Abstract

The muscle segment homeobox (MSX1) gene plays a crucial role in epithelial-mesenchymal tissue interactions in craniofacial development. It plays a regulative role in cellular proliferation, differentiation and cell death. The human MSX1 domain was also found in cow (Bt 302906), mouse (Mm 123311), rat (Rn13592001), chicken (Gg 170873) and clawed toad (XI 547690). Cleft lip and palate is the most common anomaly of the facial part of the skull. The etiology is not fully understood, but it is believed that the key role is played by the genetic factor activated by environmental factors. Among the candidate genes whose mutations could lead to formation of the cleft, the MSX1 homeobox gene is mentioned. Mutations in the gene MSX1 can lead to isolated cleft deformities, but also cause other dismorphic changes. Among the most frequently mentioned is loss of permanent tooth buds (mostly of less than 4 teeth – hypodontia, including second premolars). Mutations of MSX1 are observed in the Pierre- Robin sequence, which may be one of the features of congenital defects or is observed as an isolated defect. Mutation of the gene can lead to the occurrence of a rare congenital defect Wiktop (dental-nail) syndrome. Deletion of a fragment MSX1 (4p16.3) located in the WHS critical region, may be a cause of some symptoms of Wolf-Hirschhorn syndrome.

Introduction

The MSX1 (muscle segment homeobox) gene plays a crucial role in epithelial-mesenchymal tissue interactions in craniofacial development. It plays a regulative role in cellular proliferation, differentiation and cell death – the processes playing a key role in cell growth and morphogenesis [4]. The MSX1 gene, as well as PAX9, AXIN2, EDA and EDAR genes is responsible for tooth hypodontia [35]. The MSX1 gene is located on chromosome 4p16.1. Its mutation causes autosomally dominant agenesis of second premolars and third molars. The gene causes multiple tooth agenesis, that is a result of a change in nucleotide sequence, where proline substitutes arginine in position 196 [24]. According to Modesto et al. [37], MSX1 mutation leads to cleft lip and palate formation, when it occurs in parallel with the PAX9 gene mutation. The mutations within MSX1 may also lead to rare congenital defects such as Wiktop syndrome and Wolf-Hirschhorn syndrome. It has previously been shown that MSX1 mutations notably change the quality of dental mesenchyme, but do not have its expression in dental epithelia at the bud, cap or bell stages of dental development [60].

The human MSX1 domain was also found in cow (Bt 302906), mouse (Mm 123311), rat (Rn13592001), chicken (Gg 170873) and clawed toad (XI 547690) [23].

Nonsyndromic cleft deformities

Cleft deformities are the most common facial malformation and are observed in ca. 10% of all the facial deformities [18]. Clefts of lip, alveolar bone and palate are observed two to three times more frequently in males while as isolated cleft of the palate is more frequent in females [54,56]. The formation of facial clefts takes place within 5-12 week of fetal development, during face formation [38]. The cleft lip and/or palate is a common congenital disorder, observed in 1:700 live births. The full etiology is not known, although a genetic factor is indisputable. There are numerous genes involved in palate formation, which disturbances of which may lead to cleft formation [44].

Observation of cleft’s familial occurrence and selective presence in only some of the individuals indicates the genetic basis of the deformity, but also suggests coexistence of other factor. The etiology of clefts is multifactor, the genetics is only a basis “triggered” by environmental causes. The genetic factor is thought to play a crucial role in 20% of cases of clefts [1,43,54]. The genetic factors are divided as follows: genes encoding signaling molecules (Bmp2, Bmp4, Bmp7, Shh, Wnt5a, Smad 2-4), growth factors (Egf, Egfr, Fgf1, Fgf2, Fgf8, Tgfα, Tgfβ1-3) and their receptors (Fgfr1, Fgfr2), transcription factors (Pax9, Tbx22, Msx1, Tbx1, Ap2α, Blx1-6, Lhx6, Gli 2-3, Hoxa2, Irf6, Pitx1, Pitx2, Prx1), cellular adhesion molecules (Pvrl1, cadherin E, connexin 43), and extracellular matrix (fibronexin, Col 1A2, Col2A1, Col11A1 Mmp2, Mmp3, Mmp9, Mmp13, Timp1-3) [46,49]. Beside the multigenetic background, the MSX1 and TGFβ3 genes are found to be the genes most strongly related to cleft anomalies [59]. Many other genes related to the clefts have their loci in different regions of chromosome 6, among them 6p23-24 and 6p24.3 [8].

