Trastornos del crecimiento fetal. Definición, causas y clasificación del CIR. MACROSOMÍA

TRASTORNOS DEL CRECIMIENTO FETAL.
CIR: Definición, causas y clasificación.
MACROSOMÍA.
Laura Sotillo Mallo.

Defectosdel
crecimiento
fetal.
•  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%

Causas de PEG anormal:GENÉTICAS:
• Cromosomopatías:
• Trisomía 13.
• Trisomía 18.
• Triploidía materna.
• Deleción brazo
corto del
cromosoma 4.
• Síndromes genéticos:
• Russell-Silver.
INFECCIOSAS:
•  TORCH:
•  CMV.
•  Toxoplasmosis.
•  Malaria.
•  Chagas.
TÓXICOS:
•  Síndrome
alcohólico fetal.
•  Medicamentos:
•  Warfarina.
•  Ciclofosfamida.
•  Ácido
valproico.
•  Fenitoina.

Factores de riesgo de CIR:
}  FACTORES EPIDEMIOLÓGICOSY 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:
}  FACTORES EPIDEMIOLÓGICOSY CLÍNICOS:
}  Fetales:
}  Gestación múltiple.
}  Placentarios:
}  Arteria umbilical única.
}  Inserción velamentosa de cordón.
}  Mosaicismos confinados a la placenta.
}  MARCADORES BIOQUÍMICOS:
}  Primer trimestre:
}  êPAPPA
¨  <p5 (0.45 MoMs): OR 2.74.
¨  <p1(0.29 MoMs): OR 3.53.
}  Segundo trimestre:
}  êEstriol no conjugado.
}  éα-fetoproteina.
PREDICTION OF FETAL GROWTH
RESTRICTION
Affected Newborns
Patterson et al5
followed-up 9,596 patients throughout
two pregnancies; the overall fetal growth restriction rate
in the first child was 12.4%. Among patients without
any medical complications either in the first pregnancy
or in the second pregnancy, the prevalence of recurrent
fetal growth restriction was significantly related to the
severity of growth restriction in the first pregnancy. If
the birth weight of the first newborn was more than the
10th percentile, the risk of fetal growth restriction for
the second newborn was 8.2%. If the birth weight was
less than or equal to the 10th percentile for the first
newborn, the risk of fetal growth restriction for the
second newborn was significantly increased up to
20.1% (P,.001). The more severe the fetal growth
restriction, the higher the risk of recurrence.
Serum Analytes
Maternal serum analytes during the first and second
trimesters can be reasonable predictors of fetal growth
restriction later in pregnancy (Table 1). Pregnancy-
associated plasma protein-A levels less than the first
percentile (less than 0.29 multiples of the median) and
pregnancy-associated plasma protein-A less than the
5th percentile (less than 0.45 multiples of the
median),6,7
first trimester free b-hCG level less than
the 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 the
median) in the second trimester have been associated
with low birth weight.9,10
In our institution, we recommend a fetal growth
ultrasound examination at 32 weeks of gestation for
pregnancies complicated with pregnancy-associated
plasma protein-A less than the 2.5th percentile
or unexplained increased maternal serum alpha-
fetoprotein more than 2.0 multiples of the median. If
the follow-up growth ultrasound scan is normal, with an
estimated fetal weight more than the 10th percentile,
we resume routine prenatal care (ie, we do not add any
antepartum testing for normally grown fetuses).
Ultrasound Findings
Single umbilical artery is the most common congenital
abnormality of the umbilical cord. The prevalence of
single umbilical artery ranges from 0.2% to 11%,
