REVIEW ARTICLE
Prenatal findings and genetic diagnosis of fetal overgrowth disorders (I):
Simpson-Golabi-Behmel syndrome, Sotos syndrome and Beckwith-Wiedemann
syndrome
Chih-Ping Chen
a,b,c,d,e,f,g*a Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
b Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan c Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
d Department of Biotechnology, Asia University, Taichung, Taiwan
e School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan f Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan g Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,
Taiwan
* Correspondence to: Chih-Ping Chen, MD
Department of Obstetrics and Gynecology
Mackay Memorial Hospital
92, Section 2, Chung-Shan North Road
Taipei, Taiwan
Tel: +886-2-25433535
Fax: +886-2-25433642, +886-2-25232448
E-mail: [email protected]
Abstract
With the advent of prenatal sonography, fetal overgrowth can be easily detected. Prenatal-onset
overgrowth can be secondary due to normal variants of familial tall stature and familial rapid
maturation, diabetic macrosomia and congenital nesidioblastosis, or primary due to pathologic
overgrowth disorders. This article provides a comprehensive review of prenatal findings and
genetic diagnosis of some of the prenatal-onset pathologic overgrowth disorders such as
Simpson-Golabi-Behmel syndrome, Sotos syndrome and Beckwith-Wiedemann syndrome.
Key Words: Beckwith-Wiedemann syndrome, fetus, overgrowth, Simpson-Golabi-Behmel
syndrome, Sotos syndrome
Introduction
With the advent of prenatal sonography, fetal overgrowth can be easily detected. Prenatal-onset overgrowth can be secondary due to normal variants of familial tall stature and familial rapid maturation, diabetic macrosomia and congenital nesidioblastosis, or primary due to pathologic overgrowth disorders. This article provides a comprehensive review of prenatal findings and genetic diagnosis of some of the prenatal-onset pathologic overgrowth disorders such as Simpson-Golabi-Behmel syndrome, Sotos syndrome and Beckwith-Wiedemann syndrome.
Simpson-Golabi-Behmel syndrome
Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive disorder. Simpson et al [1] first described two maternal male cousins with macrocephaly, a coarse face, broad hands, dysplastic fingernails and apparently normal intelligence. Behmel et al [2] later reported a similar condition in a sibship of several affected males with additional findings of congenital heart defects, polydactyly and a high mortality rate in the infants. Golabi and Rosen [3] additionally reported a family with several affected males with internal organ malformations and early death. Neri et al [4] reported an Italian family with three affected males with similar anomalies as previously seen by Simpson et al [1], Behmel et al [2], and Golabi and Rosen [3], and coined the eponym “Simpson-Golabi-Behmel syndrome”.
SGBS is characterized by pre- and postnatal overgrowth, a coarse face, macrocephaly, macrosomia, macroglossia, hypertelorism, dental malocclusion, palatal abnormalities, supernumerary nipples, cryptorchidism, hypospadias, congenital heart defects, diaphragmatic hernia, polydactyly and brachydactyly of the hands, cutaneous syndactyly of the fingers and toes, hypoplasia of finger nails, vertebral segmental defects, renal dysplasia/nephromegaly, diastasis recti/umbilical hernia, enlarged internal organs, and an increased risk (10%) of developing embryonal tumors such as Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma and hepatocellular carcinoma [1-6].
SGBS type 1 (SGBS1) (OMIM 312870) is a milder form of SGBS. SGBS type 2 (SGBS2) (OMIM 300209) is a more severe form of SGBS [7-9]. SGBS1 is caused by deletion or mutation in the GPC3 gene (OMIM 300037) which maps to Xq26 [10]. SGBS2 has been associated with mutations in the CXORF5 gene (OMIM 300170) which maps to Xp22 [9]. The GPC3 gene encodes glypican 3 which acts as a negative regulator of Hedgehog signaling during development, and loss-of-function mutations in the GPC3 gene will cause hyperactivation of Hedgehog signaling and result in overgrowth and cancer [11]. The
CXORF5 gene or OFD1 gene encodes chromosome X open reading frame 5 (CXORF5) protein which is
required for the formation of primary cilia and left-right axis specification [12-14]. Loss-of-function mutations in the CXORF5 gene have been associated with X-linked dominant oral-facial-digital syndrome type 1 (OFD1) (OMIM 311200) [12-13, 15], X-linked recessive SGBS2 [9] and X-linked recessive Joubert syndrome type 10 (JBTS10) (OMIM 300804) [16]. The detection rate for GPC3 mutation and deletion has
been ranging from 37% (7/19) [17] to 70% (7/10) [18] and 70.3% (26/37) [19] in patients with SGBS. Veugelers et al [20] reported deletion of the GPC3-GPC4 gene cluster in one family with SGBS. GPC4 (OMIM 300168) maps to Xq26 centromeric to GPC3 and encodes glypican 4 which plays a role in the control of cell division and growth regulation [20]. Recently, Waterson et al [21] reported duplication of
GPC4 in the family initially described by Golabi and Rosen [3] and suggested that duplication of GPC4 may
be a cause of SGBS.
