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Pediatr Blood Cancer 2011;57:696 LETTER TO THE EDITOR Klinefelter Syndrome and Neuroblastoma To the Editor: Klinefelter syndrome (KS) has been associated to increased risk of cancer in adulthood [1]. However, the absence of epidemiological studies including children, limit the statistical data needed to assess the risk of pediatric tumors in these patients. Noteworthy is that, due to the lack of reported cases in the literature, KS has been speculated as protective against neuroblastoma [2]. A constitutional supernumerary X chromosome may protect against neuroblastoma meanwhile X monosomy, Turner syndrome, tends to be prone to neurogenic tumors and gonadal tumors [3]. We report a ten month old child with intrauterine diagnose of KS (47, XXY visible on metaphase preparations), left polycystic kidney and arthrogryposis. A routine surveillance ultrasonography dis- closed a right heterogeneous adrenal mass which contained calcium. Ferritin, lactate dehydrogenase, and urine catecholamines and metabolites, including vanillylmandelic acid, homovanillic acid and dopamine, were within normal ranges. A magnetic resonance imaging (MRI) confirmed an enlarged right adrenal gland measur- ing 6 cm 5 cm 3.5 cm. A 123 I metaiodobenzylguanidine (MIBG) scintigraphy revealed right adrenal uptake. Bone scan 99 Tc and bone marrow aspirates were negative. The patient was treated with radical excision alone according to the protocol for localized resectable neuroblastoma (LNESG2) of the International Society of Pediatric Oncology (SIOP). He also underwent left nephrourectomy due to non-functional left polycystic kidney. The histological study concluded poorly differentiated neuroblastoma, stage 2B. Cytogenetic studies showed tetraploidy by flow cytometry and no MYCN amplification or 1p deletion by fluorescence-based in situ hybridization (FISH). Five years after initial diagnosis the patient remains alive without remarkable events. Reports of constitutional chromosome anomalies in children presenting with particular embryonal tumors precludes identifica- tion of genes involved in the development of cancer. Less aggressive tumors have been seen with viable genetic conditions, whereas severe genetic conditions were associated with large and dissemi- nated tumors that occurred earlier as reported by Satge ´ et al. [4] The numerous chromosomes and chromosome regions involved in karyotype anomalies reported in neuroblastomas suggest that several pathways lead to this tumor and to different tumoral aggressivity [4]. Neuroblastoma has the highest rate of spontaneous regression among malignant tumors, especially at younger age. When screening programs have been undertaken, there has been a higher incidence of neuroblastoma reported [5]. This overdiagnosis may be due to spontaneous regression in stages 4S and in other non- stage 4S especially if primarily located in the adrenal gland. It may be adduced that genetic diagnosis of KS is usually made in adolescences and early adulthood explaining the lack of reported neuroblastomas in this age group. It is possible that lower stage neuroblastoma is more often associated to KS in early childhood that involutes and is not diagnosed, or that by itself excess X chromosome prompts involution of neuroblastoma. The case we are reporting could have probably gone unnoticed if the neuroblastoma had not been found by periodic abdominal ultrasonography exams performed due to the patient’s renal pathology; furthermore, it might have spontaneously regressed without treatment. Marı ´a Elena Mateos, MD, PhD* Pediatric Oncology Unit Department of Pediatrics University Hospital Reina Sofı ´a Co ´rdoba, Spain Eduardo Lo ´pez-Laso, MD, PhD Pediatric Neurology Unit Department of Pediatrics University Hospital Reina Sofı ´a Co ´rdoba, Spain Juan Luis Pe ´rez-Navero, MD, PhD Pediatric Intensive Care Unit Department of Pediatrics University Hospital Reina Sofı ´a Co ´rdoba, Spain REFERENCES 1. Swerdlow AJ, Schoemaker MJ, Higgins CD, et al. Cancer incidence and mortality in men with Klinefelter syndrome: A cohort study. J Natl Cancer Inst 2005;97:1204–1210. 2. Satge ´ D, Sasco AJ, Plantaz D, et al. Abnormal number of X chromosomes and neuroblastic tumors. J Pediatr Hematol Oncol 2001;23:331 –332. 3. Satge ´ D, Moore SW, Stiller CA, et al. Abnormal constitutional karyotypes in patients with neuroblastoma: A report of four new cases and review of 47 others in the literature. Cancer Genet Cytogenet 2003;147:89 –98. 4. Sasaki Y, Nakayama H, Ikeda M. Turner syndrome and ganglioneuroma. J Pediatr Hematol Oncol 2000;22:89 –90. 5. Hero B, Simon T, Spitz R, et al. Localized infant neuroblastomas often show spontaneous regression: Results of the prospective trials NB95-S and NB97. J Clin Oncol 2008;26:1504 – 1510. ß 2011 Wiley-Liss, Inc. DOI 10.1002/pbc.23089 Published online 30 June 2011 in Wiley Online Library (wileyonlinelibrary.com). —————— Abbreviations: KS, Klinefelter syndrome; SIOP, International Society of Pediatric Oncology; MRI, magnetic resonance imaging; MIBG, 123I metaiodobenzylguanidine; FISH, fluorescence-based in situ hybridization. *Correspondence to: Marı ´a Elena Mateos, MD, PhD, Pediatric Oncology Unit, Department of Pediatrics, University Hospital Reina Sofı ´a, Co ´rdoba, Av. Mene ´ndez Pidal, s/n, 14004 Co ´rdoba, Spain. E-mail: [email protected] Received 17 November 2010; Accepted 25 January 2011

Klinefelter Syndrome and Neuroblastoma

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Pediatr Blood Cancer 2011;57:696

LETTER TO THE EDITORKlinefelter Syndrome and Neuroblastoma

To the Editor: Klinefelter syndrome (KS) has been associated to

increased risk of cancer in adulthood [1]. However, the absence of

epidemiological studies including children, limit the statistical data

needed to assess the risk of pediatric tumors in these patients.