depending on the population studied.11–15
Neonates
with isolated single umbilical artery have increased
rates of growth restriction (10.9% compared with
25.0%) and estimated fetal weight less than the 10th
percentile (odds ratio 2.23; 95% confidence interval
[CI] 1.84–2.69).16
In our institution, we recommend
a fetal growth ultrasound examination at 32 weeks of
gestation 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 in
Predicting Fetal Growth Restriction (Estimated Fetal Weight Less Than the 10th Percentile)
Analyte OR 95% CI Sensitivity Specificity PPV NPV
First trimester
PAPP-A
Less than 5th percentile 2.74 2.16–2.81 10.4 95.4 18.7 91.3
Less than 1st percentile 3.53 2.74–4.55 2.9 99.2 26.3 91.0
Free b-hCG
Less than 5th percentile 1.3 0.8–2.0 5.1 95.8 7.4 93.8
Less than 1st percentile 1.3 0.8–2.0 5.1 95.8 7.4 93.8
Second Trimester
AFP
More than 1.5 MoM 1.41 1.07–1.87 19.6 90.4 3.9 98.3
More than 2.0 MoM 1.65 1.28–2.12
uE3
Less 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-associated
plasma 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 human
chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and
other 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 and
nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstetrics
Clinical Expert Series
A Practical Approach to Fetal
Growth Restriction
Joshua A. Copel, MD, and Mert Ozan Bahtiyar, MD
Fetal growth restriction is one of the most complex problems encountered by obstetrician
Ultrasound-estimated fetal weight less than the 10th percentile for the gestational age is th
most widely accepted diagnostic criterion. Management protocols vary from institution
institution. Doppler velocimetry provides valuable information about fetal status. We off
a practical approach to management and timing of delivery based on available data in th
literature.
(Obstet Gynecol 2014;123:1057–69)
DOI: 10.1097/AOG.0000000000000232
Fetal growth restriction is a complex problem from
its diagnosis to prenatal management, and regard-
ing optimal timing of delivery. It is synonymous with
the term intrauterine growth restriction. Although
there have been varying definitions of fetal growth
restriction in the past, for the purposes of this review
we used an estimated fetal weight less than the 10th
percentile for gestational age as the definition.1
There
is less consensus about how frequently to monitor
these pregnancies (antenatal testing should be used
for fetal monitoring) and when these fetuses should
be delivered. In this article we present our approach
to the management of patients with growth-restricted
fetuses.
Fetal growth restriction and small for gesta-
tional age (SGA) status are frequently used inter-
borns whose weight is less than or e
10th percentile for gestational age at bi
BACKGROUND
Fetal growth restriction is associated wi
perinatal mortality and morbidity. More s
restriction results in greater risk for wo
outcome.2
The gestational age at which gr
tion is diagnosed is important from the n
come perspective. Among preterm newb
less than 37 weeks of gestation, there is no
weight percentile at which morbidity and m
increase. At term (37 weeks of gestation o
natal mortality increases significantly amo
with birth weight less than the third percen

