RESEARCH REVIEW
Chromosomal Rearrangements in Patients With Clinical Features of Silver–Russell Syndrome Siv Fokstuen,1 and Dieter Kotzot2* 1
Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
2
Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria Manuscript Received: 21 August 2013; Manuscript Accepted: 21 October 2013
Silver–Russell syndrome (SRS) is characterized by pre- and postnatal growth retardation, relative macrocephaly, asymmetry, and a triangular facial gestalt. In 5–10% of the patients the phenotype is caused by maternal UPD 7, and 38–64% of the patients present with hypomethylation at the imprinting center region 1 (ICR1) on 11p15.5. The etiology of the remaining cases is so far not known and various (sub-)microscopic chromosome aberrations with a phenotype resembling SRS have been published, especially duplication 11p15 (n ¼ 15), deletion 12q14 (n ¼ 19), ring chromosome 15, deletion 15qter, and various other mostly unique chromosomal aberrations (n ¼ 30). In this study the phenotypes of these chromosomal aberrations were revisited and compared with the phenotypes of maternal UPD 7 and hypomethylation at ICR1 on 11p15.5. In some patients with a unique chromosomal aberration even the hallmarks of SRS were missing. Patients with duplication 11p15 show a more variable occipitofrontal head circumference at birth, a higher frequency of intellectual disability, and additional anomalies not reported in SRS. Deletion 12q14 is characterized by less severe pre- and postnatal growth retardation and less impressive relative macrocephaly. Patients with ring chromosome 15 and deletion 15qter have no relative macrocephaly (mostly even microcephaly) and more severe intellectual disability. Finally, deletion 15qter lacks the triangular facial gestalt. In summary, as SRS seems not an adequate diagnosis in many of these patients, diagnosis should focus on the chromosomal aberration than on SRS. Ó 2014 Wiley Periodicals, Inc.
Key words: chromosomal rearrangement; deletion; duplication; Silver–Russell syndrome
INTRODUCTION More than 60 years ago, Silver et al. [1953] described a 51/2-year-old girl and a 6-year-old boy with “Congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins.” Both children did not have the triangular facial gestalt (later on noted as typical) and only the boy showed a relative macrocephaly. Development was normal in both of them. One year later, Russell [1954] reported on two girls and three boys with a “Syndrome of intrauterine dwarfism
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Fokstuen S, Kotzot D. 2014. Chromosomal rearrangements in patients with clinical features of Silver–Russell syndrome. Am J Med Genet Part A 164A:1595–1605.
recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples).” All had relative macrocephaly and normal intelligence. Two showed in addition “hemiatrophy.” Later on, it was assumed that both reports describe the same genetic disorder and the eponyms Russell–Silver syndrome and Silver–Russell syndrome (SRS) were applied. Meanwhile, several hundred patients were reported and the list of associated features became longer and longer (Winter-Baraitser Dysmorphology Database, version 1.0.30). The etiology of SRS remained unknown until the report of maternal uniparental disomy (UPD) 7 in approximately 10% of the patients [Kotzot et al., 1995]. Ten years later, hypomethylation of the imprinting center region 1 (ICR1) at the IGF2/H19 locus on 11p15 was shown in around 40% of the patients [Gicquel et al., 2005]. In addition, many patients with various microscopic and submicroscopic chromosome aberrations and the diagnosis of SRS or a phenotype resembling SRS were published. However, screening for genes located in some of the rearranged chromosomal segments were disappointing and no additional gene or genetic mechanism was identified so far. In this article, the phenotypes of patients reported with a chromosomal aberration and the diagnosis of SRS or a phenotype resembling SRS are critically reviewed and compared with the phenotypes of patients with maternal UPD 7 and hypomethylation of ICR1 at 11p15.
Correspondence to: Dieter Kotzot, Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstr. 41 A-6020 Innsbruck, Austria. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 March 2014 DOI 10.1002/ajmg.a.36464
1595
1596
METHODS A PubMed search up to July 2013 with the terms “Silver–Russell syndrome” and either “chromosome aberration,” “deletion,” or “duplication” was performed and all articles were read and critically evaluated concerning the clinical and genetic data. In addition, all references of the reports were assessed to identify additional cases. As most recently several excellent reviews on submicroscopic chromosomal rearrangements within the ICR region on 11p15.5 were published [Demars et al., 2011; Begemann et al., 2012], only duplications at 11p15 larger than 1 Mb and being of maternal origin were included. Facial dysmorphism were either adopted from the clinical reports or evaluated from published photographs. As patients were originating from all over the world, populationrelated growth charts were not available for most of them. To overcome this problem the measurements for length/height, weight, and occipitofrontal head circumference (OFC) were converted to standard deviations (SD) of the Canadian Pediatric Endocrine Group (CPEG) 2012 growth charts. This procedure explains the differences to some SDs reported in the original publications. Generally, as it is a retrospective study, which compares patients from the literature it was unfortunately not possible to get all relevant and interesting data from all patients. The clinical data concerning maternal UPD 7 and hypomethylation at 11p15 were taken from [Kotzot, 2008], concerning ring chromosome 15 and terminal deletion of 15q from the ECARUCA database [http:// umcecaruca01.extern.umcn.nl:8080/ecaruca/ecaruca.jsp].
