SEARCH

SEARCH BY CITATION

Keywords:

  • trisomy 15q;
  • tetrasomy 15q;
  • overgrowth;
  • renal anomalies

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Trisomy and tetrasomy of distal chromosome 15q have rarely been reported. Although most of the described patients have some learning difficulties and are overgrown, the phenotype associated with distal trisomy/tetrasomy 15q is uncertain due to the small numbers of reported cases and the common co-occurrence of additional chromosome deletions in many patients with trisomy 15q. We present five individuals with overgrowth, learning difficulties and increased dosage of distal 15q. Partial trisomy 15q was identified in four of these cases. Two were generated through recombination of a parental pericentric inversion and two were generated through malsegregation of a maternal balanced 14;15 reciprocal translocation. In all four cases the trisomy can be considered “pure” as the 14p and 15p monosomies will exert no phenotypic effect. Partial tetrasomy 15q, as the result of an analphoid supernumerary chromosome derived from an inverted duplication of distal 15q, was identified in the fifth patient. In addition to the overgrowth and learning difficulties, all five had a characteristic facial appearance and three had renal anomalies. The gestalt consists of a long, thin face with a prominent chin and nose. Renal anomalies included renal agenesis, horseshoe kidney, and hydronephrosis. We provide further support for a distinct “15q overgrowth syndrome” caused by either trisomy or tetrasomy resulting in increased dosage of distal 15q. In addition we propose that renal anomalies and a distinctive facial appearance be considered major features of this condition. © 2009 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Trisomy or tetrasomy for distal chromosome 15q has previously been reported [Pedersen, 1976; Van Allen et al., 1992; Blennow et al., 1994; Van den Enden et al., 1996; Zollino et al., 1999; Rowe et al., 2000; Faivre et al., 2002; Hu et al., 2002; Nagai et al., 2002; Okubo et al., 2003; Spiegel et al., 2003; Chen et al., 2004; Bonati et al., 2005; Huang et al., 2005; Mahjoubi et al., 2005; Kant et al., 2007]. Trisomy of distal 15q has been described in 14 individuals with duplicated regions ranging from 15q23.1-qter to 15q26.1-qter. In most cases the trisomy 15q has arisen from a parental balanced reciprocal translocation and therefore is associated with monosomy of another chromosome region. To date deletions of 2q, 12p, 13q, and 20p have all been described in association with trisomy 15q [Pedersen, 1976; Van Allen et al., 1992; Zollino et al., 1999; Faivre et al., 2002; Nagai et al., 2002; Kant et al., 2007]. Based upon the observation that most individuals with trisomy 15q are overgrown and have learning difficulties, some authors have suggested that a distinct syndrome is associated with this terminal duplication. However, in those cases where an unbalanced reciprocal translocation is identified, it is unclear which components of the phenotype are attributable to trisomy 15q and which to the monosomic chromosome region.

Only nine cases with tetrasomy of 15q have been described [Blennow et al., 1994; Van den Enden et al., 1996; Rowe et al., 2000; Hu et al., 2002; Spiegel et al., 2003; Chen et al., 2004; Huang et al., 2005; Mahjoubi et al., 2005]. In each the tetrasomy is the result of an analphoid supernumerary marker chromosome (SMC). An analphoid SMC is generated when an acentric inverted duplication is rescued through epigenetic modification and the creation of a neocentromere, thereby conferring mitotic stability. Triplicated regions vary in size and range from 15q23-qter to 15q26-qter and in all, except one reported case, the SMC has been identified in a mosaic distribution. Where clinical features are reported, overgrowth and learning difficulties are universal findings [Blennow et al., 1994; Rowe et al., 2000; Hu et al., 2002; Huang et al., 2005].

In this communication we describe three families with increased dosage of distal 15q. Affected members of families A and B had distal 15q trisomy, overgrowth and learning difficulties. The 15q trisomy in both families A and B can be considered “pure.” In family A the 15q trisomy had arisen from a parental inversion, whereas in family B it had arisen from a balanced 14;15 reciprocal translocation. Tetrasomy for 15q was identified in the third family where the affected individual had overgrowth and learning difficulties. All patients with increased dosage of 15q, whether through trisomy or tetrasomy of 15q, had a similar and distinctive facial appearance and three had renal anomalies.

CLINICAL REPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Family A

Patient A-III2 (Fig. 1a) is the second child of healthy unrelated parents. Karyotypes had previously been performed on both parents of patient A-III2 during infertility investigations and a paternal chromosome 15 pericentric inversion with breakpoints at 15q12 and 15q26.1 had been identified. Chorionic villus sampling in the pregnancy had shown a normal male karyotype with conventional analysis and later a right hydronephrosis had been identified on fetal ultrasound scanning.

thumbnail image

Figure 1. Family pedigrees. Shaded squares or circles indicate affected individuals, central dot within circle or square indicates balanced translocation or inversion carrier.