Clasificación del CIR:
CIR PRECOZ CIRTARDÍO
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 karger@karger.com
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, including
Doppler 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-
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, Basel
1015–3837/14/0362–0086$39.50/0
www.karger.com/fdt
E. Gratacós and F. Figueras contributed equally to this work.
Downloadedby:
80.29.104.202-2/27/201510:14:07PM

MACROSOMÍA.
•  Definición.
•  Causas.
•  Diagnóstico.
•  Riesgos.

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.

EPIDEMIOLOGÍA:
}  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 postpartum
infection.5
To avoid these potential complications, it seems
reasonable to intervene, either with induction7
or
cesarean delivery,8
if the fetus is suspected of being
macrosomic. But systemic review9
and a randomized
study10
have not shown any benefit of induction. A cost
analysis suggests that the option of elective cesarean
delivery is undesirable.11
Despite the clinical evidence
against intervention for suspected macrosomia, there is
a continued tendency to either induce labor7
or to
proceed with cesarean delivery.8,12
The disconnect between clinical evidence and practice
prompted us to review the accuracy of the detection of
a macrosomic newborn infant and the management of
a pregnancy that is suspected of having a fetus who
weighs at least 4000 g.
Changing prevalence of macrosomia
The rate of macrosomia is decreasing in the United
States (Figure 1).13-19
Review of National Vital Statistics
from the Center for Disease Control and Prevention
indicates that the rate of macrosomia was 10.2% in 1996
and 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 significant
decrease in the prevalence of macrosomia is apparent for
The decrease in the rate of macrosomia is neither
recognized nor explained in the reports by National
Vital Statistics and is counterintuitive. Obesity is a risk
factor for macrosomia1
and its prevalence is increas-
ing20
; thus, it is reasonable to expect a higher prevalence
of macrosomia.21
Considering the source of the data, the
sample size, and the objective definition of macrosomia,
the observed decrease is irrefutable (Figure 1). We
speculate that the decline may be explained by routine
testing for gestational diabetes mellitus, the increasing
rates of multiple gestations,22
preterm deliveries,23
and
repeat elective cesarean delivery,24
which was scheduled
before a patient becomes postterm. Additional factors
that are responsible for the decrease in the prevalence
Figure 1 Prevalence of macrosomia in the United States.13-19
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.
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, MDc
; and Medical University of South Carolina, Charleston, SCd
Received for publication November 2, 2004; revised November 27, 2004; accepted December 8, 2004
KEY WORDS
Macrosomia
Estimate birth weight
Diabetes mellitus
Induction
Cesarean delivery
Objective: To review the prevalence of and our ability to identify macrosomic (birthw
O4000 g) fetuses. Additionally, based on the current evidence, propose an algorithm
treatment of suspected macrosomia.
Study design: A review.
Results: According to the National Vital Statistics, in the United States, the prevalen
newborns weighing at least 4000 g has decreased by 10% in seven years (10.2% in 1996 and
in 2002) and 19% for newborns with weights O5000 g (0.16% and 0.13%, respectively). Bay
calculations indicates that the posttest probability of detecting a macrosomic fetus
uncomplicated pregnancy is variable, ranging from 15% to 79% with sonographic estima
birth weight, and 40 to 52% with clinical estimates. Among diabetic patients the po
probability of identifying a newborn weighing O4000 g clinically and sonographically is
60%. Among uncomplicated pregnancies, there is sufficient evidence that suspected macro
is not an indication for induction or for primary cesarean delivery. For pregnancies compl
by diabetes, with a prior cesarean delivery or shoulder dystocia, delivery of a macrosomic
American Journal of Obstetrics and Gynecology (2005) 193, 332–46
www.aj
REVIEW ARTICLE
Suspicion and treatment of the
A review
Suneet P. Chauhan, MD,a
William A. Grobma
American Journal of Obstetrics and Gynecology (2005) 193, 332–46
MÁS FRECUENTE:
•  Diabetes.
•  Antecedentes de fetos
macrosómicos.
•  Varones.

ETIOPATIOGENIA:
FACTORES DE RIESGO: Obesidad Materna, DM, épeso 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:
}  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.
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
somia; the American College of Obstetricians an
cologists recommends 4,500 g because of the ma
crease in maternal and neonatal complication rate
weight [1]. All birth weight definitions agree, h
that birth weight is independent of gestational
consequently should not be dependent on a pop
based analysis.
This concept of the use of percentile curves
complicated due to the definition of large for ges
age (LGA) by some researchers when the 90th wei
centile is exceeded, while other researchers use ei
Key Words
Three-dimensional sonography ؒ Birth weight ؒ Prenatal
ultrasonography ؒ Fetal weight estimation ؒ Macrosomia ؒ
Clinical management
Abstract
Macrosomia 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-
Received: April 2, 2012
Accepted after revision:
Published online: Decem
DOI: 10.7860/JCDR/2014/6498.4214
Original Article
Correlation of Fetal Abdominal Subcutaneous
Tissue Thickness by Ultrasound to Predict
Birth Weight
ObstetricsandGynaecology
Section
RAJESHWARI G BHAT1
, ANITHA NATHAN2
, AMAR R3
, AKHILA VASUDEVA4
, PRASHANTH ADIGA5
, PARVATI V BHAT6
, PRATAP KUMAR N7
ABSTRACT
Introduction: 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
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.

MACROSOMÍA
SÍNDROMES DE
SOBRECRECIMIENTO
GENÉTICO.
or regional OGS include those disorders common OGS (Table I, group A) and not 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
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 by Riedel, 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
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 Review
PABLO LAPUNZINA
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic is
that either weight, height, or head circumference is 2–3 standard deviations (SD) above the mean 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 some OGS (Perlman,
Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94% of tumors
appeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, only
Wilms 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 each OGS. A schedule
with different intervals and specific tests is proposed for a more rational cost/benefit program for these
disorders. ß 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.

