine, with AFP levels as shown in Table I.

The development of a seizure disorder was unex-pected. There are currently no reports in the literature ofseizures associated with BWS beyond the risk of hypo-glycemic seizure in the newborn period [15]. BWS hasbeen speculatively grouped with other macrocephalicovergrowth syndromes [16]; however, unlike the casewith neurofibromatosis type I and Zellweger syndrome,no reports of neuronal migrational abnormality and brainmalformation have been reported [16]. Although cases ofBWS have been mapped to gene locus 11p15.5 [17],none of the numerous characterized genes has been spe-cifically implicated in brain malformations. At this timethe relationship between BWS and neuronal migrationand neurogenic tumors, if any, remains unclear.

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