CLINICAL REPORT
Genotypic and Phenotypic Variation in Six Patients with Solitary Median Maxillary Central Incisor Syndrome Simon Poelmans,1 Tatsuro Kawamoto,2,3 Francesca Cristofoli,4 Constantinus Politis,5 Joris Vermeesch,4 Isabelle Bailleul-Forestier,6,7 Greet Hens,8 Koenraad Devriendt,4 Anna Verdonck,1 and Carine Carels1,2* 1
Department of Oral Health Sciences—Orthodontics, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium 2
Department of Orthodontics and Craniofacial Biology, College of Dentistry, Radboudumc, Nijmegen, The Netherlands Department of Maxillofacial Reconstruction and Function, Maxillofacial Orthognathics, Division of Maxillofacial/Neck Reconstruction, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan 3
4
Department of Human Genetics, KU Leuven and Centre for Human Genetics, University Hospitals Leuven, Leuven, Belgium 5
Department of Oral and Maxillofacial Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium Department of Oral Health Sciences—Paediatric Dentistry and Special Care, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium 6
7
Department of Paediatric Dentistry, Paul Sabatier University, H^opitaux de Toulouse, France Department of Otorhinolaryngology, Head and Neck Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium 8
Manuscript Received: 6 February 2015; Manuscript Accepted: 3 June 2015
Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known holoprosencephaly spectrum. © 2015 Wiley Periodicals, Inc.
Key words: Single Maxillary Median Central Incisor (SMMCI); Holoprosencephaly (HPE); Copy Number Variation (CNV); Exome Sequencing (ES); mutation analysis © 2015 Wiley Periodicals, Inc.
How to Cite this Article: Poelmans S, Kawamoto T, Cristofoli F, Politis C, Vermeesch J, Bailleul-Forestier I, Hens G, Devriendt K, Verdonck A, Carels C. 2015. Genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome. Am J Med Genet Part A 167A:2451–2458.
Conflict of interest: None. Correspondence to: Prof Carels Carine, D.D.S., Ph.D., Department of Oral Sciences— Orthodontics, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 16 June 2015 DOI 10.1002/ajmg.a.37207
2451
2452
INTRODUCTION Solitary Median Maxillary Central Incisor, SMMCI (OMIM #147250), occurs in 1:50,000 live births [Hall, 2006]. Although it can be an isolated trait, the presence of a SMMCI can be part of a syndrome and predicts associated anomalies, in particular of the holoprosencephaly (HPE) spectrum [Nanni et al., 2001]. Holoprosencephaly is a developmental anomaly in which the cerebral hemisphere in the forebrain fails to lateralize [Nanni et al., 2001; Hall, 2006]. The most severe forms cause prenatal lethality. If viable, the associated neurodevelopmental, craniofacial, dental, and other anomalies vary widely and can include intellectual disability (ID), congenital heart disease, midline cleft palate, choanal atresia, midnasal stenosis or congenital pyriform aperture stenosis, a single maxillary central incisor, agenesis of the premaxilla, and proboscis-like nasal structures [Chen et al., 1999]. Nonetheless, SMMCI has been reported to be a feature of various disorders, some of which do not resemble HPE [Nanni et al., 2001; Kamnasaran et al., 2005; Hall, 2006]. These include velocardiofacial (VCF) syndrome, ectodermal dysplasia, oculofacio-cardio-dental (OFCD) syndrome and others. The etiology of HPE is heterogeneous and includes environmental and genetic factors [Chen et al., 1999; Kamnasaran et al., 2005]. Although they are generally mildly affected, patients with SMMCI belong to the HPE spectrum, and are at risk to have children with more severe forms of HPE [El-Jaick et al., 2007]. Therefore a molecular diagnosis and genetic counseling is important for patients with SMMCI and their families. The aim of this investigation was to explore both genotype and phenotype variation in six patients with SMMCI syndrome.