SÍNDROME DE BECKWITH-WIEDEMANN:
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 large
distances 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 is
shown in Figure 2. Deregulation of imprinted genes in the 11p15.5
imprinted region results in the BWS phenotype through a number of
different mechanisms leading to either primary epigenetic alterations
or genetic alterations that change the relative contributions of parental
alleles.24,31,32 These include parent-of-origin-specific duplications,
translocations/inversions, microdeletions, DNA methylation changes
at IC1 or IC2, UPD, and mutations at CDKN1C. UPD refers to the
presence of two chromosomal regions from one parent and none from
the 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 alterations
that involve both IC1 and IC2 generally indicate paternal UPD (20%
of cases) for a chromosomal segment including 11p1
Segmental UPD arises from a post-zygotic somatic recomb
event and therefore has a mosaic distribution.
Methylation-sensitive multiplex ligation probe analysis (MS-
is currently the most robust method for detecting the maj
epigenetic and genetic etiologies associated with BWS. It
microdeletions/microduplications, alterations in gene dosa
DNA methylation including UPD.37 Confirmation of UPD11
undertaken by analysis of short tandem repeats as the
mosaicism associated with this etiology may lead to weak sig
MS-MLPA. Moreover, failure to detect UPD11 in one tissue
leukocytes) is not conclusive. One should consider obtaining
tissue (such as skin), especially in the event of surgery. Ka
analysis will detect the rare de novo and maternally tran
translocations/inversions (1%) and paternally derived dupl
(1%) of chromosome 11p15.5 associated with BWS. Translo
inversions almost always disrupt the gene, KCNQ1,38 and
usually detectable by MLPA because most do not show DN
number changes or DNA methylation changes. Finally, DNA
cing is required to detect genomic alterations in CDKN1C as
H19IGF2CDKN1C KCNQ1
KCNQ1OT1
H19IGF2KCNQ1
KCNQ1OT1
PAT
MAT
CDKN1C
Map of the normal chromosome 11p15 imprinting cluster
Map of the 11p15 imprinting cluster in two types of BWS patients
H19IGF2CDKN1C KCNQ1
Domain 1Domain 1Domain 2Domain 2
a
b
1) H19 gain of methylation
IC1
KvDMR/IC2
Beckwith–Wiedemann syndrome
R Weksberg et al
10
een both sporadi-
rees modified by
40%).39 A rational
omosome 11p15.5
Developmental delay. This is associated with cytogenetically detect-
able duplications involving the paternal copy of chromosome
11p15.5.46,47
R Weksberg et al
11

Dx Ecográfico de Beckwith-Wiedemann:
Macrosomía (90%)
Macroglosia (80-100%)
Onfalocele
50%
Visceromegalia. Hipertrofia renal.
Polihidramnios y placenta quística y
engrosada.
PRACTICAL GENETICS
Beckwith–Wiedemann syndrome (BWS) is a model disorder for the study of imprint
Unique observations in this disorder point to an important embryonic developmenta
increased monozygotic twinning and an increased rate of epigenetic errors after sub
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

Conducta prenatal:
}  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:
}  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).
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-
TABLA 1. Características clínicas observadas
en el síndrome de Beckwith-Wiedemann
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:
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 overgrowth
in 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
Jung Min Ko, MD, PhD
Department of Pediatrics,
Seoul National University College of
Medicine, Seoul, Korea
http://dx.doi.org/10.6065/apem.2013.18.3.101
Ann Pediatr Endocrinol Metab 2013;18:101-105
Genetic syndromes as
Review article
http://dx.doi.org/10.6065/apem.2013.18.3.101
Ann Pediatr Endocrinol Metab 2013;18:101-105
102 www.e-apem.org
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
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.
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 ofNSD1 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 fromde 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-tryptophan-
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 entireNSD1 deletions
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:
Macrosomía
Macrocefalia
Alteraciones del SNC.
Retraso mental
Imágenes cedidas por el Servicio de Neonatología del HULP

