TRASTORNOS DEL CRECIMIENTO FETAL.
CIR: Definición, causas y clasificación. MACROSOMÍA.
Laura Sotillo Mallo.
Def
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ient
o fe
tal.
• Definición.
• Clasificación.
• Causas.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Definición y Clasificación :
• PFE < percentil 10 y estudio doppler normal. • Son fetos que no presentan anomalías asociadas ni datos de
insuficiencia placentaria. • Crecen acorde a su potencial de crecimiento.
PEG NORMAL O CONSTITUCIONAL
50-70%
• PFE < percentil 10 independientemente del estudio doppler. • Habitualmente SEVERO (PFE < percentil 3) Y PRECOZ ( <28 semanas).
PEG ANORMAL 10-20%
• PFE < percentil 10 y alteraciones del doppler (AU y/o ACM y/o Art Uterinas) o PFE < percentil 3.
• Limitación del potencial intrínseco de crecimiento como consecuencia de una insuficiencia placentariaè Hipoxia y acidemia fetal.
CIR 20-30%
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Causas de PEG anormal: G
ENÉT
ICA
S: • Cromosomopatías: • Trisomía 13. • Trisomía 18. • Triploidía materna. • Deleción brazo
corto del cromosoma 4.
• Síndromes genéticos: • Russell-Silver. IN
FEC
CIO
SAS: • TORCH:
• CMV. • Toxoplasmosis.
• Malaria.
• Chagas.
TÓ
XIC
OS: • Síndrome
alcohólico fetal.
• Medicamentos: • Warfarina. • Ciclofosfamida. • Ácido
valproico. • Fenitoina.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Factores de riesgo de CIR:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} FACTORES EPIDEMIOLÓGICOS Y CLÍNICOS: } Maternos:
} Edad avanzada. } Antecedentes de CIR en gestaciones previas (8,2% si hijo previo percentil>10
a 20,1% si hijo previo CIR).
} Enfermedades maternas: Trastornos hipertensivos del embarazo
Patología renal
Síndrome antifosfolípido
Hemoglobinopatías
Diabetes
Malnutrición: causa más frecuente en países en vías de desarrollo.
Tabaquismo: causa más frecuente en países desarrollados.
Factores de riesgo de CIR:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} FACTORES EPIDEMIOLÓGICOS Y CLÍNICOS: } Fetales:
} Gestación múltiple.
} Placentarios: } Arteria umbilical única. } Inserción velamentosa de cordón. } Mosaicismos confinados a la placenta.
} MARCADORES BIOQUÍMICOS: } Primer trimestre:
} êPAPPA ¨ <p5 (0.45 MoMs): OR 2.74. ¨ <p1(0.29 MoMs): OR 3.53.
} Segundo trimestre: } êEstriol no conjugado. } éα-fetoproteina.
PREDICTION OF FETAL GROWTHRESTRICTIONAffected NewbornsPatterson et al5 followed-up 9,596 patients throughouttwo pregnancies; the overall fetal growth restriction ratein the first child was 12.4%. Among patients withoutany medical complications either in the first pregnancyor in the second pregnancy, the prevalence of recurrentfetal growth restriction was significantly related to theseverity of growth restriction in the first pregnancy. Ifthe birth weight of the first newborn was more than the10th percentile, the risk of fetal growth restriction forthe second newborn was 8.2%. If the birth weight wasless than or equal to the 10th percentile for the firstnewborn, the risk of fetal growth restriction for thesecond newborn was significantly increased up to20.1% (P,.001). The more severe the fetal growthrestriction, the higher the risk of recurrence.
Serum AnalytesMaternal serum analytes during the first and secondtrimesters can be reasonable predictors of fetal growthrestriction later in pregnancy (Table 1). Pregnancy-associated plasma protein-A levels less than the firstpercentile (less than 0.29 multiples of the median) andpregnancy-associated plasma protein-A less than the5th percentile (less than 0.45 multiples of themedian),6,7 first trimester free b-hCG level less thanthe first percentile (less than 0.21 multiples of the
median),6 low unconjugated estriol (less than 0.5 mul-tiples of the median) level in the second trimester,8
and unexplained increased maternal serum alpha-fetoprotein level (more than 2.0 multiples of themedian) in the second trimester have been associatedwith low birth weight.9,10
In our institution, we recommend a fetal growthultrasound examination at 32 weeks of gestation forpregnancies complicated with pregnancy-associatedplasma protein-A less than the 2.5th percentileor unexplained increased maternal serum alpha-fetoprotein more than 2.0 multiples of the median. Ifthe follow-up growth ultrasound scan is normal, with anestimated fetal weight more than the 10th percentile,we resume routine prenatal care (ie, we do not add anyantepartum testing for normally grown fetuses).
Ultrasound FindingsSingle umbilical artery is the most common congenitalabnormality of the umbilical cord. The prevalence ofsingle umbilical artery ranges from 0.2% to 11%,depending on the population studied.11–15 Neonateswith isolated single umbilical artery have increasedrates of growth restriction (10.9% compared with25.0%) and estimated fetal weight less than the 10thpercentile (odds ratio 2.23; 95% confidence interval[CI] 1.84–2.69).16 In our institution, we recommenda fetal growth ultrasound examination at 32 weeks ofgestation or pregnancies complicated with single umbil-ical artery. If the follow-up growth ultrasound scan is
Table 1. Diagnostic Performance of Maternal Serum Analytes During the First and Second Trimesters inPredicting Fetal Growth Restriction (Estimated Fetal Weight Less Than the 10th Percentile)
Analyte OR 95% CI Sensitivity Specificity PPV NPV
First trimesterPAPP-A
Less than 5th percentile 2.74 2.16–2.81 10.4 95.4 18.7 91.3Less than 1st percentile 3.53 2.74–4.55 2.9 99.2 26.3 91.0
Free b-hCGLess than 5th percentile 1.3 0.8–2.0 5.1 95.8 7.4 93.8Less than 1st percentile 1.3 0.8–2.0 5.1 95.8 7.4 93.8
Second TrimesterAFP
More than 1.5 MoM 1.41 1.07–1.87 19.6 90.4 3.9 98.3More than 2.0 MoM 1.65 1.28–2.12
uE3Less than 0.5 MoM 1.79 1.79–2.44
OR, odds ratio; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; PAPP-A, pregnancy-associatedplasma protein-A; AFP, alpha-fetoprotein; uE2, unconjugated estriol; MoM, multiples of the median.
Data from Krantz D, Goetzl L, Simpson JL, Thom E, Zachary J, Hallahan TW, et al. Association of extreme first-trimester free humanchorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction andother adverse pregnancy outcomes. Am J Obstet Gynecol 2004;191:1452–8; Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D,Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations andnuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J ObstetricsGynecol 2004;191:1446–51; andDugoff L, Hobbins JC, Malone FD, Vidaver J, Sullivan L, Canick JA, et al. Quad screen as a predictor ofadverse pregnancy outcome. Obstet Gynecol 2005;106:260–7.
1058 Copel and Bahtiyar Practical Approach to Fetal Growth Restriction OBSTETRICS & GYNECOLOGY
Clinical Expert Series
A Practical Approach to FetalGrowth RestrictionJoshua A. Copel, MD, and Mert Ozan Bahtiyar, MD
Fetal growth restriction is one of the most complex problems encountered by obstetricians.Ultrasound-estimated fetal weight less than the 10th percentile for the gestational age is themost widely accepted diagnostic criterion. Management protocols vary from institution toinstitution. Doppler velocimetry provides valuable information about fetal status. We offera practical approach to management and timing of delivery based on available data in theliterature.(Obstet Gynecol 2014;123:1057–69)
DOI: 10.1097/AOG.0000000000000232
Fetal growth restriction is a complex problem fromits diagnosis to prenatal management, and regard-
ing optimal timing of delivery. It is synonymous withthe term intrauterine growth restriction. Althoughthere have been varying definitions of fetal growthrestriction in the past, for the purposes of this reviewwe used an estimated fetal weight less than the 10thpercentile for gestational age as the definition.1 Thereis less consensus about how frequently to monitorthese pregnancies (antenatal testing should be usedfor fetal monitoring) and when these fetuses shouldbe delivered. In this article we present our approachto the management of patients with growth-restrictedfetuses.
Fetal growth restriction and small for gesta-tional age (SGA) status are frequently used inter-changeably in the literature and in daily clinicalpractice. Although fetal growth restriction is a pre-natal definition, SGA describes postnatal status. Theterm “SGA” should be reserved to describe new-
borns whose weight is less than or equal to the10th percentile for gestational age at birth.1
BACKGROUNDFetal growth restriction is associated with increasedperinatal mortality and morbidity. More severe growthrestriction results in greater risk for worse perinataloutcome.2 The gestational age at which growth restric-tion is diagnosed is important from the neonatal out-come perspective. Among preterm newborns born atless than 37 weeks of gestation, there is no specific birthweight percentile at which morbidity and mortality ratesincrease. At term (37 weeks of gestation or later), neo-natal mortality increases significantly among newbornswith birth weight less than the third percentile (neonatalmortality50.3%) compared with normally grown new-borns (neonatal mortality50.03%; P,.001).3 Neonatesborn at 32 to 42 weeks of gestation with a birth weightless than the 10th percentile for gestational age werefour-times to six-times more likely to have cerebral palsythan were normally grown neonates.4
Available data suggest that in term fetuses anestimated fetal weight at or less than the thirdpercentile would more accurately predict morbidityand mortality than would higher weight cutoffs. Itremains clinically useful to use the estimated fetalweight at the 10th percentile threshold or lessbecause of the inherent imprecision of ultrasoundestimates of fetal weight to maintain a high detectionrate of fetuses with true fetal growth restriction,although some normal fetuses will be misdiagnosedas having growth restriction.
From the Departments of Obstetrics, Gynecology, and Reproductive Sciences andPediatrics, Yale University School of Medicine, New Haven, Connecticut.Continuing medical education for this article is available at http://links.lww.com/AOG/A490.
Corresponding author: Mert Ozan Bahtiyar, MD, Department of Obstetrics,Gynecology and Reproductive Sciences, 333 Cedar Street, P.O. Box 8063, NewHaven, CT 06520-8063; e-mail: [email protected].
Financial DisclosureThe authors did not disclose any potential conflicts of interest.
© 2014 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/14
VOL. 123, NO. 5, MAY 2014 OBSTETRICS & GYNECOLOGY 1057
Clasificación del CIR:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
CIR PRECOZ CIR TARDÍO
Prevalencia Baja (1-2%) Alta (3-5%)
Asociación a PE Alta Baja.
Dificultad Manejo Diagnóstico
Insuficiencia placentaria Doppler AU
SEVERA ALTERADO
LEVE NORMAL
Hipoxia Adaptación vascular
SEVERA SISTÉMICA
LEVE CENTRAL
Neonatos Inmaduros Historia natural de larga evolución. ALTA tolerancia a la hipoxia.
Maduros. Historia natural corta evolución. BAJA tolerancia a la hipoxia
Resultados perinatales ALTA morbimortalidad.
BAJA mortalidad (pero causa común de Muerte fetal tardía). Malos resultados obstétricos.
E-Mail [email protected]
Review
Fetal Diagn Ther 2014;36:86–98 DOI: 10.1159/000357592
Update on the Diagnosis and Classification of Fetal Growth Restriction and Proposal of a Stage-Based Management Protocol
Francesc Figueras Eduard Gratacós
Barcelona Center of Maternal-Fetal Medicine and Neonatology (Hospital Clinic and Hospital Sant Joan de Deu), IDIBAPS, University of Barcelona, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona , Spain
agement of FGR and the decision to deliver aims at an opti-mal balance between minimizing fetal injury or death versus the risks of iatrogenic preterm delivery. We propose a proto-col that integrates current evidence to classify stages of fetal deterioration and establishes follow-up intervals and opti-mal delivery timings, which may facilitate decisions and re-duce practice variability in this complex clinical condition.