Probably, most of the cases of isolated clefts are associated with either MSX1 or IRF6 mutation – it is assumed that the relation is observed in one third of cases [51]. The other candidate gene for cleft deformity might be MTHFR mutation of which lead to disturbances in folic acid transformation and storage [21]. MSX1 is responsible mainly for secondary palate formation, therefore mutations within that gene is responsible for isolated cleft palate. MSX1 is responsible for 2% of all non-syndromic clefts. Due to the complex cause of cleft deformities and to gene-to-gene interaction the influence on cleft palate formation is 9.7 times higher, which means it plays role in almost 20% of cases of clefts [29].

An association between MSX1-CA marker has been found. The clefts were more frequently observed in the MSX1 homozygous allele 4 individuals, whose mothers smoked cigarettes or with both parents smoking. Similar results were obtained in children of mothers without daily folic supplementation during the periconceptional period [5]. The strongest association between nonsyndromic clefts and gene mutation is observed for the rs6446693 region in the MSX1 gene [21]. Five variants of MSX1 mutation were found as responsible for cleft palate forming. There were: A34G, G110G, P147Q, M37L and G267A. Among them, the rarest polymorphic variant is G267A mutation [55]. However, the thesis that MSX1 is a factor influencing clefts is not promoted by all the reaearchers. Some claim that MSX1 might not be an etiologic factor responsible for orofacial clefting [12,30,36,37]. Therefore, further genetic analysis of other genes involved in facial development is required.

Wolf-Hirschhorn syndrome

Wolf-Hirschhorn syndrome (WHS), also known as chromosome microdeletion 4p syndrome or Dillian syndrome, is a rare congenital disorder observed in 1:50,000 live births. It was first described in 1961 by two independent researchers: Hirschhorn and Cooper. The deformity is more frequently observed in women. Wolf-Hirschhorn syndrome is probably caused by mutation of one of two candidate genes (WHS1 and WHS2). The syndrome is most frequently associated with a deletion within the 4p16.3 chromosome region (165kb), which encodes the MSX1 gene [17,47,50,61,63,65]. The deletion most probably refers to HOX7 gene, that maps to 4p16.1 gene [20]. The majority of cases is caused by “pure” de novo deletion and the greater the chromosomal material loss, the greater expression of Wolf-Hirschhorn syndrome [48,50].

Children suffer from multiple disorders, which include developmental delay and high mortality range of 30%. The patients suffer from congenital heart defects, muscle hypotonia, urinary tract malformations, cochlear hearing loss and immunodeficiency. The malformations are so much severe that they may lead to patient’s death [11,16,33,47].

The facial features include high forehead with prominent glabella, hypertelorism (with “protruding” eyes), high arched eyebrows, broad nasal bridge and short philtrum. A characteristic feature is micrognathia. In some cases they can be associated with facial asymmetry. The head and face take the characteristic look of a “Greek warrior helmet”. The mouth has short upper lip and downturned corners [3,41,47]. Multiple tooth agenesis occuring in this syndrome affects premolars and molars mainly. It is associated with MSX1 mutation and may vary much (from multiple tooth agenesis to oligodontia). Other dental anomalies include taurodontism and late dental development [2,24,25,37,40].

Pierre Robin syndrome

Pierre-Robin syndrome (or Pierre-Robin Sequence) is known from the triad of symptoms: congenital micrognathia, cleft of secondary palate and glossoptosis with upper airway obstruction. In some cases U-shaped palate and obstructive apnea are observed. The occurrence is relatively rare and ranges from 1:8,000 to 1:30,000 births. The sequence might be isolated or be associated with various congenital syndromes, eg. Treacher-Collins syndrome [13,42]. Beside the three characteristics, other defects might be observed. Those include dental anomalies, in particular hypodontia. This anomaly is observed most frequently in mandibular second premolars [31]. Hypodontia in this region accentates mandibular undergrowth, as loss of tooth buds is a factor of bone underdevelopment in this area [53].