RESULTS Apart from patients with duplication 11p15 (n ¼ 15), microdeletion 12q14 (n ¼ 19), ring chromosome 15, and deletion 15qter, at least 30 patients with various other chromosomal rearrangements (10 deletions, 9 duplications, and 11 other aberrations) have been reported (Tables I –III). Two patients from the group with various chromosomal rearrangements carry a balanced translocation (one paternally inherited 17;20 translocation and one de novo 1;17 translocation) [Ramı´rez-Duen˜as et al., 1992; Midro et al., 1993]. In six patients with duplication 11p15, additional most likely clinically relevant imbalances were described [Fisher et al., 2002; Eggermann et al., 2005; South et al., 2008; Bliek et al., 2009; Hu et al., 2013]. Furthermore, there is one familial case of duplication 11p15 with five affected members [Bonaldi et al., 2011]. All 15 patients (5 male and 10 female) with maternal duplications of 11p15 include the ICR1 locus at 11p15.5 (Table II). Size of the duplication is variable (1.2–10.3 Mb). Almost all patients show preand postnatal growth retardation as well as relative macrocephaly. Maternal UPD 7 was excluded in only five patients. At least 19 patients (9 male and 10 female) with submicroscopic deletions in 12q14 have been reported resembling clinically SRS (Table III). Size of the deletion (110 kb–10.1 Mb) is also variable. Bone age was evaluated in six patients only and four of them showed retarded bone age. Maternal UPD 7 and hypomethylation of ICR1 at 11p15 were excluded in only one patient. According to the data from the ECARUCA database, patients with ring chromosome 15 show no relative macrocephaly (mostly even microcephaly), and on average more often severe intellectual
AMERICAN JOURNAL OF MEDICAL GENETICS PART A disability, than patients with maternal UPD7 or hypomethylation of ICR1 at 11p15 (Table IV). Depending on the size of the deletion the same comes true for terminal deletions of 15q. In most of the 30 patients with unique chromosomal aberrations clinical evaluation is incomplete. Even length/height, weight, and OFC at birth and at the last clinical evaluation as well as bone age are not always reported (Table I).
DISCUSSION In about 50% of patients with a SRS phenotype, the etiology is not known and diagnosis remains purely clinical. There is however no general agreement about clinical criteria for the diagnosis of SRS syndrome. Some clinicians require pre- and postnatal growth retardation, relative macrocephaly, and facial dysmorphism (particularly the typical triangular face with a high and broad forehead and a pointed chin), while others make the diagnosis with less than these features. Lai et al. [1994] and later on Price et al. [1999], Netchine et al. [2007], and Bartholdi et al. [2009] attempted to define clinical criteria for SRS (Table V). The so-called Bartholdi score is the most complex one including all three birth parameters (weight 10th centile, length 10th centile, and OFC 1.5 SD higher than weight or length), postnatal course (height 3rd centile, OFC >3rd and 97th centile, and normal cognitive development), asymmetry (face, body, limbs), facial gestalt (triangular shaped face, high/bossing forehead, other), and other features (5th finger clinodactyly, genital abnormalities, others like brachymesophalangy, toes syndactyly, inguinal hernia, pigmentary changes) resulting in a maximum score of 15 points [Bartholdi et al., 2009]. Most recently, Dias et al. [2013] compared these four scoring systems and suggested to use birth weight below 2 SDs, postnatal short stature below 2 SDs at 2 years of age or older, relative macrocephaly (OFC 1.5 SDs than height SDs), and asymmetry. A diagnosis of SRS was made by three or more features being present. According to the criteria of all five scoring systems a diagnosis of SRS can theoretically be retained without postnatal growth retardation. In addition, all scoring systems require follow-up, which is not always possible. Finally, none of these scoring systems included retarded bone age, which is found in almost all patients with maternal UPD 7 [Kotzot, 2008]. Thus, the clinical diagnosis of SRS is not uniform. For this comprehensive review, the obligate criteria were reduced to pre- and postnatal growth retardation and relative macrocephaly. Patients fulfilling these criteria would most likely also have been diagnosed as SRS by all scores discussed above. Dysmorphism like a triangular face, asymmetry, or clinodactyly were only used to strengthen the clinical diagnosis. However, as already mentioned, even these minimal criteria were not always reported in the reviewed articles. In the 15 patients with mat dup 11p15 encompassing the SRS/ BWS region the trisomic segments mainly reflect the clinical consequences of hypomethylation at the ICR1 locus at 11p15.5. Compared with maternal UPD7 and isolated hypomethylation at 11p15.5, OFC values are more variable ranging from 1.9 to þ2.89 SD at birth and from 4.97 to þ0.19 SD at the last evaluation (Table IV). Particularly at birth the OFC SDs in patients with hypomethylation at 11p15 only are lower than in patients with
28 y 155 (2.94) 58 (1.3) 55.5 (0.82) þ
108.8 (4.06)b
49 (2.1)b þ 167/? No Delayed
7y8m 114 (2.07)
50 (1.67)
162/? þ Normal
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD)
Chromosome aberration Reference
Bone age Clinodactyly Other findings
OFC in cm (SD) Relative macrocephaly at the last evaluationa Parental height in cm (m/f) Triangular face Body asymmetry Psychomotor development
? 2.5 y (4.5)b P 0.4b
9.75 y 120 (2.7) 14.8 (4.7)
1,760 (2.77)
F 37
Yes
mos mat UPD11 Bullman et al., [2008]
F 36 35.5 (3.89) 1,100 (3.64) 26 (3.57)
del(8) q11q13)dn Schinzel et al. [1994]
þ Del (1)(q21q21)
?
