We studied the neuroimaging and neurophysiological aspects of 17 patients with midline facial defects with ocular hypertelorism (MFDH).
Methods
The investigation protocol included a previous semistructured questionnaire about family history; gestational, neonatal, and postnatal development; and dysmorphologic and neurologic evaluation. Recognized monogenic disorders and individuals with other well-known conditions were excluded. All patients had high resolution magnetic resonance imaging (MRI) with multiplanar reconstruction (MPR) and routine electroencephalograms (EEGs).
Results
We detected abnormalities in five patients whose MRIs had been previously reported as normal. MRI showed central nervous system (CNS) structural abnormalities in all patients, which included commissural alterations in 16/17 (94%), malformations of cortical development in 10/17 (58%), disturbances of neural tube closure in 7/17 (42%), and posterior fossa anomalies in 6/17 (35%). Some patients had more than one type of malformation occurring at different stages of the embryonary process. EEGs showed epileptiform activity in 4/17 (24%) and background abnormalities in 5/17 (29%) of patients.
Conclusion
This study clearly demonstrated the presence of structural and functional neurologic alterations related to MFDH. Therefore, the CNS anomalies cannot be considered incidental findings but an intrinsic part of this condition, which could be related to environmental effects and/or genetic mutations. These findings would provide a basis for future investigations on MFDH and should also be considered when planning rehabilitation.
AlzoumM.A., AlorainyI.A., A1 HusainM., A1 RuhaimiK.Multiple pericallosal lipomas in two siblings with frontonasal dysplasia.Am J Neuroradiol.2002; 23: 730–731.
2.
BarkovichA.J.Magnetic resonance imaging: role in the understanding of cerebral malformations.Brain Dev.2002; 24: 2–12.
3.
BarkovichA.J., KuznieckyR.I., JacksonG.D., GuerriniR., DobynsW.B.Classification system for malformations of cortical development: update 2001.Neurology.2001a; 57: 2168–2178.
4.
BarkovichA.J., KuznieckyR.I., DobynsW.B.Radiologic classification of malformations of cortical development.Curr Opin Neurol.2001b; 14: 145–149.
5.
BarkovichA.J., RowleyH.A., AndermannF.MR in partial epilepsy: value of high-resolution volumetric techniques.Am J Neuroradiol.1995; 16: 339–343.
6.
CohenMMJr., SedanoH.O., GorlinR.J., JirasekJ.E.Frontonasal dysplasia (median cleft face syndrome): comments on etiology and pathogenesis.Birth Defect.1971; 7: 117–119.
7.
DarabD.J., MinkoffR., ScotieJ., SulikK.K.Pathogenesis of median clefts in mice treated with methotrexate.Teratology.1987; 36: 77–86.
8.
DeMyerW.The median cleft face syndrome. Differential diagnosis of cranium bifidum occultum, hypertelorism, and median cleft nose, lip, and palate.Neurology.1967; 17: 961–971.
9.
FirnbergN., NeubuserA.FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region.Dev Biol.2002; 247: 237–250.
10.
FryburgJ.S., PersingJ.A., LinK.Y.Frontonasal dysplasia in two successive generations.Am J Med Genet.1993; 46: 712–714.
11.
FrynsJ.P., KleczkowskaA., van den BergheH.Frontonasal malformation and reciprocal translocation t(15;22)(q22;q13).Clin Genet.1993; 44: 46–47.
12.
GabrielliO., SalvoliniU., BonifaziV., CiferriL., LanzaR., RossiR., CoppaG.V., GiorgiP.L.Morphological studies of the corpus callosum by MRI in children with malformative syndromes.Neuroradiology.1993; 35: 109–112.
13.
GiffoniS.D., CendesF., ValenteM., Gil-da-Silva-LopesV.L.Midline facial defects with hypertelorism and low-grade astrocitoma: a previously undescribed association.Cleft Palate Craniofac J.2006a; 43: 748–751.
14.
GiffoniS.D., GonçalvesV.M., ZanardiV.A., Gil-da-Silva-LopesV.L.Angular analysis of corpus callosum in 18 patients with frontonasal dysplasia.Arq Neuropsiquiatr.2004; 62: 195–198.
15.
GiffoniS., GonçalvesV., ZanardiV., Gil-da-Silva-LopesV.L.Cerebellar involvement in midline facial defects with ocular hypertelorism.Cleft Palate Craniofac J.2006b; 43: 466–470.
16.
Gil-da-Silva-LopesV.L., GiffoniS.D.Central nervous system abnormalities on midline facial defects with hypertelorism detected by magnetic resonance image and computed tomography.Arq Neuropsiquiatr.2006; 64: 916–920.
17.
Gil-da-Silva-LopesV.L., Guion-AlmeidaM.L., GiffoniS.D.A.Frontonasal dysplasia, neuronal migration error and lymphoedema of limbs.Clin Dysmorphol.2004; 13: 35–37.
18.
Gil-da-Silva-LopesV.L., Maciel-GuerraA.T.A clinical study of 31 individuals with midline facial defects with hypertelorism (MFDH) and a guideline for follow-up.Arq Neuropsiquiatr.2007; 65(2B): 396–401.
19.
