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life. The 15 breastfed infants were fed every 4 hours, byhospital protocol, starting as early as 2 and as late as10 hours. The mean age of first feed was 7.8 (2.6) hours,

and infants were not roomed-in. The differences in methodsmight explain some of the differences in the results. In theMethods section of our article, we state that Only mothers.. . who remained with the infant after birth were included,which means that infants were roomed-in.

We did not account for the insensible water loss that might

occur during feeding. Casey et al5 corrected the weight on thebasis of the insensible water loss calculated by Hendriksonet al.7 They conclude that the insensible water loss was 1.9 g/kg/h over the first year of life. They stated that studies were

carried out indoors in homes heated in winter. Some usedair conditioners in the summer months. Furthermore theauthors stated that it should be noted that the humidity inDenver, Colorado, is well below the national average. Weconsidered these conditions to be too different from ours inBrazil. Besides, in our study Infant clothing was standardized

before being weighed. Infants with diaper were swaddled until

weighed after being breastfed. Swaddling infants might haveprevented weight to diminish caused by water loss, becauseperspiration, urine, and feces would remain in the fabric.We did not obtain any negative weight difference during thestudy, meaning that the amount of insensible water loss

during feeding might not be very significant in our study.For the regression equation we tried different models.

None had significant associations except for to have a com-panion. The regression presented in the article was calcu-

lated with variables that reached P # .1 in univariateanalysis. As stated in our study, Birth weight was not corre-lated with colostrum intake, either in the univariateor inthe

regression equation. In their study, Dollberg et al4

stated thatIn backward stepwise regression analysis where intake onDay 1 was the dependent variable and birth weight (or gesta-tional age), Apgar Score at five minutes, age at first feed, 24

hours weight loss and group (formula vs breast feeding)were the independent variables, only the group was signifi-cant. In contrast, Dollberg and Mimouni state in their letterthat they found a striking correlation. In any case, the birthweight of the newborns was 3145 309 gin our study and3258 408 g in the study by Dollberg et al.4 One possibilityis that the smaller variation in birth weight of our group did

not permit us to show this correlation.

Dollberg and Mimouni speculate that more mature infantsmay have a more mature suck and swallow mechanism. It isnot possible to confirm this suggestion with our data.

Walter Santoro, Jr. MD

Francisco Eulogio Martinez, MDRubens Garcia Ricco, MD

Salim Moyses Jorge, MDHospital das Clnicas de Ribeirao Preto

Departamento de PediatriaRibeirao Preto, Sao Paulo, Brazil

10.1016/j.jpeds.2010.02.060

References

1. Saint L, Smith M, Hartmann PE. The yield and nutrient content of colos-

trum and milk of women from giving birth to 1 month post-partum. Br J

Nutr 1984;52:87-95.

2. Hill PD, Aldag JC. Milk volume on day 4 and income predictive of lacta-

tion adequacy at 6 weeks of mothers of nonnursing preterm infants.

J Perinat Neonatal Nurs 2005;19:273-82.

3. Kent JC, Mitoulas LR, Cregan MD, Ramsay DT, Doherty DA,Hartmann PE. Volume and frequency of breastfeedings and fat content

of breast milk throughout the day. Pediatrics 2006;117:e387-95.

4. Dollberg S, Lahav S, Mimouni FB. A comparison of intakes of breast-fed

and bottle-fed infants during the first two days of life. J Am Coll Nutr

2001;20:209-11.

5. Casey CE, Neifert MR, Seacat JM, Neville MC. Nutrient intake by breast-fed

infants during the first five days after birth. Am J Dis Child 1986;140:933-6.

6. Neville MC, KellerR, SeacatJ, Lutes V,Neifert M,Casey C,et al. Studies in

human lactation: milk volumes in lactating women during the onset of

lactation and full lactation. Am J Clin Nutr 1988;48:1375-86.

7. Hendrikson EC, Seacat JM, Neville MC. Insensible weight loss in children

under one year of age. Acta Paediatr Scand 1985;74:678-80.

The overlap between Sotos and Beckwith-Wiedemann syndromes

To the Editor:

We read with great interest the recent report by Kato et al1

describing the noteworthy occurrence of a hepatoblastoma ina child with Sotos syndrome and typicalNSD1 microdeletion.

This is a remarkable finding, given that only one previous casehas been reported.2 Conversely, the occurrence of hepatoblas-

toma is characteristic of Beckwith-Wiedemann syndrome,another overgrowth condition with cancer predispositioncaused by epigenetic deregulation of chromosomal region11p15. In this case, despite a normal genotype, DNA methyl-

ation anomalies led to tissue growth factor overexpressionand cyclin deregulation responsible for the phenotype andcancer development.3 The mechanisms causing these methyl-ation anomalies have not yet been fully explained, however.

Actually, phenotypical overlap between Sotos and Beckwith-Wiedemann syndrome can occur. It is notable that molecular

overlap also has been demonstrated, with paradoxical 11p15epimutations in Sotos phenotypes and NSD1 mutations inBeckwith-Wiedemann phenotypes.4 These findings have ledto speculation thattheNSD1 protein,a histonemethyltransfer-ase involved in epigenetic gene regulation,5 may be involved inestablishing or maintaining 11p15 region imprinting.4

Previous studies have reported 11p15 region methylationanomalies in hepatoblastoma tissue6 and NSD1 silencingin other tumors.7 To the best of our knowledge, the co-occurrence of these 2 derangements has not yet been demon-strated or investigated, however.

