Solitary median maxillary central incisor syndrome: Clinical case with a novel mutation of sonic hedgehog

Garavelli, Livia; Zanacca, C.; Caselli, G.; Banchini, G; Dubourg, Christèle; David, Véronique; Odent, Sylvie; Gurrieri, Fiorella; Neri, Giovanni

doi:10.1002/ajmg.a.20685

Cited by 44 publications

(34 citation statements)

References 13 publications

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“…Interestingly, SMMCI is suggested as a characteristic finding in HPE patients with SHH mutations (24). In addition, SHH mutations have been identified not only in SMMCI with HPE, but also SMMCI without HPE (24,25). These findings are consistent with a primary role of Shh in PA1 as suggested in our study.…”

Section: Discussionsupporting

confidence: 92%

“…Agnathia alone occurs very rarely, and is often associated with HPE and sometimes with situs inversus totalis (25,26), all of which occur in the setting of SHH disruption in mouse and human. Moreover, Shh lies upstream of Tbx1, a major genetic determinant of DiGeorge/22q11.2 deletion syndrome that is often associated with micrognathia (15,23).…”

Section: Discussionmentioning

confidence: 99%

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Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

Yamagishi

Maeda

et al. 2006

Pediatr Res

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ABSTRACT:The secreted protein sonic hedgehog (Shh) is essential for normal development of many organs. Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches. To investigate the role of Shh signaling in early pharyngeal arch development, we analyzed Shh mutant embryos using molecular markers and found that the first pharyngeal arch (PA1) was specifically hypoplastic and fused in the midline, and remaining arches were well formed at embryonic day (E) 9.5. Molecular analyses using specific markers suggested that the growth of the maxillary arch and proximal mandibular arch was severely defective in Shh-null PA1, whereas the distal mandibular arch was less affected. TUNEL assay revealed an increase in the number of apoptotic signals in PA1 of Shh mutant embryos. Ectodermal expression of fibroblast growth factor (Fgf)-8, a cell survival factor for pharyngeal arch mesenchyme, was downregulated in the PA1 of Shh mutants. Consistent with this observation, downstream transcriptional targets of Fgf8 signaling in neural crest-derived mesenchyme, including Barx1, goosecoid, and Dlx2, were also down-regulated in Shh-null PA1. These results demonstrate that epithelial-mesenchymal signaling and transcriptional events coordinated by Shh, partly via Fgf8, is essential for cell survival and tissue outgrowth of the developing PA1. (Pediatr Res 59: 349-354, 2006)

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

Yamagishi

Maeda

et al. 2006

Pediatr Res

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“…17 The presence of SMMCI may also be a clue to HPE. [18][19][20][21] When these extracerebral anomalies are found either clinically or on imaging studies, one should perform high-resolution MR imaging. If an obvious diagnosis of classic HPE is not readily evident, careful attention should be directed to the preoptic area and septal region to look for the milder forms of HPE.…”

Section: Neuroimaging Features Comparing Lobar Versus Septopreoptic Hpementioning

confidence: 99%

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Hahn¹,

Barnes²,

Clegg³

et al. 2010

AJNR Am J Neuroradiol

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SUMMARY: HPE is a congenital brain malformation characterized by failure of the prosencephalon to divide into 2 hemispheres. We have identified 7 patients who have a mild subtype of HPE in which the midline fusion was restricted to the septal region or preoptic region of the telencephalon. This subtype, which we call septopreoptic HPE, falls in the spectrum of lobar HPE, but lacks significant frontal neocortical fusion seen in lobar HPE. Other imaging characteristics include thickened or dysplastic fornix, absent or hypoplastic anterior CC, and single unpaired ACA. The SP was fully formed in 4, partially formed in 2, and absent in 1. Mild midline craniofacial malformation, such as SMMCI and CNPAS were found in 86% and 71%, respectively. Patients outside of infancy often manifested language delay, learning disabilities, or behavioral disturbances, while motor function was relatively spared.ABBREVIATIONS: AC ϭ anterior commissure; ACA ϭ anterior cerebral artery; CC ϭ corpus callosum; CNPAS ϭ congenital nasal piriform aperture stenosis; FSPGR ϭ fast-spoiled gradient-recalled; HPE ϭ holoprosencephaly; IHF ϭ interhemispheric fissure; MPR ϭ multiplanar reconstructed; SMMCI ϭ single median maxillary central incisor; SP ϭ septum pellucidum; SPGR ϭ spoiled gradient-recalled; V3 ϭ third ventricle H PE is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into 2 hemispheres, a process normally complete by the fifth week of gestation.1 As the name "HPE" implies, these nonseparated prosencephalic structures involve parts of the telencephalon and diencephalon. HPE has traditionally been classified according to DeMyer's 3 grades of severity: alobar, semilobar, and lobar.2 In addition to these classic forms, a subtype of HPE, the middle interhemispheric variant or syntelencephaly, has been characterized. 3,4 In these types of HPE, there is significant nonseparation of the neocortex of the cerebral hemispheres. In the alobar type, the entire hemispheres are involved, and in the semilobar and lobar types, the frontal lobes are primarily involved. In the middle interhemispheric variant, there is nonseparation of the posterior frontal and anterior parietal lobes in the perirolandic region. We report a series of patients who have a very mild form of HPE, in which the nonseparation is restricted to the septal (subcallosal) and/or preoptic regions or both regions (Fig 1). Patients with this type of HPE often present initially with mild midline craniofacial malformations, including SMMCI and CNPAS. Our aim was to characterize the neuroimaging and clinical findings of a mild subtype of HPE that has less neocortical fusion than classic lobar HPE. Materials and MethodsWe searched the neuroimaging data base of the Carter Centers for Research in Holoprosencephaly and Related Malformations for patients who met the criterion for a mild subtype that we call "septopreoptic HPE." The imaging criterion for inclusion was abnormal fusion restricted to the septal (subcallosal) and preoptic telencephalic re...

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“…Interestingly, the spectrum of phenotypic severity characteristic of HPE can be seen in association with identical mutations in SHH, even among members of the same pedigree (8). SHH mutation can also lead to SMMCI in the primary or secondary dentition, occurring as an isolated syndrome (12,13) or as a manifestation of HPE (14).…”

Section: Introductionmentioning

confidence: 99%

Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

Seppälä¹,

Depew²,

Martinelli³

et al. 2007

J. Clin. Invest.

125

136

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Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest-specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1 -/-mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1 -/-background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3-q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations.

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Solitary median maxillary central incisor syndrome: Clinical case with a novel mutation of sonic hedgehog

Cited by 44 publications

References 13 publications

Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

Sonic Hedgehog Is Essential for First Pharyngeal Arch Development

Septopreoptic Holoprosencephaly: A Mild Subtype Associated with Midline Craniofacial Anomalies

Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog

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