SUBJECTS AND METHODS The medical history of six unrelated individuals identified with SMMCI at the Centre for Human Genetics, University Hospitals Leuven, were evaluated. Clinical dentofacial examination was carried out and standard dentofacial records were collected from these patients in the Department of Oral Health Sciences —Section of Orthodontics (Fig. 1; Table I) as part of the routine orthodontic treatment planning prior to the start of their orthodontic treatment. Detailed orofacial phenotyping with extraoral and intraoral evaluation, extra- and intra-oral photographs, an orthopantomogram (OPG), and a lateral headplate was performed in all six patients. Patients 2 and 3 were reported previously [Fryns et al., 1993; Frints et al., 1998b]. Array Comparative Genomic Hybridization (aCGH) analysis was performed in all six patients in the Centre for Human Genetics in Leuven. Peripheral blood-derived DNA from these patients and sex-matched reference samples were hybridized to a 180-k oligo array platform (OGT CytoSure Syndrome Plus array, OGT Oxford, UK). In one patient Exome Sequencing (ES) was performed after excluding the presence of a copy number variant (CNV). Exome sequencing was performed following library preparation with the Illumina DNA Sample Prep kit (Illumina, San Diego) and the SeqCap EZ Human Exome Library v3.0 enrichment kit (Roche, San Francisco). The sample was then sequenced on an Illumina
AMERICAN JOURNAL OF MEDICAL GENETICS PART A HiSeq 2000. Data analysis (read mapping, variant calling and annotation) was carried out using an in-house pipeline at the Genomics Core of the University Hospitals of the KU Leuven (UZ Leuven), Belgium. The variant found in this patient was submitted to the ClinVar Database (http://www.ncbi.nlm.nih.gov/clinvar/) with the following accession number: SCV000188857. The DNA sequences were submitted to the GenBank Database (http://www. ncbi.nlm.nih.gov/genbank) with the following accession number: KP061153. In the two remaining patients multiplex ligation dependent probe amplification (MLPA) and further sequencing were performed to screen for small intragenic mutations in the HPE candidate genes. To review the literature on the etiology of SMMCI, MEDLINE, and EMBASE were searched for articles on SMMCI. This study was registered and approved by the Medical Ethics Committee of the University Hospital Leuven (ML9682).
RESULTS In Table I a summary is presented on the medical history, clinical observations, and/or examinations including dentofacial features, as well as the clinical genetic diagnosis in four of the six patients. Patient 1, a girl, was born at 37-weeks of gestation. She was the second child of a 28-year-old woman and her 33-year-old husband. The pregnancy was complicated by maternal hypertension. The mother is heterozygote for sickle-cell anemia. On examination at age 5.2 years her weight was 1,860 g (50th centile), length was 107.5 cm (25th–50th centile), and OFC was 50.5 cm (50th–75th centile). She had mild intellectual disability (ID) according to the Snijders–Oomen nonverbal intelligence tests (SON-R tests). Her IQ was 57 at age 7 according to the SON-R 2,5-7. Other than SMMCI, no striking dysmorphic facial features were observed. Array CGH showed a deletion at the 18p11 chromosomal region. Patient 2, a girl, was born at 38-weeks of gestation. She is the third child of a 35-year-old woman and 38-year-old husband. At birth, an omphalocoele was present and she had respiratory distress due to macroglossia. Her birth OFC was 32 cm (qter) in a fetus with microcephaly alobar holoprosencephaly and cyclopia. Prenat Diagn 19:986–989. Chen CP, Lin SP, Su YN, Chern SR, Su JW, Lee CC, Wang W. 2012. Partial trisomy 1q (1q42.13–>qter) and partial monosomy 6q (6q27–>qter) in a girl with single median maxillary central incisor, corpus callosum dysgenesis and developmental delay. Genet Couns 23:447–455. Dolan LM, Willson K, Wilson WG. 1981. 18p—syndrome with a single central maxillary incisor. J Med Genet 18:396–398. Domene S, Roessler E, El-Jaick KB, Snir M, Brown JL, Velez JI, Bale S, Lacbawan F, Muenke M, Feldman B. 2008. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet 17:3919–3928. El-Jaick KB, Fonseca RF, Moreira MA, Ribeiro MG, Bolognese AM, Dias SO, Pereira ET, Castilla EE, Orioli IM. 2007. Single median maxillary central incisor: new data and mutation review. Birth Defects Res A Clin Mol Teratol 79:573–580. Frints SG, Schoenmakers EF, Smeets E, Petit P, Fryns JP. 1998a. De novo 7q36 deletion: Breakpoint analysis and types of holoprosencephaly. Am J Med Genet 75:153–158. Frints SG, Schrander-Stumpel CT, Schoenmakers EF, Engelen JJ, Reekers AB, Van den Neucker AM, Smeets E, Devlieger H, Fryns JP. 1998b. Strong variable clinical presentation in 3 patients with 7q terminal deletion. Genet Couns 9:5–14. Fryns JP, Kleczkowska A, Devriendt K, Devliegher H, Van den Berghe H. 1993. Wiedemann–Beckwith syndrome and chromosomal duplication 4q/deficiency 18p. Genet Couns 4:37–41.