Fetuses with SGBS may prenatally manifest macrosomia, polyhydramnios, elevated maternal serum
-fetoprotein (MSAFP), cystic hygroma, hydrops fetalis, increased nuchal translucency (NT), craniofacial abnormalities, visceromegaly, renal anomalies, congenital diaphragmatic hernia, polydactyly and single umbilical artery [7,22-26]. Chen et al [22] reported three affected males with SGBS in a family, and all were later found to have GPC4 duplication [21]. The first case had an elevated MSAFP level at 22 weeks of gestation. Prenatal ultrasound at 24 weeks of gestation revealed congenital diaphragmatic hernia, cystic hygroma and cystic ureters/kidneys. Amniocentesis revealed a karyotype of 46,XY. The second case had polyhydramnios at 18 weeks of gestation, and prenatal ultrasound showed congenital diaphragmatic hernia and polydactyly. Amniocentesis revealed a karyotype of 46,XY. The third case was terminated at 21 weeks of gestation and was associated with an elevated MSAFP level, cystic hygroma, craniofacial anomalies, congenital diaphragmatic hernia and single umbilical artery. Hughes-Benzie et al [23] reported an elevated MSAFP level at 17 weeks of gestation, macrosomia at 19 weeks of gestation and polyhydramnios at 28 weeks of gestation in a male fetus affected with SGBS. This case had a GPC3 deletion at the 3’ end of exon 1 [27]. Yamashita et al [24] reported macrosomia, severe polyhydramnios, a large liver and remarkable enlarged kidneys at 29 weeks of gestation in a male fetus affected with SGBS. The karyotype was 46,XY. Li and McDonald [25] reported an abnormal NT in the first trimester, an elevated MSAFP level at 16 weeks of gestation, macrosomia, polyhydramnios, cleft lip and palate, and an abnormal skull at 30 weeks of gestation in a male fetus affected with SGBS. The fetus had a GPC3 mutation in exon 2 (c.194_206 del) (p.cys65fs). Weichert et al [26] reported a 1-Mb microdeletion of Xq26.2 encompassing the GPC3 gene in a fetus with SGBS. The associated prenatal findings in that case included a markedly increased NT in the first trimester, and macrocephaly, asymmetric bilateral mild ventriculomegaly, down-turned corners of the permanently opened mouth, low-set ears, a flat facial profile, macrosomia and polyhydramnios at 22 weeks of gestation. Terespolsky et al [7] reported 4 maternally related male cousins with SGBS2 which was confirmed to be associated with a SGBS2 locus at Xp22 by linkage analysis [8]. In their report, one male fetus manifested renal abnormality on prenatal ultrasound, and another male fetus manifested polyhydramnios at 22 weeks of gestation, and hydrops fetalis was noted in all 3 liveborn males at birth. In instances of fetal overgrowth and polyhydramnios in association with other abnormalities such as congenital diaphragmatic hernia, increased NT, visceromegaly, renal anomalies, postaxial polydactyly,
single umbilical artery and elevated MSAFP, a differential diagnosis of SGBS should be considered. Examination of the mother for evidence of mild SGBS phenotype, investigation of the male family members with positive SGBS phenotype, mutational analysis of GPC3, GPC4, and CXORF5, and array comparative genomic hybridization (aCGH) analysis of genomic imbalance in Xp22 or Xq26 are helpful for genetic diagnosis and counseling.
Sotos syndrome
Sotos syndrome (OMIM 117550) is an autosomal dominant disorder. Sotos et al [28] first described 5 children with overgrowth, advanced bone age, acromegalic features, a high-arched palate, a prominent jaw, and mental retardation. Cole and Hughes [29] suggested that characteristic facial appearance, learning disability and childhood overgrowth are major diagnostic criteria for Sotos syndrome. Maroun et al [30] first reported a 4-year-old girl with Sotos syndrome and a karyotype of 46,XX,t(5;15)(q35;q22), and suggested that 5q35 as the site of the gene determining Sotos syndrome. Imaizumi et al [31] later reported a 15-month-old girl with Sotos syndrome and a karyotype of 46,XX,t(5;8)(q35;q24.1), and proposed that the gene responsible for Sotos syndrome is located at 5q35. Kurotaki et al [32] subsequently identified NSD1 as the gene disrupted by the 5q35 breakpoint by positional cloning.