Conducta prenatal:
}  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.
A R T I C L E
Mental Deficiency, Alterations
in Performance, and CNS Abnormalities
in Overgrowth Syndromes
M. MICHAEL COHEN, JR.*
Mental deficiency, alterations in performance, and central nervous system (CNS) abnormalities are discussed in the
following 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, PEHO
syndrome, chromosomal syndromes, and other miscellaneous syndromes. ß 2003 Wiley-Liss, Inc.
KEY WORDS: 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-Killian
syndrome; Costello syndrome
mildly to moderately retarded. The cry is
low-pitched and hoarse. Although the
appetite is voracious, hypothalamic dys-
regulation has not been demonstrated.
Difficulty in swallowing or breathing has
been noted in several cases. Other find-
ings have included cysts of the septum
pellucidum (two cases); dilation of the
been documented in approximately
13%. However, a number of patients
have had brain malformations [Cohen,
1993]. Cohen and Hayden [1979]
reported a patient with macrocephaly,
hydrocephalus, and an estimated IQ of
30–40. Cohen [1988] reported hemi-
megalencephaly, ventricular dilation,
TABLE I. Neuroimaging Findings in Sotos Syndrome
Categories Neuroimaging abnormalities
Percentage
(n ¼ 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].
a
n ¼ 36 for these entries.
50 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

Riesgos:
}  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.
A R T I C L E
Risk of Tumorigenesis in Overgrowth Syndromes:
A Comprehensive Review
PABLO LAPUNZINA
Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders in which the main characteristic is
that either weight, height, or head circumference is 2–3 standard deviations (SD) above the mean 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 some OGS (Perlman,
Beckwith-Wiedemann, and Simpson-Golabi-Behmel syndromes and hemihyperplasia) more than 94% of tumors
appeared in the abdomen usually before 10 years of age, mainly embryonal in type. In Perlman syndrome, only
Wilms 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 each OGS. A schedule
with different intervals and specific tests is proposed for a more rational cost/benefit program for these
Summers et al., 1999; Izumikawa, 2001;
Saitoh, 2001]; but no tumors have been
described to date.
The present data suggest that
screening would not be useful or cost-
effective. Moreover, since postnatal
growth tends to be slow, leading to
growth retardation, patients should not
be included in a routine tumor surveil-
lance program for OGS.
PERLMAN SYNDROME
Perlman syndrome (PS) is an autosomal
recessively inherited OGS characterized
by fetal gigantism, visceromegaly, un-
usual face, bilateral renal hamartomas
with nephroblastomatosis, and Wilms
tumor. The PS case reported by
Chernos et al. [1990] with chromosome
11 alterations probably represents an
example of BWS. Clinical overlap
between PS and BWS has been discussed
elsewhere [Grundy et al., 1992; Verloes
et al., 1995; Coppin et al., 1997; Fahmy
et al., 1998].
About 26 cases of PS have been
reported to date [Lapunzina et al., 2001].
One probable case of PS was also noted
by Narahara [2001]. In addition, Li et al.
[2001] demonstrated
with a previous diagn
by Greemberg et al.
son-Golabi-Behmel
Wilms tumor is t
reported in children w
predisposition may re
incidence of nephr
nephogenic rests (a k
Wilms tumor) or a m
position involving
[Grundy et al., 1992]
children with tumors
as 40% (n ¼ 25) (Tabl
this disorder is mand
focused on the abdom
through serial abdom
urinalysis (Table V).
SIMPSON-GOL
SYNDROME
Simpson-Golabi-Beh
(SGBS) is an X-link
acterized by pre- an
growth, organomega
malformations, coar
sia, and variable m
CPC3 mutations (p
deletions) are causativ
Veugelers et al., 19
patients with SGBS
to date [Lin et al., 19
There are at l
SGBS with neoplasi
intra-abdominal (Fi
tumors, two hepato
renal neuroblastoma
toma, and one hepat
[Lapunzina et al., 19
TABLE VIII. Malignancies Reported in Simpson-Golabi-Behmel Syndrome
(Adapted from Lapunzina et al., 1998)
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.
a
One case of hepatoblastoma Lapunzina, personal observation; not published.
TABLE IX. Malignancies Reported in Sotos Syndrome
(Adapted from Cohen, 1999)
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; Le Marec et al., 1999; Muraishi et al., 1999; Yule, 1999; Leonard,
2000; Jin et al., 2002; Al-Mulla et al., 2004.
There are at le
SGBS with n
tumors were int
(4 Wilms
2 hepatoblastom
neurobla
1 gonadobla
1 hepatocellula
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN.

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