SAM

AJCP / Case Report

Neonatal Silver-Russell Syndrome With Maternal Uniparental Heterodisomy, Trisomy 7 Mosaicism, and Dysplasia of the Cerebellum

From the 1Cytogenetics Laboratory, APHP, Cochin Hospital, Paris, France; 2Laboratory of Biochemistry and Molecular Genetics, APHP, Cochin Hospital, Paris, France; 3Paris Descartes University, Faculty of Medicine, Paris, France; 4Department of Gynecology-Obstetrics, APHP, Cochin Hospital, Paris, France; and 5Cytogenetics, Biomnis Laboratory, Paris, France. Key Words: Cerebellar dysplasia; Maternal heterodisomy 7; Prenatal trisomy 7; Silver-Russell syndrome Am J Clin Pathol August 2014;142:248-253 DOI: 10.1309/AJCPBLMPRXKU1JUE

ABSTRACT Objectives: We report here the unusual association of Silver-Russell syndrome (SRS) and cerebellar dysplasia with trisomy 7 mosaicism and maternal uniparental disomy of chromosome 7 [UPD(7)m]. Methods: Low-level trisomy 7 mosaicism was diagnosed prenatally on amniocytes, and UPD(7)m was confirmed after birth. Results: Medical examination at birth showed dysmorphic facial features of SRS. Cytogenetic analysis on several tissues and cells confirmed mosaic trisomy 7. Unusual severe psychomotor retardation, hypotonia, and choreoathetoid movement were noted at 6 months. Brain magnetic resonance imaging showed both cerebellar hypoplasia and dysplasia. Conclusions: This unusual association of SRS and dysplasia of the cerebellum might be related to the presence of the trisomy 7 mosaicism on the cerebellum. Our observation strengthens the hypothesis that the phenotype observed in patients with SRS with UPD(7)m might also result from an undetected low level of trisomy 7 mosaicism that could best be revealed by performing cytogenetic investigations.

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Am J Clin Pathol 2014;142:248-253 DOI: 10.1309/AJCPBLMPRXKU1JUE

Upon completion of this activity you will be able to: • define and compare uniparental disomy, uniparental heterodisomy, and uniparental isodisomy. • suggest a workup for patients with both the phenotype observed in Silver-Russell syndrome (SRS) patients and maternal uniparental disomy of chromosome 7 [UPD(7)m] to detect low level of trisomy 7, if present. • propose a conventional and molecular cytogenetic analysis in different tissues in order to look for trisomy 7 mosaicism when UPD(7)m is displayed in SRS patients. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 277. Exam is located at www.ascp.org/ajcpcme.

Prenatal diagnosis of trisomy 7 in chorionic villi is most often secondary to confined placental mosaicism (CPM) without consequence on fetal intrauterine growth, as observed in other CPMs,1,2 except when trisomy rescue leads to maternal uniparental disomy of chromosome 7 [UPD(7)m] in the fetus.1,3,4 In amniocytes, trisomy 7 is a rare condition that can be associated with pseudomosaicism5 or true mosaicism with normal fetal outcome in most cases.6 Phenotypic features of trisomy 7 mosaicism such a blaschkolinear skin pigmentary dysplasia, body asymmetry, enamel dysplasia, and developmental delay were reported in four prenatal cases7-10 for which UPD(7)m was not investigated. In three other cases, trisomy 7 mosaicism detected at amniocentesis was associated with UPD(7)m, leading to Silver-Russell syndrome © American Society for Clinical Pathology

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CME/SAM

Fatma Abdelhedi, MD,1 Laila El Khattabi, PharmD,1 Laurence Cuisset, PhD,2,3 Vassilis Tsatsaris, MD, PhD,3,4 Geraldine Viot, MD,3,4 Luc Druart, MD,5 Aziza Lebbar, MD,1,3 and Jean-Michel Dupont, MD, PhD1,3