© 2014 S. Karger AG, Basel
Introduction
Fetal growth restriction (FGR) is defined as a failure to achieve the endorsed growth potential. The diagnosis of fetal ‘smallness’ is currently performed on the basis of an estimated fetal weight (EFW) below a given threshold, most commonly the 10th centile. It is likely that this def-inition lacks sensitivity, so that it misses cases of growth restriction that do not fall below the 10th centile, but it identifies a subset of pregnancies at high risk of poorer perinatal outcome. Thus, detection of small fetuses is clinically relevant because as a whole this group of fetuses
Key Words Fetal growth restriction update · Stage-based management protocol · Constitutional small-for-gestational age · Early-severe versus late-mild fetal growth restriction
Abstract Small fetuses are defined as those with an ultrasound esti-mated weight below a threshold, most commonly the 10th centile. The first clinically relevant step is the distinction of ‘true’ fetal growth restriction (FGR), associated with signs of abnormal fetoplacental function and poorer perinatal out-come, from constitutional small-for-gestational age, with a near-normal perinatal outcome. Nowadays such a distinc-tion should not be based solely on umbilical artery Doppler, since this index detects only early-onset severe forms. FGR should be diagnosed in the presence of any of the factors associated with a poorer perinatal outcome, includingDoppler cerebroplacental ratio, uterine artery Doppler, a growth centile below the 3rd centile, and, possibly in the near future, maternal angiogenic factors. Once the diagnosis is established, differentiating into early- and late-onset FGR is useful mainly for research purposes, because it distin-guishes two clear phenotypes with differences in severity, association with preeclampsia, and the natural history of fe-tal deterioration. As a second clinically relevant step, man-
Received: November 19, 2013 Accepted: November 19, 2013 Published online: January 23, 2014
Francesc Figueras and Eduard Gratacós Maternal-Fetal Medicine Department Hospital Clinic, University of Barcelona Sabino de Arana 1, ES–08028 Barcelona (Spain) E-Mail ffiguera @ clinic.ub.es and egratacos @ fetalmedicinebarcelona.org
© 2014 S. Karger AG, Basel1015–3837/14/0362–0086$39.50/0
www.karger.com/fdt
E. Gratacós and F. Figueras contributed equally to this work.
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MA
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• Definición.
• Causas.
• Diagnóstico.
• Riesgos.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Definición:
} Se define como feto GRANDE PARA LA EDAD GESTACIONAL (GEG) aquel que presenta un PFE superior al percentil 90-95 para esa EG.
} No existe uniformidad de criterio en la
definición de MACROSOMIA fetal, catalogándose como tal aquellos fetos con un PFE por encima de los 4000-4500 gramos según los autores.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
EPIDEMIOLOGÍA:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Prevalencia 0,5-6% } EEUU disminución de las
tasas de macrosomías: } Aumento de la gemelaridad. } Mejor cribado de la Diabetes. } Mejor control gestacional. } Mayor tasa de cesáreas. Menor
número de recién nacidos postérmino.
} Otros países como Dinamarca o Croacia aumento de las tasas.
laceration of the anal sphincter,5,6 and postpartuminfection.5
To avoid these potential complications, it seemsreasonable to intervene, either with induction7 orcesarean delivery,8 if the fetus is suspected of beingmacrosomic. But systemic review9 and a randomizedstudy10 have not shown any benefit of induction. A costanalysis suggests that the option of elective cesareandelivery is undesirable.11 Despite the clinical evidenceagainst intervention for suspected macrosomia, there isa continued tendency to either induce labor7 or toproceed with cesarean delivery.8,12
The disconnect between clinical evidence and practiceprompted us to review the accuracy of the detection ofa macrosomic newborn infant and the management ofa pregnancy that is suspected of having a fetus whoweighs at least 4000 g.
Changing prevalence of macrosomia
The rate of macrosomia is decreasing in the UnitedStates (Figure 1).13-19 Review of National Vital Statisticsfrom the Center for Disease Control and Preventionindicates that the rate of macrosomia was 10.2% in 1996and that since then the rate has declined steadily(Figure 1). In 2002, only 9.2% of all neonates(368,184/4,021,726) weighed R4000 g. The significantdecrease in the prevalence of macrosomia is apparent fornewborn infants with weights between 4000 and 4499 gand 4500 and 4999 g and for infants who weigh at least5000 g (Table I).13-19 Compared with 1996, in 2002 therate of neonates with birth weights R4000 g wassignificantly lower (odds ratio [OR], 0.88; 95% CI,0.89, 0.90), as it was for newborn infants with birthweights between 4000 and 4449 g (OR, 0.89; 95% CI,0.88, 0.90), 4500 and 4999 g (OR, 0.84; 95% CI, 0.83,0.86) and R5000 g (OR, 0.83; 95% CI, 0.80, 0.86).Concomitant with the decrease in newborn infants whoweigh R4000 g, there has been an increase in theprevalence of newborn infants who weigh !3000 g(Figure 2).13-19
The decrease in the rate of macrosomia is neitherrecognized nor explained in the reports by NationalVital Statistics and is counterintuitive. Obesity is a riskfactor for macrosomia1 and its prevalence is increas-ing20; thus, it is reasonable to expect a higher prevalenceof macrosomia.21 Considering the source of the data, thesample size, and the objective definition of macrosomia,the observed decrease is irrefutable (Figure 1). Wespeculate that the decline may be explained by routinetesting for gestational diabetes mellitus, the increasingrates of multiple gestations,22 preterm deliveries,23 andrepeat elective cesarean delivery,24 which was scheduledbefore a patient becomes postterm. Additional factorsthat are responsible for the decrease in the prevalencecan be gleaned by a review of the reports that havenoted an increase in the rate of macrosomia.25
In contrast to the United States, the rate of macro-somia actually has increased in Denmark. Orskou et al25
reported that in 1990 the rate of neonates with birthweights R4000 g was 16.7% and 20.0% in 1999,a significant increase (P ! .05). By comparing the riskfactors and the maternal characteristics of patients whowere delivered in 1996 and in 1999, the investigatorsnoted that differences in prepregnancy height, weight,smoking habits, educational level, and caffeine intakeexplained the increase in the rate of macrosomia.26
Perhaps there are some maternal characteristics in the
Figure 1 Prevalence of macrosomia in the United States.13-19
Table I Prevalence of macrosomia in the United States (National Vital Statistics Report13-19)
Variable 2002 (n) 2001 (n) 2000 (n) 1999 (n) 1998 (n) 1997 (n) 1996 (n) P value*
Total births 4,021,726 4,025,933 4,058,814 3,959,417 3,941,553 3,880,894 3,891,494Macrosomia 368,184
(9.2%)378,976(9.4%)
401,340(9.9%)
392,683(9.9%)
396,096(10.1%)
390,071(10.1%)
398,340(10.2%)
! .0001
4000-4499 g 314,182(7.8%)
322,346(8.0%)
340,384(8.4%)
332,863(8.4%)
330,894(8.5%)
330,894(8.5%)
336,514(8.6%)
! .0001
4500-4999 g 48,606(1.2%)
51,132(1.3%)
54,748(1.3%)
53,751(1.4%)
53,936(1.4%)
53,936(1.4%)
55,558(1.4%)
! .0001
R5000 g 5396(0.1%)
5498(0.1%)
6208(0.2%)
6069(0.2%)
5941(0.2%)
5941(0.2%)
6268(0.2%)
! .0001
* c2 test for trend.
Chauhan et al 333
Prevalencia de la macrosomía en los EEUU. REVIEW ARTICLE
Suspicion and treatment of the macrosomic fetus:A review
Suneet P. Chauhan, MD,a William A. Grobman, MD,b Robert A. Gherman, MD,c
Vidya B. Chauhan, BS,a Gene Chang, MD,d Everett F. Magann, MD,a
Nancy W. Hendrix, MDa
Spartanburg Regional Medical Center, Spartanburg, SCa; Northwestern University Medical Center, Chicago, ILb;University of Maryland, Baltimore, MD c; and Medical University of South Carolina, Charleston, SCd
Received for publication November 2, 2004; revised November 27, 2004; accepted December 8, 2004
KEY WORDSMacrosomiaEstimate birth weightDiabetes mellitusInductionCesarean delivery
Objective: To review the prevalence of and our ability to identify macrosomic (birthweightO4000 g) fetuses. Additionally, based on the current evidence, propose an algorithm fortreatment of suspected macrosomia.Study design: A review.Results: According to the National Vital Statistics, in the United States, the prevalence ofnewborns weighing at least 4000 g has decreased by 10% in seven years (10.2% in 1996 and 9.2%in 2002) and 19% for newborns with weights O5000 g (0.16% and 0.13%, respectively). Bayesiancalculations indicates that the posttest probability of detecting a macrosomic fetus in anuncomplicated pregnancy is variable, ranging from 15% to 79% with sonographic estimates ofbirth weight, and 40 to 52% with clinical estimates. Among diabetic patients the post-testprobability of identifying a newborn weighing O4000 g clinically and sonographically is over60%. Among uncomplicated pregnancies, there is sufficient evidence that suspected macrosomiais not an indication for induction or for primary cesarean delivery. For pregnancies complicatedby diabetes, with a prior cesarean delivery or shoulder dystocia, delivery of a macrosomic fetusincreases the rate of complications, but there is insufficient evidence about the threshold ofestimated fetal weight that should prompt cesarean delivery.Conclusion: Due to the inaccuracies, among uncomplicated pregnancies suspicion of macrosomiais not an indication for induction or for primary cesarean delivery.! 2005 Elsevier Inc. All rights reserved.
The delivery of a macrosomic fetus (defined as a birthweight of at least 4000 g) is associated with prolongedlabor, an increased likelihood of operative delivery,shoulder dystocia, and brachial plexus injury1 that
may be permanent and lead to litigation.2 Newborninfants with a weight R4500 g are at increased risk forneonatal morbidity, which includes assisted ventilationand meconium aspiration. Those infants who weigh atleast 5000 g have increased infant mortality rates, whencompared with infants with weights between 4000 and4499 g.3 Maternal complications that are associated withthe delivery of macrosomic infants are the result of anoperative delivery and include postpartum hemorrhage,4
Reprints not available from the authors. Address correspondenceto Suneet P. Chauhan, MD, 8901 W. Lincoln Ave., West Allis, WI53227.
