Case Report Cytogenet Genome Res 2014;144:190–195 DOI: 10.1159/000369653
Accepted: September 29, 2014 by M. Schmid Published online: December 20, 2014
Partial Trisomy of the Pericentromeric Region of Chromosome 5 in a Girl with Binder Phenotype Kinga Hadzsiev a Dezső Dávid c Gyula Szabó b Márta Czakó a Béla Melegh a György Kosztolányi a Departments of a Medical Genetics and b Dentistry, Oral and Maxillofacial Surgery, University of Pécs, Pécs, Hungary; c Departamento de Genética Humana, Instituto Nacional de Saúde, Lisboa, Portugal
Key Words Array painting · Binder phenotype · Maxillonasal dysplasia · Partial 5p trisomy · Small supernumerary marker chromosome
genes localized in this genomic region should take this into consideration. To the best of our knowledge, this is the first report on a patient with association of a chromosome abnormality and clinical characteristics of Binder phenotype. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1424–8581/14/1443–0190$39.50/0 E-Mail [email protected] www.karger.com/cgr
Characterization of genomic rearrangements in patients presenting with multiple phenotypic anomalies raises the possibility to discover causal genotype/phenotype associations. The patient reported here shows the most characteristic features of a rare clinical entity enrolled in the syndrome databases as Binder syndrome (BS) or maxillonasal dysplasia (OMIM: 155050). In addition to the facial dysmorphism, our patient also had a de novo small supernumerary chromosome (sSMC) identified as ring chromosome 5. In the present study, we describe the phenotypic features and genomic alteration and also compare the findings in the patient with previously published sSMC 5 cases with similar genetic content. We also discuss a possible genotype/phenotype correlation between the pericentromeric region of chromosome 5 and features of maxillonasal dysplasia. György Kosztolányi Department of Medical Genetics, University of Pécs József A. u. 7 HU–7623 Pécs (Hungary) E-mail kosztolanyi.gyorgy @ pte.hu
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Abstract The patient reported here displayed most characteristic features of Binder syndrome (OMIM: 155050), a rare maxillonasal malformation with unknown etiology. She was sent for genetic evaluation at the age of 10 years because of facial dysmorphism and borderline intellectual disability. Cytogenetic analyses showed a de novo supernumerary small ring chromosome with a pericentromeric region of chromosome 5 in all lymphocytes. Array painting revealed that the marker contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1. Additionally, 7 reports have been published in the literature with partial trisomy of chromosome 5 overlapping with our case. These 8 cases were analyzed for phenotype/genotype correlation which suggested that the maxillonasal anomalies of Binder phenotype and trisomy of the pericentromeric region of chromosome 5 may be in causal relationship. Future functional annotation studies of
Methods
Fig. 1. Photos and skull X-ray of the patient at the age of 10 years. Note the midface hypoplasia with pointed chin, nasal deviation, short columella, and prognathism.
Karyotyping was performed on metaphase chromosome preparations obtained from peripheral lymphocytes using standard procedures. FISH analysis was performed using centromere-specific (Oncor) and whole chromosome painting probes (Vysis). For array painting, an aliquot of total genomic DNA from the patient was analyzed by high-resolution oligonucleotide array painting using a Cytogenetics Whole-Genome 2.7 M array (Affymetrix) at the Gulbenkian Institute of Sciences (Oeiras, Portugal). Fragmentation and labeling of DNA samples (100 ng), hybridization, washing, staining, and scanning of the arrays were performed according to the manufacturer’s instructions. The data were analyzed using the Chromosome Analysis Suite (ChAS) software from Affymetrix. Potential alterations or CNVs were queried in the Database of Genomic Variants (DGV; http://projects.tcag.ca/variation/?source=hg19). The reference genome assembly is GRCh37/hg19.
Case Report The patient is the third child of nonconsanguineous healthy parents who were 30 and 32 years old at the time of her birth and also had 2 healthy boys. She was born at term after an uneventful pregnancy. Teratogenic risk factors could not be identified. Her birth weight was 3,450 g (50–75th percentile), length was 56 cm (>97th percentile), and head circumference was 37 cm (>97th percentile). In infancy, facial dysmorphism and trunk hypotony were noted on pediatric charts. She walked at 24 months and begun to speak at 36 months. Because of frequent otitis media, a mastoidectomy was performed at 2 years of age. The patient was sent for genetic evaluation at 10 years of age because of facial dysmorphism and borderline intellectual disability. Her weight was 32.5 kg (50–75th percentile), length 142 cm (50–75th percentile), and head circumference 54.5 cm (+2 SD). She had a dolichocephalic skull, pointed chin, left-deviated nasal septum, short columella, flat nasal bridge, hypertelorism (interocular distance 4.8 cm, >8% of the head circumference), epicanthus, slight blepharophimosis, midface hypoplasia, low-set ears, and prognathism (fig. 1). Mild pectus excavatum and inverted nipples were noted. Using syndrome search (Oxford Medical Database), the phenotypic features suggested BS (OMIM: 155050). Radiographic survey detected an enlarged fronto-occipital diameter, hypoplastic maxilla with absence of spina nasalis, and hypoplastic cervical vertebrae I–II; no abnormality was found in the short and long bones of the limbs. At dental-orthodontic examination, severe prognathism with Angle III malocclusion and crowded tooth arches were found. Cephalometric studies confirmed maxilla hypoplasia. Ophthalmologic, laboratory, cardiologic, and EEG examinations could not detect any pathologic findings. A psychologic survey showed a slight developmental delay (IQ 77 by Stanford-Binet test). At the age of 11 years, she was hospitalized because of acute meningitis. During the treatment, brain MRI was performed which detected a septum pellucidum cyst and a cerebral cavernous malformation (20 × 18 mm of size) in the left thalamus. At present, at the age of 17 years, she is symptomless. She attends a regular school; however, her performance is poor, even at special recitation. Her elder brother has been treated because of supernumerary teeth. According to the parents, the paternal grandfather also has ‘irregular teeth’.
