Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient

Orphanet Journal of Rare Diseases

Diana Rodriguez²  Thierry Billette de Villemeur²  Jean-Pierre Siffroi^1,12  Enrico Bertini⁶  Vincent des Portes³  Didier Lacombe^1,10  Isabelle Desguerre⁵  Sylvie Joriot^1,15  Leila Lazaro^1,14  Christine Ioos¹  Aurélie Coussement^1,11  Sabina Barresi⁶  Cyril Goizet^1,10  Alexandra Afenjar²  Florence Petit⁸  Ginevra Zanni⁶  Renaud Touraine⁴  Mathieu Milh⁹  Catherine Garel^1,13  Sandra Chantot-Bastaraud^1,12  Lydie Burglen⁷ 

[1] AP-HP, Pôle de Pédiatrie, Hôpital Raymond Poincaré, Garches, France;AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France;Service de Neuropédiatrie, CHU de Lyon, et Université Lyon1, Lyon, France;Service de Génétique Médicale, Centre Hospitalier Universitaire, St Etienne, France;AP-HP, Service de Neuropédiatrie, Hôpital Necker, Paris, France;Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Pediatric Research Hospital, Rome, Italy;Inserm U676, Hôpital Robert Debré, Paris, France;Service de Génétique Médicale, Centre Hospitalier Universitaire, Lille, France;AP-HM, Hôpital La Timone Enfants, Service de Neuropédiatrie, Marseille, France;CHU Bordeaux, Service de Génétique Médicale, Université Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Bordeaux EA4576, France;AP-HP, Service de cytogénétique, Hôpital Cochin, Paris, France;AP-HP, Hôpital Trousseau, Service de Génétique et d'Embryologie Médicales, Paris, France;AP-HP, Service de Radiologie, Hôpital Trousseau, Paris, France;Service de pédiatrie, Centre hospitalier, Bayonne 64109, France;Service de Neuropédiatrie, Centre Hospitalier Universitaire, Lille, France

关键词: Array-CGH;    Mosaicism;    CASK gene;    Microcephaly;    Pontocerebellar hypoplasia;   

Others  :  864443
DOI  :  10.1186/1750-1172-7-18

 received in 2011-09-22, accepted in 2012-03-27,  发布年份 2012

【 摘 要 】

Background

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH).

Methods

Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected.

Results

We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype.

Conclusion

This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.

【 授权许可】

   
2012 Burglen et al; licensee BioMed Central Ltd.

【 图 表 】

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