E-mail: [email protected]
0002-9378/$ - see front matter ! 2005 Elsevier Inc. All rights reserved.doi:10.1016/j.ajog.2004.12.020
American Journal of Obstetrics and Gynecology (2005) 193, 332–46
www.ajog.org
REVIEW ARTICLE
Suspicion and treatment of the macrosomic fetus:A review
Suneet P. Chauhan, MD,a William A. Grobman, MD,b Robert A. Gherman, MD,c
Vidya B. Chauhan, BS,a Gene Chang, MD,d Everett F. Magann, MD,a
Nancy W. Hendrix, MDa
Spartanburg Regional Medical Center, Spartanburg, SCa; Northwestern University Medical Center, Chicago, ILb;University of Maryland, Baltimore, MD c; and Medical University of South Carolina, Charleston, SCd
Received for publication November 2, 2004; revised November 27, 2004; accepted December 8, 2004
KEY WORDSMacrosomiaEstimate birth weightDiabetes mellitusInductionCesarean delivery
Objective: To review the prevalence of and our ability to identify macrosomic (birthweightO4000 g) fetuses. Additionally, based on the current evidence, propose an algorithm fortreatment of suspected macrosomia.Study design: A review.Results: According to the National Vital Statistics, in the United States, the prevalence ofnewborns weighing at least 4000 g has decreased by 10% in seven years (10.2% in 1996 and 9.2%in 2002) and 19% for newborns with weights O5000 g (0.16% and 0.13%, respectively). Bayesiancalculations indicates that the posttest probability of detecting a macrosomic fetus in anuncomplicated pregnancy is variable, ranging from 15% to 79% with sonographic estimates ofbirth weight, and 40 to 52% with clinical estimates. Among diabetic patients the post-testprobability of identifying a newborn weighing O4000 g clinically and sonographically is over60%. Among uncomplicated pregnancies, there is sufficient evidence that suspected macrosomiais not an indication for induction or for primary cesarean delivery. For pregnancies complicatedby diabetes, with a prior cesarean delivery or shoulder dystocia, delivery of a macrosomic fetusincreases the rate of complications, but there is insufficient evidence about the threshold ofestimated fetal weight that should prompt cesarean delivery.Conclusion: Due to the inaccuracies, among uncomplicated pregnancies suspicion of macrosomiais not an indication for induction or for primary cesarean delivery.! 2005 Elsevier Inc. All rights reserved.
The delivery of a macrosomic fetus (defined as a birthweight of at least 4000 g) is associated with prolongedlabor, an increased likelihood of operative delivery,shoulder dystocia, and brachial plexus injury1 that
may be permanent and lead to litigation.2 Newborninfants with a weight R4500 g are at increased risk forneonatal morbidity, which includes assisted ventilationand meconium aspiration. Those infants who weigh atleast 5000 g have increased infant mortality rates, whencompared with infants with weights between 4000 and4499 g.3 Maternal complications that are associated withthe delivery of macrosomic infants are the result of anoperative delivery and include postpartum hemorrhage,4
Reprints not available from the authors. Address correspondenceto Suneet P. Chauhan, MD, 8901 W. Lincoln Ave., West Allis, WI53227.
E-mail: [email protected]
0002-9378/$ - see front matter ! 2005 Elsevier Inc. All rights reserved.doi:10.1016/j.ajog.2004.12.020
American Journal of Obstetrics and Gynecology (2005) 193, 332–46
www.ajog.org
MÁS FRECUENTE: • Diabetes. • Antecedentes de fetos
macrosómicos. • Varones.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
ETIO
PA
TIO
GE
NIA
: FACTORES DE RIESGO: Obesidad Materna, DM, épeso durante la gestación
HIPERGLUCEMIA
Paso de la glucosa a través de la placenta mediante difusión facilitada. No de la Insulina.
HIPERGLUCEMIA FETAL
Hiperinsulinemia
Efecto anabólico sobre las células
Liberación de factores de crecimiento (GH, IGF1)
Leptina y Grelina Leptina niveles superiores en fetos grandes asimétricos (CA>DBP)
Síndromes genéticos de sobrecrecimiento • Beckwith Wiedemann • Sotos
Diagnóstico de la macrosomía:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Altura uterina (VPP 28-53%) } Parámetros ecográficos:
} PFE (VVP 64%) } CA } DBP/CA: predicción de la distocia de hombros } Otros parámetros:
} Tejido subcutáneo del húmero proximal. } Grosor de la grasa abdominal } Mejilla-Mejilla } Muslo } Longitud hepática.
} Eco 3D.
Fax +41 61 306 12 34E-Mail [email protected]
Review
Fetal Diagn Ther 2013;33:143–148 DOI: 10.1159/000341813
Prenatal Detection and Consequences of Fetal Macrosomia
Christian Bamberg Larry Hinkson Wolfgang Henrich
Department of Obstetrics, Charité University Medical Center, Berlin , Germany
ternationally agreed established weight limits for macro-somia; the American College of Obstetricians and Gyne-cologists recommends 4,500 g because of the marked in-crease in maternal and neonatal complication rates at this weight [1]. All birth weight definitions agree, however, that birth weight is independent of gestational age and consequently should not be dependent on a population-based analysis.
This concept of the use of percentile curves issue is complicated due to the definition of large for gestational age (LGA) by some researchers when the 90th weight per-centile is exceeded, while other researchers use either the 95th percentile, the 97th percentile, or 2 standard devia-tions above the median as the cut-off. The advantage of using percentiles for the definition of macrosomia/LGA is the independence from gestational age. However, gen-der-specific values must be taken into consideration, as male newborns are on average heavier than female new-borns. Furthermore, ethnicity has a significant influence on birth weight, and given the accelerated increase in birth weights in recent decades, current reference ranges must be modified [3].
Diagnosis of Fetal Macrosomia by Ultrasound
In industrialised countries the use of prenatal ultra-sound has largely replaced clinical diagnosis for macro-somia. Fundal height measurement alone or in combina-tion with symphysis-fundal height measurement results
Key WordsThree-dimensional sonography ! Birth weight ! Prenatal ultrasonography ! Fetal weight estimation ! Macrosomia ! Clinical management
AbstractMacrosomia is diagnosed when excessive intrauterine fetal growth occurs and the birth weight surpasses an established limit. The causes and risk factors for fetal macrosomia are di-verse. Pregnancies with fetal macrosomia are considered high risk and require intensive antenatal care. Prenatal ultra-sound appears to be the best method for performing weight estimates before birth, as the correct birth weight is often underestimated when using biometric formulae to deter-mine the fetal weight. Three-dimensional volume sonogra-phy has been shown to improve estimates of fetal weight by including limbs volumes. The recent Hart formula has been specifically developed for fetal macrosomia estimation and appears to improve accuracy. Delivery of a macrosomic baby is also high risk and should be performed in tertiary centres with experienced obstetricians.
Copyright © 2012 S. Karger AG, Basel
Macrosomia is diagnosed when excessive intrauterine growth occurs and the birth weight exceeds an estab-lished limit of either 4,000 or 4,500 g [1]. Approximately 10% of all newborns have a birth weight 14,000 g, and 1.5% weigh 64,500 g [2]. There are no nationally or in-
Received: April 2, 2012 Accepted after revision: July 6, 2012 Published online: December 5, 2012
Dr. Christian Bamberg Klinik für Geburtsmedizin, Charité Universitätsmedizin Berlin Campus Virchow Klinikum, Augustenburger Platz 1 DE–13353 Berlin (Germany) E-Mail christian.bamberg @ charite.de
© 2012 S. Karger AG, Basel1015–3837/13/0333–0143$38.00/0
Accessible online at:www.karger.com/fdt
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Journal of Clinical and Diagnostic Research. 2014 Apr, Vol-8(4): OC9-OC11 99
DOI: 10.7860/JCDR/2014/6498.4214 Original Article
Correlation of Fetal Abdominal Subcutaneous Tissue Thickness by Ultrasound to Predict
Birth Weight
Obs
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RAJESHWARI G BHAT1, ANITHA NATHAN2, AMAR R3, AKHILA VASUDEVA4, PRASHANTH ADIGA5, PARVATI V BHAT6, PRATAP KUMAR N7
Keywords: Fetal abdominal subcutaneous tissue thickness, Ultrasound, Birth weight
INTRODUCTION Assessment of fetal weight in-utero leads to improved management of high risk pregnancies. It is an independent factor to determine optimal survival of fetus; fetal weight is undoubtedly one of the most significant determinants of neonatal survival. Obstetric ultrasound with its diagnostic modality helps to predict fetal weight with a certain degree of precision. Many clinical methods substantiated by various ultrasound formulas have been used to estimate weight and growth in-utero. Recently, soft tissue markers like fetal subcutaneous tissue thickness, mid-arm circumference, thigh circumference have been used to predict fetal weight in-utero.
Fetal abdominal subcutaneous tissue thickness (FASTT) is one such ultrasound parameter which is an independent factor in predicting big babies and when substantiated with other ultrasound parameters can predict fetal weight for large for gestational age babies. Number of studies done in Asian population is few; the fetuses are likely to have less subcutaneous fat compared to developed countries. The cut off value obtained for western population may not be applicable to Asian population.
OBJECTIVESThe aim of the study was to correlate fetal abdominal subcutaneous tissue thickness (FASTT) measured by ultrasound at term and birth weight measured immediately after delivery and to obtain a cut-off value of FASTT to predict large and small for gestational age babies in our population; coastal district of Southern India.
METHODSThe study was conducted in a tertiary level teaching hospital, and was a prospective observational study. Fetal Abdominal Subcutaneous Tissue Thickness (FASTT) was measured at the anterior 1/3rdof abdominal circumference between outer and inner edges of abdominal wall by ultrasound (Philips HD7) at the level of measurement of abdominal circumference [Table/Fig-1]. Large for gestational age (LGA) is defined as birth weight >90th percentile in our study population and small for gestational age (SGA) as <10th percentile.
Study included singleton term pregnancies who delivered within one week of estimation of FASTT. All fetuses with ultrasound detected congenital anomalies were excluded from this study. Pearson correlation coefficient (r) was used to study the correlation between FASTT and birth weight, paired t-test was used to compare the FASTT of average for gestational age (AGA), LGA and SGA babies. ROC curve is used to obtain a cut-off of FASTT to predict LGA and SGA babies.
RESULTSTotal of 350 antenatal women were included in the study who fulfilled the criteria during the study period, average maternal age being 27 year, 54.6% (191/350) were primigravidae.
The mean FASTT was 6 mm ± 0.94, with a range of 3.4 mm to 10 mm. Mean birth weight of babies was 2986 g ± 392.8, ranging between 1900 g and 4170 g [Table/Fig-2]. Number of babies weighed as average for gestational age (AGA, between 10th and 90th percentile) was 286 (81.7%), 25 babies (7.1%) were small for
ABSTRACTIntroduction: Fetal growth abnormality is associated with changes in the soft tissue mass, which is decreased in growth restricted fetuses and increased in macrosomia.
Objective: To correlate fetal abdominal subcutaneous tissue thickness (FASTT) measured by ultrasound at term and birth weight and to obtain a cut-off value of FASTT to predict large and small for gestational age babies in our population.
Methods: FASTT was measured at the anterior 1/3rd of abdominal circumference by ultrasound after 36 weeks and weight of the baby measured after birth.
Results:There was positive correlation between FASTT and birth weight. FASTT of 6.25 mm was sensitive to predict large for gestational age (LGA) babies and had a high negative predictive value; FASTT measurement for prediction of small babies with birth weight < 2500 g was not sensitive.
Conclusion: FASTT can be used as an additional indicator to predict large for gestational age babies along with other known birth weight indicators.
[Table/Fig-1]: Measurement of FASTT by ultrasound
MACROSOMÍA
SÍNDROMES DE SOBRECRECIMIENTO GENÉTICO.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
growth and physical development are 2–3 SD above the mean for age and sex[Weaver, 1994]. The partial, localized,or regional OGS include those disorders
in which excessive growth is confined toone or a few regions of the body.
For this review, I consider the morecommon OGS (Table I, group A) and
the localized or partial OGS (Table I,groupB). Some other disorders includedin group A and C (miscellaneous) havenot been analyzed.