Conventional chromosome analysis of PHA-stimulated peripheral blood lymphocytes at 550-band resolution showed a sSMC in all examined metaphases, with a clear ring form in several cells and fairly stable appearance. FISH studies disclosed that the marker chromosome derived from chromosome 5. No cytogenetic abnormality was detected in the parents, and the parental origin of the marker could not be identified (tests for UPD were inconclusive). Array analysis revealed that the ring chromosome 5 contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1 (fig. 2). The telomeric end of ring 5, within the intergenic region between cadherin type 2 genes CDH9 and CDH6, is bordered by marker S-2LJNL (rs6450652) in 5p14.1 at position 28,621 kb and at the other end by S-2L3LQ (rs495138) in 5q11.1 at position 49,571 kb. This end is flanked by hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (EMB 49,692,026–49,739,082), the first gene from the proximal long arm of chromosome 5. Only 4 markers from the proximal end of 5q11.1 had a positive signal (C-0ZQAD, S-2I4XL, S-2L2Kq, and S-2L3LQ), and no additional gene is localized within this or the centromeric region. Detailed analysis of the ring chromosome 5 led to the identification of 62 genes. Of these, 3 were disease-associated dosage-sensitive genes, i.e. genes leading to autosomal disorders, namely, the Nipped-B homolog gene (NIPBL), causing Cornelia de Lange syndrome type 1 (CDLS1; OMIM: 122470), the oncostatin M receptor gene (OSMR), causing familial primary localized cutaneous amyloidosis (FPLCA; OMIM: 105250), and the fibro-
Binder Phenotype and Trisomy of Chromosome 5p14.1q11.1
Cytogenet Genome Res 2014;144:190–195 DOI: 10.1159/000369653
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Results
Gain
Copy number state
Log2 ratio
a
Chromosome 5 p14.1
p13.2
BRIX1 SUB1
RAI14 RXFP3
PDZD2
TARS
CDH6
14.1 28 Mb CDH9
CCDC152 SKP2
TTC23L
NPR3
IL7R
RICTOR OSMR
SLC1A3 NIPBL#
SPEF2
EGFLAM
p13.2 32 Mb
30 Mb RNASEN
34 Mb
ADAMTS12
GOLPH3 MTMR12 ZFR
SLC4SA2 AMACR CIQTNF3
CAPSL
38 Mb
SEPP1
p12
PRLR UGT3A2 LMBRDB2 RANBP3L
42 Mb
40 Mb
NUP155
AGXT2 UGT3A1
c
MRPS30 NNT ZNF131
13.1
36 Mb
RAD1
C7 CARD6
WRD70
DNAJC21
13.3
GHR FBXO4
TTC33
OXCT1
PRKAA1
GDNF LIRF C9 DAB2
HCN1
PAIP1
RPL37 FYB
46 Mb
44 Mb
HMGCS1 CCL28 #FGF10
HEATR7B2 C6 PLCXD3
Fig. 2. Characterization of the ring chromosome 5 and its gene content. a Array painting of the proximal 5p region using Affymetrix Whole-Genome 2.7 M array showing a copy number gain from 5p14.1 to 5q11.1 (blue box). Below, log2 ratios and an ideogram of the affected chromosome region are shown. b Schematic ideogram of chromosome 5. The genomic region identified in the ring chromosome 5 is highlighted. c Physical map of this region. Arrows indicate the position of genes in sense (above the map) and anti-
sense (below the map) orientation. Only genes with attributed names in the HGNC database are indicated. Open reading frames, pseudogenes, and noncoding RNA genes are not included. The CNV content of genes is indicated by a color gradient (i.e. the brighter the gray scale, the higher the CNV content). Genes presently associated with human disorders are underlined, while those presumably implicated in the observed phenotype are indicated by a ‘#’.
blast growth factor 10 gene (FGF10), causing aplasia of lacrimal and salivary glands (ALSG; OMIM: 180920) and lacrimoauriculodentodigital syndrome (LADD; OMIM: 149730). All of these syndromes could be excluded in our patient. In addition, a 2,400-kb gain in the pericentromeric region of chromosome 15q from gene HERC2P3 to HEREP3 (position 20.176–22.583 Mb), a 270-kb gain in the pericentromeric region of chromosome 16p (position 34.476– 34.746 Mb), a 430-kb gain in the pseudoautosomal region Xp22.33 (position 185.96–619.1 kb), and a 144-kb dele-
tion at 3p26.1 (position 6,188–6,332 kb) were also identified. According to the database of genomic variants, all are most likely CNVs.