The primary anomaly of Pierre Robin syndrome is failure of mandibular growth caused by a failure in dorsal hold of the head in embryonic development. As a consequence, this forces high postion of the tongue in primordia (primary oral cavity). The final result of that is physical obstruction for the posterior palatal shelves to fuse [42]. Micrognathia is found to be connected with deletions within genes 4p16-14, 4q31-35, 6q25-27 and 11q23. Those genes might be associated with Pierre Robin sequence, though its real etiology (and its probable genetic basis) is not known. The most probable genes involved in this syndrome are: the transcription factor SOX9 (on 17q24.3- -q25.1), GAD67 (on 2q31) and PVRL1 (on 11q23-q24) [22]. The SOX9 mutation alters binding of the transcription factor MSX1 [22,58]. In experiment performed in mice, it had been proved that lacking of MSX1 function results in cleft of secondary palate, migrognathia and microgenia, which are the most characteristic features of Pierre Robin syndrome as well. Furthermore, the mutation of this transcription factor causes underdevelopment of nasal, frontal and parietal bones, and the malleus. It also disturbs tooth development [45]. In families where SOX9 mutation is the cause of Pierre Robin syndrome, the sequence is more severely expressed [42].

Wiktop syndrome

Wiktop syndrome is a rare congenital disease, inherited autosomally dominantly. It is also known as tooth and nail syndrome (TNS) or “nail dysgenesis and hypodontia”, and as a type of ectodermal dysplasia. Tooth agenesis is accompanied by nail deformities – the nail plates are defective and thinner [26]. It was firstly described by Wiktop in 1965 [62] and its prevalence is estimated to ca. 1-2:10.000 births [22]. The syndrome is inherited autosomally dominantly [10]. The symptoms are less pronounced than in other types of ectodermal dysplasia, which is why those can be missed by the clinicians [64]. In 2001 it had been proved that the mesenchyme gene MSX1 is responsible for Wiktop syndrome [26]. In 2013 the 3’-UTR region of this genewas found to be the most predominant locus [14].

In this congenital disorder, nails are dysplastic, thin, spoon-shaped (koilonychia) and easy to break (onychorrhexis). They grow slowly. Changes are more pronounced in toenails than fingernails. In some cases, nail defects are less pronounced in adulthood and less characteristic [15,19,52,55,64].

The other characteristic feature is hypodontia. There is no pattern of missing teeth – it is dependent on the individuals [19]. The most frequently missing teeth are lower incisors, secondary molars and upper canines [after 10]. The teeth (if present) show deformities such as peg- -shape (conical shape). They can also be tapered or pointed [19]. The teeth are narrower and their eruption is disturbed [55]. Due to tooth agenesis, prosthetic appliances to improve chewing function and esthetic appearance might be required. In some cases they can also play a role as space maintainers [55]. Due to the hypodontia, the alveolar bone is hypoplastic and narrowed in its vertical dimension. The jaws are underdeveloped. Loss of occlusion in the vertical dimension may lead to lip eversion [19].

Dental anomalies

Along with the PAX9 gene, MSX1 homeodomain is responsible for tooth agenesis. Both of them are expressed in dental mesenchyme. When homozygously deleted, they result in tooth development delay in an early stage. MSX1 and PAX9 mutations lead to disturbances of tooth development in the cap and/or bud stages of dental development, as they are expressed in this period of dental development. In mice, heterozygous deletion of either PAX9 or MSX1, has no expression in dental structure. However, double heterozygous mutation shows arrested tooth development. This could be still rescued by Bmp4-signaling factor expression. Unlike in mice, in humans a heterozygous mutation in either MSX1 or PAX9 leads to tooth agenesis, predominantly in the posterior area. The mutation of MSX1 leads to lack of second premolars and third molars, while PAX9 mutation is responsible for lack of “wisdom teeth” [6,28,29,59]. Although MSX1 mutation is the most frequent cause of lack of tooth buds, the mutation in A240P (rs4904210) in the PAX9 gene results in multiple tooth agenesis, called oligodontia [39].