TABLE I. Classification of
Overgrowth Syndromes
Group A—True overgrowth
syndromes
Frequent
Bannayan-Riley-Ruvalcaba
Beckwith-Wiedemann
Sotos
Weaver
Macrocephaly/cutis marmorata
telangiectatico
Marshall-Smith
Simpson-Golabi-Behmel
Perlman
Infrequent
Richieri-Costa
Teebi
MOMO
MORFAN
Nevo
Cantu
Elejalde
Fryer
Costello
Nonsyndromic
Group B—Localized/partial
overgrowth syndromes
Hemihypertrophy
Klippel Trenaunay Weber
Proteus
Group C—Miscellaneous disorders
Chromosomal
Klinefelter syndrome, 47,XYY
and 47,XXX
Pallister-Killian
Trisomy 8 mosaicism
Fragile X syndrome
Duplication 4p16.3
Endocrinological or related
disorders
Infant of diabetic mother
Familial rapid maturation/
tall stature
Gigantism (hyperpituitarism)
Congenital adrenal hyperplasia
Others
Marfan
Homocystinuria
TABLE II. Malignancies Reported in Beckwith-Wiedemann Syndrome
Type of tumor Number of cases %
Wilms tumor 49 43
Hepatoblastoma 23 20
Adrenocortical carcinoma 9 7
Rhabdomyosarcoma 8 6
Neuroblastoma 6 5
Pancreatoblastoma 4 3
Renal cell carcinoma 2 2
Pheochromocytoma 2 2
Gastric teratoma 2 2
Lymphoma 1 1
Optic nerve glioma 1 1
Yolc sac tumor of placenta 1 1
Mesoblastic nephroma 1 1
Hepatocarcinoma 1 1
Carcinoid tumor 1 1
Thyroid carcinoma 1 1
Intratubular germ cell neoplasm 1 1
Acute myeloid leukemia 1 1
Acute lymphocytic leukemia 1 1
Total 115 100
Cases reported byRiedel, 1952; Lee, 1972; Reddy et al., 1972; Sotelo-Avila and Gooch,
1976; Prevot et al., 1977; Muller et al., 1978; Sotelo-Avila et al., 1980; Tank and Kay,
1980; Gruner et al., 1981; Wojciechowski and Pritchard, 1981; Molina et al., 1981;
Bockrath et al., 1982; Emery et al., 1983; Shah, 1983; Zmudzka et al., 1984; Turleau and
de Grouchy, 1985; Haas et al., 1986; Koh et al., 1986; Potts et al., 1986; Weinstein et al.,
1986; Haas et al., 1987; Little et al., 1988; Pai, 1988; Rey et al., 1988; Drut and
Jones, 1988; Yokomori et al., 1988; Henry et al., 1989a,b; Huber and Gutjahr, 1989;
Ruiz et al., 1989; Clouston et al., 1989; Sirinelli et al., 1989; Azouz et al., 1990; Chitayat
et al., 1990; Deeg, 1990; Diaz de Bustamante et al., 1990; Beetz et al., 1991; Falik-
Borenstein et al., 1991; Orozco-Florian et al., 1991; Schneid et al., 1991; Wilfong et al.,
1992; Solsona-Narbon et al., 1992; Andrews and Amparo, 1993; Martelli et al., 1993;
Henry et al., 1993; Schneid et al., 1993; Slatter et al., 1994; Federici et al., 1994;
Matsumoto et al., 1994; Tlili-Graiess et al., 1994; Hoban et al., 1995; Reik et al., 1995;
Schofield et al., 1995; Weng et al., 1995; Vaughan et al., 1995; Yamaguchi et al., 1996;
Tsai et al., 1996;DiCataldo et al., 1996;Hatada et al., 1996;Hatada et al., 1997; Lee et al.,
1997; Catchpoole et al., 1997; Sutherland et al., 1997; O’Keefe et al., 1997; Regalado
et al., 1997; Dutly et al., 1998; Okamoto et al., 1998; Aideyan and Kao, 1998; Drut et al.,
1998; Borer et al., 1999; Lam et al., 1999; Lapunzina et al., 1999; Worth et al., 1999;
Goldman et al., 2000; Sbragia-Neto et al., 2000; Engel et al., 2000; Paterson and
Sweeney, 2000, Everman et al., 2000, Smith et al., 2001; Gaston et al., 2001; Bliek et al.,
2001; Yoon et al., 2002; Cohen et al., 2002; Jeanes et al., 2002; Houtenbos and
Ossenkoppele, 2002; Bemurat et al., 2002; Thavaraj et al., 2002; Hamada et al., 2003;
Pelizzo et al., 2003, Fukuzawa et al., 2003; Clericuzio et al., 2003; Khatib et al., 2004.
54 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE
American Journal of Medical Genetics Part C (Semin. Med. Genet.) 137C:53–71 (2005)
A R T I C L E
Risk of Tumorigenesis in Overgrowth Syndromes:A Comprehensive ReviewPABLO LAPUNZINA
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic isthat eitherweight, height, or head circumference is 2–3 standarddeviations (SD) above themean for sex and age.A striking feature of OGS is the risk of neoplasms. Here, the relative frequency of specific tumors in each OGS,topographic location, and age of appearance is determined by reviewing published cases. In someOGS (Perlman,Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94%of tumorsappeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, onlyWilms tumor has been recorded, whereas in Sotos syndrome, lympho-hematologic tumors are most frequent.Based on literature review, a specific schedule protocol for tumor screening is suggested for eachOGS.A schedulewith different intervals and specific tests is proposed for a more rational cost/benefit program for thesedisorders. ! 2005 Wiley-Liss, Inc.
KEY WORDS: Beckwith-Wiedemann syndrome; Bannayan-Riley-Ruvalcaba syndrome; macrocephaly-cutis marmorata syndrome; Marshall-Smith syndrome; Perlman syndrome; Simpson-Golabi-Behmel syndrome; Sotos syndrome; Weaver syndrome; Klippel-Trenaunay syndrome;isolated hemihyperplasia; Proteus syndrome tumor screening; cost/benefit program
INTRODUCTION
Neoplasms in children under age 15 israre with only 14.1 cases per 100,000children (1:7,100 below15 years) [Hershet al., 1992; Harras, 1996]. Incidence isslightly higher among whites (14.4 per100,000) than blacks (11.8 per 100,000)[Harras, 1996], but from a statisticalstandpoint, tumors occur with lowfrequency. Besides, the association of
increased birthweight and neoplasms,such as Wilms tumor, leukemia, neuro-blastoma, and astrocytoma has beenobserved [Cohen et al., 2002].
Overgrowth syndromes (OGS)comprise a heterogeneous group ofdisorders whose main characteristic isthat either the weight, height, or headcircumference, frequently occurringtogether are above the 97th centile or2–3 standard deviations (SD) above themean for age and sex. One strikingfeature of OGS is their risk of tumor-igenesis [Cohen, 1989]. There areseveral reports of predisposition ofneoplasms with particular OGS. Somerecommendations for tumor screeningin children with Beckwith-Wiedemannsyndrome, Simpson-Golabi Behmelsyndrome, hemihyperplasia, and Cost-ello syndrome are available [Cohen,1989; Clericuzio, 1999; DeBaunet al., 2001; Li et al., 2001; Gripp et al.,2002]. However, most of these re-commendations were focused on theabdominal region and/or biochemicalmarkers.
The aims of this article are: (1) toevaluate the risk of tumors in OGS bycomprehensively reviewing reportedcases of OGS and tumors; (2) to describetheir relative frequencies, locations, and
age of appearance of specific tumors ineach OGS; and (3) to propose a tumorscreening protocol and guide to follow-up for children with each different typeof OGS.
By providing a specific schedule foreach disorder (physical examination,ultrasound, biochemical markers, urina-lysis, radiographs, etc.), this guide willprobably optimize the cost/benefit ofOGS surveillance.
DEFINITION ANDCLASSIFICATION
Several terms are used, such as macro-somia,macrosomic baby, giant, and largefor gestational age [Lapunzina et al.,2002]. Most OGS result from hyperpla-sia, hypertrophy, an increase in theinterstitium, or some combination ofthese factors [Cohen, 1989]. Thus, anOGS may be defined as a condition inwhich there is either localized or gen-eralized excessive growth and develop-ment for age and sex [Weaver, 1994].There are several classifications of OGS[Beighton, 1988; Cohen, 1989; Weaver,1994; Sotos, 1997; Lapunzina, 2000;Cohen et al., 2002]. Generalized OGSincludes the classic overgrowth disordersin which all of most parameters of
Dr. Pablo Lapunzina. Pediatrician, Clinicaland Molecular Geneticist, and Specialist inEmbryofetal Medicine. He trained in Pedia-trics and then in Medical Genetics andDysmorphology at the Children’s Hospitalof Buenos Aires, University of Buenos Aires,Argentina. He also completed 3 years oftraining inMolecular Genetics at the InstitutoNacional de Genetica y Biologıa Molecular(INGEBI-CONICET), Buenos Aires. He is nowon the Staff of the Department of Genetics,Hospital Universitario La Paz, AutonomaUniversity of Madrid, Spain. His interestsspan dysmorphology, clinical genetics, andmolecular genetics. He is author or coauthorof over 70 articles in the medical andscientific literature, 18 book chapters, and1 book. He now focuses on ovegrowthsyndromes.
Correspondence to: Dr. M. MichaelCohen Jr, Dalhousie University, 5981 Uni-versity Ave., Halifax, Nova Scotia B3H 3J5,Canada. E-mail: [email protected]
DOI 10.1002/ajmg.c.30064
! 2005 Wiley-Liss, Inc.
SÍNDROME DE BECKWITH-WIEDEMANN:
DEFINICIÓN: • Síndrome genético de sobrecrecimiento más frecuente. • Fue descrito por primera vez por el patólogo pediátrico americano Beckwith y por el
genetista alemán Wiedemann en los años 1963-1964. • En los inicios denominado Síndrome EMG (Exomphalos-Macroglosia-Gigantismo).
DEMOGRAFÍA: • Prevalencia: 1/14.000 RN vivos. • Incidencia en aumento. • Aumento con TRA (X4) • No diferencia entre sexos.
Trastornos del crecimiento fetal. Laura Sotillo Mallo
SÍNDROME DE BECKWITH-WIEDEMANN:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
ETIPATIOGENIA: • Genes relacionados con el cremiento localizados crom 11 (11p15.5).
• Gen promotor de crecimiento (IGF-2): alelo paterno. • Gen supresor de crecimiento (H19): alelo materno.
• Entidad genética compleja y heterogénea • Mecanismos:
• Fenómenos epigenéticos (metilación) en los genes implicados. • Disomía uniparental de origen paterno (pUDP11). • Microdelecciones de origen materno. • Duplicaciones de origen paterno.
• 85%-90% Mutaciones de “novo”. Riesgo de recurrencia <1%.
DNA that regulate the expression of imprinted genes in cis over largedistances and show differential methylation of the parental alleles.Therefore, they are also termed differentially methylated regions(DMRs).
The regulation of imprinted genes on chromosome 11p15.5 isshown in Figure 2. Deregulation of imprinted genes in the 11p15.5imprinted region results in the BWS phenotype through a number ofdifferent mechanisms leading to either primary epigenetic alterationsor genetic alterations that change the relative contributions of parentalalleles.24,31,32 These include parent-of-origin-specific duplications,translocations/inversions, microdeletions, DNA methylation changesat IC1 or IC2, UPD, and mutations at CDKN1C. UPD refers to thepresence of two chromosomal regions from one parent and none fromthe other.
Sporadic loss of methylation at IC2 occurs in 50% of patients.33
Gain-of-methylation defects occur at IC1 (5%); some of these methy-lation alterations have been associated with genomic alterations.34–36
Methylation changes that occur in conjunction with genomic altera-tions are important because of their heritability. Epigenetic alterationsthat involve both IC1 and IC2 generally indicate paternal UPD (20%
of cases) for a chromosomal segment including 11p15.5.24,33
Segmental UPD arises from a post-zygotic somatic recombinationevent and therefore has a mosaic distribution.
