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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.

Burglen L, 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 - Orphanet J Rare Dis (2012)

Bottom Line: Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy.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.

View Article: PubMed Central - HTML - PubMed

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

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.

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.

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Facial features of CASK-positive patients. A and B: patient 8 (1 year (A) and 4 years (B)). C: patient 7 (18 months). D: patient 12 (13 years). E: patient 9 (13 years). F: patient 4 (12 years). Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protuding maxilla, in the older patients. Signed informed consent was obtained from the parents of the affected children for publication of the images.
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Figure 3: Facial features of CASK-positive patients. A and B: patient 8 (1 year (A) and 4 years (B)). C: patient 7 (18 months). D: patient 12 (13 years). E: patient 9 (13 years). F: patient 4 (12 years). Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protuding maxilla, in the older patients. Signed informed consent was obtained from the parents of the affected children for publication of the images.

Mentions: Birth occipitofrontal head circumference (OFC) was in the normal or low normal range in all patients. Feeding difficulties were frequently (8/11) noticed during the first months of life (gastroesophageal reflux, sucking and swallowing difficulties). In four patients these difficulties and excessive drooling persisted at last examination (3-14 years) and one patient had been fed via a gastrostomy tube since the age of five years. Progressive microcephaly was present in all patients. Psychomotor development was variable but intellectual development was severely impaired in all patients. All patients had eye contact and acquired head control in the age range of three to 24 months. Purposeful hand control was achieved in six patients. Among the nine patients older than three years, eight were able to sit (acquired at one to three years), only one was able to walk unaided and seven patients were wheelchair bound. Language was nearly absent in 7/9 of the older patients and reduced to a few words in two. Neurologic examination displayed extrapyramidal symptoms (dystonia, buccolingual dyskinesia) and/or spasticity in 8/11. One patient had axial hypotonia and peripheral hypertonia in the first years but presented with near normal neurological examination at 11 years. The behavioral phenotype included sleep disturbances (multiple awakening during the first years) in at least seven patients and hand stereotypies and self-biting in five. Epilepsy was present in three patients: two had atypical absences and patient 7 had West syndrome in infancy. One patient presented with disabling massive myoclonias. Scoliosis and constipation were frequent. Various ophthalmologic anomalies were noted: retinopathy (5, all had abnormal ERG and two had salt-and-pepper retinopathy), optic atrophy (2), glaucoma/megalocornea (2) and nystagmus (1). Three patients had sensorineural hearing loss. One patient developed type 1 diabetes mellitus at the age of 14 years. Minor dysmorphism was observed: round face tending to lengthen in older patients, well-drawn arched eyebrows, large nasal bridge, protruding maxilla and maxillar incisors in older patients (Figure 3). No other visceral malformation was detected in any patient.


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.

Burglen L, 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 - Orphanet J Rare Dis (2012)

Facial features of CASK-positive patients. A and B: patient 8 (1 year (A) and 4 years (B)). C: patient 7 (18 months). D: patient 12 (13 years). E: patient 9 (13 years). F: patient 4 (12 years). Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protuding maxilla, in the older patients. Signed informed consent was obtained from the parents of the affected children for publication of the images.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351739&req=5

Figure 3: Facial features of CASK-positive patients. A and B: patient 8 (1 year (A) and 4 years (B)). C: patient 7 (18 months). D: patient 12 (13 years). E: patient 9 (13 years). F: patient 4 (12 years). Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protuding maxilla, in the older patients. Signed informed consent was obtained from the parents of the affected children for publication of the images.
Mentions: Birth occipitofrontal head circumference (OFC) was in the normal or low normal range in all patients. Feeding difficulties were frequently (8/11) noticed during the first months of life (gastroesophageal reflux, sucking and swallowing difficulties). In four patients these difficulties and excessive drooling persisted at last examination (3-14 years) and one patient had been fed via a gastrostomy tube since the age of five years. Progressive microcephaly was present in all patients. Psychomotor development was variable but intellectual development was severely impaired in all patients. All patients had eye contact and acquired head control in the age range of three to 24 months. Purposeful hand control was achieved in six patients. Among the nine patients older than three years, eight were able to sit (acquired at one to three years), only one was able to walk unaided and seven patients were wheelchair bound. Language was nearly absent in 7/9 of the older patients and reduced to a few words in two. Neurologic examination displayed extrapyramidal symptoms (dystonia, buccolingual dyskinesia) and/or spasticity in 8/11. One patient had axial hypotonia and peripheral hypertonia in the first years but presented with near normal neurological examination at 11 years. The behavioral phenotype included sleep disturbances (multiple awakening during the first years) in at least seven patients and hand stereotypies and self-biting in five. Epilepsy was present in three patients: two had atypical absences and patient 7 had West syndrome in infancy. One patient presented with disabling massive myoclonias. Scoliosis and constipation were frequent. Various ophthalmologic anomalies were noted: retinopathy (5, all had abnormal ERG and two had salt-and-pepper retinopathy), optic atrophy (2), glaucoma/megalocornea (2) and nystagmus (1). Three patients had sensorineural hearing loss. One patient developed type 1 diabetes mellitus at the age of 14 years. Minor dysmorphism was observed: round face tending to lengthen in older patients, well-drawn arched eyebrows, large nasal bridge, protruding maxilla and maxillar incisors in older patients (Figure 3). No other visceral malformation was detected in any patient.

Bottom Line: Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy.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.

View Article: PubMed Central - HTML - PubMed

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

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.

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.

Show MeSH
Related in: MedlinePlus