The nonsence mutation within the MSX1 gene (eg. c.C565T in exon 2 or intron 1) dramatically reduces mRNA expression, suggesting that it may lead to rapid degradation of the mutated transcript, and cause the tooth agenesis [6,34]. Hypodontia (lack of 4 or fewer tooth buds) may also be a result of heterozygous R151S mutation. The allele is mildly deleterious for familial hypodontia. The mutation within this allele itself is insufficient to cause orofacial clefting. When other factors are involved (environmental or other, genetic ones), the cleft might occur [32]. It has also been shown that MSX1 gene mutation (Ala219Thr, specifically), might be a reason for oligodontia, though due to the fact that lack of more than 4 tooth buds is more characteristic for other genes mutations, further studies of that topic are required [7,12,27]. There are studies, however, indicating that MSX1 mutation is not a factor causing hypodontia. They point to WNT10A as a major cause of isolated congenital lack of teeth [57].

Beside tooth agenesis, underdevelopment of nails (its thinner and defective structure) in MSX1-null mice was observed [26]. Eexpression of the gene is unequal in the individuals and families. It takes place not only in mesenchyme structures, but also in the neural crest, cranial sensory placodes and bones [6,9]. Other developmental anomalies could be a result of MSX1 mutation as well. Those could be deformities such as choanal atresia, anophthalmia, microphthalmia, cataracts, pachygyria, dispigmentation and mental retardation were observed in mice with MSX1 mutated gene. It might be the main responsibility of MSX1 gene to modulate the growth and inhibit differentiation. The outgrowth could be reduced by the early differentiation in progress zone of facial processes [1]. Summing up, MSX1 is an important gene expressing in mesenchyme. Its mutations may lead to developmental disorders such as variety of clefts, tooth and nail anomalies, and many others. The MSX1 mutation is observed in Pierre-Robin sequence. The mutations may lead to Witkop syndrome or Wolf-Hirschorn syndrome. Further research is required to establish the exact role of this gene.