Download figure to PowerPoint

Patient A-III2 was born at term weighing 4,170 g [91st centile, UK90 charts Wright et al., 2002]. During the neonatal period, he was sleepy, a poor feeder and mildly jaundiced although he did not require treatment for the latter. Post-natal ultrasound scanning demonstrated a right renal agensis.

He was first referred to the child development team at age 10 months with concerns that he was delayed. He was noted to be passive and not responding appropriately to auditory and visual stimuli. His head circumference was described as large but measurements were not recorded.

He was evaluated by clinical genetics at 18 months of age. He was moderately delayed in all developmental milestones and his asymptomatic right renal agenesis was noted. His head circumference was 53.5 cm (>99.6th centile). He was mildly dysmorphic with frontal bossing, a high hairline and prominent chin (Fig. 2a). His fingers were tapering and he had overlapping toes on his right foot.

thumbnail image

Figure 2. The facial gestalt associated with increased dosage of 15q with dolicocephaly, high anterior hairline and prominent chin and nose.

Download figure to PowerPoint

The growth and development of Patient A-III2 continued to be monitored by both the clinical geneticists and developmental pediatricians over the next 18 months. All growth parameters were consistently greater than the 99.6th centile and he was moderately delayed in his speech and motor development during the next 18 months.

The parents of Patient A-III2 had normal intelligence and paternal height was between the 50th and 75th centile and maternal height was on the 50th centile. The paternal aunt of Patient A-III2 (A-II3, Fig. 1a) also had learning difficulties, tall stature (180 cm, >99.6th centile) and a horseshoe kidney. She had some dysmorphic features including downslanting palpebral fissures, broad nasal bridge and large chin (Fig. 2b).

Family B

The two affected patients in family B are siblings (Patients B-II2 and B-II6, Fig. 1b). Patient B-II2 was 38 years old at the time of her initial assessment in clinical genetics. She was born in good condition after an uneventful pregnancy weighing 3,400 g (50th centile). She was noted to have natal teeth and talipes equinovarus. In infancy she had a right unilateral strabismus, which was surgically corrected. Her speech was significantly delayed. She had poor eye contact, communication problems, learning difficulties and compulsive behavioral traits. In adulthood she was living independently with some support and working as a clerical assistant. She had a normal renal ultrasound scan.

Her height was 178.5 cm (98th–99.6th centile) and head circumference was 56 cm (50th–75th centile). She had a long prominent nose, tall chin, fifth finger clinodactyly and overlapping 1st and 2nd toes (Fig. 2c).

The brother of Patient B-II2 (Patient B-II6) was initially assessed at age 33 years. He was born at term after an uneventful pregnancy and weighed 3,710 g (50th–75th centile). He had some respiratory problems after birth and spent 10 days on a neonatal unit. In childhood he had mild speech and language delay and later developed a stammer. He also developed mild asthma. He had learning difficulties and left school at the age of 16 years. There was no history of behavioral problems and he had always been very sociable. A renal ultrasound was normal. On examination he was tall and slim with a height of 187.4 cm (91st–98th centile) and a head circumference of 59 cm (75th–91st centile). He was dolicocephalic and facially very similar to his sister with a prominent nose and chin (Fig. 2d). Unfortunately parental heights were not available but the parents were noted to be considerably shorter than Patients B-II2 and B-II6.

Family C

Patient C-II3 is a male, the third child of healthy unrelated parents (Fig. 1c). The pregnancy was normal but prenatal ultrasound scans demonstrated bilateral hydronephrosis. He was delivered at 37 weeks gestation by elective caesarean for macrocephaly. At birth all growth parameters were greater than the 99.6th centile (his weight was 4,750 g, length was 60 cm and head circumference was 41.7 cm). A postnatal renal ultrasound scan confirmed the hydronephrosis.

He was referred to clinical genetics at 6½ years of age with overgrowth, delayed psychomotor development and indistinct speech. His height was 140 cm (>99.6th centile), weight was 22 kg (50th centile) and head circumference was 55 cm (75th–91st centile). He was noted to be dysmorphic with a long, thin face, a tall, pointed chin, downslanting palpebral fissures and a broad nasal bridge (Fig. 2e). Bone age was 9 years at chronological age of 6½ years.