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Cytogenet Genome Res 2014;144:190–195 DOI: 10.1159/000369653
Discussion
The cardinal questions to be discussed are whether the clinical features of our patient could be identified as BS and whether the association of the maxillofacial anomalies with the genomic alteration is causal or coincidental. Hadzsiev /Dávid /Szabó /Czakó /Melegh / Kosztolányi
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p15.2
b
and Valentin [1988] concluded that the condition is either inherited as an autosomal recessive trait with an incomplete penetrance or by multifactorial inheritance. Horswell et al. [1987] argued just the opposite. After examination of 24 patients, they suggested a dominant inheritance with reduced penetrance. Quarrell et al. [1990] concluded that the phenotype of BS may be heterogeneous, and no reliable recurrence risks are available for genetic counseling purposes. The additional small chromosome found in our patient deserves further discussion. sSMCs present difficulties in clinical cytogenetics, since each sSMC has unique breakpoints and thus results in a different clinical outcome. Moreover, mosaicism is an important factor in clinical manifestation, and cases may differ significantly in the ratio of cells with sSMC in various tissues. Although they may be present in individuals with no phenotypic abnormalities, the great majority of carriers of sSMCs derived from chromosomes other than chromosome 15 showed clinical symptoms [Liehr et al., 2006]. The small marker derived from chromosome 5 in our patient seems to contain euchromatin; accordingly it may contribute to the malformations detected. At least 21 cases have been identified with sSMCs containing chromosome 5 material [Melo et al., 2011]. For genotype/phenotype correlation analysis, we selected the reports with trisomy of the proximal 5p overlapping our case and then omitted those which did not contain detailed clinical or cytogenetic description. Since the case published by Ohashi et al. [2011] had a complex duplication/deletion rearrangement and the triplicated segment in the patient reported by Melo et al. [2011] was assigned exclusively to the long arm, these 2 reports were not considered. Finally, 7 cases were enrolled for further evaluation: Avansino et al. [1999], Schuffenhauer et al. [1996], Stankiewicz et al. [2000], D’Amato Sizonenko et al. [2002] (2 cases), Liehr et al. [2006], and Sarri et al. [2006]. Although significant trisomy of the proximal long arm of chromosome 5 could be identified in the ring of the patient observed by Stankiewicz et al. [2000], in case 2 of D’Amato Sizonenko et al. [2002], and that by Sarri et al. [2006], and, in addition to sSMC 5, a deletion of 5p was also identified by Schuffenhauer et al. [1996], these 4 cases were included in the evaluation. However, the modifying effect of the additional genomic rearrangement should be kept in mind when the cases are compared. In addition to cases with sSMC 5, our patient was also compared to those having a pure duplication of the pericentromeric region of chromosome 5. Among the 5 cases reported by Yan et al. [2009] with a duplicated genomic
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BS is a rare condition characterized by abnormal development of the maxillonasal region. In general, the diagnosis is based on the presence of some characteristic features like midface hypoplasia, underdeveloped upper jaw, hypoplastic flattened nose, flat nasal bridge, short columella, acute nasolabial angle, and a tendency to a class III malocclusion and prognathism. Radiographically, there is aplasia or hypoplasia of the anterior nasal spine and malformations of the cervical spine. In some patients, cleft palate, absent maxillary teeth, and a mildly decreased intelligence were also found. Many researchers have raised the question whether or not BS is a distinct entity or is a nonsyndromic association of maxillonasal abnormalities and should be designated as Binder phenotype (BP) [Quarrell et al., 1990]. Sheffield et al. [1976] concluded that BS should be classified as a mild form of chondrodysplasia punctata (CDP, OMIM: 118650), assuming that punctate epiphyses disappear with age. Other authors [Horswell et al., 1987; Levaillant et al., 2009; Chummun et al., 2012] also argued whether BS and CDP can be clearly differentiated from each other. Analyzing prenatally diagnosed cases, Levaillant et al. [2009] raised the possibility that BP may be the result of an anomaly in vitamin K metabolism, acting in a mild CDP background. Colin et al. [2012] emphasized the importance of systematic tests for maternal autoimmune diseases in cases of prenatally diagnosed BP. Some reports indicated that BS might be an allelic variant of Keutel syndrome (OMIM: 245150) which also presents with midface hypoplasia and has been shown to be due to mutations in the gene encoding matrix Gla protein (MGP) [Munroe et al., 1999; Demirel et al., 2012]. Although there is no agreement in these reports in the understanding what is the diagnostic hallmark of this entity and the minimal diagnostic criteria have not yet been established, BS or BP is an accepted disease in databases, and many reports are published under this term, mainly in oral or plastic surgery journals. Taking into consideration the features listed in syndrome databases and those found by us, we suggest that the condition of our patient belongs to the spectrum of BP or maxillonasal dysplasia. As for a possible genetic background, to the best of our knowledge, no patient with BP has been reported in whom a chromosome aberration was identified (in 1 of the cases published by Levaillant et al., [2009], a 47,XXX was found, however, any causal relationship between this karyotype and the phenotype is largely unlikely). Familial cases have also been reported, suggesting a genetic contribution to disease causality [Chummun et al., 2012]. After pedigree analysis of 50 patients, Olow-Nordenram
+ + + +
+
+ + + + + + +
+
Sex Age of identification Age of last examination Cells with ring, % Hypotonia Psychomotor retardation Macrocephaly Dolichocephaly Enlarged anterior fontanelle Epicanthal folds Upslanting palpebral fissures Hypertelorism Broad nasal bridge Short nose Midface hypoplasia High-arched palate Microretrognathia Low-set dysplastic ears Arachnodactyly Club feet/malformed feet Congenital heart defect Facial asymmetry