?
þ Cafe au lait spots, attention deficit hyperactivity disorder
M 37 45 (2.5) 1,960 (1.65)
F 40 47 (1.38) 2,480 (2.33)
M 40 50 (0.69) 3,050 (1.3) 34 (0.5)
8y8m 97.5 (5.43) 11 (5.56)
F 40 43 (2.6) 2,100 (3.2) 35 (þ0.28) þ
t(17;20) (q25;q13) Ramı´rez-Duen˜as et al. [1992]
Feeding difficulties, scoliosis
Delayed
149/? þ þ Delayed
Yes
1.8 Yes Yes
1.65 Yes Yes
8y 116 (1.93) 18 (2.58)
M 40 49 (0.99) 2,550 (2.41) 30 (2.39)
2y1m 80 (2.56)
M 40 42 (3.06) 3,280 (0.79) 35 (0.03) þ
0.8 Yes Yes
1y7m 76 (2.63)
M 40 49 (0.99) 2,925 (1.57) 34 (0.5)
0.67 Yes Yes
(5.2)b (3.6)b
34 (1.7)b (3.1)b (2.5)b
3.86 Yes Yes
15 y 158 (1.35) 48 (0.94)
?
M 38 46 (1.59) 2,600 (1.63)
Yes Yes
14 y 149 (1.77) 48 (0.28)
?
16 m 70 (3.95) 7.1 (3.5)
2,070 (2.82) Large ?
M 38
Chauvel et al. [1975] Christensen and Nielsen [1978]
M 38 43 (2.54) 1,750 (3.53)
mos t(18)
M
Nakabayashi et al. [2002]
inv(7)(p14p21)
del(18p)dn
þ Hypoglycemia, increased sweating
142/? þ Moderately delayed
?
4y 90.2 (2.96)
?
F 36 47.5 (0.28) 1,880 (1.96)
16.0 Yes
dup(7) (p11.2p13)dn Monk et al. [2000]
dup(17) (p13.1p13.1)dn Coutton et al. [2012]
Truncal obesity
Learning difficulties
n/n
50 (3.18)
Adult 150 (2.01)
del(17) (q24q24)dn Fuke et al. [2013]
þ þ Learning difficulties Delayed þ
46 (3.95)
6.3 y 98.1 (3.61) 13.3 (3.31)
2,270
2,360 (1.42) 31 (1.15) ? ?
F
dup(7) (p12.1p13)dn Joyce et al. [1999] (patient 2) 8.0 Yes
F 37
dup(7) (p12.1p13)mat Joyce et al. [1999] (patient 1) 8.0 Yes
del(17) (p13.3p13.3)dn Spengler et al. [2012]
Scoliosis, hyperactivity
del(17) (p13.3p13.3)dn Spengler et al. [2012]
Oligohydramnios, cafe au lait spots, inguinal hernia, hearing loss, ventricular septal defect
Normal
Delayed
Mildly delayed Delayed
50 (1.18)
7y5m 117 (1.1) 21.6 (0.52)
F 40 48 (1.07) 2,400 (2.51) 32 (1.19)
16.0 Yes
del(7) (q21q21.3)dn Courtens et al. [2005]
155/179 þ
Low 14.4 (10 y) (5.16) Low ?
M 35 39.5 (2.56) 1,825 (2.41) 29.2 (1.74)
Lacassie et al. [1999]
r(2)dn
t(1;17) (q31;q25)dn Midro et al. [1993]
inv ins(1) (q32.1q42.1)dn Van Haelst et al. [2002]
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birth length in cm (SD) Birth weight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD)
Reference
del(1) (q21q21)mat Spengler et al. [2012]
del(1) (q21q21)dn Spengler et al. [2012]
Chromosome aberration
TABLE I. Rare Chromosomal Aberrations With Clinical Features Reported as Silver–Russell Syndrome
(Continued)
12.2 y 127.8 (3.13) 29.4 (1.74)
M 42 48 (1.54) 2,600 (2.56) 36 (þ0.14) þ
Yes Yes
dup(21) (q22 q22)pat Eggermann et al. [2010a]
Buphthalmos, 11 ribs, t(7;15)pat
150/150 þ þ Severely delayed
52.5 (2.77) þ
28 y 127 (6.77) 20 (7.39)
M 39 44 (2.48) 2,300 (2.69) 29 (2.74)
dup(7)(q34qter)/ del(15)(q26.3-qter) Kato et al. [2001]
FOKSTUEN AND KOTZOT 1597
48 (1.69)b
53.2 (þ0.52)
þ Scoliosis, hip dislocation, VSD
þ
þ Mother þ sister also dup(22) (q13.1)
þ þ Normal
F 40 46 (1.68) 2,510 (2.26) 32 (1.19)
dup(22) (q13.1q13.1)mat Spengler et al. [2012] 1.0 Yes Yes
þ Bicuspid aortic valve, horse-shoe kidney
þ Normal
n/n
?