AJCP / Case Report

Case Report A 43-year-old woman, gravida 6, para 4, aborta 2, underwent amniocentesis at 19 weeks’ gestation (WG) because of advanced maternal age and an increased risk for Down syndrome after maternal serum screening (1/180). The parents were healthy and consanguineous. Family history had noted mild psychomotor retardation and hypospadias in their 14-year-old son. Cytogenetic analysis on cultured and uncultured amniocytes revealed a male karyotype with a low-level trisomy 7 mosaicism (14% of cells displayed trisomy 7 on uncultured amniocytes). A detailed level II ultrasound examination performed at 23 WG failed to detect IUGR or any other congenital malformation. The parents refused any other analysis and decided to continue with the pregnancy, although they were informed about the risk of SRS. Therefore, UPD(7)m was not tested during the prenatal period. Fetal ultrasonography at 32 WG showed an isolated IUGR (femur was below the third percentile, craniocaudal length was at the 25th percentile, and biparietal diameter was at the 10th-50th percentile) without any structural or visceral anomalies. © American Society for Clinical Pathology

At 36 WG, a caesarian section was performed because of premature rupture of membranes leading to maternal-fetal streptococcus B infection and perturbed fetal heart rate. A male infant was delivered with a birth weight of 1,960 g (below the 10th percentile), length of 43 cm (below the 10th percentile), and head circumference of 32 cm (25th percentile). Apgar score was 4 at 1 minute and 10 at 5 minutes after brief ventilation. Physical examination showed a hypotonic baby with some minor dysmorphic features, including small triangular face, prominent forehead, narrow palpebral fissures, anteverted nostrils, downturned corners of mouth, posterior-rotated low-set ears, small and pointed chin, clinodactyly of the left fifth finger, single crease on the left hand, hypospadias, and angled penis. No body asymmetry was noted. After birth, cytogenetic analysis on various cells confirmed the true fetal mosaicism, with trisomic cells in the urinary pellet but not in lymphocytes or in jugal cells. The infant had a complicated neonatal period, with severe feeding difficulties requiring nutrition by a nasogastric tube and neonatal jaundice with unconjugated hyperbilirubinemia (at 206 mol/L). Transfontanel ultrasound, echocardiography, and ophthalmologic examination were normal. Examination at 3 months showed depigmented skin areas in limbs. A skin biopsy was not performed. Asymmetry in inferior limb length was noted clinically but not confirmed by x-ray examination. Unusual severe psychomotor delay, hypotonia, and choreoathetoid movement were noted at 6 months. Brain magnetic resonance imaging (MRI) showed both hypoplasia and dysplasia of the cerebellum.

Cytogenetic Investigations Prenatal Studies Cytogenetic analysis on cultured amniocytes revealed the presence of a cell line with an extra chromosome 7 in eight (32%) of 25 colonies: 47,XY+7. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes using a chromosome 7 centromeric probe (D7Z1; Vysis, Downers Grove, IL) showed that 21 (14%) of 160 cells analyzed had three chromosome 7. Postnatal Studies After birth, karyotype on chorionic villus tissue showed trisomy 7 in about 40% of the 54 analyzed cells, while all cord blood samples had a normal karyotype. Interphase FISH analysis using the chromosome 7 centromeric probe (D7Z1; Vysis) on urinary cells showed that 16% displayed trisomy 7 ❚Image 1A❚, whereas 84% had only two chromosomes ❚Image 1B❚. No trisomic cells were found on uncultured lymphocytes and jugal cells (100 cells were analyzed for each).