Cytogenet Genome Res 2014;144:190–195 DOI: 10.1159/000369653
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+
+ + + + +
+ + + + +
+ +
+ + + + +
+
+ +
+ + + +
+ +
+ + + +
mild
+ + +
+
+
borderline + +
XX 10 years 12 years 100 + mild + + XX 1 month 9.5 years 14–60 XY fetus
present case Sarri et al. [2006] Liehr et al. [2006]
D’Amato Sizonenko et al. [2002]; case 2 XY infant 12 month 81 + + + + + + + + + + + D’Amato Sizonenko et al. [2002]; case 1 XX 3.5 months 3.25 years, deceased 77 + + + + + + + + + + + Stankiewicz et al. [2000] XX 27 years 30 years 57
Schuffenhauer et al. [1996] XY 2 months 2.5 years 97 + + + + Reference
Avansino et al. [1999] XY fetus 5.5 month 100 + + + + + + + + + + + + + prearic pit + +
5p14.1q11.1 5p13.2~13.3q11.2 5p12~13.1q10 5p13.3q12.3 5p13.3q10 5p14q11.2 5p12q1 5p13q10::p13q10 Trisomic region
Table 1. Main features of all cases with an sSMC involving the proximal region of chromosome 5p
194
region of 36.84–37.55 kb encompassing NIPBL, prognathism was mentioned in one and flat wide nose in another patient; however, no other features of midface hypoplasia were described. Only a depressed nasal bridge is mentioned in the case enrolled in the Decipher Database (ID 1227, with genomic duplication of region 6,622 kb; position: chr5:36,240,080–42,862,390), and no feature of midface hypoplasia is registered in the case enrolled in the ISCA Database (ID nssv579008, with a 9,559-kb gain; position chr5:35,700,582–45,260,131[GRCh37/hg19]). Accordingly, these cases were not included in our further evaluation. Table 1, adapted from D’Amato Sizonenko et al. [2002], summarizes the main features of the 8 cases compared. The phenotypes in these cases are determined by the size of the triplicated segment, being proximal 5p as the putative critical region, possibly as narrow as centromere→13.1 [Chia et al., 1987; D’Amato Sizonenko et al., 2002]. At least 5 of the most frequently noted phenotypic anomalies of trisomy of the proximal short arm of chromosome 5 involve the nasomaxillary region and coincide with the classical features of BP. As for other characteristic signs of BP, hypoplastic columella was mentioned only by Masuno et al. [1999]. Unfortunately, the report did not give breakpoints of the triplicated segment of sSMC 5, and therefore, it was omitted from the comparison. Dental anomalies and prognathia, 2 age-dependent features of BP which were present only in the 35-year-old patient of Melo et al. [2011], were also omitted from the comparison. According to this phenotype/genotype correlation analysis, a causal relationship between the abnormal phenotype of our patient and the presence of sSMC 5 cannot be excluded. The map of genes and diseases assigned to the pericentromeric region of chromosome 5 may be an alternative approach to evaluate a possible association of BP and the cytogenetic abnormality in our patient (fig. 2c). However, neither of the selected mapped genes provided useful insights for better understanding the relationship to BP. Cornelia de Lange syndrome (mutations in NIPBL) as well as familial cutaneous amyloidosis (mutations in OSMR) can easily be excluded in our patient. Although BP and lacrimoauriculodentodigital or Levy-Hollister syndrome (mutations in FGF10), which are mapped to 5p13p12, share maxillodental involvement, the lack of lacrimal, auricular, and digital features in our case makes this diagnosis unlikely. Nevertheless, we have to have in mind that the reported phenotypes are the results of haploinsufficiencies, and the interpretation of any functional effect of a supernumerary gene owing to a partial trisomy,
as in our case, is quite difficult. Furthermore, we cannot exclude a possible cumulative interaction of the genes from the ring chromosome 5. Finally, it is worth to mention that in 6 of the 8 cases (table 1) the sSMC could not be identified in all cells analyzed. Mosaicism can never be excluded; however, in our case no suspicion evolved for it, not even in repeated tests of blood lymphocytes. In conclusion, based on the phenotype/genotype correlation analysis in our patient and in cases with similar chromosome imbalances, it is admissible to suppose that the developmental anomalies of the maxillonasal region and trisomy of the pericentromeric region of chromo-
some 5 may be in a causal relationship. This possibility might be considered in further functional annotation studies of genes located in this genomic region. Any additional observations and descriptions of the clinical characteristics of BP associated with genetic abnormalities should contribute to the elucidation of the origin and base of this obscure disorder. Acknowledgements This work was partially supported by Fundação para a Ciência e a Tecnologia research grant PTDC/SAU-GMG/118140/2010 and by the Portugal-Hungary Bilateral Cooperation Program.
References
Binder Phenotype and Trisomy of Chromosome 5p14.1q11.1
Levaillant JM, Moeglin D, Zouiten K, Bucourt M, Burglen L, et al: Binder phenotype: clinical and etiological heterogeneity of the so-called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature. Prenat Diagn 29:140–150 (2009). Liehr T, Mrasek K, Weise A, Dufke A, Rodríguez L, et al: Small supernumerary marker chromosomes – progress towards a genotype-phenotype correlation. Cytogenet Genome Res 112:23–34 (2006). Masuno M, Imaizumi K, Ishii T, Kimura J, Kuroki Y: Supernumerary ring chromosome 5 identified by FISH. Am J Med Genet 84:381– 381 (1999). Melo JB, Backx L, Vermeesch JR, Santos HG, Sousa AC, et al: Chromosome 5 derived small supernumerary marker: towards a genotype/ phenotype correlation of proximal chromosome 5 imbalances. J Appl Genet 52:193–200 (2011). Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, et al: Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet 21: 142– 144 (1999). Ohashi H, Suzumori K, Chisaka Y, Sonta S, Kobayashi T, et al: Implications of prenatal diagnosis of the fetus with both interstitial deletion and a small marker ring originating from chromosome 5. Am J Med Genet 155A:192– 196 (2011).