16.8 y 140.9 (4.41) 36 (3.94)
?
M 38 43 (2.54) 2,000 (2.97)
dup(X) (p22.33p22.33)dn Bruce et al. [2010] 2.7 Yes Yes
þ Normal
þ
del(17) (p13.3p13.3)dn 48 (0.57)
þ þ
?
3y 83 (3.16) 50 (þ0.79)
?
F
dup(X) (q25q27) Spengler et al. [2012] 9.2 Yes Yes
þ Normal
þ
del(17) (p13.3p13.3)dn 48 (þ0.04)
TABLE I. (Continued )
þ
þ
þ
þ
Feeding difficulties
þ Moderately delayed
Maternal uniparental isodisomy in amniocentesis
þ þ Moderately delayed
34 y 120.5 (6.52) 37.5 (3.16) 51.2 (2.35) þ
F 40 44 (2.29) 2,100 (3.2) 30.5 (1.92)
þ Moderately delayed Delayed þ Cafe au lait spots
þ Hypospadia, left hip dislocation
þ þ Normal
50 (0.54) þ
4y 83 (4.85)
?
M 40 42 (3.06) 1,750 (4.18)
Tulinius et al. [1972]
Delayed þ Cafe au lait spots
þ þ
?
3y7m
Delayed þ
þ þ
?
1 y 10 m
?
1,750 (4.18)
1,950 (3.74) ?
M 40
Bianchi et al. [1983]
47,XXY
Hypospadia, hip dysplasia
Delayed
Normal
þ
dup(21) (q22 q22)pat 49 (3.47) 168/172
M 40
Severi et al. [1974]
47,XXY
Delayed
þ þ IQ ¼ 40
þ
46.5 (0.67)
Normal þ
mos t(18)
del(18p)dn
45,X/46,XY
dup(17) (p13.1p13.1)dn 53 (1.47)
Yamazawa et al. [2010]
45,X/46,XX
del(17) (q24q24)dn (1.7)b
b
a
Relative macrocephaly (D 1.5 SD). Del, deletion; dn, de novo; dup, duplication; F, female; ins, insertion; inv, inverted; IQ, intelligence quotient; M, male; m, month; Mb, megabases; m/f, mother/father; n, normal; r, ring chromosome; SD, standard deviation; OFC, occipitofrontal head circumference; UPD, uniparental disomy; y, year; ?, not known; þ, present; , absent; SD taken from the original publications.
Bone age Clinodactyly Other findings
þ þ Motor delay
þ þ No Normal
92 (2.96)b
7 y 10 m 120 (1.14)
12.4 y 134.7 (2.74) 28.5 (2.31) 2 SD n/n
?
M 40 49 (0.99) 3,130 (1.12) 36 (þ0.44) þ
F 36 41 (2.32) 1,930 (1.85)
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at cbirtha Age at last evaluation Height in cm (SD) Weight in kg (SD) OFC in cm (SD) Relative macrocephaly at the last evaluationa Parental height in cm (m/f) Triangular face Body asymmetry Psychomotor developpment
Reference
del(22) (q11.2q11.2)dn Spengler et al. [2012] 2.5 Yes Yes
Scoliosis
Delayed
þ þ Mildly delayed
t(1;17) (q31;q25)dn 49 (2.43)
del(22) (q11.2q11.2)dn Bruce et al. [2010] 0.45 Yes Yes
t(17;20)pat
Delayed
þ IQ ¼ 88
t(17;20) (q25;q13) 49.5 (1.89) 154/160 þ
Chromosome aberration
þ Cleft palate, feeding difficulties
Motor delay
þ
þ
mos mat UPD11 P 75b
Normal
þ IQ ¼ 80
del(8) q11q13)dn 46.8 (4.14) 186/170
Bone age Clinodactyly Other findings
Chromosome aberration OFC in cm (SD) Parental height in cm (m/f) Relative macrocephaly at the last evaluationa Triangular face Body asymmetry Psychomotor development
1598 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Mat UPD7 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD) OFC in cm (SD) Relative macrocephaly at the last evaluationa
2,040
43 2,495
?
? 31 y 125 (5.83) 45 (1.66) 50.5 (2.83) þ
F
? 24 y 132 (4.76) 37 (3.26)
Mother BeckwithWiedemann syndrome (dup11p15)
Muscular hypotonia
þ
?