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(SRS).11-14 After birth, mosaic trisomy 7 was confirmed on cultured fibroblasts but was absent in lymphocytes.7,9,10 The etiology of SRS is heterogeneous. Most cases are associated with hypomethylation of the paternally derived differentially methylated region on chromosome 11p15 (about 50% of cases), while 5% to 10% of patients with SRS are associated with UPD(7)m.15,16 SRS is a congenital imprinting disorder characterized by severe intrauterine growth restriction (IUGR) and a preserved head circumference in association with a spectrum of additional dysmorphic features first described by Silver et al17 and Russell.18 Postnatal examination of patients with SRS has shown postnatal growth retardation, retarded bone age, body asymmetry, relative macrocephaly, typical triangular face, downturned mouth corners, brachydactyly, fifth-finger clinodactyly, and other less constant abnormalities such as genital abnormalities in males, psychomotor retardation, and café au lait spots. Patients with UPD(7)m have shared most of the same features.15,19,20 These relatively nonspecific features of SRS present a challenge to elaborate diagnostic criteria and genotype/ phenotype correlation for this syndrome, especially when UPD(7)m is associated with mosaic trisomy 7, and reflect the complexity of chromosomal mechanisms leading to the SRS phenotype.21 To our knowledge, no SRS has been reported in association with cerebellar abnormalities. We report on a prenatal SRS case with mosaic trisomy 7, UPD(7)m, and cerebellar dysplasia and discuss their possible relationships.

Abdelhedi et al / Neonatal Silver-Russell Syndrome

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Molecular Studies Polymerase chain reaction–based analysis for microsatellite markers on chromosome 7 was performed using fluorescent primers. Repeat alleles were resolved on an ABI PRISM 3130 capillary automate (Applied Biosystems, Foster City, CA) and analyzed by standard semiautomatic methods according to the manufacturer’s protocols (GeneMapper; Applied Biosystems). Microsatellite marker analyses revealed maternal heterodisomy on chromosome 7 ❚Figure 1❚. Biparental inheritance was ascertained using markers on chromosome 15 (sample controls; data not shown). A 4,000

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Discussion We report on a patient with prenatally ascertained SRS with trisomy 7 mosaicism and cerebellar hypoplasia. Trisomy 7 was detected in cultured and uncultured amniocytes with fractions of 32% and 14% of trisomic cells, respectively. Despite the discovery of fetal growth retardation on ultrasound examination, the parents declined further analysis for UPD(7)m. Trisomy 7 mosaicism was confirmed after birth in cultured chorionic villi (40%) and in urinary cells (16%) but was absent in peripheral blood

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❚Figure 1❚ Microsatellite analysis of D7S684 marker on chromosome 7 for the father (A), mother (B), and child(C). 250 250


© American Society for Clinical Pathology


❚Image 1❚ Interphase fluorescence in situ hybridization analysis on uncultured urinary cells using a chromosome 7 centromeric probe (D7Z1) (spectrum red) shows (A) three red signals in abnormal cells with trisomy 7 and (B) two red signals in normal cells with disomy 7.

AJCP / Case Report


cases ❚Table 1❚.11-14 All those cases were associated with severe developmental delay and typical facial dysmorphism. The first one had facial dysmorphism, severe growth retardation, hypoglycemia, and severe development delay. Font-Montgomery et al14 hypothesize that the patient’s exceedingly poor growth before growth hormone therapy and her subsequent response to hormonal replacement might be due to homozygosity of a mutant growth hormone–releasing hormone receptor, which is located in the short arm of chromosome 7. The authors also suggested that her severe developmental delay might be related to her UPD that was associated with mosaic trisomy 7. In the second case, Flori et al12 reported the unusual association of SRS with UPD(7)m, trisomy 7 mosaicism, and Hirschsprung disease. Trisomy 7 mosaicism was present in nervous plexuses of the intestine as well as in the epithelium or the connective and muscular tissues. Therefore, it was suggested that an increased dosage of a nonimprinted gene due to trisomy 7 mosaicism in the intestine results in Hirschsprung disease. Our case presents the unique association of hypoplasia and dysplasia of the cerebellum, which to our knowledge has never reported in patients with SRS with UPD(7)m. However, cerebellar hypoplasia was reported in a girl with mosaic trisomy 7.22 This girl had psychomotor delay and facial dysmorphism, including high forehead, antimongolian slant, deep-set eyes, esotropia, myopia, depressed nasal bridge, dysplastic low-set ears, short neck, and widely spaced inverted nipples. She had also lesions of depigmentation on the trunk and all four limbs. Brain MRI demonstrated mild hypoplasia of the cerebellum and midbrain. Therefore, we suggest that cerebellar hypoplasia might be related to the presence of trisomic cells in the cerebellum, leading to an increased dosage of nonimprinted genes or an overexpression of specifically maternally expressed imprinted alleles. In fact, the human growth factor receptor–bound protein 10 (GRB10) mapped on 7p is an imprinted gene that is implicated in the developing central nervous system, including brain and fetal spinal cord.23,24 Moreover, it is known that overexpression of certain GRB10 isoforms has been shown to inhibit tyrosine kinase activity, resulting in growth suppression and fetal CNS development inhibition.23 Thus, our report strengthens the hypothesis that the SRS phenotype observed in patients with UPD(7)m might also result from an undetected low-level trisomy 7 mosaicism. We do not have any information regarding trisomy 7 mosaicism for most patients with postnatally ascertained UPD(7)m SRS. Such information would help refine the genotype/phenotype correlation between patients with and without mosaicism. In fact, the phenotype can be modified by the presence of trisomic cells in some tissues, such as observed in our case. In this regard, the urinary cells represent one biologic sample that can be easily studied by FISH to search for this mosaic trisomy.