There was no family history of learning difficulties. The father's height was between the 75th and 91st centile and mother's height was on the 98th centile.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Laboratory Investigations

Cytogenetic analysis of peripheral lymphocytes was performed on all probands according to standard protocols. In addition, DNA from Patient A-III2 was analyzed using Multiplex Ligation-dependent Probe Amplification (MLPA) with the SALSA P069 and P036 subtelomere kits according to the MRC Holland protocol [Schouten et al., 2002]. Dual color fluorescence in situ hybridization (FISH) was undertaken in Family A using standard methods with bacterial artificial chromosomes (BACs) selected from the Ensembl tiling path cytoview as well as the 15q subtelomere [National Institutes of Health and Institute of Molecular Medicine Collaboration, 1996]. The size of the duplication and breakpoints were delineated using oligonucleotide array comparative genomic hybridization (oaCGH) with test and normal human male reference DNA using a customized 4 × 44 K array (NGRL WESSEX CONSTITUTIONAL ARRAY CGH V1 design # 015543, Agilent Technologies, Inc., Santa Clara, CA) as previously described [Barber et al., 2008].

In Family B, FISH for subtelomeric rearrangements, was undertaken in Patient B-II2 using the Vysis ToTelVysion kit. A custom designed oligonucleotide microarray [Baldwin et al., 2008] was used to delineate size and breakpoints.

Array-CGH using the BlueGnome CytoChip was undertaken in Family C. Subsequently FISH was undertaken with Vysis15q telomeric and 15 alpha-satellite centromeric probes.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Conventional cytogenetic analysis of pre- and post-natal demonstrated a grossly normal male karyotype, 46,XY, in Patient A-III2. Subsequent MLPA indicated trisomy of chromosome 15q and FISH showed additional 15q subtelomeric signals distal to the 15p12 satellite stalks. Trisomy of the IGFR1 gene was confirmed using the contiguous RP11 BACs 379D8 and 279M20 which span the gene. OaCGH showed that the duplication was a minimum of 15.56 Mb in size between oligo A_14_P107730 at 84,610,650 base pairs in 15q25.3 and oligo A_14_P127599 at 100,168,659 base pairs which is the closest oligo to the 15q telomere (Fig. 3). The proximal breakpoint was within the 6.8 kb between base pairs 84,603,831 (oligo A_14_P202117) and 84,610,650 (oligo A_14_P107730) and interrupts the ATP/GTP binding protein-like 1 gene (AGBL1). However, a normal copy of this gene would remain and this member of the cytosolic carboxypeptidase protein family has no known pathological associations.

thumbnail image

Figure 3. FISH and array-CGH results for chromosome 15 from Family A with a 15.56 Mb duplication (A), Family B with a 14.56 Mb duplication (B) and Family C with a 11.6 Mb triplication (C). The x-axis is showing the log2 ratios. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Download figure to PowerPoint

This cryptic recombinant chromosome 15 had been derived from a balanced paternal inversion. FISH on Patient A-III2's paternal aunt, Patient A-II3, was consistent with the same partial 15q trisomy and oaCGH confirmed a duplication of the same size. No further imbalances of known clinical significance were detected in either the proband or his aunt and the karyotype of the proband was: 46,XY.ish rec(15)dup(15q)inv(15)(qter [RIGHTWARDS ARROW] q25.3::p12 [RIGHTWARDS ARROW] qter)(154P1+,RP11-379D8+,RP11-279M20+,pTRA25+,RP11-279M20+,RP11-379D8+,154P1+)pat.arr cgh rec(15)(B35:CHR15:84610650 [RIGHTWARDS ARROW] 100168659) × 3.

Cytogenetic analysis of peripheral lymphocytes from Patient B-II2 (Family B) demonstrated a normal karyotype, 46,XX. However, a variant of the short arm of chromosome 14 was noted. Subsequent subtelomeric FISH studies showed an abnormal hybridization pattern with three signals for the 15q subtelomeric probe: one signal on each of the normal chromosome 15 homologues and an additional signal was observed on the short arm of one chromosome 14 homologue. Patient B-II6 had the same unbalanced translocation as his sister, and array-CGH and confirmatory FISH analyses were used to determine the size of the duplication, which was found to be approximately 14.56 Mb. The proximal breakpoint on 15q of the duplication was between base pair position 85,563,464 (oligo A_16_P03078311, normal result on array; build 35 hg17 on UCSC genome browser) and 85,645,087 (oligo A_16_P20336705, duplicated on array, Fig. 3). The duplication extended to the end of the chromosome and included the IGF1R gene. Analysis of parental chromosomes demonstrated a maternal balanced reciprocal translocation between chromosomes 14 and 15 with breakpoints at p11.2 and q26.1 respectively. The karyotype of the offspring was therefore reported as, 46,XX or XY,der(14)t(14;15)(p11.2;q25.3)mat.ish der(14)(15qtel+).arr cgh der(14)(B35:CHR15:85645087 [RIGHTWARDS ARROW] 100200997) × 3.