References

• 1. Abu-Hussein M.: Cleft lip and palate – etiological factors. Dent.Med. Probl., 2012; 49: 149-156
  Google Scholar
• 2. Babich S.B., Banducci C., Teplitsky P.: Dental characteristics ofthe Wolf-Hirschhorn syndrome: a case report. Spec. Care Dentist.,2004; 24: 229-231
  Google Scholar
• 3. Battaglia A., Filippi T., Carey J.C.: Update on the clinical featuresand natural history of Wolf-Hirschhorn (4p-) syndrome: experiencewith 87 patients and recommendations for routine health supervision.Am. J. Med. Genet. C Semin. Med. Genet., 2008: 148C: 246-251
  Google Scholar
• 4. Bendall A.J., Abate-Shen C.: Roles for Msx and Dlx homeoproteinsin vertebrate development. Gene, 2000; 247: 17-31
  Google Scholar
• 5. Benko S., Fantes J.A., Amiel J., Kleinjan D.J., Thomas S., RamsayJ., Jamshidi N., Essafi A., Heaney S., Gordon C.T., McBride D., GolzioC., Fisher M., Perry P., Abadie V., Ayuso C., et al.: Highly conservednon-coding elements on either side of SOX9 associated with PierreRobin sequence. Nat. Genet., 2009; 41: 359-364
  Google Scholar
• 6. Brook A.H.: Multilevel complex interactions between genetic,epigenetic and environmental factors in the aetiology of anomaliesof dental development. Arch. Oral Biol., 2009; 54, S3-S17
  Google Scholar
• 7. Chishti M.S., Muhammad D., Haider M., Ahmad W.: A novel missensemutation MSX1 underlines autosomal recessive oligodontiawith associated dental anomalies in Pakistani families. J. Hum. Genet.,2006; 51: 872-878
  Google Scholar
• 8. Cobourne M.T.: The complex genetics of cleft lip and palate. Eur.J. Orthod., 2004; 26: 7-16
  Google Scholar
• 9. Davidson D.: The function and evolution of Msx genes: pointersand paradoxes. Trends Genet., 1995; 11: 405-411
  Google Scholar
• 10. Devadas S., Varma B., Mungara J., Joseph T., Saraswathi T.R.: Witkoptooth and nail syndrome: a case report. Int. J. Paediatr. Dent.,2005; 15: 364-369
  Google Scholar
• 11. Elder F.F., Colasurdo G.N., Rose V.M.: Wolf-Hirschhorn-Pitt-Rogers-Danksphenotype with no detectable deletion. Am. J. Hum.Genet., 2000; 67; suppl. 2: 119
  Google Scholar
• 12. Etheredge A.J., Christensen K., Del Junco D., Murray J.C., MitchellL.E.. Evaluation of two methods for assessing gene-environmentinteractions using data from the Danish case-control studyof facial clefts. Birth Defects Res. A Clin. Mol. Teratol., 2005; 73:541-546
  Google Scholar
• 13. Figueroa A.A., Glupker T.J., Fitz M.G., BeGole E.A.: Mandible,tongue and airway in Pierre Robin sequence: a longitudinal cephalometricstudy. Cleft Palate Craniofac. J., 1991; 28: 425-434
  Google Scholar
• 14. Ghaderi F., Hekmat S., Ghaderi R., Fardei M.: MSX1 mutation inWitkop syndrome; a case report. Iran J. Med. Sci., 2013; 38: 191-194
  Google Scholar
• 15. Giansanti J.S., Long S.M., Rankin J.L.: The “tooth and nail” typeof autosomal dominant ectodermal dysplasia. Oral Surg. Oral Med.Oral Pathol., 1974; 37: 576-582
  Google Scholar
• 16. Hanley-Lopez J., Estabrooks L.L., Stiehm R.: Antibody deficiencyin Wolf-Hirschhorn syndrome. J. Pediatr., 1998; 133: 141-143
  Google Scholar
• 17. Hirschhorn K, Cooper H.L.: Apparent deletion of one chromosome(4 or 5) in a child with defects of midline fusion. Hum. Chrom.News, 1961; 4: 14
  Google Scholar
• 18. Hozyasz K.: Wpływ czynników środowiskowych na występowaniewad rozszczepowych twarzoczaszki. Med. Rodz., 1999; 2: 11-17
  Google Scholar
• 19. Hudson C.D., Witkop C.J.: Autosomal dominant hypodontia withnail dysgenesis. Report of twenty-nine cases in six families. OralSurg. Oral Med. Oral Pathol., 1975; 39: 409-423