Noteworthy is that, due to the lack of reported cases in the literature,

KS has been speculated as protective against neuroblastoma [2]. A

constitutional supernumerary X chromosome may protect against

neuroblastomameanwhile Xmonosomy, Turner syndrome, tends to

be prone to neurogenic tumors and gonadal tumors [3].

We report a tenmonth old child with intrauterine diagnose of KS

(47,XXYvisible onmetaphase preparations), left polycystic kidney

and arthrogryposis. A routine surveillance ultrasonography dis-

closed a right heterogeneous adrenalmasswhich contained calcium.

Ferritin, lactate dehydrogenase, and urine catecholamines and

metabolites, including vanillylmandelic acid, homovanillic acid and

dopamine, were within normal ranges. A magnetic resonance

imaging (MRI) confirmed an enlarged right adrenal gland measur-

ing 6 cm� 5 cm� 3.5 cm. A 123I metaiodobenzylguanidine

(MIBG) scintigraphy revealed right adrenal uptake. Bone scan99Tc and bone marrow aspirates were negative. The patient was

treated with radical excision alone according to the protocol for

localized resectable neuroblastoma (LNESG2) of the International

Society of Pediatric Oncology (SIOP). He also underwent left

nephrourectomy due to non-functional left polycystic kidney. The

histological study concluded poorly differentiated neuroblastoma,

stage 2B. Cytogenetic studies showed tetraploidy by flow cytometry

and noMYCNamplification or 1p deletion by fluorescence-based in

situ hybridization (FISH). Five years after initial diagnosis the

patient remains alive without remarkable events.

Reports of constitutional chromosome anomalies in children

presenting with particular embryonal tumors precludes identifica-

tion of genes involved in the development of cancer. Less aggressive

tumors have been seen with viable genetic conditions, whereas

severe genetic conditions were associated with large and dissemi-

nated tumors that occurred earlier as reported by Satge et al. [4] The

numerous chromosomes and chromosome regions involved in

karyotype anomalies reported in neuroblastomas suggest that

several pathways lead to this tumor and to different tumoral

aggressivity [4]. Neuroblastoma has the highest rate of spontaneous

regression among malignant tumors, especially at younger age.

When screening programs have been undertaken, there has been a

higher incidence of neuroblastoma reported [5]. This overdiagnosis

may be due to spontaneous regression in stages 4S and in other non-

stage 4S especially if primarily located in the adrenal gland. It may

be adduced that genetic diagnosis of KS is usually made in

adolescences and early adulthood explaining the lack of reported

neuroblastomas in this age group. It is possible that lower stage

neuroblastoma is more often associated to KS in early childhood

that involutes and is not diagnosed, or that by itself excess X

chromosome prompts involution of neuroblastoma.

The casewe are reporting could have probably gone unnoticed if

the neuroblastoma had not been found by periodic abdominal

ultrasonography exams performed due to the patient’s renal

pathology; furthermore, it might have spontaneously regressed

without treatment.

Marıa Elena Mateos, MD, PhD*

Pediatric Oncology Unit

Department of Pediatrics

University Hospital Reina Sofıa

Cordoba, Spain

Eduardo Lopez-Laso, MD, PhD

Pediatric Neurology Unit

Department of Pediatrics

University Hospital Reina Sofıa

Cordoba, Spain

Juan Luis Perez-Navero, MD, PhD

Pediatric Intensive Care Unit

Department of Pediatrics

University Hospital Reina Sofıa

Cordoba, Spain

REFERENCES

1. Swerdlow AJ, Schoemaker MJ, Higgins CD, et al. Cancer incidence and

mortality inmenwithKlinefelter syndrome:A cohort study. JNatl Cancer Inst

2005;97:1204–1210.

2. Satge D, Sasco AJ, Plantaz D, et al. Abnormal number of X chromosomes and

neuroblastic tumors. J Pediatr Hematol Oncol 2001;23:331–332.

3. Satge D, Moore SW, Stiller CA, et al. Abnormal constitutional karyotypes in

patients with neuroblastoma: A report of four new cases and review of 47

others in the literature. Cancer Genet Cytogenet 2003;147:89–98.

4. Sasaki Y, Nakayama H, Ikeda M. Turner syndrome and ganglioneuroma.

J Pediatr Hematol Oncol 2000;22:89–90.

5. Hero B, Simon T, Spitz R, et al. Localized infant neuroblastomas often show

spontaneous regression: Results of the prospective trials NB95-S and NB97.

J Clin Oncol 2008;26:1504–1510.

� 2011 Wiley-Liss, Inc.DOI 10.1002/pbc.23089Published online 30 June 2011 in Wiley Online Library(wileyonlinelibrary.com).

——————Abbreviations: KS, Klinefelter syndrome; SIOP, International Society

of Pediatric Oncology; MRI, magnetic resonance imaging; MIBG,

123I metaiodobenzylguanidine; FISH, fluorescence-based in situ

hybridization.

*Correspondence to: Marıa Elena Mateos, MD, PhD, Pediatric

Oncology Unit, Department of Pediatrics, University Hospital Reina

Sofıa, Cordoba, Av. Menendez Pidal, s/n, 14004 Cordoba, Spain.

E-mail: [email protected]

Received 17 November 2010; Accepted 25 January 2011