Olow-Nordenram M, Valentin J: An etiologic study of maxillonasal dysplasia – Binder’s syndrome. Scand J Dent Res 96:69–74 (1988). Quarrell OW, Koch M, Hughes HE: Maxillonasal dysplasia (Binder’s syndrome). J Med Genet 27:384–387 (1990). Sarri C, Gyftodimou Y, Grigoriadou M, Pandelia E, Kalogirou S, et al: Supernumerary marker chromosome 5 diagnosed by M-FISH in a child with congenital heart defect and unusual face. Cytogenet Genome Res 114:330–337 (2006). Schuffenhauer S, Kobelt A, Daumer-Haas C, Löffler C, Müller G, et al: Interstitial deletion 5p accompanied by dicentric ring formation of the deleted segment resulting in trisomy 5p13-cen. Am J Med Genet 65:56–59 (1996). Sheffield LJ, Danks DM, Mayne V, Hutchinson AL: Chondrodysplasia punctata-23 cases of a mild and relatively common variety. J Pediat 89:916–923 (1976). Stankiewicz P, Bocian E, Jakubow-Durska K, Obersztyn E, Lato E, et al: Identification of supernumerary marker chromosomes derived from chromosomes 5, 6, 19, and 20 using FISH. J Med Genet 37:114–120 (2000). Yan J, Zhang F, Brundage E, Scheuerle A, Lanpher B, et al: Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange. J Med Genet 46:626–634 (2009).
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Accepted: September 29, 2014 by M. Schmid Published online: December 20, 2014
Partial Trisomy of the Pericentromeric Region of Chromosome 5 in a Girl with Binder Phenotype Kinga Hadzsiev a Dezső Dávid c Gyula Szabó b Márta Czakó a Béla Melegh a György Kosztolányi a Departments of a Medical Genetics and b Dentistry, Oral and Maxillofacial Surgery, University of Pécs, Pécs, Hungary; c Departamento de Genética Humana, Instituto Nacional de Saúde, Lisboa, Portugal
Key Words Array painting · Binder phenotype · Maxillonasal dysplasia · Partial 5p trisomy · Small supernumerary marker chromosome
genes localized in this genomic region should take this into consideration. To the best of our knowledge, this is the first report on a patient with association of a chromosome abnormality and clinical characteristics of Binder phenotype. © 2014 S. Karger AG, Basel
© 2014 S. Karger AG, Basel 1424–8581/14/1443–0190$39.50/0 E-Mail [email protected] www.karger.com/cgr
Characterization of genomic rearrangements in patients presenting with multiple phenotypic anomalies raises the possibility to discover causal genotype/phenotype associations. The patient reported here shows the most characteristic features of a rare clinical entity enrolled in the syndrome databases as Binder syndrome (BS) or maxillonasal dysplasia (OMIM: 155050). In addition to the facial dysmorphism, our patient also had a de novo small supernumerary chromosome (sSMC) identified as ring chromosome 5. In the present study, we describe the phenotypic features and genomic alteration and also compare the findings in the patient with previously published sSMC 5 cases with similar genetic content. We also discuss a possible genotype/phenotype correlation between the pericentromeric region of chromosome 5 and features of maxillonasal dysplasia. György Kosztolányi Department of Medical Genetics, University of Pécs József A. u. 7 HU–7623 Pécs (Hungary) E-mail kosztolanyi.gyorgy @ pte.hu
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Abstract The patient reported here displayed most characteristic features of Binder syndrome (OMIM: 155050), a rare maxillonasal malformation with unknown etiology. She was sent for genetic evaluation at the age of 10 years because of facial dysmorphism and borderline intellectual disability. Cytogenetic analyses showed a de novo supernumerary small ring chromosome with a pericentromeric region of chromosome 5 in all lymphocytes. Array painting revealed that the marker contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1. Additionally, 7 reports have been published in the literature with partial trisomy of chromosome 5 overlapping with our case. These 8 cases were analyzed for phenotype/genotype correlation which suggested that the maxillonasal anomalies of Binder phenotype and trisomy of the pericentromeric region of chromosome 5 may be in causal relationship. Future functional annotation studies of
Methods
Fig. 1. Photos and skull X-ray of the patient at the age of 10 years. Note the midface hypoplasia with pointed chin, nasal deviation, short columella, and prognathism.
Karyotyping was performed on metaphase chromosome preparations obtained from peripheral lymphocytes using standard procedures. FISH analysis was performed using centromere-specific (Oncor) and whole chromosome painting probes (Vysis). For array painting, an aliquot of total genomic DNA from the patient was analyzed by high-resolution oligonucleotide array painting using a Cytogenetics Whole-Genome 2.7 M array (Affymetrix) at the Gulbenkian Institute of Sciences (Oeiras, Portugal). Fragmentation and labeling of DNA samples (100 ng), hybridization, washing, staining, and scanning of the arrays were performed according to the manufacturer’s instructions. The data were analyzed using the Chromosome Analysis Suite (ChAS) software from Affymetrix. Potential alterations or CNVs were queried in the Database of Genomic Variants (DGV; http://projects.tcag.ca/variation/?source=hg19). The reference genome assembly is GRCh37/hg19.