Cytogenetic analysis in Patient C-II3 demonstrated an abnormal male karyotype with an unidentified supernumerary marker chromosome, 47,XY,+mar[5]/46,XY[5] in 5 of 10 metaphases. Increased dosage of chromosome 15q was demonstrated with array-CGH and subsequent FISH analysis with 15q telomeric and chromosome 15 α-satellite centromeric probes identified an analphoid supernumerary marker chromosome consisting of an inverted duplication of the distal long arm of chromosome 15. The size of the triplicated region was estimated at 11.6 Mb with a proximal breakpoint located between base pair position 83,685,716 and 83,883,618 (build 35 hg17 on UCSC genome browser, Fig. 3). This breakpoint interrupts the A-kinase anchor protein 13 gene (AKAP13; OMIM 604686) which is a member of a family of genes that regulate the Rho/Rac GTPase cycle. However, two normal copies of this gene would remain and this gene has not been associated with congenital abnormalities to date. The karyotype was revised to 47,XY,+mar[5].ish inv dup(15)(qter [RIGHTWARDS ARROW] q25.3 [RIGHTWARDS ARROW] neo [RIGHTWARDS ARROW] q25.3 [RIGHTWARDS ARROW] qter)/46,XY[5].arr cgh 15q25.3q26.3 (RP11-535P8 [RIGHTWARDS ARROW] qter) × 4. Both parents had a normal karyotype.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

Over 20 patients with increased dosage of distal chromosome 15q, due either to trisomy or tetrasomy 15q, are reported in the literature (Table I). In most cases the trisomy 15q has arisen from a parental balanced reciprocal translocation and so duplication of 15q is associated with deletion of another chromosome region. It is therefore unclear which clinical features are attributable to the trisomy and which to the monosomy. Only three patients have previously been reported with a “pure” trisomy 15q. Although it is likely that the clinical features in this group are due to the increased dosage of terminal 15q, the normal sequence of genes will be altered because of the chromosomal rearrangement. Some genes will therefore have new neighboring genes which may effect their expression and have some influence on the phenotype [Van Karnebeek et al., 2002].

Table I. Summary of the Clinical Phenotype of the Current 15q Trisomy/Tetrasomy Cases and Those Reported in the Literature
 ReferenceTrisomic/tetrasomic componentMonosomic componentSexGrowth parametersaRenalGestaltLearning diffsOther
HtWtOFC
  • +, feature present; −, feature absent; nk, not known; na, not applicable; M, male; F, female; SMC, analphoid supernumerary marker chromosome; LD, learning difficulties; VUR, vesico-ureteric reflux; PDA, patent ductus arteriosus; AS, aortic stenosis; SNHL, sensori-neural hearing loss; PCK, polycystic kidney.

  • a

    ≥Centile using UK90 charts, Wright et al. 2002.

  • b

    Fetus terminated.

Trisomy 15q casesCurrent study, case A-III215q26.1-qter15p12-pterM99.699.699.6Single L kidney+ModNystagmus
 Current study, case A-II315q26.1-qter15p12-pterF99.6nk75Horseshoe kidney+Mild 
 Current study, case B-II215q26-qter14p11.2-pterF98nk50+Mild-modStrabismus, compulsive behaviour
 Current study, case B-II615q26-qter14p11.2-pterM91nk75+Mild 
 Kant et al., patient A15q26.1-qterNoneF99.69150nk+Mild-ModHypotonia
 Kant et al., patient B15q22.3-qter2q37.1-qterF99.69898Hydronephrosis, VUR+Mod-severe 
 Bonati et al.15q25.2-qterNoneM989198nknkSevereAutism, strabismus, seizures
 Okubo et al.15q25-qterNoneM99.691nknk+Mod 
 Faivre et al., case V415q26.1-qter20p13-pterF507599.6+Mild 
 Faivre et al., case V115q26.1-qter20p13-pterF987599.6+Mild 
 Faivre et al., case III-115q26.1-qter13q34-qterF99.699.699.6+Mild 
 Faivre et al., case III-215q26.1-qter13q34-qterF99.699.699.6+MildPDA, coloboma
 Nagai et al., case III-315q26.1-qter13q34-qterM99.65050nk+SevereHypospadius, craniosynostosis
 Nagai et al., case III-515q26.1-qter13q34-qterF509<0.4nk+NoneCraniosynostosis
 Zollino et al., case IV-415q25.1-qter13q34-qterF980.475R pelvic duplication+MildScoliosis, craniosynostosis
 Zollino et al., case III-315q25.1-qter13q34-qterM50275nk+SevereScoliosis, AS
 Van Allen et al.15q26-qter2q37-qterM5029Horseshoe kidney+nkSNHL, craniosynostosis
 Pedersen et al.15q25-qter12p13-qterMnknknknkSevereCraniosynostosis
Tetrasomy 15q casesCurrent study, case C-II315q25.3-qterMosaic, SMCM99.65075Hydronephrosis+Mild 
 Huang et al.15q25-qterSMCM99.67575+MildStrabismus, hydrocoele
 Mahjoubi et al.15q26.1-qterMosaic, SMCnkbnknknknk+naAbnormal genitalia, corneal dystrophy
 Chen et al.15q25.3-qterMosaic, SMCMbnananaHorseshoe kidney+naPulmonary hypoplasia
 Spiegel et al.15q24-qterMosaic, SMCFbnananaHydronephrosis, L PCKnknaIUGR, complex cardiac defect
 Hu et al.15q25.3-qterMosaic, SMCF99.65050nk+SevereCraniosynostosis, bilat Wilms
 Rowe et al.15q25-qterMosaic, SMCF985050nk+Mod-severeHypomelanosis of Ito
 Van den Enden et al.15125-qterMosaic, SMCMnananaHydronephrosis+naASD, PDA
 Blennow et al., case A15q23-qterMosaic, SMCM99.6nknknk+Mod-severeKyphosis, SNHL, hydrocephalus
 Blennow et al., case B15q24-qterMosaic, SMCFnknknknk+ModScoliosis, SNHL