F 34 37 (2.29) 1,185 (2.57) 39 (þ2.89) þ 2y (
Chromosomal Rearrangements in Patients With Clinical Features of Silver–Russell Syndrome Siv Fokstuen,1 and Dieter Kotzot2* 1
Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
2
Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria Manuscript Received: 21 August 2013; Manuscript Accepted: 21 October 2013
Silver–Russell syndrome (SRS) is characterized by pre- and postnatal growth retardation, relative macrocephaly, asymmetry, and a triangular facial gestalt. In 5–10% of the patients the phenotype is caused by maternal UPD 7, and 38–64% of the patients present with hypomethylation at the imprinting center region 1 (ICR1) on 11p15.5. The etiology of the remaining cases is so far not known and various (sub-)microscopic chromosome aberrations with a phenotype resembling SRS have been published, especially duplication 11p15 (n ¼ 15), deletion 12q14 (n ¼ 19), ring chromosome 15, deletion 15qter, and various other mostly unique chromosomal aberrations (n ¼ 30). In this study the phenotypes of these chromosomal aberrations were revisited and compared with the phenotypes of maternal UPD 7 and hypomethylation at ICR1 on 11p15.5. In some patients with a unique chromosomal aberration even the hallmarks of SRS were missing. Patients with duplication 11p15 show a more variable occipitofrontal head circumference at birth, a higher frequency of intellectual disability, and additional anomalies not reported in SRS. Deletion 12q14 is characterized by less severe pre- and postnatal growth retardation and less impressive relative macrocephaly. Patients with ring chromosome 15 and deletion 15qter have no relative macrocephaly (mostly even microcephaly) and more severe intellectual disability. Finally, deletion 15qter lacks the triangular facial gestalt. In summary, as SRS seems not an adequate diagnosis in many of these patients, diagnosis should focus on the chromosomal aberration than on SRS. Ó 2014 Wiley Periodicals, Inc.
Key words: chromosomal rearrangement; deletion; duplication; Silver–Russell syndrome
INTRODUCTION More than 60 years ago, Silver et al. [1953] described a 51/2-year-old girl and a 6-year-old boy with “Congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins.” Both children did not have the triangular facial gestalt (later on noted as typical) and only the boy showed a relative macrocephaly. Development was normal in both of them. One year later, Russell [1954] reported on two girls and three boys with a “Syndrome of intrauterine dwarfism
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Fokstuen S, Kotzot D. 2014. Chromosomal rearrangements in patients with clinical features of Silver–Russell syndrome. Am J Med Genet Part A 164A:1595–1605.
recognizable at birth with cranio-facial dysostosis, disproportionately short arms, and other anomalies (5 examples).” All had relative macrocephaly and normal intelligence. Two showed in addition “hemiatrophy.” Later on, it was assumed that both reports describe the same genetic disorder and the eponyms Russell–Silver syndrome and Silver–Russell syndrome (SRS) were applied. Meanwhile, several hundred patients were reported and the list of associated features became longer and longer (Winter-Baraitser Dysmorphology Database, version 1.0.30). The etiology of SRS remained unknown until the report of maternal uniparental disomy (UPD) 7 in approximately 10% of the patients [Kotzot et al., 1995]. Ten years later, hypomethylation of the imprinting center region 1 (ICR1) at the IGF2/H19 locus on 11p15 was shown in around 40% of the patients [Gicquel et al., 2005]. In addition, many patients with various microscopic and submicroscopic chromosome aberrations and the diagnosis of SRS or a phenotype resembling SRS were published. However, screening for genes located in some of the rearranged chromosomal segments were disappointing and no additional gene or genetic mechanism was identified so far. In this article, the phenotypes of patients reported with a chromosomal aberration and the diagnosis of SRS or a phenotype resembling SRS are critically reviewed and compared with the phenotypes of patients with maternal UPD 7 and hypomethylation of ICR1 at 11p15.
Correspondence to: Dieter Kotzot, Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schoepfstr. 41 A-6020 Innsbruck, Austria. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 24 March 2014 DOI 10.1002/ajmg.a.36464
1595
1596
METHODS A PubMed search up to July 2013 with the terms “Silver–Russell syndrome” and either “chromosome aberration,” “deletion,” or “duplication” was performed and all articles were read and critically evaluated concerning the clinical and genetic data. In addition, all references of the reports were assessed to identify additional cases. As most recently several excellent reviews on submicroscopic chromosomal rearrangements within the ICR region on 11p15.5 were published [Demars et al., 2011; Begemann et al., 2012], only duplications at 11p15 larger than 1 Mb and being of maternal origin were included. Facial dysmorphism were either adopted from the clinical reports or evaluated from published photographs. As patients were originating from all over the world, populationrelated growth charts were not available for most of them. To overcome this problem the measurements for length/height, weight, and occipitofrontal head circumference (OFC) were converted to standard deviations (SD) of the Canadian Pediatric Endocrine Group (CPEG) 2012 growth charts. This procedure explains the differences to some SDs reported in the original publications. Generally, as it is a retrospective study, which compares patients from the literature it was unfortunately not possible to get all relevant and interesting data from all patients. The clinical data concerning maternal UPD 7 and hypomethylation at 11p15 were taken from [Kotzot, 2008], concerning ring chromosome 15 and terminal deletion of 15q from the ECARUCA database [http:// umcecaruca01.extern.umcn.nl:8080/ecaruca/ecaruca.jsp].