GrippK.W., McDonald-McGinnD.M., DriscollD.A., ReedL.A., EmanuelB.S., ZackaiE.H.Nasal dimple as part of the 22q11.2 deletion syndrome.Am J Med Genet.1997; 69: 290–292.
20.
GuerriniR., DobynsW.B.Bilateral periventricular nodular heterotopia with mental retardation and frontonasal malformation.Neurology.1998; 51: 499–503.
21.
Guion-AlmeidaM.L., Richieri-CostaA.Frontonasal malformation, first branchial arch anomalies, congenital heart defect, and severe central nervous system involvement: a possible “new” autosomal recessive syndrome?Am J Med Genet.2006; 140: 2478–2481.
22.
Guion-AlmeidaM.L., Richieri-CostaA.Frontonasal dysplasia, severe neuropsychological delay, and midline central nervous system anomalies: report of 10 Brazilian male patients.Am J Med Genet A.2009: 13;149A: 1006–1011.
23.
Guion-AlmeidaM.L., Richieri-CostaA., SaavedraD., CohenMMJr.. Frontonasal dysplasia: analysis of 21 cases and literature review.Int J Oral Maxillofac Surg.1996; 25: 91–97.
24.
HennekanR.C.M., BeemerF.A., van MerrienboerF., van KetelB.A., KramerP.G.Congenital hypothalamic hamartoma associated with severe midline defect. Report of a case.Am J Med Genet.1986; 2: 45–52.
25.
KunugiH., LeeK.B., NankoS.Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9.Schizophr Res.1999; 40: 43–47.
26.
LeesM.M., HodgkinsP., ReardonW., TaylorD., StanhopeR., JonesB., HaywardR., HockleyA.D., BaraitserM., WinterR.M.Frontonasal dysplasia with optic disc anomalies and other midline craniofacial defects: a report of six cases.Clin Dysmorphol.1998; 7: 157–162.
27.
MachinG.A.Some causes of genotypic and phenotypic discordance in monozygotic twin pairs.Am J Med Genet.1996; 61: 216–228.
28.
Martinez-FríasM.L.Primary midline developmental field I.Am J Med Genet.1995; 56: 374–381.
29.
MeguidN.A.Frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot.Clin Genet.1983; 44: 95–97.
30.
MohammedS.N., SwanM.C., WallS.A., WilkieA.O.Monozygotic twins discondant for frontonasal malformation.Am J Med Genet.2004; 130: 384–388.
31.
MontenegroM.A., GuerreiroM.M., Lopes-CendesI., GuerreiroC.A., CendesF.Interrelationship of genetics and prenatal injury in the genesis of malformations of cortical development.Arch Neurol.2002; 59: 1147–1153.
32.
MontenegroM.A., LiL.M., GuerreiroM.M., GuerreiroC.A., CendesF.Focal cortical dysplasia: improving diagnosis and localization with magnetic resonance imaging multiplanar and curvilinear reconstruction.J Neuroimaging.2002; 12: 224–230.
33.
NaidichT.P., OsbornR.E., BauerB., NaidichM J.Median cleft face syndrome: MR and CT data from 11 children.J Comput Assist Tomogr.1988; 12: 57–64.
34.
NevinN.C., LeonardA.G., JonesB.Frontonasal dysostosis in two successive generations.Am J Med Genet.1999; 87: 251–253.
35.
OpitzJ.M.The developmental field concept in clinical genetics.J Pediatr.1982; 101: 805–809.
36.
PaiG.S., LevkoffA.H., LeithisierREJr.. Median cleft of the upper lip associated with lipomas of the central of central nervous system and cutaneous polyps.Am J Med Genet.1987; 26: 921–924.
37.
Pascual-CastroviejoI., Pascual-PascualS.I., Péréz-HiguerasA.Frontonasal dysplasia and lipoma of the corpus callosum.Eur J Pediatr.1985; 144: 66–71.
38.
Richieri-CostaA., Guion-AlmeidaM.L.The syndrome of frontonasal dysplasia, callosal agenesis, basal encephalocele, and eye anomalies—phenotypic and aetiological considerations.Int J Med Sci.2004; 1: 34–42.
SedanoH.O., GorlinR.J.Frontonasal malformation as a field defect and in syndromic associations.Oral Surg Oral Med Oral Pathol.1988; 65: 704–710.
41.
SlavkinH.C.Regulatory issues during early craniofacial development: a summary.Cleft Palate J.1990; 27: 101–109.
42.
StrattonR.F., PayneR.M.Frontonasal malformation with tetralogy of Fallot associated with a submicroscopic deletion of 22q11.Am J Med Genet.1997; 69: 287–289.
43.
TeoS.H., TanM., KnightL., YeoS.H., NgI.Pericentric inversion 9-incidence and clinical significance.Ann Acad Med Singapore.1995; 24: 302–304.
44.
Van der MeulenJ.C., MazzolaR., Vermey-KeersC., StriekerM., RaphaelB.A morphogenetic classification of craniofacial malformations.Plast Reconstr Surg.1983; 71: 560–572.
45.
YasuharaT., OkamotoA., KitagawaT., NikaidoT., YoshimuraT., YanaiharaN., TakakuraS., TanakaT., OchiaiK., OhtakeY.FGF7-like gene is associated with pericentric inversion of chromosome 9, and FGF7 is involved in the development of ovarian cancer.Int J Oncol.2005; 26: 1209–1216.