All three of the “pure” trisomy 15q cases previously reported were overgrown (defined as height at least two standard deviations above the mean) and all had learning difficulties [Table I, Okubo et al., 2003; Bonati et al., 2005; Kant et al., 2007]. The severity of the learning difficulties varied from mild to severe. Additional clinical features described in this “pure” group include hypotonia, autism and seizures.

Overgrowth was described in 60% (6/10) and learning difficulties, ranging from mild to severe, in 90% (9/10) of the mixed trisomy/monosomy cases in the literature. In addition cardiac anomalies (patent ductus arteriosus and aortic stenosis), ophthalmological abnormalities (coloboma and strabismus), hypotonia, scoliosis, sensori-neural hearing loss, craniosynostosis and renal anomalies have all been reported (Table I) [Pedersen, 1976; Van Allen et al., 1992; Zollino et al., 1999; Faivre et al., 2002; Nagai et al., 2002; Kant et al., 2007].

The facial gestalt is common to both the “pure” and “mixed” groups and is reminiscent of Sotos syndrome; indeed many of the reported cases had initially been referred for NSD1 analysis. The head is dolicocephalic and the chin prominent. The nose is long and there is a broad nasal bridge. The frontal hairline is high and there is some bi-temporal narrowing giving the impression of frontal bossing.

It has been suggested that the overgrowth and learning difficulties associated with trisomy 15q constitute a distinct phenotype [Faivre et al., 2002; Kant et al., 2007]. Through our presentation of four additional cases with trisomy 15q, all of whom effectively have a “pure” trisomy 15 as the associated monosomy 14p and 15p is unlikely to affect the phenotype, we provide further support for this “15q overgrowth syndrome”: 75% (3/4) of the currently reported cases are overgrown and 100% (4/4) have some degree of learning difficulties. In addition, all the current trisomy 15q cases had the characteristic facial appearance. Combining our data with that previously reported in the literature, 71% (12/17) of trisomy 15q cases (whether “mixed” or “pure”) are overgrown, 100% (17/17) have some degree of learning difficulties and 94% (16/17) have a characteristic facial appearance (Table I).

Tetrasomy 15q is rare and has previously been reported in nine cases. As with the trisomy 15q cases, a common phenotype has emerged consisting of overgrowth (100% (4/4) reported cases) and learning difficulties (100% (5/5) reported cases, Table I). Features that have been described in one or more cases include renal anomalies, kyphosis, joint contractures, sensori-neural hearing loss, ptosis, pulmonary hypoplasia, craniosynostosis and cardiac anomalies (Table I). The facial gestalt is similar to that of the trisomy 15q cases with a long, thin face, broad nasal bridge and prominent forehead (100% (8/8) reported cases, Table I).