RESULTS Apart from patients with duplication 11p15 (n ¼ 15), microdeletion 12q14 (n ¼ 19), ring chromosome 15, and deletion 15qter, at least 30 patients with various other chromosomal rearrangements (10 deletions, 9 duplications, and 11 other aberrations) have been reported (Tables I –III). Two patients from the group with various chromosomal rearrangements carry a balanced translocation (one paternally inherited 17;20 translocation and one de novo 1;17 translocation) [Ramı´rez-Duen˜as et al., 1992; Midro et al., 1993]. In six patients with duplication 11p15, additional most likely clinically relevant imbalances were described [Fisher et al., 2002; Eggermann et al., 2005; South et al., 2008; Bliek et al., 2009; Hu et al., 2013]. Furthermore, there is one familial case of duplication 11p15 with five affected members [Bonaldi et al., 2011]. All 15 patients (5 male and 10 female) with maternal duplications of 11p15 include the ICR1 locus at 11p15.5 (Table II). Size of the duplication is variable (1.2–10.3 Mb). Almost all patients show preand postnatal growth retardation as well as relative macrocephaly. Maternal UPD 7 was excluded in only five patients. At least 19 patients (9 male and 10 female) with submicroscopic deletions in 12q14 have been reported resembling clinically SRS (Table III). Size of the deletion (110 kb–10.1 Mb) is also variable. Bone age was evaluated in six patients only and four of them showed retarded bone age. Maternal UPD 7 and hypomethylation of ICR1 at 11p15 were excluded in only one patient. According to the data from the ECARUCA database, patients with ring chromosome 15 show no relative macrocephaly (mostly even microcephaly), and on average more often severe intellectual
AMERICAN JOURNAL OF MEDICAL GENETICS PART A disability, than patients with maternal UPD7 or hypomethylation of ICR1 at 11p15 (Table IV). Depending on the size of the deletion the same comes true for terminal deletions of 15q. In most of the 30 patients with unique chromosomal aberrations clinical evaluation is incomplete. Even length/height, weight, and OFC at birth and at the last clinical evaluation as well as bone age are not always reported (Table I).
DISCUSSION In about 50% of patients with a SRS phenotype, the etiology is not known and diagnosis remains purely clinical. There is however no general agreement about clinical criteria for the diagnosis of SRS syndrome. Some clinicians require pre- and postnatal growth retardation, relative macrocephaly, and facial dysmorphism (particularly the typical triangular face with a high and broad forehead and a pointed chin), while others make the diagnosis with less than these features. Lai et al. [1994] and later on Price et al. [1999], Netchine et al. [2007], and Bartholdi et al. [2009] attempted to define clinical criteria for SRS (Table V). The so-called Bartholdi score is the most complex one including all three birth parameters (weight 10th centile, length 10th centile, and OFC 1.5 SD higher than weight or length), postnatal course (height 3rd centile, OFC >3rd and 97th centile, and normal cognitive development), asymmetry (face, body, limbs), facial gestalt (triangular shaped face, high/bossing forehead, other), and other features (5th finger clinodactyly, genital abnormalities, others like brachymesophalangy, toes syndactyly, inguinal hernia, pigmentary changes) resulting in a maximum score of 15 points [Bartholdi et al., 2009]. Most recently, Dias et al. [2013] compared these four scoring systems and suggested to use birth weight below 2 SDs, postnatal short stature below 2 SDs at 2 years of age or older, relative macrocephaly (OFC 1.5 SDs than height SDs), and asymmetry. A diagnosis of SRS was made by three or more features being present. According to the criteria of all five scoring systems a diagnosis of SRS can theoretically be retained without postnatal growth retardation. In addition, all scoring systems require follow-up, which is not always possible. Finally, none of these scoring systems included retarded bone age, which is found in almost all patients with maternal UPD 7 [Kotzot, 2008]. Thus, the clinical diagnosis of SRS is not uniform. For this comprehensive review, the obligate criteria were reduced to pre- and postnatal growth retardation and relative macrocephaly. Patients fulfilling these criteria would most likely also have been diagnosed as SRS by all scores discussed above. Dysmorphism like a triangular face, asymmetry, or clinodactyly were only used to strengthen the clinical diagnosis. However, as already mentioned, even these minimal criteria were not always reported in the reviewed articles. In the 15 patients with mat dup 11p15 encompassing the SRS/ BWS region the trisomic segments mainly reflect the clinical consequences of hypomethylation at the ICR1 locus at 11p15.5. Compared with maternal UPD7 and isolated hypomethylation at 11p15.5, OFC values are more variable ranging from 1.9 to þ2.89 SD at birth and from 4.97 to þ0.19 SD at the last evaluation (Table IV). Particularly at birth the OFC SDs in patients with hypomethylation at 11p15 only are lower than in patients with
28 y 155 (2.94) 58 (1.3) 55.5 (0.82) þ
108.8 (4.06)b
49 (2.1)b þ 167/? No Delayed
7y8m 114 (2.07)
50 (1.67)
162/? þ Normal
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD)
Chromosome aberration Reference
Bone age Clinodactyly Other findings
OFC in cm (SD) Relative macrocephaly at the last evaluationa Parental height in cm (m/f) Triangular face Body asymmetry Psychomotor development
? 2.5 y (4.5)b P 0.4b
9.75 y 120 (2.7) 14.8 (4.7)
1,760 (2.77)
F 37
Yes
mos mat UPD11 Bullman et al., [2008]
F 36 35.5 (3.89) 1,100 (3.64) 26 (3.57)
del(8) q11q13)dn Schinzel et al. [1994]
þ Del (1)(q21q21)
?
