Document GKGQrGqx0rKkGL7GMYQRVoKXY

Case Reports . Familial Neuroblastoma Kusumakumary P. Ravindran Ankathil Priyakumari T. Krishnan Nair Neuroblastoma is the common extracranial solid tumor in children. The cause of neuroblastoma is unknown in most cases. No prenatal or postnatal exposure to drugs, chemicals or radiation has been associated unequivocally with an increased incidence of neuroblastoma. Neuroblastomas usually occur sporadically,but familial incidences have been reported(1,2). This indicates that some patients exhibit a genetic predisposition to develop neuroblastomas. We have come across two families-in one family two siblings were affected and in the other first cousins were affected by neuroblastoma. The clinical features of these four patients and a discussionon genetic aspects of neuroblastomas are. included in this report. Case Reports Family 1 Patienr I: A 9-month-old female patient was brought to us in November 1992 with one month history of irregular fever, abdominal distension and proptosis of left eye. On From the Regional Cancer Center, Trivandnun 695 001. India. Reprint requests: Dr. P. Kusumakumay, Associate Professor, Division of Pedurrir OncologyB Regional Caner Gnter. Trivandrum 695 001, India. E-mail: rcctvm@rndZ.vsnl.ner.in Manuscript Rereived. April 19, 1999, Iniriul review.completed: M a y 25, 1999, Revision Accepted: Ju!.v 26, 1999 examination she was found to have proptosis and periorbital ecchymosisof left eye, swelling of left parietal bone-and a hard nontender fixed nodular mass in the left hypochondirum crossing the midline. CI'scan c o n f i i d a mass in the paravertebral region below the left kidney, extending downwards to left iliac fossa. Laparotomy showed a large unresectable left paravertebral tu= which was biopsied and the histopathological report was neuroblastoma. Bone scan revealed.increased uptake over left parietal bone and marrow aspirate was positive for neuroblastoma cells. The patient was categorized as having stage IV disease. Treatment consisted of 6 cycles of chemotherapy with injection vincristine, cyclophosphamide and doxorubicin at 3 weekly intervals. Tumor was found to be unresectable after 6 courses of chemotherapy. Parents shifted their residence to some other state and were lost for follow up. The child was brought along with her sibling after 5 years and re-evaluation did not reveal any evidence of disease. farienr II: In June 1997, 3-year-old younger brother of patient I was brought with complaints of progressive pallor, irregular fever, pain right leg and ecchymosis around both eyes. On general examination he was found to have anemia, periorbital ecchymosis, scalp swelling over left temporal region and bilateral cervical lymphadenopathy. Abdominal examination revealed a mass in right lumbar region which was hard in consistency.CI'scan showed mixed density masses in both suprarenal region with areas of calcification. Biopsy from the scalp swelling was diagnostic of neuroblastoma. Skeletal survey revealed lytic lesions of left femur and sutural diastasis in skull bones. Bone marrow examination showed infiltration with INDIAN PEDIATRICS 85 VOLUME 37- JANUARY 2000 CASE REP9RTS neuroblastoma cells. Parents refused chemotherapy and the patient was lost for follow up. The pedigree of these 2 patients is shown in Fig. 1 . Family 2 Patient I l l A 5-year-old girl was brought on 71-98 with the complaints of multiple scalp swelling of one month duration and swelling of right side of neck of 2 weeks duration. On general examination she was found to have pallor, multiple scalp swelling and right cervical adenopathy. Abdominal examination revealed moderate hepatomegaly and a mass in the right hypochondrium. Ultrasound and CI' scan abdomen showed a fairly large mass of mixed echogenicity in the right suprarenal area, multiple paraaortic nodes and multiple metastasisin the liver. Skeletal survey and bone scan showed evidence of