Kantaputra PN, Limwongse C, Tochareontanaphol C, Mutirangura A, Mevatee U, Praphanphoj V. 2006. Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: Association with an 18p11.3 deletion. Am J Med Genet A 140:2598–2602. Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domene S, Velez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njolstad PR, Brunner HG, Carey JC, Hehr U, Musebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van HA, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. 2009. Clinical spectrum of SIX 3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet 46:389–398. Lin D, Huang Y, He F, Gu S, Zhang G, Chen Y, Zhang Y. 2007. Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev Dyn 236:1307–1312. Masuno M, Fukushima Y, Sugio Y, Ikeda M, Kuroki Y. 1990. Two unrelated cases of single maxillary central incisor with 7q terminal deletion. Jinrui Idengaku Zasshi 35:311–317. Miertus J, Borozdin W, Frecer V, Tonini G, Bertok S, Amoroso A, Miertus S, Kohlhase J. 2006. A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome. Hum Genet 119:154–161. Miura M, Kato N, Kojima H, Oguchi H. 1993. Triple-X syndrome accompanied by single maxillary central incisor: Case report. Pediatr Dent 15:214–217. Moog U, De Die-Smulders CE, Schrander-Stumpel CT, Engelen JJ, Hamers AJ, Frints S, Fryns JP. 2001. Holoprosencephaly: The Maastricht experience. Genet Couns 12:287–298. Muenke M, Gurrieri F, Bay C, Yi DH, Collins AL, Johnson VP, Hennekam RC, Schaefer GB, Weik L, Lubinsky MS,. 1994. Linkage of a human brain malformation, familial holoprosencephaly, to chromosome 7 and evidence for genetic heterogeneity. Proc Natl Acad Sci USA 91: 8102–8106. Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M. 2001. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Am J Med Genet 102:1–10. Naudi AB, Fung DE. 2007. A child with 18p- syndrome: A case report. Spec Care Dentist 27:12–14.
2458 Pasquier L, Dubourg C, Blayau M, Lazaro L, Le MB, David V, Odent S. 2000. A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J Hum Genet 8:797–800. Sanchez ZJ, Andres CM, Lopez Garcia MJ. 2008. Mosaic trisomy 9: Report of a new case with a long-term survival. An Pediatr (Barc) 68:273–276. Strehle EM, Gruszfeld D, Schenk D, Mehta SG, Simonic I, Huang T. 2012. The spectrum of 4q- syndrome illustrated by a case series. Gene 506: 387–391. Taine L, Goizet C, Wen ZQ, Chateil JF, Battin J, Saura R, Lacombe D. 1997. 18p monosomy with midline defects and a de novo satellite identified by FISH. Ann Genet 40:158–163. Taniguchi K, Anderson AE, Sutherland AE, Wotton D. 2012. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet 8:e1002524. Tavin E, Stecker E, Marion R. 1994. Nasal pyriform aperture stenosis and the holoprosencephaly spectrum. Int J Pediatr Otorhinolaryngol 28:199–204.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tubbs RS, Oakes WJ. 2004. Lumbosacral agenesis and anteroposterior split cord malformation in a patient with single central maxillary incisor: Case report and review of the literature. J Child Neurol 19: 544–547. Yang HC, Shyur SD, Huang LH, Chang YC, Wen DC, Liang PH, Lin MT. 2005. DiGeorge syndrome associated with solitary median maxillary central incisor. Asian Pac J Allergy Immunol 23:159–163. Zahnleiter D, Trautmann U, Ekici AB, Goehring I, Reis A, Dorr HG, Rauch A, Thiel CT. 2011. Familial short stature due to a 5q22.1–q23.2 duplication refines the 5q duplication spectrum. Eur J Med Genet 54: e521–e524.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Genotypic and Phenotypic Variation in Six Patients with Solitary Median Maxillary Central Incisor Syndrome Simon Poelmans,1 Tatsuro Kawamoto,2,3 Francesca Cristofoli,4 Constantinus Politis,5 Joris Vermeesch,4 Isabelle Bailleul-Forestier,6,7 Greet Hens,8 Koenraad Devriendt,4 Anna Verdonck,1 and Carine Carels1,2* 1
Department of Oral Health Sciences—Orthodontics, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium 2