Sotos syndrome is characterized by cardinal features ( 90%) of a characteristic facial appearance of a high broad forehead, an inverted pear-like head, sparse frontotemporal hair, molar flushing, down-slanting palpebral fissures, a long face and a point chin, learning disability and overgrowth; major features ( 15%) of advanced bone age, cranial abnormalities in diagnostic computed tomographic scans and magnetic resonance imaging, poor feeding in infancy, neonatal jaundice and hypotonia, seizures, scoliosis, cardiac anomalies, renal anomalies, joint laxity and pes planus, and a slightly increased risk (2.2% or < 3%) of developing neoplasm such as sacrococcygeal teratoma, neuroblastoma, presacral ganglioma, acute lymphoblastic leukemia and small cell lung cancer, Wilms tumor, hepatocellular carcinoma, cardiac/ovarian fibroma and germ cell tumor [33-36].
Sotos syndrome is caused by deletion or mutation in the NSD1 gene (OMIM 606681) which maps to 5q35 [32,37-38]. The NSD1 gene encodes nuclear receptor set domain protein 1 which acts to enhance androgen receptor transactivation [39]. At least 90% of patients with Sotos syndrome have NSD1 abnormalities [40-41]. Intragenic mutations cause 27%-93% of non-Japanese Sotos syndrome cases and about 12% of Japanese Sotos syndrome cases, and 5q35 microdeletions cause about 50% of Japanese cases and about 10% of non-Japanese Sotos syndrome cases [36,40-51]. However, in about 10% of classic Sotos syndrome,
NSD1 abnormalities have not been identified [41]. Most cases with Sotos syndrome have arisen de novo,
and familial Sotos syndrome with vertical transmission has occurred in less than 10% of the cases with Sotos syndrome [48-49,52].
Fetuses with Sotos syndrome may prenatally manifest increased NT, an increased Down syndrome risk on maternal serum screen, macrocephaly, polyhydramnios, fetal overgrowth, renal abnormalities and central nervous system abnormalities [53-55]. Chen et al [53] reported macrocephaly, an irregular skull shape, ventriculomegaly, corpus callosum hypoplasia, enlarged cistern magna, overgrowth, unilateral hydronephrosis and polyhydramnios on prenatal ultrasound in the third trimester in a fetus with familial Sotos syndrome. The pregnancy was associated with an abnormal maternal serum screen result with a Down syndrome risk of 1/212 and a 46,XY karyotype in the fetus. Thomas and Lemire [54] reported macrocephaly and an increased Down syndrome risk of 1/8 on maternal serum screen at 17 weeks of gestation, and macrosomia and polyhydramnios at 34 weeks of gestation in a fetus with familial Sotos syndrome and a frameshift mutation (5712delC) in the NSD1 gene. Schou et al [55] reported increased NT (7 mm) and large for date on prenatal ultrasound in a fetus with a de novo mutation in the NSD1 gene. Schaefer et al [56] and Gusmão Melo et al [57] found abnormal neuroimaging findings in all patients with Sotos syndrome. The reported neuroimaging findings include enlargement of lateral ventricles, trigones and occipital horns, corpus callosum hypoplasia, persistence of cavum septum pellucidum, cavum vergae and cavum velum interpositum, enlarged cisterna magna, heterotopias, macrocerebellum and periventricular leukomalacia [56-57].
In instances of fetal overgrowth, macrocephaly and polyhydramnios in association with other abnormalities such as renal anomalies, central nervous system abnormalities, increased NT and abnormal maternal serum screening results, a differential diagnosis of Sotos syndrome should be considered. Examination of the parents for evidence of Sotos syndrome phenotype, investigation of family members with positive Sotos syndrome phenotype, mutational analysis of NSD1, and molecular cytogenetic analysis of 5q35 microdeletion by fluorescence in situ hybridization (FISH) and/or aCGH are helpful for genetic diagnosis and counseling.
Beckwith-Wiedemann syndrome
Beckwith-Wiedemann syndrome (BWS) (OMIM 130650) is an imprinting disorder. Beckwith [58] and Wiedemann [59] first described an EMG syndrome characterized by the clinical findings of exomphalos (omphalocele), macroglossia and gigantism (macrosomia). Waziri et al [60] first reported 2 unrelated children with features of BWS. In their study, one child had duplication of 11p13-p15, and the other had duplication of 11p15. They reviewed 6 other reported cases with partial dup(11p) and identified the features of BWS. The region 11p15 contains the genes associated with BWS.
BWS is characterized by macrosomia, ear creases/pits, macroglossia, omphalocele/umbilical hernia, visceromegaly, hemihypertrophy, cleft palate, adrenocortical cytomegaly, renal medullary dysplasia, nephromegaly, nephrocalcinosis, nephrolithiasis, polyhydramnios, placental mesenchymal dysplasia, placentomegaly, cardiomegaly, structural cardiac anomalies, facial nevus flammeus, hemangiomata, neonatal
hypoglycemia, midface hypoplasia, diastasis recti, advanced bone age, and an increased risk (7.5%) of developing embryonal tumors such as Wilms tumor, hepatoblastoma, rhabdomyosarcoma, adrenocortical carcinoma and neuroblastoma [61-65].