disease in the skull bones. Biopsy from the node was consistent with neuroblastoma. Bone marrow was infiltrated with neuroblastoma cells. Parents refused treatment and the child was lost for follow up. Patient IV: A 2Y~year-oldmale child (1st cousin of patient No. III) was brought on 12-2-98with pain right leg of 2 weeks duration and swelling of left temporal region and right cervical region of 1H week duration. He had mild pallor. Lymph nodes were palpable 2 x 2 cm on right side of neck.Bony swelling 5 x 5 cm was present over left temporal region. Systemic examination did not reveal any abnormalityexcept mild hepatomegaly. Biopsy from the lymph node was consistent with neuroblastoma. Skeletal survey showed sutural separation and lytic lesions of skull bones. Ultrasound abdomen did not reveal any abnormality. ff scan abdomen showed 'a 2.5 cm x 3 cm partly hypoechoic mass in left suprarenal area. Bone marrow examination showed evidence of disease. Patient was on combination chemotherapy with injection cisplatin, adriamycin, endoxan and VP-16. Lymphnodes and skull swellingsr e p s s e d after 2 months of chemotherapy. Child was taken abroad as the parents were working there. The pedigree of this family is shown in Fig. 2. I * F T ? # bU Y dM 65 62 58 W 58 49 Oral cancer a u0 0a 0a [I s * A?&:MIL; 4 8 4 4 3 8 36 niJ7 2.112 5 2 In w 63 Fig. I. Pedigree of Neuroblastomafamily 1. Fig. 2. Pedigree of Neuroblastomafamily 2. lNDiAN PEDIATRICS 86 VOLUME 37-JANUARY 2000 CASE REPORTS Dkcmsion neuroblastoma have bilateral adrenal or multi- focal primaries. In the present r e p o d families, hstances of familial neuroblastoma are Patient I was diagnosed at the age of 9 months, being reported with increasing frequency. but the other 3 patients ages approximate the Kushner et al.(2) in their review of literature median age at diagnosis in unselected patient, reported 23 familial aggregations of neuro- and are well beyond the peak age of diagnosis blastoma and or ganglioneuroblastoma. of familial and hereditary case (3 yr, 5 yr and Relationship of affected subjects included 2%yr). Patient IIhad bilateral adrenal primaries siblings, monozygotic twins, half siblings, which is more common in familial neuro- cousins and parent child. Draper er aL(3)had blastomas. With the important excepon of m d three families in which both children were diagnosed to have neuroblastoma. We have come across 2 neuroblastoma families in multiple primaries clinical findings do not identify hereditary cases. i whichtwo out ofthethree siblingswere affected Knudson and Strong(8) postulated aJwo ham?family and two firstcousins were affected stage genetic model for NB similar t o b for in the second family. Cases have been reported retinoblastoma. In familial or h e r e d i d cases hr which offsprings have neuroblastomas and of NB,the first hit is an inherited gemline parents had ganglioneuroma(4.5). The pre- mutation present in all cells of body and 2nd hit disposition to neuroblastoma in families has occurs post zygotically in only the somatic krenreportedto follow an autosomal dominant target cell, the neuroblast. In sporadic non- of inheritance(6). According to Draper hereditary cases, both mutations are postzygotic et a1.(3) the occurrence of cancer in multiple events in the same neuroblast. This theory members of a family can sometimes be confirm with the finding that the familial neural accounted for by the existence of known genetic crest tumors tend to cluster in the earlier years conditions predisposing to cancer. In other of life. Knudson and Strong(8) estimated that families however, the pattern of familial cancer as many as 22% of all neuroblastoma may be might be attributable either to currently un- the result of a germ line mutation. Reports from mognized cancer family syndromes or to the Childhood Cancer Research Group utposure of family members to a common (CCRG)(4) showed that the risk for a sibling of UlVkvnmental