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cells and jugal cells. Maternal heterodisomy was confirmed after birth on diploid peripheral lymphocytes. Trisomy 7 mosaicism has been diagnosed at least 14 times during the prenatal period by amniocentesis,5-14 with reported fractions of trisomic cells in amniocytes ranging from 5% to 78%. Among the prenatal mosaic trisomy 7 cases, seven were associated with minor phenotypic abnormalities7-13 that can be observed in SRS such as intrauterine and postnatal growth retardation, triangular facies, body asymmetry, and fifth-finger clinodactyly. For these cases associated with phenotypic anomalies, fractions of trisomic cells ranged from 23% to 78%7,8,10-12 in cultured amniocytes. The remaining cases with a normal phenotype at birth had a wide range of trisomic cells (from 5%-48%) in cultured amniocytes. In our case, the proportion of trisomic cells in cultured and uncultured amniocytes was 32% and 14%, respectively. These results emphasize that a high level of trisomy 7 in cultured amniocytes might be derived from a cell culture effect, as suggested by Chen et al.8 Among the true mosaic trisomy 7 cases diagnosed prenatally and associated with minor phenotypic abnormalities of SRS after birth, UPD(7)m was documented in only three cases.11-14 In all these cases, microsatellite analyses revealed maternal heterodisomy of chromosome 7, as in our case. Uniparental disomy (UPD) is the inheritance of two homologous chromosomes from one parent in a euploid offspring. Two types of UPDs can be distinguished: uniparental heterodisomy, which occurs when both homologous chromosomes are transmitted from the same parent, and uniparental isodisomy, in which two copies of the same parental chromosome are present. Heterodisomy associated with mosaic trisomy 7 in our case indicates that the etiology of mosaicism is likely conception of the trisomy 7 zygote following a maternal meiotic nondisjunction event with incomplete trisomy rescue by loss of one chromosome 7 in some cell lineages. In this situation, maternal heterodisomy arises when the paternal homologue is lost. Thus, the most likely mechanism of UPD(7)m in our case should be a trisomic zygote rescue. Kalousek et al1 reported 14 cases with CPM for trisomy 7. In five of six cases studied for the origin of placental mosaicism, DNA evidence suggests that the trisomic cell line arose by a somatic duplication event within the placental lineage. Their study substantiates the hypothesis that UPD(7)m is most frequently due to somatic duplication; therefore, they conclude that the risk of fetal UPD(7)m is low. However, our observation provides evidence that UPD(7)m should be considered when trisomy 7 mosaicism is detected prenatally, because the association of mosaic trisomy 7 and UPD(7)m may lead to a poorer condition than isolated UPD(7)m, hence modifying genetic counseling. To our knowledge, the association between SRS and trisomy 7 mosaicism has been documented in only three