?
þ Cafe au lait spots, attention deficit hyperactivity disorder
M 37 45 (2.5) 1,960 (1.65)
F 40 47 (1.38) 2,480 (2.33)
M 40 50 (0.69) 3,050 (1.3) 34 (0.5)
8y8m 97.5 (5.43) 11 (5.56)
F 40 43 (2.6) 2,100 (3.2) 35 (þ0.28) þ
t(17;20) (q25;q13) Ramı´rez-Duen˜as et al. [1992]
Feeding difficulties, scoliosis
Delayed
149/? þ þ Delayed
Yes
1.8 Yes Yes
1.65 Yes Yes
8y 116 (1.93) 18 (2.58)
M 40 49 (0.99) 2,550 (2.41) 30 (2.39)
2y1m 80 (2.56)
M 40 42 (3.06) 3,280 (0.79) 35 (0.03) þ
0.8 Yes Yes
1y7m 76 (2.63)
M 40 49 (0.99) 2,925 (1.57) 34 (0.5)
0.67 Yes Yes
(5.2)b (3.6)b
34 (1.7)b (3.1)b (2.5)b
3.86 Yes Yes
15 y 158 (1.35) 48 (0.94)
?
M 38 46 (1.59) 2,600 (1.63)
Yes Yes
14 y 149 (1.77) 48 (0.28)
?
16 m 70 (3.95) 7.1 (3.5)
2,070 (2.82) Large ?
M 38
Chauvel et al. [1975] Christensen and Nielsen [1978]
M 38 43 (2.54) 1,750 (3.53)
mos t(18)
M
Nakabayashi et al. [2002]
inv(7)(p14p21)
del(18p)dn
þ Hypoglycemia, increased sweating
142/? þ Moderately delayed
?
4y 90.2 (2.96)
?
F 36 47.5 (0.28) 1,880 (1.96)
16.0 Yes
dup(7) (p11.2p13)dn Monk et al. [2000]
dup(17) (p13.1p13.1)dn Coutton et al. [2012]
Truncal obesity
Learning difficulties
n/n
50 (3.18)
Adult 150 (2.01)
del(17) (q24q24)dn Fuke et al. [2013]
þ þ Learning difficulties Delayed þ
46 (3.95)
6.3 y 98.1 (3.61) 13.3 (3.31)
2,270
2,360 (1.42) 31 (1.15) ? ?
F
dup(7) (p12.1p13)dn Joyce et al. [1999] (patient 2) 8.0 Yes
F 37
dup(7) (p12.1p13)mat Joyce et al. [1999] (patient 1) 8.0 Yes
del(17) (p13.3p13.3)dn Spengler et al. [2012]
Scoliosis, hyperactivity
del(17) (p13.3p13.3)dn Spengler et al. [2012]
Oligohydramnios, cafe au lait spots, inguinal hernia, hearing loss, ventricular septal defect
Normal
Delayed
Mildly delayed Delayed
50 (1.18)
7y5m 117 (1.1) 21.6 (0.52)
F 40 48 (1.07) 2,400 (2.51) 32 (1.19)
16.0 Yes
del(7) (q21q21.3)dn Courtens et al. [2005]
155/179 þ
Low 14.4 (10 y) (5.16) Low ?
M 35 39.5 (2.56) 1,825 (2.41) 29.2 (1.74)
Lacassie et al. [1999]
r(2)dn
t(1;17) (q31;q25)dn Midro et al. [1993]
inv ins(1) (q32.1q42.1)dn Van Haelst et al. [2002]
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birth length in cm (SD) Birth weight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD)
Reference
del(1) (q21q21)mat Spengler et al. [2012]
del(1) (q21q21)dn Spengler et al. [2012]
Chromosome aberration
TABLE I. Rare Chromosomal Aberrations With Clinical Features Reported as Silver–Russell Syndrome
(Continued)
12.2 y 127.8 (3.13) 29.4 (1.74)
M 42 48 (1.54) 2,600 (2.56) 36 (þ0.14) þ
Yes Yes
dup(21) (q22 q22)pat Eggermann et al. [2010a]
Buphthalmos, 11 ribs, t(7;15)pat
150/150 þ þ Severely delayed
52.5 (2.77) þ
28 y 127 (6.77) 20 (7.39)
M 39 44 (2.48) 2,300 (2.69) 29 (2.74)
dup(7)(q34qter)/ del(15)(q26.3-qter) Kato et al. [2001]
FOKSTUEN AND KOTZOT 1597
48 (1.69)b
53.2 (þ0.52)
þ Scoliosis, hip dislocation, VSD
þ
þ Mother þ sister also dup(22) (q13.1)
þ þ Normal
F 40 46 (1.68) 2,510 (2.26) 32 (1.19)
dup(22) (q13.1q13.1)mat Spengler et al. [2012] 1.0 Yes Yes
þ Bicuspid aortic valve, horse-shoe kidney
þ Normal
n/n
?