Case Report The patient is the third child of nonconsanguineous healthy parents who were 30 and 32 years old at the time of her birth and also had 2 healthy boys. She was born at term after an uneventful pregnancy. Teratogenic risk factors could not be identified. Her birth weight was 3,450 g (50–75th percentile), length was 56 cm (>97th percentile), and head circumference was 37 cm (>97th percentile). In infancy, facial dysmorphism and trunk hypotony were noted on pediatric charts. She walked at 24 months and begun to speak at 36 months. Because of frequent otitis media, a mastoidectomy was performed at 2 years of age. The patient was sent for genetic evaluation at 10 years of age because of facial dysmorphism and borderline intellectual disability. Her weight was 32.5 kg (50–75th percentile), length 142 cm (50–75th percentile), and head circumference 54.5 cm (+2 SD). She had a dolichocephalic skull, pointed chin, left-deviated nasal septum, short columella, flat nasal bridge, hypertelorism (interocular distance 4.8 cm, >8% of the head circumference), epicanthus, slight blepharophimosis, midface hypoplasia, low-set ears, and prognathism (fig. 1). Mild pectus excavatum and inverted nipples were noted. Using syndrome search (Oxford Medical Database), the phenotypic features suggested BS (OMIM: 155050). Radiographic survey detected an enlarged fronto-occipital diameter, hypoplastic maxilla with absence of spina nasalis, and hypoplastic cervical vertebrae I–II; no abnormality was found in the short and long bones of the limbs. At dental-orthodontic examination, severe prognathism with Angle III malocclusion and crowded tooth arches were found. Cephalometric studies confirmed maxilla hypoplasia. Ophthalmologic, laboratory, cardiologic, and EEG examinations could not detect any pathologic findings. A psychologic survey showed a slight developmental delay (IQ 77 by Stanford-Binet test). At the age of 11 years, she was hospitalized because of acute meningitis. During the treatment, brain MRI was performed which detected a septum pellucidum cyst and a cerebral cavernous malformation (20 × 18 mm of size) in the left thalamus. At present, at the age of 17 years, she is symptomless. She attends a regular school; however, her performance is poor, even at special recitation. Her elder brother has been treated because of supernumerary teeth. According to the parents, the paternal grandfather also has ‘irregular teeth’.
Conventional chromosome analysis of PHA-stimulated peripheral blood lymphocytes at 550-band resolution showed a sSMC in all examined metaphases, with a clear ring form in several cells and fairly stable appearance. FISH studies disclosed that the marker chromosome derived from chromosome 5. No cytogenetic abnormality was detected in the parents, and the parental origin of the marker could not be identified (tests for UPD were inconclusive). Array analysis revealed that the ring chromosome 5 contains a 20,950-kb genomic region comprising cytogenetic band 5p14.1q11.1 (fig. 2). The telomeric end of ring 5, within the intergenic region between cadherin type 2 genes CDH9 and CDH6, is bordered by marker S-2LJNL (rs6450652) in 5p14.1 at position 28,621 kb and at the other end by S-2L3LQ (rs495138) in 5q11.1 at position 49,571 kb. This end is flanked by hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (EMB 49,692,026–49,739,082), the first gene from the proximal long arm of chromosome 5. Only 4 markers from the proximal end of 5q11.1 had a positive signal (C-0ZQAD, S-2I4XL, S-2L2Kq, and S-2L3LQ), and no additional gene is localized within this or the centromeric region. Detailed analysis of the ring chromosome 5 led to the identification of 62 genes. Of these, 3 were disease-associated dosage-sensitive genes, i.e. genes leading to autosomal disorders, namely, the Nipped-B homolog gene (NIPBL), causing Cornelia de Lange syndrome type 1 (CDLS1; OMIM: 122470), the oncostatin M receptor gene (OSMR), causing familial primary localized cutaneous amyloidosis (FPLCA; OMIM: 105250), and the fibro-
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Results
Gain
Copy number state
Log2 ratio
a
Chromosome 5 p14.1
p13.2
BRIX1 SUB1
RAI14 RXFP3
PDZD2
TARS
CDH6
14.1 28 Mb CDH9
CCDC152 SKP2
TTC23L
NPR3
IL7R
RICTOR OSMR
SLC1A3 NIPBL#
SPEF2
EGFLAM
p13.2 32 Mb
30 Mb RNASEN
34 Mb
ADAMTS12
GOLPH3 MTMR12 ZFR
SLC4SA2 AMACR CIQTNF3
CAPSL
38 Mb
SEPP1
p12
PRLR UGT3A2 LMBRDB2 RANBP3L
42 Mb
40 Mb
NUP155
AGXT2 UGT3A1
c
MRPS30 NNT ZNF131
13.1
36 Mb
RAD1
C7 CARD6
WRD70
DNAJC21
13.3
GHR FBXO4
TTC33
OXCT1
PRKAA1
GDNF LIRF C9 DAB2
HCN1
PAIP1
RPL37 FYB
46 Mb
44 Mb
HMGCS1 CCL28 #FGF10
HEATR7B2 C6 PLCXD3
Fig. 2. Characterization of the ring chromosome 5 and its gene content. a Array painting of the proximal 5p region using Affymetrix Whole-Genome 2.7 M array showing a copy number gain from 5p14.1 to 5q11.1 (blue box). Below, log2 ratios and an ideogram of the affected chromosome region are shown. b Schematic ideogram of chromosome 5. The genomic region identified in the ring chromosome 5 is highlighted. c Physical map of this region. Arrows indicate the position of genes in sense (above the map) and anti-
sense (below the map) orientation. Only genes with attributed names in the HGNC database are indicated. Open reading frames, pseudogenes, and noncoding RNA genes are not included. The CNV content of genes is indicated by a color gradient (i.e. the brighter the gray scale, the higher the CNV content). Genes presently associated with human disorders are underlined, while those presumably implicated in the observed phenotype are indicated by a ‘#’.
blast growth factor 10 gene (FGF10), causing aplasia of lacrimal and salivary glands (ALSG; OMIM: 180920) and lacrimoauriculodentodigital syndrome (LADD; OMIM: 149730). All of these syndromes could be excluded in our patient. In addition, a 2,400-kb gain in the pericentromeric region of chromosome 15q from gene HERC2P3 to HEREP3 (position 20.176–22.583 Mb), a 270-kb gain in the pericentromeric region of chromosome 16p (position 34.476– 34.746 Mb), a 430-kb gain in the pseudoautosomal region Xp22.33 (position 185.96–619.1 kb), and a 144-kb dele-
tion at 3p26.1 (position 6,188–6,332 kb) were also identified. According to the database of genomic variants, all are most likely CNVs.