Methylation-sensitive multiplex ligation probe analysis (MS-MLPA)is currently the most robust method for detecting the majority ofepigenetic and genetic etiologies associated with BWS. It detectsmicrodeletions/microduplications, alterations in gene dosage, andDNA methylation including UPD.37 Confirmation of UPD11 may beundertaken by analysis of short tandem repeats as the somaticmosaicism associated with this etiology may lead to weak signals onMS-MLPA. Moreover, failure to detect UPD11 in one tissue (usuallyleukocytes) is not conclusive. One should consider obtaining anothertissue (such as skin), especially in the event of surgery. Karyotypeanalysis will detect the rare de novo and maternally transmittedtranslocations/inversions (1%) and paternally derived duplications(1%) of chromosome 11p15.5 associated with BWS. Translocation/inversions almost always disrupt the gene, KCNQ1,38 and are notusually detectable by MLPA because most do not show DNA copynumber changes or DNA methylation changes. Finally, DNA sequen-cing is required to detect genomic alterations in CDKN1C associated
H19IGF2CDKN1C KCNQ1KCNQ1OT1
H19IGF2KCNQ1KCNQ1OT1
PAT
MATCDKN1C
Map of the normal chromosome 11p15 imprinting cluster
Map of the 11p15 imprinting cluster in two types of BWS patients
H19IGF2CDKN1C KCNQ1KCNQ1OT1
H19IGF2KCNQ1KCNQ1OT1
PAT
MATCDKN1C
Domain 1Domain 1Domain 2Domain 2
a
b
Domain 1 Domain 1 Domain 2Domain 2
H19IGF2CDKN1C KCNQ1KCNQ1OT1
H19IGF2KCNQ1KCNQ1OT1
PAT
MATCDKN1C
Domain 1Domain 1Domain 2Domain 2
1) H19 gain of methylation
2) KvDMR1 loss of methylation
IC1
KvDMR/IC2
KvDMR/IC2
KvDMR/IC2
IC1
IC1
IC1
Figure 2 (a) Schematic representation of the chromosome 11p15.5 imprinted region that is functionally divided into two domains. In the distal domain 1are two imprinted genes, H19 and insulin-like growth factor 2 (1GF2). IGF2 is a paternally expressed fetal growth factor and H19 is a noncoding RNA. TheH19-associated imprinting center (IC1) is usually methylated on the paternal chromosome and unmethylated on the maternal chromosome. Normally, theH19 gene is expressed from the maternal allele and IGF2 from the paternal allele. Domain 2 contains several imprinted genes, including KCNQ1,KCNQ1OT1, and CDKN1C. A differentially methylated region (IC2) contains the promoter for KCNQ1OT1, a paternally expressed noncoding transcript thatregulates in cis the expression of the maternally expressed imprinted genes in domain 2. Two examples of imprinting alterations leading to Beckwith–Wiedemann syndrome (BWS) are shown in (b1) and (b2). (b1) IC1 gain of methylation in BWS is found in B5% of patients and leads to biallelic expressionof IGF2. (b2) Loss of methylation at the KvDMR differentially methylated region (IC2) is found in 50% of BWS patients. This epigenetic alteration leads toreduced expression of CDKN1C. Red corresponds to preferential maternal allelic expression, blue corresponds to preferential paternal allelic expression.Filled rectangles indicate expressed genes and empty rectangles indicate non-expressed gene. Lollipops correspond to methylated sites.
Beckwith–Wiedemann syndromeR Weksberg et al
10
European Journal of Human Genetics
with BWS. The CDKN1C (p57kip2) mutations are seen both sporadi-cally (5%) and in autosomal dominant pedigrees modified bypreferential parent of origin-specific transmission (40%).39 A rationalclinical approach to test these varied defects on chromosome 11p15.5is presented in Figure 3.
Current studies of BWS patient cohorts identify a chromosome11p15 molecular alteration in only 75–80% of individuals.Therefore, other genomic loci are likely involved in the etiology ofBWS.40 Recent molecular studies have shown two genes, NALP2 onchromosome 1941 and ZFP57 on chromosome 642 that can modulateimprinting at IC2.
Clinical findings relevant to molecular etiologyTumor development. Individuals with UPD of 11p15.5 or gain ofmethylation at the H19 IC carry the highest risk to develop Wilmstumor or hepatoblastoma.19,20–24,30 Those with loss of maternalmethylation at IC2 carry a lower tumor risk; as well, the tumors inthis molecular subgroup do not include Wilms tumor. Lastly, indivi-duals with mutations in CDKN1C seem to have the lowest risk withonly a small number of cases reported. In cases with CDKN1Cmutation, only neuroblastoma has been reported to date.
Hemihyperplasia in cases of BWS. Alterations have includedmosaicism for UPD 11p15.5 with hemihyperplasia and or molecularalterations at IC2 or IC1.32,43
Positive family history. This is associated with mutations in CDKN1Cor microdeletions of IC1 and very rarely IC2.32,33,35–37,40,44,45
Omphalocele. This is associated with an IC2 defect or CDKN1Cmutation.32
Developmental delay. This is associated with cytogenetically detect-able duplications involving the paternal copy of chromosome11p15.5.46,47
A severe BWS phenotype. This seems to be associated, at least incertain cases, with very high levels of paternal chromosome 11p15.48
An increased frequency of female monozygotic twins discordant forBWS has been reported.49 These females usually show loss of methyla-tion at IC2. In contrast, the less frequently observed male monozygotictwins show a broad spectrum of BWS-associated molecularalterations.48
Subfertility/assisted reproductive technologies (ARTs). This seem to beassociated with an increased risk of BWS cases with loss of methyla-tion at IC2 (Figure 4).43,50–52 No specific aspect of subfertility or itstreatment has been specifically associated with the increased risk ofepigenetic defects associated with BWS after ART.
MANAGEMENT TREATMENT AND CAREThe management of BWS patients typically involves standard suppor-tive medical and surgical strategies (eg, surgical repair of omphalo-cele). In addition, anticipatory medical management for certainfindings should be invoked if the diagnosis of BWS is established oreven suspected. If there are prenatal findings suggestive of or diag-nostic for BWS,53 screening for hypoglycemia should be undertaken inthe first few days of life. As well, parents should be advised of thetypical clinical manifestations of hypoglycemia in the event that itmanifests after discharge from hospital.
Tumor surveillance should be initiated if BWS is diagnosed orsuspected. Current tumor surveillance protocols may vary among
TESTING APPROACHES FOR BWS
Karyotype
Chromosome 11p15 abnormalityidentified
Indicates etiology is a heritablechromosomal duplication translocation or
inversion
Positive family historyand/or
cleft palate
BWS etiology is a heritableCDKN1C mutation
Screen parents and other relevantfamily members for alteration
CDKN1C testing
Pathogenic mutation identified
Screen parents and other relevantfamily members for alteration
No
MLPA or other tests for methylation andcopy number changes on chromosome 11p15
Supports UPD
Both gain of methylation H19 andloss of methylation at KvDMR Gain of methylation at H19 Loss of methylation at
KvDMR
Associated genomic alterations orpositive FH indicates BWS etiology is
heritable
If no associated genomic alterationsand negative FH- indicates etiology islikely a sporadic epigenetic alteration
Karotypeandand
Methylation and/or copy numberabnormalities identified:
If confirmed by microsatelliteanalysis, indicates etiology isUPD for chromosome 11p15,
which is sporadic
Negative family historyand/or
no cleft palate
No
Figure 3 A clinical approach to testing for BWS.
Beckwith–Wiedemann syndromeR Weksberg et al
11
European Journal of Human Genetics
Dx Ecográfico de Beckwith-Wiedemann:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Macrosomía (90%)
Macroglosia (80-100%)
Onfalocele 50%
Visceromegalia. Hipertrofia renal.
Polihidramnios y placenta quística y engrosada.
PRACTICAL GENETICS In association with
Beckwith–Wiedemann syndrome
Beckwith–Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis.Unique observations in this disorder point to an important embryonic developmental window relevant to the observations ofincreased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.
INTRODUCTIONBeckwith–Wiedemann syndrome (BWS) is a pediatric overgrowthdisorder involving a predisposition to tumor development. Theclinical presentation is highly variable; some cases lack the hallmarkfeatures of exomphalos, macroglossia, and gigantism as originallydescribed by Beckwith and Wiedemann.1,2 BWS is a panethnicdisorder with an estimated population incidence of 1 in 13 700.This figure is likely an underestimate as milder phenotypes may notbe ascertained. The incidence is equal in males and females with thenotable exception of monozygotic twins that show a dramatic excessof females. In addition to clinical heterogeneity, BWS also exhibitsetiologic molecular heterogeneity. A variety of genetic and/or epi-genetic alterations in growth regulatory genes on chromosome11p15.5 are associated with specific phenotype–epigenotype/genotypecorrelations including different recurrence risks. BWS usually occurssporadically (85%), but familial transmission occurs in B15% of cases.
CLINICAL OVERVIEWIndividuals with BWS may grow at an increased rate during the latterhalf of pregnancy and in the first few years of life. Growth parameters
typically show height and weight around the 97th percentile with headsize closer to the 50th percentile. Adult heights are generally in thenormal range.3,4 Abnormal growth may also manifest as hemihyper-plasia and/or macroglossia; the latter can lead to difficulties in feeding,speech and less frequently, sleep apnea. A recognizable facial gestalt iscommon and may include prominent eyes with infraorbital creases,facial nevus flammeus, midfacial hypoplasia, macroglossia, full lowerface with a prominent mandible, anterior earlobe creases and posteriorhelical pits3 (Figure 1). The BWS facies often normalizes across child-hood so that evaluation of adolescents or adults suspected to have BWSbenefits from assessment of early childhood photographs. Developmentis usually normal unless there is chromosome 11p15.5 duplication orserious perinatal complications, including prematurity or uncontrolledhypoglycemia. Hypoglycemia is reported in 30–50% of babies withBWS,3,5 likely caused by islet cell hyperplasia and hyperinsulinemia.
Individuals with BWS have an increased frequency of malforma-tions and medical complications, including abdominal wall defects(omphalocele, umbilical hernia, and diastasis recti); visceromegalyinvolving any single or combination of organs: liver, spleen, pancreas,kidneys, and adrenals. Fetal adrenocortical cytomegaly is a pathogno-monic finding for BWS. Unilateral or bilateral renal anomalies mayinclude primary malformations, renal medullary dysplasia, nephro-calcinosis, and nephrolithiasis.6–8 Cardiac malformations are found inB20% of children with BWS; approximately half manifest cardio-megaly that resolves spontaneously.3,9 Cardiomyopathy is rare.
Of major concern in children with BWS is the predisposition toembryonal malignancies. Most of the tumors associated with BWSoccur in the first 8–10 years of life with very few being reportedbeyond this age;10,11 most common are Wilms tumor and hepato-blastoma. Other embryonal tumors include rhabdomyosarcoma,adrenocortical carcinoma, and neuroblastoma.3,10–14 A variety ofother malignant and benign tumors have been reported.12–14 Theoverall risk for tumor development in children with BWS has beenestimated at 7.5% with a range of risk estimates between 4 and21%.3,10–12,13,15–17 Clinical findings associated with higher risks oftumor development include hemihyperplasia, nephromegaly, andnephrogenic rests.10,18 Although different molecular subgroups havebeen shown to be associated with different tumor rates and tumor
Rosanna Weksberg*,1,2,3,4, Cheryl Shuman1,2,3 and J Bruce Beckwith5
1Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto,Canada; 2Division of Clinical and Metabolic Genetics, The Hospital for Sick Children,Toronto, Canada; 3Department of Molecular Genetics, University of Toronto, Toronto,Canada; 4Institute of Medical Sciences, University of Toronto, Toronto, Canada;5Department of Pathology and Human Anatomy, Loma Linda University, LomaLinda, CA, USA
*Correspondence: Dr R Weksberg, Division of Clinical and Metabolic Genetics, TheHospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada.Tel: +1 416 813 6386; Fax: +1 416 813 5345; E-mail: [email protected]
Received 8 December 2008; revised 1 May 2009; accepted 7 May 2009; publishedonline 24 June 2009
European Journal of Human Genetics (2010) 18, 8–14; doi:10.1038/ejhg.2009.106;published online 24 June 2009
Keywords: Beckwith-Wiedeman syndrome; genomic imprinting; epigenetics; chromo-some 11; tumor predisposition
European Journal of Human Genetics (2010) 18, 8–14& 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10 $32.00
www.nature.com/ejhg
In brief
! Beckwith–Wiedemann syndrome (BWS) is a disorder ofgrowth regulation exhibiting somatic overgrowth and apredisposition to embryonal tumors.