Department of Orthodontics and Craniofacial Biology, College of Dentistry, Radboudumc, Nijmegen, The Netherlands Department of Maxillofacial Reconstruction and Function, Maxillofacial Orthognathics, Division of Maxillofacial/Neck Reconstruction, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan 3
4
Department of Human Genetics, KU Leuven and Centre for Human Genetics, University Hospitals Leuven, Leuven, Belgium 5
Department of Oral and Maxillofacial Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium Department of Oral Health Sciences—Paediatric Dentistry and Special Care, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium 6
7
Department of Paediatric Dentistry, Paul Sabatier University, H^opitaux de Toulouse, France Department of Otorhinolaryngology, Head and Neck Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium 8
Manuscript Received: 6 February 2015; Manuscript Accepted: 3 June 2015
Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background. Using array comparative genomic hybridization, pathogenic copy number variants were found in three of the six patients. Two patients had a deletion at the 18p11 chromosomal region that includes TGIF1 while the other patient had a deletion at 7q36, including the SHH gene. In one patient, a mutation in SIX3 was detected with exome sequencing, while in the two remaining patients all known holoprosencephaly genes were excluded using multiplex ligation-dependent probe amplification and sequencing, and remain unsolved. One of the two latter patients had isolated solitary median maxillary central incisor without other visible dentofacial anomalies, while the other had clinical features not part of the known holoprosencephaly spectrum. © 2015 Wiley Periodicals, Inc.
Key words: Single Maxillary Median Central Incisor (SMMCI); Holoprosencephaly (HPE); Copy Number Variation (CNV); Exome Sequencing (ES); mutation analysis © 2015 Wiley Periodicals, Inc.
How to Cite this Article: Poelmans S, Kawamoto T, Cristofoli F, Politis C, Vermeesch J, Bailleul-Forestier I, Hens G, Devriendt K, Verdonck A, Carels C. 2015. Genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome. Am J Med Genet Part A 167A:2451–2458.
Conflict of interest: None. Correspondence to: Prof Carels Carine, D.D.S., Ph.D., Department of Oral Sciences— Orthodontics, KU Leuven and Dentistry, University Hospitals Leuven, Leuven, Belgium. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 16 June 2015 DOI 10.1002/ajmg.a.37207
2451
2452
INTRODUCTION Solitary Median Maxillary Central Incisor, SMMCI (OMIM #147250), occurs in 1:50,000 live births [Hall, 2006]. Although it can be an isolated trait, the presence of a SMMCI can be part of a syndrome and predicts associated anomalies, in particular of the holoprosencephaly (HPE) spectrum [Nanni et al., 2001]. Holoprosencephaly is a developmental anomaly in which the cerebral hemisphere in the forebrain fails to lateralize [Nanni et al., 2001; Hall, 2006]. The most severe forms cause prenatal lethality. If viable, the associated neurodevelopmental, craniofacial, dental, and other anomalies vary widely and can include intellectual disability (ID), congenital heart disease, midline cleft palate, choanal atresia, midnasal stenosis or congenital pyriform aperture stenosis, a single maxillary central incisor, agenesis of the premaxilla, and proboscis-like nasal structures [Chen et al., 1999]. Nonetheless, SMMCI has been reported to be a feature of various disorders, some of which do not resemble HPE [Nanni et al., 2001; Kamnasaran et al., 2005; Hall, 2006]. These include velocardiofacial (VCF) syndrome, ectodermal dysplasia, oculofacio-cardio-dental (OFCD) syndrome and others. The etiology of HPE is heterogeneous and includes environmental and genetic factors [Chen et al., 1999; Kamnasaran et al., 2005]. Although they are generally mildly affected, patients with SMMCI belong to the HPE spectrum, and are at risk to have children with more severe forms of HPE [El-Jaick et al., 2007]. Therefore a molecular diagnosis and genetic counseling is important for patients with SMMCI and their families. The aim of this investigation was to explore both genotype and phenotype variation in six patients with SMMCI syndrome.