The case reported by Kato et al was investigated by single-ucleotide polymorphism array technology, which identified,along with the germline 5q35 microdeletion encompassing

NSD1, a somatic gain of chromosome 2 and a uniparental18q disomy. However, as the authors discuss, that techniquedoes not provide information about DNA epigenetic status.

In this respect, we believe that investigating 11p15 region

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epigenetic anomalies in both blood leukocytes and cancer tis-sues might help unravel the still-unexplained overlap be-tween these two overgrowth syndromes.

Alessandro Mussa, MDBiochemical Genetics Laboratory

Division of Laboratory GeneticsDepartment of Laboratory Medicine and Pathology

Mayo Clinic College of Medicine

Department of PediatricsUniversity of Torino

Nicoletta Chiesa, PhDDepartment of Pediatrics

University of Torino

Francesco Porta, MDBiochemical Genetics Laboratory

Division of Laboratory GeneticsDepartment of Laboratory Medicine and Pathology

Mayo Clinic College of MedicineRochester, Minnesota

Department of Pediatrics

University of Torino

Giuseppina Baldassarre, MDMargherita Cirillo Silengo, MD

Giovanni Battista Ferrero, MD, PhDDepartment of Pediatrics

University of TorinoTorino, Italy

10.1016/j.jpeds.2010.02.063

References

1. Kato M, Takita J, Takahashi K, Mimaki M, Chen Y, Koh K, et al. Hepato-

blastoma in a patient with Sotos syndrome. J Pediatr 2009;155:937-9.

2. Saugier-Veber P, Bonnet C, Afenjar A, Drouin-Garraud V, Coubes C,

Fehrenbach S, et al. Heterogeneity of NSD1 alterations in 116 patients

with Sotos syndrome. Hum Mutat 2007;28:1098-107.

3. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome.Eur J Hum Genet 2009;18:8-14.

4. Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, et al.

Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and

11p15 anomalies in Sotos syndrome. Am J Hum Genet 2004;74:715-20.

5. Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K,

Song L, et al. NSD1is essential for early post-implantation development

and has a catalytically active SET domain. EMBO J 2003;22:3153-63.

6. Honda S, Arai Y, Haruta M, Sasaki F, Ohira M, Yamaoka H, et al. Loss of

imprinting ofIGF2correlates with hypermethylation of the H19 differen-

tially methylated region in hepatoblastoma. Br J Cancer 2008;99:1891-9.

7. Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Losson R, et al.

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone

methyltransferase NSD1 in human neuroblastoma and glioma. Proc

Natl Acad Sci USA 2009;106:21830-5.

Reply

To the Editor:

We greatly appreciate the interest of Mussa et al in our studyand would like to address their concerns. In our genome-widescanning, copy number abnormalities of 11p were not detected

in the tumor sample from our patient; however, as Mussa et al

suggest, single-nucleotidepolymorphism arraytechnology doesnot provide information about epigenetic alterations. Becauseaberrant genomic imprinting of the 11p15 locus plays a pivotalrole in the pathogenesis of Beckwith-Wiedemann syndrome,1

we further investigated the methylation status of theH19gene

within this region in both tumor tissue and corresponding nor-mal tissue of our patient, as well as in a normal control, bymethylation-specific polymerase chain reaction (PCR).2

In our analysis, the tumor and the peripheral blood sam-ples demonstrated the same DNA methylation pattern, inwhich PCR products from both methylated and unmethy-

lated alleles were obtained, indicating that the methylationstatus of theH19locus in the tumor remained normal. Giventhat normally, the paternal copy of the H19gene is methyl-ated and the maternal copy is nonmethylated,3 our findingsindicate that both paternal and maternal 11p15 alleles are

preserved in the tumor sample.On the other hand, given that NSD1 encodes a histone

methyltransferase,4 loss ofNSD1might leadto epigenetic de-regulation of 11p15 genes, includingIGF2,5 via altered chro-matin status without accompanying DNA methylation. Thus,it would have been intriguing to determine the status of his-

tone methylation ofIGF2 in the hepatoblastoma sample ofthe current case; unfortunately, however, insufficient tumormaterial precluded further analysis. The molecular mecha-

nisms by which NSD1 deletion is associated with the over-growth sydrome and tumorigenesis remain to be elucidated.

Junko Takita, MD, PhDDepartment of Cell Therapy and Transplantation Medicine

University of Tokyo

Tokyo, Japan10.1016/j.jpeds.2010.02.069

References

1. Reik W, Brown KW, Slatter RE, Sartori P, Elliott M, Maher ER. Allelic

methylation ofH 19 and IGF2 in the Beckwith-Wiedemann syndrome.Hum Mol Genet 1994;3:1297-301.

2. Suzuki M, Kato M, Yuyan C, Takita J, Sanada M, Nannya Y, et al. Whole-

genome profiling of chromosomal aberrations in hepatoblastoma using

high-density single-nucleotide polymorphism genotyping microarrays.

Cancer Sci 2008;99:564-70.

3. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP,

Feinberg AP. Epigenetic alterations ofH19and LIT1distinguish patients

with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J

Hum Genet 2002;70:604-11.

4. Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K,

Song L, et al. NSD1is essential for early post-implantation development

and has a catalytically active SET domain. EMBO J 2003;22:3153-63.

5. Smith AC, Choufani S, Ferreira JC, Weksberg R. Growth regulation, im-

printed genes,and chromosome 11p15.5. Pediatr Res 2007;61(5 Pt 2):43R-7.

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