! The incidence of BWS is estimated to be 1 out of 13 700.
! Current tumor surveillance protocols include abdominalultrasounds and alpha-fetoprotein (AFP) assays.
! BWS is caused by various epigenetic and/or genetic alterationsthat dysregulate the imprinted genes on chromosome 11p15.5.
! The BWS molecular subgroups are associated with differentrecurrence risks.
! Subfertility/assisted reproduction is associated with anincreased frequency of BWS.
Conducta prenatal:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Comprobar una correcta datación de la gestación. } Valorar a los progenitores. } Descartar una DM. } Realizar una ecografía morfológica detallada. } Amniocentesis. } Estudios ecográficos seriados:
} Macrosomia (PFE): Vía del parto. } Polihidramnios y Cervicometría: Riesgo de APP. } Malformaciones asociadas. (Ej: Tamaño del onfalocele)
} Macroglosia. Valoración de la vía aérea. } Necesario EXIT (Ex Utero Intrapartum Treatment).
Imágenes cedidas por el Servicio de Neonatología del HULP
Riesgos:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Perinatal: } 10-20% de mortalidad perinatal por prematuridad, malformaciones
asociadas o por la obstrucción de la vía aérea.
} Postnatal: } Alteraciones del metabolismo neonatal (hipoglucemia) e Hipotonía. } Riesgo tumoral.
} 5-10%. } Marcado por la mutación genética. } Origen embrionario: Wilms y hepatoblastoma. } 95% <10 años (edad media la debut 2 años). } X 4 en pacientes con hipertrofia renal o hemihipertrofia corporal.
} Cociente intelectual normal e la mayoría de los casos (DD Sotos).
An Pediatr (Barc) 2006;64(3):252-9 253
Lapunzina Badía P, et al. Guía para el síndrome de Beckwith-Wiedemann
El SBW se debe a alteraciones genéticas complejas (me-canismos epigenéticos que alteran el imprinting, peque-ñas deleciones y duplicaciones, mutaciones concretas engenes de la región 11p, disomía uniparental, transloca-ción y reordenamientos cromosómicos). La frecuenciade cada mecanismo patogénico es diferente y el diag-nóstico molecular final se realiza, en general, en centrosespecializados en estas patologías.
El objetivo de este trabajo es presentar una guía clínicapreventiva y anticipatoria para el seguimiento de pacien-tes con SBW, que contribuya a mejorar la calidad asisten-cial y la salud de esta población.
CARACTERÍSTICAS CLÍNICAS DEL SBWExiste un número importante de hallazgos en el SBW.
Los más frecuentes se enumeran en la tabla 1. Aunqueno hay consenso absoluto sobre los criterios clínicosdiagnósticos para el SBW, varios autores han sugeridoen publicaciones diferentes criterios mayores y meno-res (tabla 2).
CARACTERÍSTICAS GENÉTICAS Y SUBVARIANTESMOLECULARES DEL SBW
La tabla 3 presenta los distintos subgrupos genéticos yepigenéticos identificados en el SBW agrupados por sufrecuencia relativa y muestra que es una entidad genéti-camente heterogénea y con un efecto dependiente delorigen parental de los genes heredados1-6. En la figu-ra 1 se observan algunos genes de la región 11p, activoso reprimidos en condiciones fisiológicas. A día de hoyhay 12 grupos o formas genéticas/epigenéticas diferentes,con distintas formas de herencia, diferentes genes y va-rios mecanismos moleculares implicados. La mayoría delos pacientes con SBW (alrededor del 90%) son esporá-
TABLA 1. Características clínicas observadas en el síndrome de Beckwith-Wiedemann
Muy frecuentesMacrosomíaPliegues en lóbulos de la orejaFosetas en hélix posteriorMacroglosiaOnfaloceleHernia umbilicalHipotoníaHipercrecimiento en la infanciaNefromegaliaHepatoesplenomegaliaHemihiperplasiaHipoglucemia
FrecuentesCitomegalia adrenocorticalPolihidramniosEdad ósea avanzadaErupción prematura de los dientesPrematuridadGemelaridadMalformación capilar (hemangioma plano)
Poco frecuentesDiastasis de rectosFacies característicaPie equinovaroNistagmo y estrabismoTumores embrionariosDéficit de atención con hiperactividad
OcasionalesMalformación anatómica cerebralConvulsionesRetraso mental leve/fracaso escolarEscoliosisCardiopatía congénita o arritmiasDiabetes o prediabetes
TABLA 2. Criterios diagnósticos utilizados por varios autores para el síndrome de Beckwith-Wiedemann (SBW)
ReferenciasCaracterísticas
Elliot et al, 1994 DeBaun y Tucker, 1998 Weksberg et al, 2001
Modificada de Rump et al49.
Criterios mayores
Criterios menores
Definición de SBW
Defecto de pared abdominal anteriorCrecimiento prenatal o posnatal > P90
Pliegues o fosetas en orejasNevus flammeus facialHipoglucemiaNefromegaliaHemihiperplasia
Al menos 3 criterios mayores o2 mayores y 3 o más menores
MacroglosiaPeso al nacimiento > P90
Hipoglucemia en el período neonatalPliegues o fosetas en orejasDefecto de pared abdominal
(onfalocele, diastasis recti o herniaumbilical)
Diagnóstico clínico hecho por unmédico con al menos 2 de los5 criterios
MacroglosiaMacrosomíaHemihiperplasiaPliegues o fosetas en orejasDefecto de pared abdominal
(onfalocele, diastasis recti o herniaumbilical)
Tumor embrionarioVisceromegalia abdominalMalformación renal
Al menos 3 criterios mayores o2 mayores y 1 o más menores
Documento descargado de http://analesdepediatria.elsevier.es el 12/02/2015. Copia para uso personal, se prohíbe la transmisión de este documento por cualquier medio o formato.
SÍNDROME DE SOTOS o GIGANTISMO CEREBRAL:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
DEFINICIÓN: • El síndrome de Sotos o gigantismo cerebral es el síndrome genético de
sobrecrecimiento más frecuente tras el SBW. • Prevalencia 1/15-20.000 RN vivos.
ETIOPATOGENIA: • El gen NSD1 localizado en el cromosoma
5q35. • 95% de los casos se trata de mutaciones
“de novo”, por lo que el riesgo de recurrencia es inferior al 1%.
• Mecanismo: • Mutaciones intragénicas: 80% en
población Europea o Americana. • Microdelecciones: 50-60% en la
población Japonesa. Genetic syndromes associated with overgrowthin childhood
Review article
Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians’ ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.
Keywords: Macrosomia, Sotos syndrome, Beckwith-Wiedemann syndrome, genomic imprinting
Jung Min Ko, MD, PhD
Department of Pediatrics,Seoul National University College of Medicine, Seoul, Korea
http://dx.doi.org/10.6065/apem.2013.18.3.101Ann Pediatr Endocrinol Metab 2013;18:101-105
©2013 Annals of Pediatric Endocrinology & Metabolism
Received: 20 August, 2013 Accepted: 26 August, 2013
Address for correspondence: Jung Min Ko, MD, PhDDepartment of Pediatrics,Seoul National University Children’s Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, KoreaTel: +82-2-2072-3570Fax: +82-2-743-3455E-mail: [email protected]
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Introduction
Somatic growth is dependent on an increase in both cell size and number. Human growth comes from a complex interplay of various factors including genetic backgrounds and environmental influences. However, complex mechanisms involved in the regulation of somatic growth remains to be completely understood particularly in the molecular level of genetic field. Overgrowth refers to a condition characterized by extreme physical size and stature including tall stature or generalized/localized overgrowth of tissues1). The condition originates during infancy, childhood or adolescence while epiphyseal growth plates remain open. Among various conditions showing overgrowth, genetic overgrowth syndrome refers to a nonhormonally mediated overgrowth condition which can accompany increased height and/or head circumference, various degrees of mental retardation, or physical dysmorphisms in children1). It is clearly distinguished from pituitary gigantism which is caused by excess of growth hormone. However, there are overlaps in clinical and molecular features between overgrowth syndromes, thus making a specific diagnosis is often difficult.
This paper reviews clinical characteristics and molecular basis of typical genetic overgrowth syndromes, focusing on Sotos syndrome (OMIM#117550) and Beckwith-Wiedemann syndrome (OMIM#130650).
Genetic syndromes associated with overgrowthin childhood
Review article
Overgrowth syndromes comprise a diverse group of conditions with unique clinical, behavioral and molecular genetic features. While considerable overlap in presentation sometimes exists, advances in identification of the precise etiology of specific overgrowth disorders continue to improve clinicians’ ability to make an accurate diagnosis. Among them, this paper introduces two classic genetic overgrowth syndromes: Sotos syndrome and Beckwith-Wiedemann syndrome. Historically, the diagnosis was based entirely on clinical findings. However, it is now understood that Sotos syndrome is caused by a variety of molecular genetic alterations resulting in haploinsufficiency of the NSD1 gene at chromosome 5q35 and that Beckwith-Wiedemann syndrome is caused by heterogeneous abnormalities in the imprinting of a number of growth regulatory genes within chromosome 11p15 in the majority of cases. Interestingly, the 11p15 imprinting region is also associated with Russell-Silver syndrome which is a typical growth retardation syndrome. Opposite epigenetic alterations in 11p15 result in opposite clinical features shown in Beckwith-Wiedemann syndrome and Russell-Silver syndrome. Although the exact functions of the causing genes have not yet been completely understood, these overgrowth syndromes can be good models to clarify the complex basis of human growth and help to develop better-directed therapies in the future.
Keywords: Macrosomia, Sotos syndrome, Beckwith-Wiedemann syndrome, genomic imprinting
Jung Min Ko, MD, PhD
Department of Pediatrics,Seoul National University College of Medicine, Seoul, Korea
http://dx.doi.org/10.6065/apem.2013.18.3.101Ann Pediatr Endocrinol Metab 2013;18:101-105
©2013 Annals of Pediatric Endocrinology & Metabolism
Received: 20 August, 2013 Accepted: 26 August, 2013
Address for correspondence: Jung Min Ko, MD, PhDDepartment of Pediatrics,Seoul National University Children’s Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, KoreaTel: +82-2-2072-3570Fax: +82-2-743-3455E-mail: [email protected]
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Introduction
Somatic growth is dependent on an increase in both cell size and number. Human growth comes from a complex interplay of various factors including genetic backgrounds and environmental influences. However, complex mechanisms involved in the regulation of somatic growth remains to be completely understood particularly in the molecular level of genetic field. Overgrowth refers to a condition characterized by extreme physical size and stature including tall stature or generalized/localized overgrowth of tissues1). The condition originates during infancy, childhood or adolescence while epiphyseal growth plates remain open. Among various conditions showing overgrowth, genetic overgrowth syndrome refers to a nonhormonally mediated overgrowth condition which can accompany increased height and/or head circumference, various degrees of mental retardation, or physical dysmorphisms in children1). It is clearly distinguished from pituitary gigantism which is caused by excess of growth hormone. However, there are overlaps in clinical and molecular features between overgrowth syndromes, thus making a specific diagnosis is often difficult.