SUBJECTS AND METHODS The medical history of six unrelated individuals identified with SMMCI at the Centre for Human Genetics, University Hospitals Leuven, were evaluated. Clinical dentofacial examination was carried out and standard dentofacial records were collected from these patients in the Department of Oral Health Sciences —Section of Orthodontics (Fig. 1; Table I) as part of the routine orthodontic treatment planning prior to the start of their orthodontic treatment. Detailed orofacial phenotyping with extraoral and intraoral evaluation, extra- and intra-oral photographs, an orthopantomogram (OPG), and a lateral headplate was performed in all six patients. Patients 2 and 3 were reported previously [Fryns et al., 1993; Frints et al., 1998b]. Array Comparative Genomic Hybridization (aCGH) analysis was performed in all six patients in the Centre for Human Genetics in Leuven. Peripheral blood-derived DNA from these patients and sex-matched reference samples were hybridized to a 180-k oligo array platform (OGT CytoSure Syndrome Plus array, OGT Oxford, UK). In one patient Exome Sequencing (ES) was performed after excluding the presence of a copy number variant (CNV). Exome sequencing was performed following library preparation with the Illumina DNA Sample Prep kit (Illumina, San Diego) and the SeqCap EZ Human Exome Library v3.0 enrichment kit (Roche, San Francisco). The sample was then sequenced on an Illumina
AMERICAN JOURNAL OF MEDICAL GENETICS PART A HiSeq 2000. Data analysis (read mapping, variant calling and annotation) was carried out using an in-house pipeline at the Genomics Core of the University Hospitals of the KU Leuven (UZ Leuven), Belgium. The variant found in this patient was submitted to the ClinVar Database (http://www.ncbi.nlm.nih.gov/clinvar/) with the following accession number: SCV000188857. The DNA sequences were submitted to the GenBank Database (http://www. ncbi.nlm.nih.gov/genbank) with the following accession number: KP061153. In the two remaining patients multiplex ligation dependent probe amplification (MLPA) and further sequencing were performed to screen for small intragenic mutations in the HPE candidate genes. To review the literature on the etiology of SMMCI, MEDLINE, and EMBASE were searched for articles on SMMCI. This study was registered and approved by the Medical Ethics Committee of the University Hospital Leuven (ML9682).
RESULTS In Table I a summary is presented on the medical history, clinical observations, and/or examinations including dentofacial features, as well as the clinical genetic diagnosis in four of the six patients. Patient 1, a girl, was born at 37-weeks of gestation. She was the second child of a 28-year-old woman and her 33-year-old husband. The pregnancy was complicated by maternal hypertension. The mother is heterozygote for sickle-cell anemia. On examination at age 5.2 years her weight was 1,860 g (50th centile), length was 107.5 cm (25th–50th centile), and OFC was 50.5 cm (50th–75th centile). She had mild intellectual disability (ID) according to the Snijders–Oomen nonverbal intelligence tests (SON-R tests). Her IQ was 57 at age 7 according to the SON-R 2,5-7. Other than SMMCI, no striking dysmorphic facial features were observed. Array CGH showed a deletion at the 18p11 chromosomal region. Patient 2, a girl, was born at 38-weeks of gestation. She is the third child of a 35-year-old woman and 38-year-old husband. At birth, an omphalocoele was present and she had respiratory distress due to macroglossia. Her birth OFC was 32 cm (qter) in a fetus with microcephaly alobar holoprosencephaly and cyclopia. Prenat Diagn 19:986–989. Chen CP, Lin SP, Su YN, Chern SR, Su JW, Lee CC, Wang W. 2012. Partial trisomy 1q (1q42.13–>qter) and partial monosomy 6q (6q27–>qter) in a girl with single median maxillary central incisor, corpus callosum dysgenesis and developmental delay. Genet Couns 23:447–455. Dolan LM, Willson K, Wilson WG. 1981. 18p—syndrome with a single central maxillary incisor. J Med Genet 18:396–398. Domene S, Roessler E, El-Jaick KB, Snir M, Brown JL, Velez JI, Bale S, Lacbawan F, Muenke M, Feldman B. 2008. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet 17:3919–3928. El-Jaick KB, Fonseca RF, Moreira MA, Ribeiro MG, Bolognese AM, Dias SO, Pereira ET, Castilla EE, Orioli IM. 2007. Single median maxillary central incisor: new data and mutation review. Birth Defects Res A Clin Mol Teratol 79:573–580. Frints SG, Schoenmakers EF, Smeets E, Petit P, Fryns JP. 1998a. De novo 7q36 deletion: Breakpoint analysis and types of holoprosencephaly. Am J Med Genet 75:153–158. Frints SG, Schrander-Stumpel CT, Schoenmakers EF, Engelen JJ, Reekers AB, Van den Neucker AM, Smeets E, Devlieger H, Fryns JP. 1998b. Strong variable clinical presentation in 3 patients with 7q terminal deletion. Genet Couns 9:5–14. Fryns JP, Kleczkowska A, Devriendt K, Devliegher H, Van den Berghe H. 1993. Wiedemann–Beckwith syndrome and chromosomal duplication 4q/deficiency 18p. Genet Couns 4:37–41.
