Pediatric Article
NEOPLASMS ASSOCIATED WITH HEMIHYPERTROPHY, BECKWITH- WIEDEMANN SYNDROME AND ANIRIDIA
EDWARD S. TANK AND ROBERT KAY From the Division of Urology, University of Oregon Health Sciences Center, Portland, Oregon
ABSTRACT
Hemihypertrophy and the Beckwith-Wiedemann syndrome are associated with Wilms tumor and adrenocortical carcinoma. These conditions also have a relationship with nodular renal blastema, nephroblastomatosis and adrenocortical adenomas, all of which are pre-malignant lesions. Children with aniridia also are predisposed to development of Wilms tumors.
Herein we describe 4 cases of nephroblastoma in combination with hemihypertrophy. In 1 of these cases body asymmetry and the Beckwith-Wiedemann syndrome were present in associa- tion with bilateral multifocal Wilms tumor and renal nodular blastema. We also report on another child with adrenocortical carcinoma presenting as the Cushing’s syndrome who had hemihypertrophy and 1 child with aniridia and Wilms tumor. A regimen for following children after recognition of these conditions predisposing to malignancy is presented.
HEMIHYPERTROPHY
A definite relationship has long been established between hemihypertrophy and the development in childhood of Wilms tumor, adrenocortical carcinoma and primary hepatocellular carcinoma.1-5 In addition, pre-malignant lesions, such as nodular renal blastema, nephroblastomatosis, adenomas of the adrenal cortex and focal nodular hyperplasia of the liver, have been associated with body asymmetry.6, 7
Hemihypertrophy must be distinguished from hemiatrophy and hemidystrophy. Hemihypertrophy is always present at birth but often becomes more apparent at puberty. The birth weight of these children is normal. The patient has bony and soft tissue enlargement of the involved body parts. On the other hand, hemiatrophy is associated with somatic underdevelop- ment and often with intrauterine growth retardation. The larger half of the body is normal in size. Frequently, hemidystrophy follows neurologic disorders and is characterized by diminished fat and subcutaneous tissues.
Hemihypertrophy is found more frequently on the right side of the body. Ipsilateral tumors are seen in only 60 per cent of the cases. Family history usually is negative, although there is a report of a woman with hemihypertrophy who had 3 of 4 children with Wilms tumor.8
Case reports. K. M., a 5-year 7-month-old girl, was discovered to have a left Wilms tumor and, subsequently, right lower extremity hemihypertrophy. Her mother also had right lower extremity hemihypertrophy. The patient had stage I disease and is considered cured 6 years after radical nephrectomy.
C. C., a 5-year-old boy, had a right flank mass that was defined as a Wilms tumor by retrograde pyelography and nephrectomy. The patient had contralateral whole body hemi- hypertrophy. At diagnosis of the primary tumor pulmonary metastases were present. He died despite irradiation and che- motherapy.
Accepted for publication October 5, 1979.
S. B. had right hemihypertrophy as an infant. Excretory urograms (IVPs) were normal when the patient was 9 months and 2 years 10 months old. When the child was 4 years 5 months old a right upper quadrant mass was discovered. An extensive Wilms tumor was defined by selective renal angiog- raphy and bilateral pulmonary metastases were present. Che- motherapy was effective in reducing dramatically the size of the primary tumor. At nephrectomy there was extension through the capsule and 1 of 7 hilar nodes was positive. Despite post- operative chemotherapy and irradiation therapy the patient died.
S. I. was normal until she was 1 year old when Cushing’s syndrome gradually developed. Initial examination when she was 18 months old revealed left whole body hemihypertrophy (fig. 1). An IVP demonstrated a left suprarenal mass with displacement of the kidney. A 7 x 5 cm. adrenocortical carci- noma was removed. Her appearance and habitus returned to normal postoperatively and the patient continues to be free of tumor 15 years later.
Comment. In most instances hemihypertrophy is a retrospec- tive finding, discovered after the patient has been diagnosed as having a Wilms tumor or adrenal carcinoma. This was true in our experience, since only 1 of the 5 children we have seen presented with a tumor after recognition of the body asymme- try. In 2 cases the patients already had pulmonary metastases when the neoplasm was first detected, did not respond to therapy and died. In 1 instance recognition of the hemihyper- trophy was at birth. Despite awareness of the significance of this abnormality the surveillance schedule was inadequate and the tumor was discovered late.
Adrenocortical carcinoma associated with hemihypertrophy has now been documented in 3 instances, including our case 4. Another child with adrenocortical adenoma and hemihypertro- phy who subsequently had a Wilms tumor has been reported.
