Molar Tooth Sign and Superior Vermian Dysplasia: A Radiological, Clinical, and Genetic Study

Abstract

We have identified a group of 13 patients with a homogeneous radiological pattern at MRI consisting of the molar tooth sign (MTS) and superior vermian dysplasia. The patients represent a relatively heterogeneous clinical group with variable severity of developmental delay, ataxia, hypotonia, and apnea. Careful examination of MRI prompted us to split our series of patients into two groups, based on IVth ventricle dilatation. In 4/13 patients the IVth ventricle was judged to be dilated and those patients were less severely affected while most clinically affected patients had a normal IVth ventricle. DNA samples of blood leukocytes from 6/13 consanguineous patients were genotyped using polymorphic markers encompassing the Joubert syndrome loci. We therefore sequenced AHI1 located in 6q23 in two patients who were homozygous at the locus and in four sporadic cases. Only one homozygous nonsense mutation was identified. Clinically, the patient exhibiting the AHI1 mutation was the most severely affected child with a profound encephalopathy, major hypotonia, ataxia, Leber congenital amaurosis, and normal IVth ventricle at the MRI. The present study suggests that the syndrome associating MTS and dysplasia of the superior vermis of the cerebellum is a clinically and genetically heterogeneous entity and that Jouberin (AHI1) mutations account for a marginal fraction of patients.

Key words

Cerebellum - Joubert syndrome - AHI1 - molar tooth sign - MRI

References

• 1 Boddaert N, Klein O, Ferguson N, Sonigo P, Parisot D, Hertz-Pannier L. et al . Intellectual prognosis of the Dandy-Walker malformation in children: the importance of vermian lobulation.  Neuroradiology. 2003;  45 320-324
• 2 Dixon-Salazar T, Silhavy J L, Marsh S E, Louie C M, Scott L C, Gururaj A. et al . Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria.  Am J Hum Genet. 2004;  75 979-987
• 3 Ferland R J, Eyaid W, Collura R V, Tully L D, Hill R S, Al-Nouri D. et al . Abnormal development and axonal decussation due to mutations in AHI1 in Joubert syndrome.  Nat Genet. 2004;  36 1008-1013
• 4 Gleeson J G, Keeler L C, Parisi M A, Marsh S E, Chance P F, Glass I A. et al . Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes.  Am J Med Genet A. 2004;  125 125-134
• 5 Lagier-Tourenne C, Boltshauser E, Breivik N, Gribaa M, Betard C, Barbot C. et al . Homozygosity mapping of a third Joubert syndrome locus to 6q23.  J Med Genet. 2004;  41 273-277
• 6 Patel S, Barkovich A J. Analysis and classification of cerebellar malformations.  Am J Neuroradiol. 2002;  23 1074-1087
• 7 Saar K, Al-Gazali L, Sztriha L, Rueschendorf F, Nur E KM, Reis A. et al . Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity.  Am J Hum Genet. 1999;  65 1666-1671
• 8 Satran D, Pierpont M E, Dobyns W B. Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: more than just variants of Joubert syndrome.  Am J Med Genet. 1999;  86 459-469
• 9 Castori M, Valente E M, Donati M A, Salvi S, Fazzi E, Procopio E. et al . NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders.  J Med Genet. 2005;  42 e9
• 10 Valente E M, Salpietro D C, Brancati F, Bertini E, Galluccio T, Tortorella G. et al . Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation.  Am J Hum Genet. 2003;  73 663-670