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Beware the solitary maxillary median central incisor

Department of Orthodontics, East Kent Hospitals NHS Trust, Canterbury, Kent, UK

Martyn T. Cobourne

Department of Orthodontics and Craniofacial Development, King’s Dental Institute, King’s College London, London, UK

Address for correspondence: Dr Martyn Cobourne, Senior Lecturer/Hon Consultant in Orthodontics, Department of Orthodontics and Craniofacial Development, Floor 22, King’s Dental Institute, King’s College London, London SE1 9RT, UK. Email: martyn.cobourne{at}kcl.ac.uk

Received 28 March 2007; accepted 24 June 2007

	Abstract

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

 
The incidence of a solitary maxillary median central incisor (SMMCI) tooth in the general population is low, in either the primary or secondary dentition. The most common cause of a missing maxillary central incisor is trauma, or more rarely hypodontia. However, SMMCI is also a recognized genetic anomaly and affected individuals can be carriers for a potentially more serious condition affecting midline development of the brain and face, holoprosencephaly (HPE). The presence of an SMMCI of unknown aetiology is therefore considered a risk factor for HPE, even in the absence of any other clinical signs. The orthodontist may be responsible for diagnosing cases of SMMCI with no obvious cause, and in these subjects due consideration should be given to referral for the appropriate genetic testing and counselling.

Key words: Solitary median maxillary central incisor, genetic testing, orthodontics, sonic hedgehog

	Introduction

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

 
All syndromic conditions affecting the head and neck have a characteristic range of clinical features and nowhere is this more dramatic than in holoprosencephaly (HPE)¹ (Figure 1). HPE is a congenital malformation sequence, which involves impaired cleavage of the embryonic forebrain in association with varying degrees of facial dysmorphism.² In the most severe form of HPE, the early forebrain fails to divide into right and left cerebral hemispheres, the olfactory and optic tracts remain as single midline structures and the face exhibits cyclopia, with a proboscis or rudimentary nose sitting above a single midline eye.³ In contrast, milder or microforms of this condition can present with normal brain morphology, but varying degrees of midline facial dysmorphogenesis, including clefting. The mildest manifestation of HPE is represented by normal development of the central nervous system (CNS) and face, but the presence of only a solitary maxillary median central incisor (SMMCI). This diverse range of clinical presentation can even occur within members of the same pedigree.⁴ Importantly, individuals affected by SMMCI can be carriers for HPE, and the presence of unexplained SMMCI is therefore considered a risk factor even in the absence of any other clinical signs. The orthodontist may be responsible for diagnosing cases of SMMCI with no obvious aetiological basis, and in these subjects due consideration should be given to referral for the appropriate genetic testing.

View larger version (112K): [in this window] [in a new window]   Figure 1 The clinical spectrum of HPE. (A) Microcephaly with absence of nasal bones and median cleft lip/palate. (B) Premaxillary agenesis and midline cleft lip/palate. (C,D) Severe semilobar HPE but relatively normal facies. (E,F) Microcephaly, premaxillary agenesis and cleft lip. (G,H) Microcephaly, ocular hypotelorism, flat nose and hypoplasia of the midface and lip philtrum, but normal brain scan. (I) Severe alobar HPE with cyclopia and midline proboscis above the eye. (J) Microcephaly, ocular hypotelorism, right-sided cleft lip and palate (repaired) and normal brain. (K) Microcephaly, philtrum hypoplasia and normal brain. (L) Lobar HPE, microcephaly and philtrum hypoplasia. All these individuals have mutations in the sonic hedgehog gene. Reproduced from Nanni et al.,10 by permission of Oxford University Press patterning can lead to such a spectrum of malformation severity.15

	HPE is a common cause of inherited birth defect

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

	SMMCI is a feature of HPE

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

 
Solitary maxillary median central incisor can occur as one manifestation of a cyclopic phenotype associated with HPE, as part of a group of abnormalities unrelated to HPE or as an isolated condition in its own right.^16,17 Mutation in the human SHH gene has been associated with isolated SMMCI, and individuals with this condition demonstrating both normal intelligence and brain imaging, have been reported to have children affected with HPE.^16,17 The HPE spectrum can demonstrate incomplete penetrance and it is estimated that only 70% of obligate carriers show some clinical feature of this condition.¹⁸ Therefore, the presence of SMMCI must be considered a risk factor for HPE, even in the absence of any other clinical signs.

	A role for the orthodontist?

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

 
The absence of a maxillary central incisor is most commonly due to trauma (Figure 2a), especially when there is an increased overjet. Hypodontia affecting the primary dentition is very rare and in the permanent dentition congenital tooth absence more frequently affects the maxillary lateral incisor,¹⁹ but rarely the central incisor can be affected. Therefore, in cases where SMMCI cannot be explained on the basis of the clinical history, it is suggested that the subject is referred for further genetic analysis (Figure 2b). Other clinical signs associated with SMMCI as part of the spectrum of HPE are a very symmetrical upper central incisor²⁰ and the presence of a prominent mid-palatal vomerine ridge.²¹

View larger version (49K): [in this window] [in a new window]   Figure 2 Similarities in presentation of a missing maxillary central incisor. (a) Loss of a single maxillary central incisor due to trauma, the symmetrical position of the remaining maxillary incisor is suggestive of SMMCI. (b) SMMCI as part of a spectrum of microform HPE. Brain imaging in this subject was normal

More recently, it has been shown that a loss of function affecting the mouse Gas1 gene is associated with microform HPE.²² Gas1 encodes a GPI-linked membrane protein that facilitates sonic hedgehog signalling at long range ans is important during normal development of midline structures in the craniofacial region. Gas1^–/– mice have SMMCI, cleft palate and maxillary hypoplasia.

	Acknowledgments

 
The authors are grateful to Professor Maximilian Muenke for allowing them to reproduce Figure 1.

	References

Top Abstract Introduction HPE is a common... SMMCI is a feature... A role for the... References

 
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12 Pasquier L, Dubourg C, Gonzales M, et al. First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations. J Med Genet 2005; 42: e4.[Free Full Text]

13 Gripp KW, Wotton D, Edwards MC, et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 2000; 25: 205–8.[CrossRef][Medline]

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20 DiBiase AT, Elcock C, Smith RN, Brook AH. A new technique for symmetry determination in tooth morphology using image analysis: application in the diagnosis of solitary maxillary median central incisor. Arch Oral Biol 2006; 51: 870–75.[CrossRef][Medline]

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