  Google Scholar
• 20. Ivens A., Flavin N., Williamson R., Dixon M., Bates G., BuckinghamM., Robert B.: The human homeobox gene HOX7 maps tochromosome 4p16.1 and may be implicated in Wolf-Hirschhornsyndrome. Hum. Genet., 1990; 84: 473-476
  Google Scholar
• 21. Jagomӓgi T., Nikopensius T., Kjutskov K., Tammekivi V., ViltropT., Saag M., Metspalu A.: MTHFR and MSX1 contribute to the risk ofnonsyndromic cleft lip/palate. Eur. J. Oral Sci., 2010; 118: 213-220
  Google Scholar
• 22. Jakobsen L.P., Knudsen M.A., Lespinasse J., Ayuso C.G., Ramos C.,Fryns J.P., Bugge M., Tommerup N.: The genetic basis of Pierre RobinSequence. Cleft Palate Craniofac. J., 2006; 43: 155-159
  Google Scholar
• 23. Jezewski P.A., Vieira A.R., Nishimura C., Ludwig B., Johnson M.,O’Brien S.E., Daack-Hirsch S., Schultz R.E., Weber A., Nepomucena B.,Romitti P.A., Christensen K., Orioli I.M., Castilla E.E., Machida J., NatsumeN., Murray J.C.: Complete sequencing shows a role for MSX1 innon-syndromic cleft lip and palate. J. Med. Genet., 2003; 40: 399-407
  Google Scholar
• 24. Jędryszek A., Kmiecik M., Paszkiewicz A.: Review of modernknowledge on hypodontia. Dent. Med. Probl., 2009; 46: 118-125
  Google Scholar
• 25. Johnston N.J. Franklin D.L.: Dental findings of a child with Wolf–Hirschhorn syndrome. Int. J. Paediatr. Dent., 2006; 16: 139-142
  Google Scholar
• 26. Jumlongras D., Bei M., Stimson J.M., Wang W.F., DePalma S.R.,Seidman C.E., Felbor U., Maas R., Seidman J.G., Olsen B.R.: A nonsensemutation in MSX1 causes Witkop syndrome. Am. J. Hum. Genet.,2001; 69: 67-74
  Google Scholar
• 27. Kamamoto M., Machida J., Yamaguchi S., Kimura M., Ono T., JezewskiP.A., Higashi Y., Nakayama A., Shimozato K., Tokita Y.: Clinicaland functional data implicate the Arg(151)Ser variant of MSX1 infamilial hypodontia. Eur. J. Hum. Genet., 2011; 19: 844-850
  Google Scholar
• 28. Kapadia H., Mues G., D’Souza R.: Genes affecting tooth morphogenesis.Orthod. Craniofac. Res., 2007; 10: 105-113
  Google Scholar
• 29. Kohli S.S., Kohli V.S.: A comprehensive review of the geneticbasis of cleft lip and palate. J. Oral Maxillofac. Pathol., 2012; 16: 64-72
  Google Scholar
• 30. Koillinen H., Ollikainen V., Rautio J., Hukki J., Kere J.: Linkageand linkage disequilibrium searched for between non-syndromiccleft palate and four candidate loci. J. Med. Genet., 2003; 40: 464-468
  Google Scholar
• 31. Larson M., Helidust R., Jakobsson O.P.: Dentalabnormalities andectopic eruption in patients with isolated cleft palate. Scand. J. Plast.Reconstr. Surg. Hand Surg., 1997; 32: 203-212
  Google Scholar
• 32. Liang J., Zhu L., Meng L., Chen D., Bian Z.: Novel nonsense mutationin MSX1 causes tooth agenesis with cleft lip in a Chinese family.Eur. J. Oral Sci., 2012; 120: 278-282
  Google Scholar
• 33. Lurie I.W., Lazjuk G.I., Ussova Y.I., Presman E.B., Burevich D.B.:The Wolf-Hirschhorn syndrome. I. Genetics. Clin. Genet., 1980; 17:375-384
  Google Scholar
• 34. MacKenzie A., Leeming G.L., Jowett A.K., Ferguson M.W., SharpeP.T.: The homeobox gene Hox 7.1 has specific regional and temporalexpression patterens during early murine craniofacial embryogenesis,especially tooth development in vivo and in vitro. Development,1991; 111: 269-285
  Google Scholar
• 35. Mielnik-Błaszczak M., Piątkowska A., Machowska A., BukowskaB.: Tooth Genesis – a review of literture and own case studies. Dent.Med. Probl., 2012; 49: 293-298