Abdelhedi et al / Neonatal Silver-Russell Syndrome

❚Table 1❚ Prenatal Patients With Silver-Russell Syndrome With the Combination of Mosaic Trisomy 7 and Maternal Heterodisomy of Chromosome 7

Present Case

Indication for amniocentesis

Abnormal triple marker screen

Abnormal triple marker screen

IUGR and moderate oligoamnios

Severe IUGR; abnormal triple marker screen

Prenatal findings

IUGR

Two-vessel cord at birth; slight cardiomegaly; IUGR

IUGR

IUGR

Prenatal cytogenetic analysis

47,XY,+7[5]/46,XY[17] (32% of colonies)

47,XX,+7[13]/46,XX[19] (41% of colonies)

47,XY,+7[8]/46,XY[18] (44% of colonies)

46,XY (100% of colonies); 47,XY,+7[20]/46,XY[30] (flask culture)

Postnatal cytogenetic analysis

47,XY,+7[21]/46,XY[33]: placenta (32% of colonies); 46,XY[50]: cord blood

47,XX,+7[9]/46,XX[20]: skin fibroblasts; 47,XX,+7[19]: chorionic villi; 46,XX[50]: cord blood

47,XX,+7[15]/46,XX[85]: intestine; 46,XX[100]: skin fibroblasts; 46,XX[100]: cord blood

46,XY[100]: blood; 46,XY[12]/47,XY,+7[8]: skin fibroblasts

Maternal heterodisomy

+

+

+

+

Dysmorphic features

Triangular face, prominent forehead, narrow palpebral fissures, anteverted nostrils, downturned corners of mouth, posterior-rotated low-set ears, small and pointed chin, clinodactyly of left fifth finger, single crease on left hand, hypospadias, and angled penis

Triangular-shaped face, broad forehead, short nose with prominent nasal bridge, thin lips with downturned corners, broad and low-set ears, micrognathia, fifth-finger clinodactyly

Triangular-shaped face, frontal bosses, narrow palpebral fissures, small mouth with thin lips, pointed chin, low-set posteriorly rotated ears, fifth-finger clinodactyly

Low-set and posteriorly rotated ears

Pigmentary anomalies

+

+

–

+

Developmental delay

Severe developmental delay

Severe developmental delay

Developmental delay

Developmental delay

Other features

Feeding difficulties, hypotonia, choreoathetoid movement, cerebellar dysplasia, hypoplasia, limb asymmetry, and failure to thrive

Hypoglycemia, failure to thrive, patent ductus arteriosus, diminished subcutaneous fat, mild peripheral hypotonia

Feeding difficulties, postnatal growth retardation, ventricular septal defect, Hirschsprung disease

Patent ductus arteriosus, ventricular septal defect, Dandy-Walker variant, failure to thrive

Age at last examination

13 mo

25 mo

5y

4.5 y

Flori et al12

Petit et al13

IUGR, intrauterine growth retardation; –, negative; +, positive.

Address reprint requests to Dr Abdelhedi: Cytogenetics Laboratory, APHP, Cochin Hospital, 53, Avenue de l’observatoire, Paris, 75014, France; [email protected].

References 1. Kalousek DK, Langlois S, Robinson WP, et al. Trisomy 7 CVS mosaicism: pregnancy outcome, placental and DNA analysis in 14 cases. Am J Med Genet. 1996;65:348-352. 2. Wolstenholme J. Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16 and 22: their incidence, likely origins, and mechanisms for cell lineage compartmentalization. Prenat Diagn. 1996;16:511-524. 252 252


