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

Lydie Burglen, Sandra Chantot-Bastaraud, Catherine Garel, Mathieu Milh, Renaud Touraine, Ginevra Zanni, Florence Petit, Alexandra Afenjar, Cyril Goizet, Sabina Barresi, Aurélie Coussement, Christine Ioos, Leila Lazaro, Sylvie Joriot, Isabelle Desguerre, Didier Lacombe, Vincent des Portes, Enrico Bertini, Jean-Pierre Siffroi, Thierry Billette de Villemeur, Diana Rodriguez
Orphanet Journal of Rare Diseases. 2012-01-01; 7(1): 18
DOI: 10.1186/1750-1172-7-18

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1. Orphanet J Rare Dis. 2012 Mar 27;7:18. doi: 10.1186/1750-1172-7-18.

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

Burglen L(1), Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, Petit F,
Afenjar A, Goizet C, Barresi S, Coussement A, Ioos C, Lazaro L, Joriot S,
Desguerre I, Lacombe D, des Portes V, Bertini E, Siffroi JP, de Villemeur TB,
Rodriguez D.

Author information:
(1)Centre de Référence Maladies Rares « malformations et maladies congénitales du
cervelet », Hôpital Trousseau-Paris, CHU de Lyon, CHU de Lille, Paris, France.

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
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.

DOI: 10.1186/1750-1172-7-18
PMCID: PMC3351739
PMID: 22452838 [Indexed for MEDLINE]

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