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Genetic Considerations in the Prenatal Diagnosis of Overgrowth Syndromes

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Genetic Considerations in the Prenatal Diagnosis of Overgrowth Syndromes PRENATAL DIAGNOSIS Prenat Diagn 2009; 29: 923–929. Published online 16 July 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2319 REVIEW Genetic considerations in the prenatal diagnosis of overgrowth syndromes Neeta Vora1,2 and Diana W. Bianchi1,2* 1Division of Genetics, Department of Pediatrics, Department of Obstetrics, Floating Hospital for Children and Tufts Medical Center, Boston, MA, USA 2Division of Maternal Fetal Medicine, Department of Obstetrics, Floating Hospital for Children and Tufts Medical Center, Boston, MA, USA Large (>90%) for gestational age (LGA) fetuses are usually identified incidentally. Detection of the LGA fetus should first prompt the provider to rule out incorrect dates and maternal diabetes. Once this is done, consideration should be given to certain overgrowth syndromes, especially if anomalies are present. The overgrowth syndromes have significant clinical and molecular overlap, and are associated with developmental delay, tumors, and other anomalies. Although genetic causes of overgrowth are considered postnatally, they are infrequently diagnosed prenatally. Here, we review prenatal sonographic findings in fetal overgrowth syndromes, including Pallister-Killian, Beckwith-Wiedemann, Sotos, Perlman, and Simpson-Golabi-Behmel. We also discuss prenatal diagnosis options and recurrence risks. Copyright 2009 John Wiley & Sons, Ltd. KEY WORDS: overgrowth; genetic syndrome; prenatal diagnosis; Beckwith-Wiedemann syndrome; Pallister- Killian syndrome; Simpson-Golabi-Behmel syndrome; Sotos syndrome; Weaver syndrome INTRODUCTION cases, a prenatal diagnosis will not be made. How- ever, increased awareness of the differential diagnosis of overgrowth syndromes can prepare the neonatologist for Large (>90%) for gestational age (LGA) fetuses are usu- potential neonatal problems associated with these syn- ally identified during a routine office visit when fundal dromes. Many overgrowth syndromes exist, but in this height is measured, or during an ultrasound examina- review, we will focus on the overgrowth syndromes that tion performed for other reasons. The most common have been described with a prenatal presentation and that reason for an LGA fetus is maternal diabetes mel- have clinically available molecular testing. litus or incorrect dates. When these two causes are ruled out, attention should be given to other etiolo- gies of fetal overgrowth. Generally, macrosomia is not CONSIDERATIONS IN THE DIFFERENTIAL detectable at the 16–20-week anatomy survey. Many DIAGNOSIS fetuses with overgrowth syndromes will fall into the normal weight range until later in gestation. This makes early diagnosis of overgrowth syndromes difficult. How- Many of the overgrowth syndromes have overlapping ever, many fetuses with overgrowth syndromes will clinical and molecular features. A suggested approach have other anomalies detectable in the second trimester. to the prenatal diagnosis of overgrowth syndromes is The overgrowth syndromes have significant clinical and given in Figure 1. molecular overlap, and are associated with developmen- tal delay, tumors, and other anomalies (Baujat et al., Chromosomal abnormalities 2005). It is our impression that although genetic condi- tions are considered in the postnatal differential diagno- Several chromosomal abnormalities are associated with sis of overgrowth, they are relatively infrequently diag- fetal overgrowth, including trisomy 12p, mosaic tetra- nosed prenatally. Genetic causes of overgrowth include somy 12p (also known as Pallister-Killian syndrome), chromosomal abnormalities, as well as syndromes such trisomy 4p16.3, trisomy 5p, trisomy 15q25, mosaic tri- as Sotos, Beckwith-Wiedemann, Perlman, and Simpson- somy 8 and monosomy 22q13 (Segel et al., 2006; Cohen Golabi-Behmel. When an overgrowth syndrome is sus- et al., 2005). With the introduction of chromosome pected prenatally, it is essential that a clinical geneticist microarrays into clinical medicine, chromosome abnor- be involved to assist in the differential diagnosis and malities associated with overgrowth will be more com- selection of appropriate tests. In the majority of these monly found. For example, a case report described two unrelated patients with trigonocephaly, overgrowth, and macrocephaly with a de novo microdeletion in 9q22.32- *Correspondence to: Diana W. Bianchi, Division of Genetics, Department of Pediatrics, Tufts Medical Center, 800 Washington q22.33 found by array comparative genomic hybridiza- Street, Box 394, Boston, MA 02111, USA. tion (Redon et al., 2006). Prenatal microarrays are cur- E-mail: [email protected] rently available that can diagnose microdeletions in the Copyright 