Kantaputra PN, Limwongse C, Tochareontanaphol C, Mutirangura A, Mevatee U, Praphanphoj V. 2006. Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: Association with an 18p11.3 deletion. Am J Med Genet A 140:2598–2602. Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domene S, Velez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njolstad PR, Brunner HG, Carey JC, Hehr U, Musebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van HA, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. 2009. Clinical spectrum of SIX 3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet 46:389–398. Lin D, Huang Y, He F, Gu S, Zhang G, Chen Y, Zhang Y. 2007. Expression survey of genes critical for tooth development in the human embryonic tooth germ. Dev Dyn 236:1307–1312. Masuno M, Fukushima Y, Sugio Y, Ikeda M, Kuroki Y. 1990. Two unrelated cases of single maxillary central incisor with 7q terminal deletion. Jinrui Idengaku Zasshi 35:311–317. Miertus J, Borozdin W, Frecer V, Tonini G, Bertok S, Amoroso A, Miertus S, Kohlhase J. 2006. A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome. Hum Genet 119:154–161. Miura M, Kato N, Kojima H, Oguchi H. 1993. Triple-X syndrome accompanied by single maxillary central incisor: Case report. Pediatr Dent 15:214–217. Moog U, De Die-Smulders CE, Schrander-Stumpel CT, Engelen JJ, Hamers AJ, Frints S, Fryns JP. 2001. Holoprosencephaly: The Maastricht experience. Genet Couns 12:287–298. Muenke M, Gurrieri F, Bay C, Yi DH, Collins AL, Johnson VP, Hennekam RC, Schaefer GB, Weik L, Lubinsky MS,. 1994. Linkage of a human brain malformation, familial holoprosencephaly, to chromosome 7 and evidence for genetic heterogeneity. Proc Natl Acad Sci USA 91: 8102–8106. Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M. 2001. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Am J Med Genet 102:1–10. Naudi AB, Fung DE. 2007. A child with 18p- syndrome: A case report. Spec Care Dentist 27:12–14.
2458 Pasquier L, Dubourg C, Blayau M, Lazaro L, Le MB, David V, Odent S. 2000. A new mutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J Hum Genet 8:797–800. Sanchez ZJ, Andres CM, Lopez Garcia MJ. 2008. Mosaic trisomy 9: Report of a new case with a long-term survival. An Pediatr (Barc) 68:273–276. Strehle EM, Gruszfeld D, Schenk D, Mehta SG, Simonic I, Huang T. 2012. The spectrum of 4q- syndrome illustrated by a case series. Gene 506: 387–391. Taine L, Goizet C, Wen ZQ, Chateil JF, Battin J, Saura R, Lacombe D. 1997. 18p monosomy with midline defects and a de novo satellite identified by FISH. Ann Genet 40:158–163. Taniguchi K, Anderson AE, Sutherland AE, Wotton D. 2012. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet 8:e1002524. Tavin E, Stecker E, Marion R. 1994. Nasal pyriform aperture stenosis and the holoprosencephaly spectrum. Int J Pediatr Otorhinolaryngol 28:199–204.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Tubbs RS, Oakes WJ. 2004. Lumbosacral agenesis and anteroposterior split cord malformation in a patient with single central maxillary incisor: Case report and review of the literature. J Child Neurol 19: 544–547. Yang HC, Shyur SD, Huang LH, Chang YC, Wen DC, Liang PH, Lin MT. 2005. DiGeorge syndrome associated with solitary median maxillary central incisor. Asian Pac J Allergy Immunol 23:159–163. Zahnleiter D, Trautmann U, Ekici AB, Goehring I, Reis A, Dorr HG, Rauch A, Thiel CT. 2011. Familial short stature due to a 5q22.1–q23.2 duplication refines the 5q duplication spectrum. Eur J Med Genet 54: e521–e524.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