This paper reviews clinical characteristics and molecular basis of typical genetic overgrowth syndromes, focusing on Sotos syndrome (OMIM#117550) and Beckwith-Wiedemann syndrome (OMIM#130650).
Ko JM • Genetic overgrowth syndromes
102 www.e-apem.org
Sotos syndrome
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Sotos syndrome (SS, OMIM#117550), also known as cerebral gigantism, is a prenatal and postnatal overgrowth syndrome characterized by excessive growth resulting in tall stature and macrocephaly, distinctive craniofacial features, and developmental delay. These three cardinal features are each present in over 90% of cases with SS2,3). Since the first description by Sotos et al.4) in 1964, hundreds of cases have been reported to date, and the estimated incidence is 1/15,000–1/20,0001).
The typical overgrowth pattern of SS starts prenatally, resul-ting in higher mean birth length and weight5). Pronounced postnatal growth is obvious in the first 6 years of life, consistently displaying height above the 97th percentile6). However, the final adult height is usually within the upper normal range due to accompanied bone age advancement6).
A characteristic facial appearance consists of a high and broad forehead, sparse fronto-temporal hair, malar flushing, down-slanted palpebral fissures and a pointed chin7). The head circumference is increased above the 97th percentile in most SS patients, and it is thought to be the most consistent indicator of SS at any age5).
The majority of SS patients have some degree of develop-mental delay/learning disability. Achievement of developmental milestones such as walking and speech is commonly delayed. However, most patients have mild to moderate intellectual impairment, and the severity is very broad, ranging from intelligence quotient below 30 to above 1002).
Besides, there are other commonly associated features including a history of neonatal jaundice and feeding difficulty, variable types of cardiac and renal anomalies, seizure, scoliosis, strabismus, attention deficit hyperactivity disorder, nonspecific
abnormal brain image findings such as ventriculomegaly and corpus callosum hypoplasia. Patients with overgrowth syndromes including SS have higher risks for the development of neoplasias, particularly in their childhood. In SS patients, the frequency of tumor development has been reported to be 2–7%8,9), and the relative risk of certain malignancies including neural crest tumors, saccrococcygeal teratomas and some hematological malignancies is increased2). However, routine screening of tumor development is not a standardized recommendation.
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In 2002, the nuclear receptor set domain containing protein 1 gene, NSD1, on chromosome 5q35 was identified as a causing gene of SS10). SS is caused by haploinsufficiency of NSD1 in 60–90% of clinically diagnosed SS patients and can be transmitted in an autosomal dominant manner, although more than 95% of patients gain the disease from de novo mutation11).
The NSD1 gene consists of 23 exons and encodes multiple functional domains, including the SU(VAR)3-9, E(Z), tirthorax (SET), SET-associated domains, which mediate histone methyltransferase activity, five plant homeo-domains implicated in chromatin regulation, and two proline-tr yptophan-tryptophan-proline domains that may mediate protein interactions3). NSD1 is expressed in several tissues including the brain, kidney, skeletal muscle, spleen, and thymus12). Although the exact role of the NSD1 protein has not been identified, the presence of two different ligand binding domains suggests that NSD1 enables the regulation of both negative and positive transcription13).
Several reports have demonstrated NSD1 abnormalities in patients with Sotos syndrome. NSD1 abnormalities include microdeletion of 5q35, encompassing the entire NSD1 deletions
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Fig. 1. Chromosome 5q35 microdeletions are more frequently found in Japanese patients with Sotos syndrome, whereas 5q35 microdeletions are uncommon in patients outside of Japan.
SÍNDROME DE SOTOS o GIGANTISMO CEREBRAL:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
Macrosomía
Macrocefalia
Alteraciones del SNC. Retraso mental
Imágenes cedidas por el Servicio de Neonatología del HULP
Conducta prenatal:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Realizar una ecografía morfológica detallada.
} Amniocentesis. } Resonancia Magnética para
una mejor valoración del Sistema Nervioso Central: } Ventriculomegalia. } Anomalías de la fosa posterior. } Cavum del SP o del Velum
interpositum prominentes. } Hipoplasia del cuerpo calloso.
American Journal of Medical Genetics Part C (Semin. Med. Genet.) 117C:49–56 (2003)
A R T I C L E
Mental Deficiency, Alterationsin Performance, and CNS Abnormalitiesin Overgrowth SyndromesM. MICHAEL COHEN, JR.*
Mental deficiency, alterations in performance, and central nervous system (CNS) abnormalities are discussed in thefollowing overgrowth syndromes: Sotos syndrome, Weaver syndrome, Proteus syndrome, neurofibromatosis type 1,fragile X syndrome, syndromes with neonatal hypoglycemia, Simpson-Golabi-Behmel syndrome, hemihyperplasia,Sturge-Weber syndrome, Bannayan-Riley-Ruvalcaba/Cowden syndrome, macrocephaly-autism syndrome, PEHOsyndrome, chromosomal syndromes, and other miscellaneous syndromes. ! 2003 Wiley-Liss, Inc.
KEYWORDS: Sotos syndrome; Weaver syndrome; Proteus syndrome; neurofibromatosis type I; fragile X syndrome; neonatal hypoglycemia;infants of diabetic mothers; Beckwith-Wiedemann syndrome; Perlman syndrome; Simpson-Golabi-Behmel syndrome; hemihyperplasia;Sturge-Weber syndrome; Bannayan-Riley-Ruvalcaba/Cowden syndrome; macrocephaly-autism syndrome; PEHO syndrome; Pallister-Killiansyndrome; Costello syndrome
INTRODUCTION
Overgrowth syndromes include infantswho are large for gestational age withor without excessive postnatal growth.The definition also includes increasedweight, length, or head circumference,and/or asymmetric enlargement, singlyor in combination. The subject of over-growth syndromes has been reviewedextensively by Cohen et al. [2002]. Thisarticle discusses mental deficiency,alterations in performance, and centralnervous system (CNS) abnormalities inovergrowth syndromes.
SOTOS SYNDROME
Neonatal hypotonia and early feedingdifficulties are common [Cole andHughes, 1994]. Most patients havenonprogressive neurologic dysfunctionmanifested by clumsiness and poor co-ordination. Cole and Hughes [1994]reported a mean DQ/IQ of 78 with arange of 40–129 (n¼ 23), but indicatedthat their figures probably underesti-mated ability in Sotos syndrome becausesome children from regular schoolscould not be formally assessed. Delay inexpressive language and motor devel-
opment during infancy is particularlycommon, and in some instances, may befollowed by attainment of normal ornear-normal intelligence.Delay inwalk-ing until after 15 months of age andspeech delay until after 2.5 years areusual. Seizures are found in about 50% ofpatients, but in about half the cases, theyare febrile. Drooling is often observed.Attention deficit may also be a com-ponent in some instances. There is atendency for tone to improve with age,although many children have persistenthypotonic posture and gait [Cohen,1989, 1999; Cole and Hughes, 1990,1994].
Dilation of the cerebral ventricles iscommon. Other abnormalities includeabsent corpus callosum, prominent cor-tical sulci, cavum septum pellucidum,and cavum velum interpositi [Schaeferet al., 1997; Melo et al., 1999; Schaefer,2000]. In a neuroimaging study of40 patients, Schaefer et al. [1997] foundprominence of the trigone in 90%,prominence of the occipital horns in75%, and ventriculomegaly in 63%(Table I).
WEAVER SYNDROME
Mild hypertonia or hypotonia is com-mon, and psychomotor development is
Dr. M. Michael Cohen, Jr., D.M.D., Ph.D., F.C.C.M.G., holds five professorships at DalhousieUniversity: Oral & Maxillofacial Pathology, Pediatrics, Community Health & Epidemiology, HealthServices Administration, and Sociology & Social Anthropology. He has five university degrees: BAfrom the University of Michigan in 1965; DMD from the Tufts University in 1966; MSD from theUniversity of Minnesota in 1969; PhD from the University of Minnesota in 1979; and MPH fromBoston University in 1996. He trained in medical genetics and syndromology at the University ofMinnesota from 1966 to 1971. His is the author or coauthor of over 300 articles in the medicaland scientific literature, author or coauthor of over 35 book chapters, and author, coauthor, oreditor of 14 books including The Child with Multiple Birth Defects; Craniosynostosis: Diagnosis,Evaluation, and Management; Syndromes of the Head and Neck; Mental Retardation andCongential Malformations of the Central Nervous System; Holoprosencephaly: An Overview andAtlas of Cases; The Gorlin Symposium on Overgrowth; Studies in Stomatology and CraniofacialBiology; The Gorlin Symposium on Asymmetry; and Overgrowth Syndromes.
Dr. Cohen’s university teaching is in three different disciplines: pathology, medical genetics,and international health. He has given keynote addresses and has been a visiting professor atnumerous universities throughout the United States, Europe, South America, Asia, Australia, andAfrica. He has many honors and awards. He is an Associate Editor of the American Journal ofMedical Genetics.
*Correspondence to: Dr. M. Michael Cohen, Jr., Dalhousie University, Halifax, B3H 3J5 NovaScotia, Canada. E-mail: [email protected]
DOI 10.1002/ajmg.c.10013
! 2003 Wiley-Liss, Inc.
mildly tomoderately retarded. The cry islow-pitched and hoarse. Although theappetite is voracious, hypothalamic dys-regulation has not been demonstrated.Difficulty in swallowing or breathing hasbeen noted in several cases. Other find-ings have included cysts of the septumpellucidum (two cases); dilation of theventricles, basal cisterns, sylvian cistern,and interhemispheric fissure, consistentwith nonspecific cerebral atrophy (onecase); enlarged vessels and hypervascu-larization in the areas of the middle andleft posterior cerebral arteries (one case);and pachygyria (one case) [Ardingeret al., 1986; Opitz et al., 1998; Cohen,1999; Freeman et al., 1999]. The widerange of intelligence found withWeaversyndrome and the brain abnormalitiesreported in some cases suggest that mag-netic resonance imaging (MRI) shouldbe considered as part of the work-up.
PROTEUS SYNDROME
In Proteus syndrome, intelligence maybe normal, although some degree ofmental deficiency has been evident inabout 20% of cases, and seizures have
been documented in approximately13%. However, a number of patientshave had brain malformations [Cohen,1993]. Cohen and Hayden [1979]reported a patient with macrocephaly,hydrocephalus, and an estimated IQ of30–40. Cohen [1988] reported hemi-megalencephaly, ventricular dilation,severe mental deficiency, and seizures.Autopsy showed polymicrogyria andheterotopic gray matter nodules in thesubcortical and periventricular whitematter. Bizarre neurons were founddeep in the cortex and white matter.Cohen [1993] reported a third patientwith severe mental deficiency and sei-zures accompanied by hydrocephalusand an arachnoid cyst of the posteriorfossa. Malamitsi-Puchner et al. [1987]described macrocephaly, enlarged ven-tricles, and asymmetry of the frontalhorns in association with seizures.Mayatepek et al. [1989] noted oncomputed tomography (CT) dilatedventricles, cortical atrophy, and possibleabsence of the corpus callosum. Rizzoet al. [1990] reported severe mental de-ficiency, seizures, hemimegalencephaly,and a head circumference above the 97th
centile. The CT showed hypodensity ofthe periventricular white matter.
Cohen [1993] described a facialphenotype in Proteus syndrome patientswith mental deficiency and, in somecases, seizures and/or brain malforma-tions. Manifestations include dolicho-cephaly, long face, minor downslantingof the palpebral fissures and/or minorptosis, low nasal bridge, wide or ante-verted nares, and an open mouth at rest.These facial manifestations may evenoverride the severe craniofacial distor-tion produced by bony overgrowth insome cases.