Van den Enden et al. 1996 previously suggested that trisomy and tetrasomy 15q cases are phenotypically similar. Through the presentation of four cases with trisomy 15q and one case with tetrasomy 15q, all with learning difficulties, a similar facial appearance and 80% with overgrowth, we provide additional support for this assertion. In addition, we suggest that renal anomalies be considered a major feature of this “15q overgrowth syndrome.” Renal anomalies were identified in 3/5 of our reported cases; absence of the right kidney in A-III2, horseshoe kidney in A-II3, and hydronephrosis in C-II3. Combining our data with previously reported cases, renal anomalies were identified in 45% (5/11) of 15q trisomy cases and 80% (4/5) of 15q tetrasomy cases where renal investigations were performed. The described renal anomalies included three cases with horseshoe kidney, one with renal agenesis, two with hydronephrosis, one with vesico-ureteric reflux, one with polycystic kidney and one with right pelvic duplication (Table I). In 12 reported cases investigations for renal anomalies had not been performed.

Other diagnoses to consider in the assessment of the child with overgrowth and learning difficulties include Sotos syndrome, Weaver syndrome, Bannayan–Riley–Ruvalcaba syndrome and Simpson–Golabi–Behmel syndrome. It is usually possible to distinguish each of these conditions through thorough clinical evaluation, but ultimately genetic testing should enable differentiation (Table II). Perhaps the greatest facial similarity is evident between Sotos syndrome and the “15q overgrowth syndrome.” Indeed 3/5 of the cases reported here were diagnosed with Sotos syndrome prior to genetic assessment. We therefore suggest that the 15q overgrowth syndrome be considered in those cases with a clinical diagnosis of Sotos syndrome without an associated abnormality of NSD1 and that investigation of the 15q telomere be undertaken.

Table II. Summary of the Conditions Which Should Be Considered in the Differential Diagnosis of the 15q Overgrowth Syndrome
ConditionOMIM#Clinical featuresClinical overlap with the 15q overgrowth syndromeInheritance patternGene
Beckwith–Wiedemann syndrome130650Overgrowth, abdominal wall defects, macroglossia, ear lobe creases, helical pits, visceromegaly, hemihypertrophy, neonatal hypoglycemia, renal abnormalities and embryonal tumorsOvergrowth with macrocephalyImprinting conditionAbnormalities of 11p15 region
   Renal abnormalities  
Simpson–Golabi–Behmel syndrome312870Overgrowth, learning difficulties, supernumerary nipples, polydactyly and cardiac/gastrointestinal malformations. Coarse facial features with hypertelorism, downslanting palpebral fissures, epicanthic folds, short nose, macrostomia, macroglossia and central groove of the lower lip. Predisposition to development of Wilms tumorsOvergrowthX-linked recessiveGPC3
   Learning difficulties  
Sotos syndrome117550Overgrowth, learning difficulties, scoliosis, cardiac and renal anomalies and seizures. Facial gestalt consists of downslanting palpebral fissures, fronto-temporal hair sparsity, bi-temporal narrowing and prominent chinOvergrowthAutosomal dominantNSD1
   Learning difficulties  
   Renal anomalies  
   Facial gestalt is similar both in childhood and adulthood  
Weaver syndrome277590Overgrowth, learning disability, neonatal hypertonia and contractures. Metaphyseal flaring may be seen on radiograph. Facial gestalt consists of a broad forehead with macrocephaly, hypertelorism, “stuck-on” chin and horizontal chin creaseOvergrowthAutosomal dominantUnknown
   Learning difficulties  

Nearly 200 known genes are located in the 15q26.1-qter region (University of California at Santa Cruz genome browser). Many of these genes have not yet been characterized but, included amongst their number is IGF1R. Insulin-like growth factor receptor 1 (IGF1R) is an important component of the insulin-like growth factor axis. Other components of the axis include IGF2R, insulin-like growth factor ligands (IGF1 and IGF2) and insulin-like growth factor binding proteins (IGFBP1-6). The axis is critical to pre- and postnatal growth. Early in embryonic life, growth is predominantly regulated by IGF2 whereas later in embryonic and in postnatal life IGF1 is the primary ligand. Both IGF1 and IGF2 are ligands for IGF1R and their binding results in autophosphorylation of the intracellular tyrosine kinase domain and activation of the PI3K/mTOR pathway, a key pathway involved in cell growth and proliferation [Sarbassov et al., 2005]. IGF1R is not known to be imprinted but other growth pathway genes are. These include IGF2 on 11p and the IGF signaling modulator growth factor receptor bound protein 10 (GRB10) on 7p [Eggermann et al., 2008]. It is therefore interesting that we have found overgrowth in duplications of both paternal (Family A) and maternal (Family B) origin.

Increased dosage of IGF1R, through duplication or triplication of the 15q26.1-qter region, could therefore lead to overgrowth. Okubo et al. 2003 provided robust support for this when they demonstrated increased rate of cell proliferation and autophosphorylation of IGF1R in skin fibroblasts from an individual with duplication of IGF1R arising from a parental pericentric inversion.