BECKWITH-WIEDEMANN SYNDROME
The Beckwith-Wiedemann syndrome is a constellation of clinical abnormalities that include varying combinations of omphalocele or umbilical hernia, macroglossia, natal or post- natal gigantism, nephromegaly, hepatomegaly, neonatal hypo- glycemia, microcephaly, hemihypertrophy and mental retarda- tion (fig. 2). There have been 14 such cases of the Beckwith- Wiedemann syndrome and malignant tumors reported. These tumors include Wilms tumors (6), adrenocortical carcinoma (5), hepatoblastoma (1), alveolar rhabdomyosarcoma (1) and brain stem astrocytoma (1).9 Of these patients 2 had 2 separate
NEOPLASMS ASSOCIATED WITH HEMIHYPERTROPHY, BECKWITH-WIEDEMANN SYNDROME AND ANIRIDIA 267
primaries. A malignant tumor will develop in 1 of 10 patients with the Beckwith-Wiedemann syndrome and 1 of 8 patients also will have associated hemihypertrophy. Of 17 patients re- ported on with the Beckwith-Wiedemann syndrome 3 had nodular renal blastema and/or nephroblastomatosis. Nodular renal blastema is characterized by microscopic nodules of prim- itive metanephric epithelium, which are multicentric, bilateral and subcapsular.1º Nephroblastomatosis identifies massive and confluent lesions of the same character. Nodular renal blastema is found in 1 of 1,000 autopsies in the general autopsy population and in 1 of 235 postmortem examinations of infants <4 months old. There seems to be a definite analogy here with Beckwith’s observations of the high incidence of in situ neuroblastomas in infants dying of congenital anomalies.11
Case report. K. M. was born with the Beckwith-Wiedemann syndrome characterized by macroglossia, omphalocele and he- mihypertrophy of the entire right side of the body. When she was 4 years old bilateral flank masses were noted. An IVP revealed bilateral caliceal distortion consistent with a Wilms tumor. Angiography defined diffuse involvement of the right kidney and upper pole involvement of the left kidney. A right nephrectomy and left renal biopsy were performed. Histologic evaluation revealed bilateral, multifocal Wilms tumors with areas of nodular renal blastema. Postoperative treatment con- sisted of actinomycin D, vincristine and irradiation. The pye- logram of the remaining solitary kidney 1 year later had re- turned to normal and has remained so for 4 years. However, a solitary left pulmonary metastasis developed 3 years after the
initial operation, which responded to chemotherapy. The pa- tient is now free of disease on sustained chemotherapy.
ANIRIDIA
Congenital aniridia is almost always bilateral and occurs in from 1 in 50,000 to 100,000 live births. It is seen as a familial and sporadic condition. The familial type constitutes approxi- mately two-thirds of the patients with bilateral aniridia and the sporadic only one-third of such cases. All but 1 case of Wilms tumor reported in the literature have been associated with the sporadic type.12, 13 Nephroblastoma will develop in one-third of the patients with sporadic aniridia. There is even a higher risk if sporadic aniridia is associated with genitourinary malforma- tion and mental retardation.
Case report. J. C. was born with bilateral aniridia, congenital cataracts, duplication of the right renal collecting system, mi- cropenis, bifid scrotum, bilateral undescended testes, congenital hydrocephalus and mental retardation. When he was 18 months old a left flank mass was found, which proved to be a stage I Wilms tumor. Post-nephrectomy irradiation therapy was given. He is considered cured 12 years later.
DISCUSSION
Followup surveillance of these children is essential after recognition of hemihypertrophy, Beckwith-Wiedemann syn- drome or aniridia. Optimally, these anomalies should be de- tected at birth. Surveillance should include a careful physical
examination every 3 months until the patient is 15 years old. An IVP should be done at the discovery of the congenital abnormalities and every 6 months after that until the patient is 7 years old, then it is done yearly. These pyelograms should be abbreviated. The remainder of the body, especially the gonads, should be shielded, since only the renal and adrenal areas need to be exposed to irradiation. The value of ultrasonography in the early detection of subclinical renal tumors in children has not been established. Annual liver function tests, liver-spleen scans and serum a-fetoprotein evaluations should be done for early detection of hepatocellular carcinoma.
REFERENCES
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EDITORIAL COMMENT
The authors have emphasized well the important point that when one of these infants is recognized it is not enough to screen them once but instead interval, repeated screening is necessary. We also have had 1 of these infants in whom a Wilms tumor developed late, despite 2 prior negative IVPs. The followup program outlined in this paper seems entirely reasonable and justified.
W. Hardy Hendren Department of Pediatric Surgery Massachusetts General Hospital Boston, Massachusetts