title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre de Référence Maladies Rares « malformations et maladies congénitales du cervelet », Hôpital Trousseau-Paris, CHU de Lyon, CHU de Lille, Paris, France. lydie.burglen@trs.aphp.fr
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: Sandra
authors.initials: S
authors.lastname: Chantot-Bastaraud
authors.forename: Catherine
authors.initials: C
authors.lastname: Garel
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.forename: Renaud
authors.initials: R
authors.lastname: Touraine
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Sabina
authors.initials: S
authors.lastname: Barresi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Coussement
authors.forename: Christine
authors.initials: C
authors.lastname: Ioos
authors.forename: Leila
authors.initials: L
authors.lastname: Lazaro
authors.forename: Sylvie
authors.initials: S
authors.lastname: Joriot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.forename: Thierry Billette
authors.initials: TB
authors.lastname: de Villemeur
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
mesh_terms: D005260:Female; D051528:Guanylate Kinases / Q000235:genetics*; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation; D009849:Olivopontocerebellar Atrophies / Q000235:genetics*; D010641:Phenotype; D049951:X Chromosome Inactivation
chemical_list: C106868:CASK kinases; D051528:Guanylate Kinases