hazard, or simply due to chance. a neuroblastomapatient of developingthe same P&cse 2 reported families, neither the patients cancer is of the order of I per 1ooO. This figure I bar their unaffected family members have had implies that only a very small proportion of W exposure to a common environmental cases are transmitted from a parent, Le., either h w d . Moreover, no constitutional genetic the proportion of parents with g e m cell -me or congenital anomaly that is mutation is low or that manifestation rate of -istently associated with predisposition to potential genetic cases is low. Thus, for both M~roblastoma were identified in those 2 Wilms tumorand neuroblastoma, the hereditary families. element has been suggested to be much smaller Most of the diagnosis of familial than originally suggested by Knudson and -blastoma is made in the first 18 months of Smng(8).For families in which no clear ge&c rife,the median age of diagnosisis 9 months(?). pattern emerges, some may be caused by an This is in contrast with a median age of 22 unknown genetic predisposition and some by months for neuroblastoma in general ppula- shared environmental exposure, some are tion. At leas1 20% of patients with familial undoubtedly due to chance. Kushner and M A N PEDIATRICS 87 VOLUME 37-JANUARY 2000 CASE REPORTS Helson(9) studied monozygotic twins concordant and discordant for neuroblastoma and this adds to the hypothesisthat hereditaryfactors may predominate in neuroblastoma diagnosed in infants whereas nonheritable random mutational genetic events may be more important in neuroblastoma diagnosed after infancy. From data available so far, no specific gene locus is yet definite for familial neuroblastoma. This necessitates the need for examination of other candidate loci or even a genome wide search to identify the familial neuroblastoma predisposing gene. Genetic heterogeneity with several predisposing genes is yet another possibility that also has tobe taken into consideration. REFERENCES 1. Chatten J, Voohees ML. Familial neuro- blastoma. N Eng J Med 1967; 277: 1230-1236. 2. Kushner BH, Gilbert F, Helson L Familial neuroblastoma: Case reports, literature review and etiologic considerations.Cancer 1986; 57: 1887-1893. 3. DraperGI,Sanders BM, Lennox EL BmwaLia PA. pananSofchildhoodcanrxramong~~ Brit J Cancer 1996.74: 152-158. 4. RobertsonCM,Tyrrel IC,Ritchard J. FamiHal neuralcnstturmrs.EurJ Pediatr 1991; 1% 78% 792. 5. Gerson JM,chatten I, Eisman S. Familial neuroblastoma - A follow up. N Eng J Mcd 1974;290: 1487. 6. Knudson AG, Mcadows AT. Developmental genetics of neuroblastoma J Natl Can= Inct 1976; 57: 675-682. 7. Buckley JD.Buckley CM,Breslow NE, kapm GJ. Robenon PK,Mack TM.Concotdamxfor childhood cancer in twins.Med Pediatr Oncol 19w.26: 223-229. 8. Knudson AG. StrongE.Mutation and cancer. Neuroblastoma and pheochromocytoma Am J Hum Genet 1972; 24: 514-532. 9. Kushm BH, H e h L. Monozygotic sibrings discordantfor neuroblsstoma:Ebiobgic i m p b tions. J Pediatr 1985: 107: 405-409. Dorfman-Chanarin Syncrome: A Rare Neutral Lipid Storage Disease Milind S. Tullu Mamta N. Muranjan Sushma U. Save Chandrahas T. Deshmukh Shaila R. Khubchandani* Burjor A. Bharucha' In 1953, Jordans described two brothers with progressive muscular dystrophy whose leukocytes condnec t vacoules(1). Similar abnormalities of the leukocytes (Jordan's From the GeneticsDivision, Department of Pediatrics, Seth G.S. Medical College and K.E.M. Hospital, Pare1 M&i 400 012, India und *Department of Histopthology and Electtun Microscopy, Jaslok Hospital and Research Centre, I S , Dr. G.Desh- muWl Marg, Mwnbai 400 026, India. + Deceased. Reprint requestr: Dr. C.T.Deshmukh, 'Baug-E-Sara', Ground Floor, 16 Nepean SCO R& Mwnbai 400 036, Maharashtra, India. E - 4 : cdeshmukh@ usa.net Manuscript Received: May 21. 1999; Initial review completed: July 7, 1999; Revision Accepted: July 26. 1999 INDIAN PEDIATRICS 88 VOLUME 37-JANUARY 2000