NEUROFIBROMATOSISTYPE I
Neurofibromatosis type 1 (NF1) can beregarded as an overgrowth syndrome byvirtue of several of its features: macro-cephaly, the presence of tumors, and, onoccasion, hemihyperplasia of a limb ordigit.
Mental deficiencywith an IQunder70 occurs in about 8% of NF1 patients.Learning disabilities have been reportedwith frequencies ranging from 30–60%.There is no characteristic profile; find-ings have included easy distractibility,impulsiveness, deficient visual-motorcoordination, excessive scatter of scoresfrom one set of test items to another, andlanguage and vocabulary deficits. Sei-zures occur in about 6.5%, and frankhydrocephalus with aqueductal stenosis,as well as asymptomatic ventricular dila-tion, have been recorded in about 4% ofpatients. NF1 is increased about 150-fold in a population of autistic patients.
TABLE I. Neuroimaging Findings in Sotos Syndrome
Categories Neuroimaging abnormalities
Percentage
(n¼ 40)
Ventricles Large 63
Prominent trigone 90
Prominent occipital horn 75
Extracerebral fluid Supratentorial 70
Posterior fossa 70
Midline anomalies Cavum septum pellucidum 40
Cavum vergae 37.5
Cavum velum interpositum 17.5
Macrocisterna magna 16.7a
Agenesis of the corpus callosum 2.5
Hypoplasia of the corpus callosum 97.5a
Migration abnormalities Heterotopias 8.3a
Other abnormalities Periventricular leukomalacia 13.8a
Macrocerebellum 5.5a
Open operculum 2.5
Adapted from Schaefer et al. [1997].an¼ 36 for these entries.
Neurofibromatosis type 1
(NF1) can be regarded as an
overgrowth syndrome by virtue
of several of its features:
macrocephaly, the presence of
tumors, and, on occasion,
hemihyperplasia of a limb
or digit.
50 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE
Riesgos:
Trastornos del crecimiento fetal. Laura Sotillo Mallo
} Perinatal: } Microdelección mayor tendencia
} Cardiopatías: defectos septales y persistencia de DA. } Renales: RVU. } Retraso mental. } Menor estatura.
} Postnatal: } Riesgo tumoral 2-7%.
} Tumores de la cresta neural. } Hematológicos.
American Journal of Medical Genetics Part C (Semin. Med. Genet.) 137C:53–71 (2005)
A R T I C L E
Risk of Tumorigenesis in Overgrowth Syndromes:A Comprehensive ReviewPABLO LAPUNZINA
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic isthat eitherweight, height, or head circumference is 2–3 standarddeviations (SD) above themean for sex and age.A striking feature of OGS is the risk of neoplasms. Here, the relative frequency of specific tumors in each OGS,topographic location, and age of appearance is determined by reviewing published cases. In someOGS (Perlman,Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94%of tumorsappeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, onlyWilms tumor has been recorded, whereas in Sotos syndrome, lympho-hematologic tumors are most frequent.Based on literature review, a specific schedule protocol for tumor screening is suggested for eachOGS.A schedulewith different intervals and specific tests is proposed for a more rational cost/benefit program for thesedisorders. ! 2005 Wiley-Liss, Inc.
KEY WORDS: Beckwith-Wiedemann syndrome; Bannayan-Riley-Ruvalcaba syndrome; macrocephaly-cutis marmorata syndrome; Marshall-Smith syndrome; Perlman syndrome; Simpson-Golabi-Behmel syndrome; Sotos syndrome; Weaver syndrome; Klippel-Trenaunay syndrome;isolated hemihyperplasia; Proteus syndrome tumor screening; cost/benefit program
INTRODUCTION
Neoplasms in children under age 15 israre with only 14.1 cases per 100,000children (1:7,100 below15 years) [Hershet al., 1992; Harras, 1996]. Incidence isslightly higher among whites (14.4 per100,000) than blacks (11.8 per 100,000)[Harras, 1996], but from a statisticalstandpoint, tumors occur with lowfrequency. Besides, the association of
increased birthweight and neoplasms,such as Wilms tumor, leukemia, neuro-blastoma, and astrocytoma has beenobserved [Cohen et al., 2002].
Overgrowth syndromes (OGS)comprise a heterogeneous group ofdisorders whose main characteristic isthat either the weight, height, or headcircumference, frequently occurringtogether are above the 97th centile or2–3 standard deviations (SD) above themean for age and sex. One strikingfeature of OGS is their risk of tumor-igenesis [Cohen, 1989]. There areseveral reports of predisposition ofneoplasms with particular OGS. Somerecommendations for tumor screeningin children with Beckwith-Wiedemannsyndrome, Simpson-Golabi Behmelsyndrome, hemihyperplasia, and Cost-ello syndrome are available [Cohen,1989; Clericuzio, 1999; DeBaunet al., 2001; Li et al., 2001; Gripp et al.,2002]. However, most of these re-commendations were focused on theabdominal region and/or biochemicalmarkers.
The aims of this article are: (1) toevaluate the risk of tumors in OGS bycomprehensively reviewing reportedcases of OGS and tumors; (2) to describetheir relative frequencies, locations, and
age of appearance of specific tumors ineach OGS; and (3) to propose a tumorscreening protocol and guide to follow-up for children with each different typeof OGS.
By providing a specific schedule foreach disorder (physical examination,ultrasound, biochemical markers, urina-lysis, radiographs, etc.), this guide willprobably optimize the cost/benefit ofOGS surveillance.
DEFINITION ANDCLASSIFICATION
Several terms are used, such as macro-somia,macrosomic baby, giant, and largefor gestational age [Lapunzina et al.,2002]. Most OGS result from hyperpla-sia, hypertrophy, an increase in theinterstitium, or some combination ofthese factors [Cohen, 1989]. Thus, anOGS may be defined as a condition inwhich there is either localized or gen-eralized excessive growth and develop-ment for age and sex [Weaver, 1994].There are several classifications of OGS[Beighton, 1988; Cohen, 1989; Weaver,1994; Sotos, 1997; Lapunzina, 2000;Cohen et al., 2002]. Generalized OGSincludes the classic overgrowth disordersin which all of most parameters of
Dr. Pablo Lapunzina. Pediatrician, Clinicaland Molecular Geneticist, and Specialist inEmbryofetal Medicine. He trained in Pedia-trics and then in Medical Genetics andDysmorphology at the Children’s Hospitalof Buenos Aires, University of Buenos Aires,Argentina. He also completed 3 years oftraining inMolecular Genetics at the InstitutoNacional de Genetica y Biologıa Molecular(INGEBI-CONICET), Buenos Aires. He is nowon the Staff of the Department of Genetics,Hospital Universitario La Paz, AutonomaUniversity of Madrid, Spain. His interestsspan dysmorphology, clinical genetics, andmolecular genetics. He is author or coauthorof over 70 articles in the medical andscientific literature, 18 book chapters, and1 book. He now focuses on ovegrowthsyndromes.
Correspondence to: Dr. M. MichaelCohen Jr, Dalhousie University, 5981 Uni-versity Ave., Halifax, Nova Scotia B3H 3J5,Canada. E-mail: [email protected]
DOI 10.1002/ajmg.c.30064
! 2005 Wiley-Liss, Inc.
Summers et al., 1999; Izumikawa, 2001;Saitoh, 2001]; but no tumors have beendescribed to date.
The present data suggest thatscreening would not be useful or cost-effective. Moreover, since postnatalgrowth tends to be slow, leading togrowth retardation, patients should notbe included in a routine tumor surveil-lance program for OGS.
PERLMAN SYNDROME
Perlman syndrome (PS) is an autosomalrecessively inherited OGS characterized
by fetal gigantism, visceromegaly, un-usual face, bilateral renal hamartomaswith nephroblastomatosis, and Wilmstumor. The PS case reported byChernos et al. [1990] with chromosome11 alterations probably represents anexample of BWS. Clinical overlapbetween PS andBWShas been discussedelsewhere [Grundy et al., 1992; Verloeset al., 1995; Coppin et al., 1997; Fahmyet al., 1998].
About 26 cases of PS have beenreported to date [Lapunzina et al., 2001].One probable case of PS was also notedby Narahara [2001]. In addition, Li et al.
[2001] demonstrated that one patientwith a previous diagnosis of PS describedby Greemberg et al. [1988] had Simp-son-Golabi-Behmel syndrome.
Wilms tumor is the only malignancyreported in childrenwith PS. This specificpredisposition may reflect either the highincidence of nephroblastomatosis andnephogenic rests (a known precursor ofWilms tumor) or a more genetic predis-position involving a ‘‘Wilms gene’’[Grundy et al., 1992]. The proportion ofchildrenwith tumors in PSmay be as highas 40% (n¼ 25) (Table VII). Screening inthis disorder is mandatory and should befocused on the abdominal cavity, mainlythrough serial abdominal ultrasound andurinalysis (Table V).
SIMPSON-GOLABI-BEHMELSYNDROME
Simpson-Golabi-Behmel syndrome(SGBS) is an X-linked condition char-acterized by pre- and post-natal over-growth, organomegaly,multiplemidlinemalformations, coarse face, macroglos-sia, and variable mental retardation.CPC3 mutations (point mutations anddeletions) are causative [Pilia et al., 1996;Veugelers et al., 1998]. Close to 100patients with SGBS have been reportedto date [Lin et al., 1999].
There are at least nine cases ofSGBS with neoplasia; all tumors wereintra-abdominal (Fig. 1) (four Wilmstumors, two hepatoblastomas, one ad-renal neuroblastoma, one gonadoblas-toma, and one hepatocellular carcinoma[Lapunzina et al., 1998; Li et al., 2001].
TABLE VIII. Malignancies Reported in Simpson-Golabi-Behmel Syndrome
(Adapted from Lapunzina et al., 1998)
Type of tumor Number of cases %
Wilms tumor 4 44
Hepatoblastomaa 3 22
Hepatocarcinoma 1 11
Gonadoblastoma 1 11
Neuroblastoma 1 11
Total 10 100
Cases reported by Harrod and Kettman, 1992; Hughes-Benzie et al., 1996; Pilia et al.,
1996; Lindsay et al., 1997; Lapunzina et al., 1998; Li et al., 2001.aOne case of hepatoblastoma Lapunzina, personal observation; not published.
TABLE IX. Malignancies Reported in Sotos Syndrome
(Adapted from Cohen, 1999)
Type of tumor Number of cases %
Acute leukemia 4 10
Wilms tumor 4 15
Lymphomas 3 15
Sacrococcygeal teratoma 3 15
Neuroblastoma 2 10
Epidermoid carcinoma of vagina 1 5
Hepatocarcinoma 1 5
Blastoma of lung 1 5
Small cell carcinoma of the lung 1 5
Yolk sac tumor of testis 1 5
Diffuse gastric carcinoma 1 5
Total 22 100
Cases reported by Sugarman et al., 1977; Seyedabadi et al., 1981;Maldonado et al., 1984;
Nance et al., 1990; Cole et al., 1992; Hersh et al., 1992; Lippert, 1993; Corsello et al.,
1996; Fabryet al., 1997; LeMarec et al., 1999;Muraishi et al., 1999;Yule, 1999; Leonard,
2000; Jin et al., 2002; Al-Mulla et al., 2004.
There are at least 9 cases of
SGBS with neoplasia; all
tumors were intra-abdominal
(4 Wilms tumors,
2 hepatoblastomas, 1 adrenal
neuroblastoma,
1 gonadoblastoma and
1 hepatocellular carcinoma.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 59
MUCHAS GRACIAS POR SU ATENCIÓN
Trastornos del crecimiento fetal. Laura Sotillo Mallo
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