Further support for a dosage effect of IGF1R is provided by several reports of children with monosomy for 15q26.1-qter who are prenatally growth retarded and do not exhibit catch up growth in childhood [Roback et al., 1991; Nagai et al., 2002; Okubo et al., 2003; Pinson et al., 2005; Poot et al., 2007]. In addition, these children often have learning difficulties and may have renal, lung, cardiac and limb malformations. It is interesting that children with a discrete IGF1R intragenic mutation have also been reported with isolated growth retardation but without the other associated features such as learning difficulties [Walenkamp et al., 2006; Inagaki et al., 2007]. It is likely that the overgrowth associated with increased dosage of distal chromosome 15q is due to IGF1R duplication/triplication, whereas the renal anomalies associated with duplication/triplication of this region may be due to other genes in the region. Although none of the principal genes implicated in renal development are located at the 15q telomere, it is possible that novel genes, either directly or through their interactions with other well-characterized genes, are responsible for the renal anomalies described in ours and previously reported 15q trisomy/tetrasomy cases.

In summary, we present five cases with increased dosage of distal 15q, overgrowth, learning difficulties and a characteristic facial appearance. In addition three of the five cases had renal anomalies. We therefore provide further evidence for a “15q overgrowth syndrome” and suggest that renal anomalies should be considered a newly recognized major component of the syndrome.

WEB RESOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES

The URLs for data presented herein are as follows:

University of Santa Cruz genome browser (http://genome.ucsc.edu/);