  Google Scholar
• 36. Mitchell L.E., Murray J.C., O’Brien S., Christensen K.: Evaluationof two putative susceptibility loci for oral clefts in the Danish population.Am. J. Epidemiol., 2001; 153: 1007-1015
  Google Scholar
• 37. Modesto A., Moreno L.M., Krahn K., King S., Lidra A.C.: MSX1and orofacial clefting with and without tooth agenesis. J. Dent. Res.,2006; 85: 542-546
  Google Scholar
• 38. Moore G., Ivens A., Chambers J., Bjornsson A., Arnason A., JenssonO., Williamson R.: The application of molecular genetics to detectionof craniofacial abnormality. Development, 1988; 103: 233-239
  Google Scholar
• 39. Mostowska A., Biedziak B., Jagodziński P.P.: Analysis of the codingsequence of the MSX1 and PAX9 gnes in patients with congenitallack of permanent teeth. Dent. Med. Probl., 2012; 49: 157-165
  Google Scholar
• 40. Nieminen P., Kotilainen J., Aalto Y., Knuutila S., Pirinen S., ThesleffI.: MSX1 gene is deleted in Wolf-Hirschhorn syndrome patientswith oligodontia. J. Dent. Res., 2003; 82: 1013-1017
  Google Scholar
• 41. Pitt, D.B., Rogers, J.G., Danks, D.M.: Mental retardation, unusualface, and intrauterine growth retardation: a new recessive syndrome?Am. J. Med. Genet., 1984; 19: 307-313
  Google Scholar
• 42. Rainger J.K., Bhatia S., Bengani H., Gautier P., Rainger J., PearsonM., Ansari M., Crow J., Mehendale F., Palinkasova B., Dixon M.J.,Thompson P.J., Martin M., Sisodiya S.M., Kleinjan D.A., FitzpatrickD.R.: Disruption of SATB2 or its long-range cis-regulation by SOX9causes a syndromic form of Pierre Robin sequence. Hum. Mol. Genet.,2014; 15: 2569-2579
  Google Scholar
• 43. Rychlik D., Wójcicki P., Koźlik M.: Osteoplasty of the alveolarcleft defect. Adv. Clin. Exp. Med., 2012; 21: 255-262
  Google Scholar
• 44. Salahshourifar I., Halim A.S., Wan Sulaiman W.A., ZilfalilB.A.: Contribution of MSX1 variants to the risk of non-syndromiccleft lip and palate in a Malay population. J. Hum. Genet.,2011; 56: 755-758
  Google Scholar
• 45. Satokata I., Maas R.: Msx1 deficient mice exhibit cleft palateand abnormalities of craniofacial and tooth development. Nat. Genet.,1994;6: 348-356
  Google Scholar
• 46. Schutte B.C., Murray J.C.: The many faces and factors of orofacialclefts. Hum. Mol. Genet., 1999; 8: 1853-1859
  Google Scholar
• 47. Shannon N.L., Maltby E.L., Rigby A.S., Quarrell O.W.: An epidemiologicalstudy of Wolf-Hirschhorn syndrome: life expectancy andcause of mortality. J. Med. Genet., 2001; 38: 674-679
  Google Scholar
• 48. Sifakis S., Manolakos E., Vetro A., Kappou D., Peitsidis P.,Kontodiou M., Garas A., Vrachnis N., Konstandinidou A., ZuffardiO., Orru S., Papoulidis I.: Prenatal diagnosis of Wolf-Hirschhornsyndrome confirmed by comparative genomic hybridization array:report of two cases and review of the literature. Mol. Cytogenet.,2012; 5: 12
  Google Scholar
• 49. Stanier P., Moore G.E.: Genetics of cleft lip and palate: syndromicgenes contribute to the incidence of non-syndromic clefts. Hum.Mol. Genet., 2004; 13: R73-R81
  Google Scholar
• 50. Stec I., Wright T.J., van Ommen G.J., de Boer P.A., van HaeringenA., Moorman A.F., Altherr M.R., den Dunnen J.T.: WHSC1, a 90 kbSET domain containing gene, expressed in early development andhomologous to a Drosophila dysmorphy gene maps in the Wolf–Hirschhorn syndrome critical region and is fused to IgH in t(4;14)multiple myloma. Hum. Mol. Genet., 1998; 7: 1071-1082
  Google Scholar