2009 John Wiley & Sons, Ltd. Received: 11 September 2008 Revised: 22 April 2009 Accepted: 20 May 2009 Published online: 16 July 2009 924 N. VORA AND D. W. BIANCHI LGA>90% Check Dates Incorrect Dates Correct Dates Re-date Screen for Diabetes Diabetes Ruled Out Targeted Ultrasound Overgrowth + other Overgrowth +brain Normal growth or Overgrowth (may not be abnormalities (congenital abnormalities overgrowth, congenital present prenatally), diaphragmatic hernia, diaphragmatic hernia, omphalocele, body postaxial polydactyly. congenital heart disease, asymmetry, ventriculomegaly)+/- postaxial polydactyly polyhydramnios, renal and increased AFP cardiac abnormalities, Consider Sotos syndrome. large tongue +/-increased AFP Offer karyotype, fetal MRI, FISH for 5q35 (especially if Consider SGBS. Examine Japanese) NSD1 sequencing mother for evidence of Consider Pallister Killian available. Consider BWS. mild phenotype. syndrome. Offer karyotype, FISH for GPC3 sequencing Offer karyotype and FISH 11p15. available. for 12p. Figure 1—Suggested algorithm for the diagnostic workup of the fetus with overgrowth and other anomalies following genomic regions; Sotos (5q35), Beckwith- (Struthers et al., 1999). This results in an isochromo- Wiedemann (11p15), and 22q13. A prenatal microarray some 12p. Tetrasomy 12p can be detected by amnio- study may be useful if there is evidence of overgrowth centesis and confirmed with FISH studies using spe- with other abnormalities. Clinical trials are in progress cific probes for 12p. The detection of tetrasomy 12p is to determine the clinical utility of prenatal micorarrays. affected by the tissue type. It is more readily detected in amniocytes and skin because it is thought that peripheral blood lympocytes lose the extra chromosome due to their Pallister-Killian syndrome more frequent cell division. In an affected infant, if the peripheral blood karyotype is normal, then skin biopsy Pallister-Killian syndrome (Online Mendelian Inheri- or karyotype of other tissue sources should be consid- tance in Man [OMIM] #601 803) is caused by mosaicism ered. Recurrence risk is low because this is a sporadic for tetrasomy of chromosome 12p. Clinical features condition. include severe mental retardation, hypo- or hyperpig- The most common prenatal sonographic findings seen mentation, seizures, postaxial polydactyly, and facial in Pallister-Killian syndrome and other conditions are dysmorphism, including prominent forehead with sparse listed in Table 1 (Doray et al., 2002; Bresson et al., anterior scalp hair, hypertelorism, flat occiput, short, 1991; Paladini et al., 2000; Liberati et al., 2008). It is anteverted nose, and short neck. Skeletal anomalies, important to distinguish this syndrome, which occurs congenital heart defects, and congenital diaphragmatic sporadically, from Fryns syndrome, an autosomal reces- hernia are also seen in this condition. Pallister-Killian sive condition, which is also associated with skeletal syndrome is associated with advanced maternal age, anomalies and diaphragmatic hernia. Patients with Fryns and is thought to be caused by nondisjunction, followed syndrome, however, typically have intrauterine growth by an abnormal centromere division in meiosis I or II restriction and die more often in the newborn period. Copyright 2009 John Wiley & Sons, Ltd. Prenat Diagn 2009; 29: 923–929. DOI: 10.1002/pd OVERGROWTH SYNDROMES: GENETICS AND PRENATAL DIAGNOSIS 925 Table 1—Differential diagnosis of genetic overgrowth syndromes Possible sonographic Other aids to Syndrome Gene location Inheritance findings diagnosis Beckwith- 11p15 Variable; sporadic in Macrosomia, polyhydramnios, Karyotype but <1% of BWS Wiedemann 85% of cases but can omphalocele, enlarged have cytogenetically detectable be autosomal tongue, placentomegaly, long abnormalities; examination of dominant; also can be umbilical cord, enlarged parents by clinical geneticist caused by uniparental echogenic kidneys, pancreatic disomy and cystic dysplasia imprinting defects Pallister- Tetrasomy 12p Sporadic Polyhydramnios, rhizomelic Karyotype; confirm diagnosis Killian micromelia, congenital heart with FISH probes for 12p disease, diaphragmatic hernia (Figure 3), increased nuchal translucency, facial abnormalities Sotos NSD1 on 5q35 Sporadic in 95% of Brain abnormalities, Fetal MRI; Karyotype, FISH cases macrocephaly for 5q35, NSD1 sequencing Perlman Unknown Autosomal recessive Polyhydramnios, macrosomia, visceromegaly, enlarged echogenic kidneys, cystic hygroma Simpson- GPC3 on Xp26 X-linked recessive Polyhydramnios, Elevated MSAFP level; Golabi-Behmel omphalocele, cystic hygroma, examination of mother by diaphragmatic hernia, clinical geneticist; determine enlarged or cystic kidneys, fetal gender; GPC3 sequencing agenesis of the corpus callosum, Dandy Walker malformation, and macrosomia, placentomegaly Significantly,
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