BWS is caused by epigenetic alterations or genomic imbalances at the chromosome 11p15.5 imprinting cluster which is functionally divided into domain 1 containing two imprinted genes: IGF2 (OMIM 147470) (expressed from the paternal allele) and H19 (OMIM 103280) (expressed from the maternal allele); and domain 2 containing three imprinted genes: CDKN1C (OMIM 600856) (expressed from the maternal allele),
KCNQ1 (OMIM 607542) (expressed from the maternal allele) and KCNQ1OT1 (OMIM 604115) (expressed
from the paternal allele). The H19-associated imprinting center 1 (IC1) or differentially methylated region 1 (DMR1) is usually methylated on the paternal chromosome and unmethylated on the maternal chromosome. The KCNQ1OT1-associated imprinting center 2 (IC2), or KvDMR1, or DMR2, is usually methylated on the maternal chromosome and unmethylated on the paternal chromosome, and regulates in cis the expression of the maternally expressed imprinted genes in domain 2 [62,64-65]. Analysis of frequency of genetic abnormalities in patients with BWS has found: loss of methylation at IC2 on the maternal chromosome in 50%; gain of methylation at IC1 on the maternal chromosome in 5%; CDKN1C mutations in 10% (5% in patients with no family history of BWS and ~40% in patients with positive family history of BWS); paternal uniparental disomy (UPD) of 11p15.5 in 20%; duplication, inversion or translocation of 11p15.5 in 1% and submicroscopic genomic alteration within 11p15.5 in unknown % [65].
Fetuses with BWS may prenatally manifest macrosomia, polyhydramnios, macroglossia, omphalocele, placentomegaly, a long umbilical cord, echogenic kidney and pancreatic cystic dysplasia [66]. Reish et al [67] suggested that fetal overgrowth, polyhydramnios, enlarged placenta and distended abdomen are constant prenatal findings of BWS. Williams et al [68] suggested that BWS can be reliable made by either two major criteria (macroglossia, macrosomia and abdominal wall defect) or one major criterion plus two minor criteria (nephromegaly/dysgenesis, adrenal cytomegaly, aneuploidy/abnormal loci and polyhydramnios).
Children conceived by in vitro fertilization (IVF) have an increased risk of BWS [69]. Halliday et al [69] suggested that the overall risk of BWS in the population of children conceived by IVF is about 1/4,000 (4/14,894), or nine times greater than that in the general population. Recently, Gomes et al [70] found an abnormal methylation at IC2 (KvDMR1 or DMR2) in clinically normal children conceived by assisted reproductive technologies (ARTs). Hypomethylation at IC2 (KvDMR1 or DMR2) was observed in 3/18 clinically normal children conceived by ARTs [2 conceived by IVF and 1 by intracytoplasmic sperm injection (ICSI)]. Lim et al [71] additionally found that ART may also be associated with disturbed normal genomic imprinting in imprinting control regions other than 11p15.5 such as DMRs at 6q24, 7q32 and 15q13. In a study of 25 cases with post-ART BWS of which 24 cases had an IC2 epimutation (KvDMR1 loss of methylation), they found that loss of maternal allele methylation in DMRs at 6q24, 7q32 and 15q13
occurred in 37.5% of post-ART BWS IC2 defect cases compared with 6.4% of non-ART BWS IC2 defect cases. Their finding indicates that more generalized DMR hypomethylation is more frequent in post-ART BWS cases than in those with non-ART BWS cases.
In instances of fetal overgrowth, macrocephaly and polyhydramnios in association with other abnormalities such as macroglossia, omphalocele, placentomegaly, enlargement of kidneys and adrenal glands, and an obstetric history of ART, a differential diagnosis of BWS should be considered. Examination of the parents for evidence of BWS phenotype, investigation of family members with positive BWS phenotype, cytogenetic analysis of 11p15.5 chromosome aberrations such as duplication, inversion or translocation, mutational analysis of CDKN1C, molecular tests for methylation and/or copy number changes on chromosome 11p15.5 such as gain of methylation at H19, loss of methylation at IC2 (KvDMR1 or DMR2) or both, and the UPD test for paternal UPD 11p15.5 are helpful for genetic diagnosis and counseling.
Acknowledgements
This work was supported by research grants NSC-97-2314-B-195-006-MY3 and NSC-99-2628-B-195-001-MY3 from the National Science Council, and MMH-E-100-04 from Mackay Memorial Hospital, Taipei, Taiwan.
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