16.8 y 140.9 (4.41) 36 (3.94)
?
M 38 43 (2.54) 2,000 (2.97)
dup(X) (p22.33p22.33)dn Bruce et al. [2010] 2.7 Yes Yes
þ Normal
þ
del(17) (p13.3p13.3)dn 48 (0.57)
þ þ
?
3y 83 (3.16) 50 (þ0.79)
?
F
dup(X) (q25q27) Spengler et al. [2012] 9.2 Yes Yes
þ Normal
þ
del(17) (p13.3p13.3)dn 48 (þ0.04)
TABLE I. (Continued )
þ
þ
þ
þ
Feeding difficulties
þ Moderately delayed
Maternal uniparental isodisomy in amniocentesis
þ þ Moderately delayed
34 y 120.5 (6.52) 37.5 (3.16) 51.2 (2.35) þ
F 40 44 (2.29) 2,100 (3.2) 30.5 (1.92)
þ Moderately delayed Delayed þ Cafe au lait spots
þ Hypospadia, left hip dislocation
þ þ Normal
50 (0.54) þ
4y 83 (4.85)
?
M 40 42 (3.06) 1,750 (4.18)
Tulinius et al. [1972]
Delayed þ Cafe au lait spots
þ þ
?
3y7m
Delayed þ
þ þ
?
1 y 10 m
?
1,750 (4.18)
1,950 (3.74) ?
M 40
Bianchi et al. [1983]
47,XXY
Hypospadia, hip dysplasia
Delayed
Normal
þ
dup(21) (q22 q22)pat 49 (3.47) 168/172
M 40
Severi et al. [1974]
47,XXY
Delayed
þ þ IQ ¼ 40
þ
46.5 (0.67)
Normal þ
mos t(18)
del(18p)dn
45,X/46,XY
dup(17) (p13.1p13.1)dn 53 (1.47)
Yamazawa et al. [2010]
45,X/46,XX
del(17) (q24q24)dn (1.7)b
b
a
Relative macrocephaly (D 1.5 SD). Del, deletion; dn, de novo; dup, duplication; F, female; ins, insertion; inv, inverted; IQ, intelligence quotient; M, male; m, month; Mb, megabases; m/f, mother/father; n, normal; r, ring chromosome; SD, standard deviation; OFC, occipitofrontal head circumference; UPD, uniparental disomy; y, year; ?, not known; þ, present; , absent; SD taken from the original publications.
Bone age Clinodactyly Other findings
þ þ Motor delay
þ þ No Normal
92 (2.96)b
7 y 10 m 120 (1.14)
12.4 y 134.7 (2.74) 28.5 (2.31) 2 SD n/n
?
M 40 49 (0.99) 3,130 (1.12) 36 (þ0.44) þ
F 36 41 (2.32) 1,930 (1.85)
Size of the aberration in Mb Mat UPD7 excluded Hypomethylation 11p15 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at cbirtha Age at last evaluation Height in cm (SD) Weight in kg (SD) OFC in cm (SD) Relative macrocephaly at the last evaluationa Parental height in cm (m/f) Triangular face Body asymmetry Psychomotor developpment
Reference
del(22) (q11.2q11.2)dn Spengler et al. [2012] 2.5 Yes Yes
Scoliosis
Delayed
þ þ Mildly delayed
t(1;17) (q31;q25)dn 49 (2.43)
del(22) (q11.2q11.2)dn Bruce et al. [2010] 0.45 Yes Yes
t(17;20)pat
Delayed
þ IQ ¼ 88
t(17;20) (q25;q13) 49.5 (1.89) 154/160 þ
Chromosome aberration
þ Cleft palate, feeding difficulties
Motor delay
þ
þ
mos mat UPD11 P 75b
Normal
þ IQ ¼ 80
del(8) q11q13)dn 46.8 (4.14) 186/170
Bone age Clinodactyly Other findings
Chromosome aberration OFC in cm (SD) Parental height in cm (m/f) Relative macrocephaly at the last evaluationa Triangular face Body asymmetry Psychomotor development
1598 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Mat UPD7 excluded Sex Week of gestation at birth Birthlength in cm (SD) Birthweight in g (SD) Birth-OFC in cm (SD) Relative macrocephaly at birtha Age at last evaluation Height in cm (SD) Weight in kg (SD) OFC in cm (SD) Relative macrocephaly at the last evaluationa
2,040
43 2,495
?
? 31 y 125 (5.83) 45 (1.66) 50.5 (2.83) þ
F
? 24 y 132 (4.76) 37 (3.26)
Mother BeckwithWiedemann syndrome (dup11p15)
Muscular hypotonia
þ
?
F 34 37 (2.29) 1,185 (2.57) 39 (þ2.89) þ 2y (