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Discussion
The cardinal questions to be discussed are whether the clinical features of our patient could be identified as BS and whether the association of the maxillofacial anomalies with the genomic alteration is causal or coincidental. Hadzsiev /Dávid /Szabó /Czakó /Melegh / Kosztolányi
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p15.2
b
and Valentin [1988] concluded that the condition is either inherited as an autosomal recessive trait with an incomplete penetrance or by multifactorial inheritance. Horswell et al. [1987] argued just the opposite. After examination of 24 patients, they suggested a dominant inheritance with reduced penetrance. Quarrell et al. [1990] concluded that the phenotype of BS may be heterogeneous, and no reliable recurrence risks are available for genetic counseling purposes. The additional small chromosome found in our patient deserves further discussion. sSMCs present difficulties in clinical cytogenetics, since each sSMC has unique breakpoints and thus results in a different clinical outcome. Moreover, mosaicism is an important factor in clinical manifestation, and cases may differ significantly in the ratio of cells with sSMC in various tissues. Although they may be present in individuals with no phenotypic abnormalities, the great majority of carriers of sSMCs derived from chromosomes other than chromosome 15 showed clinical symptoms [Liehr et al., 2006]. The small marker derived from chromosome 5 in our patient seems to contain euchromatin; accordingly it may contribute to the malformations detected. At least 21 cases have been identified with sSMCs containing chromosome 5 material [Melo et al., 2011]. For genotype/phenotype correlation analysis, we selected the reports with trisomy of the proximal 5p overlapping our case and then omitted those which did not contain detailed clinical or cytogenetic description. Since the case published by Ohashi et al. [2011] had a complex duplication/deletion rearrangement and the triplicated segment in the patient reported by Melo et al. [2011] was assigned exclusively to the long arm, these 2 reports were not considered. Finally, 7 cases were enrolled for further evaluation: Avansino et al. [1999], Schuffenhauer et al. [1996], Stankiewicz et al. [2000], D’Amato Sizonenko et al. [2002] (2 cases), Liehr et al. [2006], and Sarri et al. [2006]. Although significant trisomy of the proximal long arm of chromosome 5 could be identified in the ring of the patient observed by Stankiewicz et al. [2000], in case 2 of D’Amato Sizonenko et al. [2002], and that by Sarri et al. [2006], and, in addition to sSMC 5, a deletion of 5p was also identified by Schuffenhauer et al. [1996], these 4 cases were included in the evaluation. However, the modifying effect of the additional genomic rearrangement should be kept in mind when the cases are compared. In addition to cases with sSMC 5, our patient was also compared to those having a pure duplication of the pericentromeric region of chromosome 5. Among the 5 cases reported by Yan et al. [2009] with a duplicated genomic
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BS is a rare condition characterized by abnormal development of the maxillonasal region. In general, the diagnosis is based on the presence of some characteristic features like midface hypoplasia, underdeveloped upper jaw, hypoplastic flattened nose, flat nasal bridge, short columella, acute nasolabial angle, and a tendency to a class III malocclusion and prognathism. Radiographically, there is aplasia or hypoplasia of the anterior nasal spine and malformations of the cervical spine. In some patients, cleft palate, absent maxillary teeth, and a mildly decreased intelligence were also found. Many researchers have raised the question whether or not BS is a distinct entity or is a nonsyndromic association of maxillonasal abnormalities and should be designated as Binder phenotype (BP) [Quarrell et al., 1990]. Sheffield et al. [1976] concluded that BS should be classified as a mild form of chondrodysplasia punctata (CDP, OMIM: 118650), assuming that punctate epiphyses disappear with age. Other authors [Horswell et al., 1987; Levaillant et al., 2009; Chummun et al., 2012] also argued whether BS and CDP can be clearly differentiated from each other. Analyzing prenatally diagnosed cases, Levaillant et al. [2009] raised the possibility that BP may be the result of an anomaly in vitamin K metabolism, acting in a mild CDP background. Colin et al. [2012] emphasized the importance of systematic tests for maternal autoimmune diseases in cases of prenatally diagnosed BP. Some reports indicated that BS might be an allelic variant of Keutel syndrome (OMIM: 245150) which also presents with midface hypoplasia and has been shown to be due to mutations in the gene encoding matrix Gla protein (MGP) [Munroe et al., 1999; Demirel et al., 2012]. Although there is no agreement in these reports in the understanding what is the diagnostic hallmark of this entity and the minimal diagnostic criteria have not yet been established, BS or BP is an accepted disease in databases, and many reports are published under this term, mainly in oral or plastic surgery journals. Taking into consideration the features listed in syndrome databases and those found by us, we suggest that the condition of our patient belongs to the spectrum of BP or maxillonasal dysplasia. As for a possible genetic background, to the best of our knowledge, no patient with BP has been reported in whom a chromosome aberration was identified (in 1 of the cases published by Levaillant et al., [2009], a 47,XXX was found, however, any causal relationship between this karyotype and the phenotype is largely unlikely). Familial cases have also been reported, suggesting a genetic contribution to disease causality [Chummun et al., 2012]. After pedigree analysis of 50 patients, Olow-Nordenram