Ensembl tiling path cytoview (http://www.ensembl.org/homo_sapiens/cytoview).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORT
  5. MATERIALS AND METHODS
  6. RESULTS
  7. DISCUSSION
  8. WEB RESOURCES
  9. REFERENCES
  • Baldwin EL, Lee JY, Blake DM, Bunke BP, Alexander CR, Kogan AL, Ledbetter DH, Martin CL. 2008. Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med 10: 415429.
  • Barber JCK, Maloney VK, Huang S, Bunyan DJ, Cresswell L, Kinning E, Benson A, Cheetham T, Wyllie J, Lynch SA, Zwolinski S, Prescott L, Crow Y, Morgan R, Hobson E. 2008. 8p23.1 duplication syndrome; a novel genomic condition with unexpected complexity revealed by array CGH. Eur J Hum Genet 16: 1827.
  • Blennow E, Telenius H, de Vos D, Larsson C, Henriksson P, Johansson O, Carter NP, Nordenskjold M. 1994. Tetrasomy 15q: Two marker chromosomes with no detectable alpha-satellite DNA. Am J Hum Genet 54: 877883.
  • Bonati M, Finelli P, Giardino D, Gottardi G, Roberts W, Larizza L. 2005. Trisomy 15q25.2-qter in an Autistic child: Genotype-phenotype correlations. Am J Med Genet Part A 133A: 184188.
  • Chen CP, Lin CC, Li YC, Chern SR, Lee CC, Chen WL, Lee MS, Wang W, Tzen CY. 2004. Clinical, cytogenetic, and molecular analyses of prenatally diagnosed mosaic tetrasomy for distal chromosome 15q and review of the literature. Prenat Diagn 24: 767773.
  • Eggermann T, Eggermann K, Schönherr N. 2008. Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome. Trends Genet 24: 195204.
  • Faivre L, Gosset P, Cormier-Daire V, Odent S, Amiel J, Giurgea I, Nassogne MC, Pasquier L, Munnich A, Romana S, Prieur M, Vekemans M, De Blois MC, Turleau C. 2002. Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: Report of two families and review of the literature. Eur J Hum Genet 10: 699706.
  • Hu J, McPherson E, Surti U, Hasegawa SL, Gunawardena S, Gollin SM. 2002. Tetrasomy 15q25.3 [RIGHTWARDS ARROW] qter resulting from an analphoid supernumerary marker chromosome in a patient with multiple anomalies and bilateral Wilms tumors. Am J Med Genet 113: 8288.
  • Huang XL, de Michelena MI, Mark HF, Harston R, Benke PJ, Price SJ, Milunsky A. 2005. Characterization of an analphoid supernumerary marker chromosome derived from 15q25 [RIGHTWARDS ARROW] qter using high-resolution CGH and multiplex FISH analyses. Clin Genet 68: 513519.
  • Inagaki K, Tiulpakov A, Rubtsov P, Sverdlova P, Peterkova V, Yakar S, Terekhov S, LeRoith D. 2007. A familial insulin-like growth factor-I receptor mutant leads to short stature: Clinical and biochemical characterization. J Clin Endocrinol Metab 92: 15421548.
  • Kant SG, Kriek M, Walenkamp MJ, Hansson KB, van Rhijn A, Clayton-Smith J, Wit JM, Breuning MH. 2007. Tall stature and duplication of the insulin-like growth factor I receptor gene. Eur J Med Genet 50: 110.
  • Mahjoubi F, Peters GB, Malafiej P, Shalhoub C, Turner A, Daniel A, Hill RJ. 2005. An analphoid marker chromosome inv dup(15)(q26.1qter), detected during prenatal diagnosis and characterized via chromosome microdissection. Cytogenet Genome Res 109: 485490.
  • Nagai T, Shimokawa O, Harada N, Sakazume S, Ohashi H, Matsumoto N, Obata K, Yoshino A, Murakami N, Murai T, Sakuta R, Niikawa N. 2002. Postnatal overgrowth by 15q-trisomy and intrauterine growth retardation by 15q-monosomy due to familial translocation t(13;15): Dosage effect of IGF1R? Am J Med Genet 113: 173177.
  • National Institutes of Health and Institute of Molecular Medicine Collaboration. 1996. A complete set of human telomeric probes and their clinical application. Nat Genet 14: 8689.
  • Okubo Y, Siddle K, Firth H, O'Rahilly S, Wilson LC, Willatt L, Fukushima T, Takahashi S, Petry CJ, Saukkonen T, Stanhope R, Dunger DB. 2003. Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab 88: 59815988.
  • Pedersen C. 1976. Letter: Partial trisomy 15 as a result of an unbalanced 12/15 translocation in a patient with a cloverleaf skull anomaly. Clin Genet 9: 378380.
  • Pinson L, Perrin A, Plouzennec C, Parent P, Metz C, Collet M, Le Bris MJ, Douet-Guilbert N, Morel F, De Braekeleer M. 2005. Detection of an unexpected subtelomeric 15q26.2 [RIGHTWARDS ARROW] qter deletion in a little girl: Clinical and cytogenetic studies. Am J Med Genet Part A 138A: 160165.
  • Poot M, Eleveld MJ, van't Slot R, van Genderen MM, Verrijn Stuart AA, Hochstenbach R, Beemer FA. 2007. Proportional growth failure and oculocutaneous albinism in a girl with a 6.87 Mb deletion of region 15q26.2 [RIGHTWARDS ARROW] qter. Eur J Med Genet 50: 432440.
  • Roback EW, Barakat AJ, Dev VG, Mbikay M, Chrétien M, Butler MG. 1991. An infant with deletion of the distal long arm of chromosome 15 (q26.1----qter) and loss of insulin-like growth factor 1 receptor gene. Am J Med Genet 38: 7479.
  • Rowe AG, Abrams L, Qu Y, Chen E, Cotter PD. 2000. Tetrasomy 15q25 [RIGHTWARDS ARROW] qter: Cytogenetic and molecular characterization of an analphoid supernumerary marker chromosome. Am J Med Genet 93: 393398.
  • Sarbassov DD, Ali SM, Sabatini DM. 2005. Growing roles for the mTOR pathway. Curr Opin Cell Biol 17: 596603.
  • Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. 2002. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acid Res 30: e57.
  • Spiegel M, Hickmann G, Senger G, Kozlowski P, Bartsch O. 2003. Two new cases of analphoid marker chromosomes. Am J Med Genet Part A 116A: 284289.
  • Van Allen MI, Siegel-Bartelt J, Feigenbaum A, Teshima IE. 1992. Craniosynostosis associated with partial duplication of 15q and deletion of 2q. Am J Med Genet 43: 688692.
  • Van den Enden A, Verschraegen-Spae MR, Van Roy N, Decaluwe W, De Praeter C, Speleman F. 1996. Mosaic tetrasomy 15q25 [RIGHTWARDS ARROW] qter in a newborn infant with multiple anomalies. Am J Med Genet 63: 482485.
  • Van Karnebeek C, Quik S, Sluijter S, Hulsbeek M, Hoovers J, Hennekam R. 2002. Further delineation of the chromosome 14q terminal deletion syndrome. Am J Med Genet 110: 6572.
  • Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, Breuning MH, Romijn JA, Karperien M, Wit JM. 2006. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab 91: 30623070.
  • Wright CM, Booth IW, Buckler JM, Cameron N, Cole TJ, Healy MJ, Hulse JA, Preece MA, Reilly JJ, Williams AF. 2002. Growth reference charts for use in the United Kingdom. Arch Dis Child 86: 1114.
  • Zollino M, Tiziano F, Di Stefano C, Neri G. 1999. Partial duplication of the long arm of chromosome 15: Confirmation of a causative role in craniosynostosis and definition of a 15q25-qter trisomy syndrome. Am J Med Genet 87: 391394.