3. Langlois S, Yong SL, Wilson RD, et al. Prenatal and postnatal growth failure associated with maternal heterodisomy for chromosome 7. J Med Genet. 1995;32:871-875. 4. Mergenthaler S, Wollman H, Burger B, et al. Formation of uniparental disomy delineated from new cases and a UPD7 case after trisomy 7 rescue: presentation of own results and review of the literature. Ann Genet. 2000;43:15-21. 5. Chen CP, Chern SR, Chen LF, et al. Prenatal diagnosis of low-level mosaic trisomy 7 by amniocentesis. Prenat Diagn. 2005;25:1067-1069. 6. Hsu LY, Yu MT, Neu RL, et al. Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20, and 21: karyotype/phenotype correlations. Prenat Diagn. 1997;17:201-242. 7. Kivirikko S, Salonen R, Salo A, et al. Prenatally detected trisomy 7 mosaicism in a dysmorphic child. Prenat Diagn. 2002;22:541-544. © American Society for Clinical Pathology


Characteristic

Bilimoria and Rothenberg11 and FontMontgomery et al14

AJCP / Case Report


17. Silver HK, Kiyasu W, George J, et al. Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics. 1953;12:368-376. 18. Russell A. A syndrome of intra-uterine dwarfism recognizable at birth with craniofacial dysostosis, disproportionately short arms, and other anomalies (5 examples). Proc R Soc Med. 1954;47:1040-1044. 19. Kotzot D, Balmer D, Baumer A, et al. Maternal uniparental disomy 7—review and further delineation of the phenotype. Eur J Pediatr. 2000;159:247-256. 20. Eggermann T, Wollmann HA, Kuner R, et al. Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy. Hum Genet. 1997;100:415419. 21. Price SM, Stanhope R, Garrett C, et al. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet. 1999;36:837842. 22. Knopf C, Rod R, Jaeken J, et al. Transferrin protein variant mimicking carbohydrate-deficient glycoprotein syndrome in trisomy 7 mosaicism. J Inherit Metab Dis. 2000;23:399-403. 23. Blagitko N, Mergenthaler S, Schulz U, et al. Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum Mol Genet. 2000;9:1587-1595. 24. Hitchins MP, Monk D, Bell GM, et al. Maternal repression of the human GRB10 gene in the developing central nervous system: evaluation of the role for GRB10 in Silver-Russell syndrome. Eur J Hum Genet. 2001;9:82-90.

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8. Chen CP, Huang HK, Su YN, et al. Trisomy 7 mosaicism at amniocentesis: interphase FISH, QF-PCR, and aCGH analyses on uncultured amniocytes for rapid distinguishing of true mosaicism from pseudomosaicism. Taiwan J Obstet Gynecol. 2012;51:77-82. 9. Jenkins D, Martin K, Young ID. Hypomelanosis of Ito associated with mosaicism for trisomy 7 and apparent “pseudomosaicism” at amniocentesis. J Med Genet. 1993;30:783-784. 10. Chen CP, Su YN, Chern SR, et al. Mosaic trisomy 7 at amniocentesis: prenatal diagnosis and molecular genetic analyses. Taiwan J Obstet Gynecol. 2010;49:333-340. 11. Bilimoria KY, Rothenberg JM. Prenatal diagnosis of a trisomy 7/maternal uniparental heterodisomy 7 mosaic fetus. Am J Med Genet A. 2003;118A:60-63. 12. Flori E, Girodon E, Samama B, et al. Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung’s disease in a child with Silver-Russell syndrome. Eur J Hum Genet. 2005;13:1013-1018. 13. Petit F, Holder-Espinasse M, Duban-Bedu B, et al. Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and RussellSilver syndrome. Clin Genet. 2012;81:265-271. 14. Font-Montgomery E, Stone KM, Weaver DD, et al. Clinical outcome and follow-up of the first reported case of RussellSilver syndrome with the unique combination of maternal uniparental heterodisomy 7 and mosaic trisomy 7. Birth Defects Res A Clin Mol Teratol. 2005;73:577-582. 15. Eggermann T, Spengler S, Gogiel M, et al. Epigenetic and genetic diagnosis of Silver-Russell syndrome. Expert Rev Mol Diagn. 2012;12:459-471. 16. Gicquel C, Rossignol S, Cabrol S, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005;37:1003-1007.