+ + + +
+
+ + + + + + +
+
Sex Age of identification Age of last examination Cells with ring, % Hypotonia Psychomotor retardation Macrocephaly Dolichocephaly Enlarged anterior fontanelle Epicanthal folds Upslanting palpebral fissures Hypertelorism Broad nasal bridge Short nose Midface hypoplasia High-arched palate Microretrognathia Low-set dysplastic ears Arachnodactyly Club feet/malformed feet Congenital heart defect Facial asymmetry
Cytogenet Genome Res 2014;144:190–195 DOI: 10.1159/000369653
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+
+ + + + +
+ + + + +
+ +
+ + + + +
+
+ +
+ + + +
+ +
+ + + +
mild
+ + +
+
+
borderline + +
XX 10 years 12 years 100 + mild + + XX 1 month 9.5 years 14–60 XY fetus
present case Sarri et al. [2006] Liehr et al. [2006]
D’Amato Sizonenko et al. [2002]; case 2 XY infant 12 month 81 + + + + + + + + + + + D’Amato Sizonenko et al. [2002]; case 1 XX 3.5 months 3.25 years, deceased 77 + + + + + + + + + + + Stankiewicz et al. [2000] XX 27 years 30 years 57
Schuffenhauer et al. [1996] XY 2 months 2.5 years 97 + + + + Reference
Avansino et al. [1999] XY fetus 5.5 month 100 + + + + + + + + + + + + + prearic pit + +
5p14.1q11.1 5p13.2~13.3q11.2 5p12~13.1q10 5p13.3q12.3 5p13.3q10 5p14q11.2 5p12q1 5p13q10::p13q10 Trisomic region
Table 1. Main features of all cases with an sSMC involving the proximal region of chromosome 5p
194
region of 36.84–37.55 kb encompassing NIPBL, prognathism was mentioned in one and flat wide nose in another patient; however, no other features of midface hypoplasia were described. Only a depressed nasal bridge is mentioned in the case enrolled in the Decipher Database (ID 1227, with genomic duplication of region 6,622 kb; position: chr5:36,240,080–42,862,390), and no feature of midface hypoplasia is registered in the case enrolled in the ISCA Database (ID nssv579008, with a 9,559-kb gain; position chr5:35,700,582–45,260,131[GRCh37/hg19]). Accordingly, these cases were not included in our further evaluation. Table 1, adapted from D’Amato Sizonenko et al. [2002], summarizes the main features of the 8 cases compared. The phenotypes in these cases are determined by the size of the triplicated segment, being proximal 5p as the putative critical region, possibly as narrow as centromere→13.1 [Chia et al., 1987; D’Amato Sizonenko et al., 2002]. At least 5 of the most frequently noted phenotypic anomalies of trisomy of the proximal short arm of chromosome 5 involve the nasomaxillary region and coincide with the classical features of BP. As for other characteristic signs of BP, hypoplastic columella was mentioned only by Masuno et al. [1999]. Unfortunately, the report did not give breakpoints of the triplicated segment of sSMC 5, and therefore, it was omitted from the comparison. Dental anomalies and prognathia, 2 age-dependent features of BP which were present only in the 35-year-old patient of Melo et al. [2011], were also omitted from the comparison. According to this phenotype/genotype correlation analysis, a causal relationship between the abnormal phenotype of our patient and the presence of sSMC 5 cannot be excluded. The map of genes and diseases assigned to the pericentromeric region of chromosome 5 may be an alternative approach to evaluate a possible association of BP and the cytogenetic abnormality in our patient (fig. 2c). However, neither of the selected mapped genes provided useful insights for better understanding the relationship to BP. Cornelia de Lange syndrome (mutations in NIPBL) as well as familial cutaneous amyloidosis (mutations in OSMR) can easily be excluded in our patient. Although BP and lacrimoauriculodentodigital or Levy-Hollister syndrome (mutations in FGF10), which are mapped to 5p13p12, share maxillodental involvement, the lack of lacrimal, auricular, and digital features in our case makes this diagnosis unlikely. Nevertheless, we have to have in mind that the reported phenotypes are the results of haploinsufficiencies, and the interpretation of any functional effect of a supernumerary gene owing to a partial trisomy,
as in our case, is quite difficult. Furthermore, we cannot exclude a possible cumulative interaction of the genes from the ring chromosome 5. Finally, it is worth to mention that in 6 of the 8 cases (table 1) the sSMC could not be identified in all cells analyzed. Mosaicism can never be excluded; however, in our case no suspicion evolved for it, not even in repeated tests of blood lymphocytes. In conclusion, based on the phenotype/genotype correlation analysis in our patient and in cases with similar chromosome imbalances, it is admissible to suppose that the developmental anomalies of the maxillonasal region and trisomy of the pericentromeric region of chromo-
some 5 may be in a causal relationship. This possibility might be considered in further functional annotation studies of genes located in this genomic region. Any additional observations and descriptions of the clinical characteristics of BP associated with genetic abnormalities should contribute to the elucidation of the origin and base of this obscure disorder. Acknowledgements This work was partially supported by Fundação para a Ciência e a Tecnologia research grant PTDC/SAU-GMG/118140/2010 and by the Portugal-Hungary Bilateral Cooperation Program.
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Binder Phenotype and Trisomy of Chromosome 5p14.1q11.1
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