• 51. Steponavičiūtė D., Kasnauskienė J., Kučinskas V.: Nucleotidesequence changes in the MSX1 and IRF6 genes in Lithuanian patientswith nonsyndromic orofacial clefting. Acta Med. Lithuanica,2006; 13: 216-225
  Google Scholar
• 52. Subramaniam P., Neeraja G.: Witkop’s tooth and nail syndrome:a multifaceted approach to dental management. J. Indian. Soc. Pedod.Prev. Dent., 2008; 26: 22-25
  Google Scholar
• 53. Suri S., Ross R.B., Tompson B.D.: Mandibular morphology andgrowth with and without hypodontia in subjects with Pierre Robinsequence. Am. J. Orthod. Dentofac. Orthop., 2006; 130: 37-46
  Google Scholar
• 54. Szeląg J., Noga L., Orłowska K., Pałka Ł., Paradowska A.: Analizawpływu endo- i egzogennych czynników ryzyka w etiologii rozszczepówpodniebienia pierwotnego i wtórnego. Dent. Med. Probl.,2006; 43: 556-562
  Google Scholar
• 55. Świder K., Szozda A., Tokarski T.: Prosthodontic treatment ofchildren – case reports. Dent. Med. Probl., 2013; 50: 106-113
  Google Scholar
• 56. Tortora C., Meazzini M.C., Garratini G., Brusati R.: Prevalence ofabnormalities in dental structure, position and eruption pattern ina population of unilateral and bilateral cleft lip and palate patients.Cleft Palate Craniofac. J., 2008; 45: 154-162
  Google Scholar
• 57. van den Boogaard M.J., Creton M., Bronkhorst Y., van der HoutA., Hennekam E., Lindhout D., Cune M., Ploos van Amstel H.K.:WNT10A, rather than MSX1 is a major cause of non-syndromic hypodontia.J. Med. Genet., 2012; 49: 327-331
  Google Scholar
• 58. van den Boogaard M.J., de Costa D., Krapels I.P., Liu F., van DuijnC., Sinke R.J., Lindhout D., Steegers-Theunissen R.P.: The MSX1allele 4 homozygous child exposed to smoking at periconception ismost sensitive in developing nonsyndromic orofacial clefts. Hum.Genet., 2008; 124: 525-534
  Google Scholar
• 59. Vieira A.R., Orioli I.M., Castilla E.E., Cooper M.E., Marazita M.L.,Murray J.C.: MSX1 and TGFβ3 contribute to clefting in south America.J. Dent. Res., 2003; 82: 289-292
  Google Scholar
• 60. Wang J., Jjan F., Chen J., Wang H., Lin Y., Yang Z., Pan X., Lai W.:Sequence analysis of PAX9, MSX1 and AXIN2 genes in a Chinese oligodontiafamily. Arch. Oral Biol., 2011; 56: 1027-1034
  Google Scholar
• 61. Wieczorek D., Krause M., Majewski F., Albrecht B., Horn D., RiessO, Gillessen-Kaesbach G.: Effect of the size of the deletion and clinicalmanifestation in Wolf-Hirschhorn syndrome: analysis of 13 patientswith a de novo deletion. Eur. J. Hum. Genet., 2000; 8: 519-526
  Google Scholar
• 62. Witkop C.J.: Genetic disease of the oralcavity. In: Tiecke R.W.(ed.) Oralpathology. Blakiston Division, McGraw-Hill, New York,1965, 810-814
  Google Scholar
• 63. Wright T.J., Ricke D.O., Denison K., Abmayr S., Cotter P.D., HirschhornK., Keinanen M., McDonald-McGinn D., Somer M., SpinnerN., Yang-Feng T., Zackai E., Altherr M.R.: A transcript map of thenewly defined 165kb Wolf-Hirschhorn syndrome critical region.Hum. Mol. Genet., 1997; 6: 317-324
  Google Scholar
• 64. Zabawski E.J.Jr., Cohen J.B.: Hereditary hypodontia and onochorrhexisof the fingernails and toenail koilonychias: Witkop’s toothand nail syndrome. Dermatol. Online J., 1999; 5: 3
  Google Scholar
• 65. Zollino M., Lecce R., Fischetto R., Murdolo M., Faravelli F., SelicorniA., Buttè C., Memo L., Capovilla G., Neri G.: Mapping the Wolf–Hirschhorn syndrome phenotype outside the currently acceptedWHS critical region and defining a new critical region, WHSCR-2.Am. J. Hum. Genet.,. 2003; 75: 590-597
  Google Scholar

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