Ocular features in Aicardi syndrome: A case report.

RATIONALE: Aicardi syndrome is a genetic malformation syndrome with a triad of dysgenesis or agenesis of the corpus callosum, distinctive chorioretinal lacunae and infantile spasms. It is a rare developmental disorder first described in 1965. The disease affects 1 in 100,000 live births. PATIENT CONCERNS: We describe a 34-month-old girl diagnosed with Aicardi Syndrome. DIAGNOSIS: Based on the results of color images of the fundus, medical history as well as the analysis of karyotype and DNA microarrays, the patient was diagnosed with Aicardi's syndrome. INTERVENTIONS: Additionally an B-scan ultrasonography and an electrophysiological test was performed. OUTCOME: Fundoscopic examination revealed optic disc colobomas in both eyes, extensive chorioretinal lacunae at the posterior pole with retinal pigment epithelium regrouping and atrophy. Flash visual evoked potentials (FVEP) P2 amplitude was lower than normal range. B-scan ultrasonography revealed an optic disc lesion consistent with optic disk coloboma. LESSONS: Children with congenital central nervous system malformations should undergo regular ophthalmic checkups to facilitate diagnosis and determine prognosis of visual function development.

Severe CNS involvement in WWOX mutations: Description of five new cases.

Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting.

Síndrome de Aicardi con malformación tipo Dandy-Walker / Aicardi syndrome with Dandy-Walker type malformation

Introducción. El síndrome de Aicardi (OMIM 304050) fue descrito en 1965. Su tríada clásica está compuesta por espasmos infantiles, agenesia parcial o total del cuerpo calloso y alteraciones oculares, como lagunas coriorretinianas. Se postula un mecanismo de herencia ligado a X dominante. Caso clínico. Niña nacida a término, sin antecedentes familiares patológicos ni consanguinidad parental, con diagnóstico prenatal de malformación tipo Dandy-Walker, quien presentó episodios convulsivos, coloboma del nervio óptico, bloque vertebral torácico con presencia de escoliosis, ecografía transfontanelar con agenesia del cuerpo calloso y cariotipo 46,XX. Se diagnosticó de síndrome de Aicardi y falleció con mes y medio de edad. En la autopsia se evidenció hidrocefalia supratentorial con presencia de papiloma de los plexos coroideos, quiste en la fosa posterior (cuarto ventrículo), hipoplasia del vermis cerebeloso, agenesia del hemisferio del cuerpo calloso y cerebeloso izquierdo, rasgos faciales característicos del síndrome, paladar ojival, pectus excavatum, escoliosis, quiste paraovárico y hepatomegalia. Conclusiones. Pocos casos han descrito la asociación de la patología y la presencia de malformación de Dandy-Walker. Se comunica un nuevo caso con esta asociación, teniendo en cuenta que las alteraciones relacionadas, principalmente agenesia o hipoplasia del cuerpo calloso, sugieren que tiene un componente genético de base. El estudio de búsqueda de la etiología de centrarse en evaluar aquellos genes que tengan relación con el neurodesarrollo y su activación en la etapa de organogenia. El diagnóstico definitivo establece el pronóstico, manejo y asesoría genética a la familia (AU)

Introduction. Aicardi syndrome (OMIM 304050) was first described in 1965. Its classic triad consists of infantile spasms, partial or total agenesis of the corpus callosum and ocular disorders, such as chorioretinal lacunae. It has been posited that it is due to a mechanism involving X-linked dominant inheritance. Case report. We report the case of a full-term female, with no pathological familial history or parental consanguinity, with a prenatal diagnosis of Dandy-Walker type malformation, who presented convulsions, coloboma of the optic nerve, thoracic vertebral block with presence of scoliosis, transfontanellar ultrasound imaging showing agenesis of the corpus callosum and karyotype 46,XX. She was diagnosed with Aicardi syndrome and died at the age of one and a half months. The autopsy revealed supratentorial hydrocephalus with the presence of choroid plexus papilloma, a cyst in the posterior fossa (fourth ventricle), hypoplasia of the cerebellar vermis, agenesis of the left hemisphere of the corpus callosum and cerebellum, characteristic facial features of the syndrome, ogival palate, pectus excavatum, scoliosis, paraovarian cyst and hepatomegaly. Conclusions. Few cases of an association between the pathology and the presence of Dandy-Walker malformation have been described. We report a new case of the association, bearing in mind that the related disorders, mainly agenesis or hypoplasia of the corpus callosum, suggest the existence of an underlying genetic component. A study of the search for the aetiology must be focused on evaluating those genes that are related with neurodevelopment and its activation in the organogenesis stage. The definitive diagnosis establishes the prognosis, management and genetic counselling of the family (AU)

Variable clinical expression in patients with mosaicism for KCNQ2 mutations.

Mutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity. Patients affected by benign familial neonatal epilepsy (BFNE) are at the milder end of the spectrum, they are affected by early onset epilepsy but their subsequent neurological development is usually normal. Mutations causing BFNE are often inherited from affected parents. Early infantile epileptic encephalopathy type 7 (EIEE7) is at the other end of the severity spectrum and, although EIEE7 patients have early onset epilepsy too, their neurological development is impaired and they will present motor and intellectual deficiency. EIEE7 mutations occur de novo. Electrophysiological experiments suggested a correlation between the type of mutation and the severity of the disease but intra and interfamilial heterogeneity exist. Here, we describe the identification of KCNQ2 mutation carriers who had children affected with a severe epileptic phenotype, and found that these individuals were mosaic for the KCNQ2 mutation. These findings have important consequences for genetic counseling and indicate that neurological development can be normal in the presence of somatic mosaicism for a KCNQ2 mutation.

Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing.

INTRODUCTION: CDKL5-related encephalopathy is an X-linked dominantly inherited disorder that is characterized by early infantile epileptic encephalopathy or atypical Rett syndrome. We describe a 5-year-old Japanese boy with intractable epilepsy, severe developmental delay, and Rett syndrome-like features. Onset was at 2 months, when his electroencephalogram showed sporadic single poly spikes and diffuse irregular poly spikes. METHODS: We conducted a genetic analysis using an Illumina® TruSight™ One sequencing panel on a next-generation sequencer. RESULTS: We identified two epilepsy-associated single nucleotide variants in our case: CDKL5 p.Ala40Val and KCNQ2 p.Glu515Asp. CDKL5 p.Ala40Val has been previously reported to be responsible for early infantile epileptic encephalopathy. In our case, the CDKL5 heterozygous mutation showed somatic mosaicism because the boy's karyotype was 46,XY. The KCNQ2 variant p.Glu515Asp is known to cause benign familial neonatal seizures-1, and this variant showed paternal inheritance. CONCLUSIONS: Although we believe that the somatic mosaic CDKL5 mutation is mainly responsible for the neurological phenotype in the patient, the KCNQ2 variant might have some neurological effect. Genetic analysis by next-generation sequencing is capable of identifying multiple variants in a patient.

Aicardi syndrome in a 47 XXY male - a variable developmental phenotype?

BACKGROUND: Aicardi syndrome (AS) is a rare neurodevelopmental disorder characterized by the triad of corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. Most patients with AS also have intractable epilepsy, moderate to severe learning disability, and a reduced life expectancy. An X-linked dominant inheritance caused by de novo mutations pattern, lethal in males, is postulated, but the gene has not yet been isolated. There are three case reports of 47 XXY males with classic features of AS who all had severe developmental disability. CASE REPORT: We report a case of a 3.5-year old 47 XXY male with the classic triad of Aicardi syndrome but with good seizure control and mild learning disability.

[Aicardi syndrome: retrospective study of a series of seven case reports]. / Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.

INTRODUCTION: The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. PATIENTS AND METHODS: Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. RESULTS: We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. CONCLUSIONS: The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation.

TITLE: Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.Introduccion. El sindrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clasicamente definido por la triada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y metodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediatrica de sindrome de Aicardi en dos hospitales universitarios durante un periodo de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolucion fue a espasmos mas alla de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, ademas de lesiones oftalmologicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio optico (n = 3). Otros hallazgos fueron cardiopatia congenita, anomalias costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El sindrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmologicas, las anomalias de la migracion y organizacion neuronal y los quistes intracraneales. El pronostico es grave por su elevada morbimortalidad y por la frecuente evolucion a epilepsia refractaria y retraso mental grave.

Serial fetal MRI for the diagnosis of Aicardi syndrome.

Aicardi syndrome (AS) is defined by the triad of corpus callosum agenesis, chorioretinal "lacunae" and infantile spasms. Additional neuroimaging findings including migrational abnormalities are common. We report on serial neuroimaging findings of a female fetus with ventriculomegaly, corpus callosum agenesis and focal migrational abnormalities, suggestive of AS. Postnatal neuroimaging follow-up as well as ophthalmological evaluation and occurrence of infantile spasms confirmed the prenatally suspected diagnosis of AS. This case points out the key role of serial fetal magnetic resonance imaging (MRI) in detecting the full spectrum of pathologies associated with fetal ventriculomegaly. The associated neuroimaging findings may go undetected on prenatal ultrasound, but are important in terms of diagnosis and counseling of the parents. Additionally, this case emphasizes the importance of serial fetal MRI studies to more accurately delineate the progression of findings during brain development.

Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms.

X-linked Infantile Spasms Syndrome (ISSX) is a catastrophic epilepsy of early childhood with intractable seizures, intellectual disability, and poor prognosis. A spectrum of mutations in the Aristaless-Related Homeobox gene (ARX) has been linked to ISSX, and downstream targets of this interneuron-expressed transcription factor are being defined. Recent advances combining in vitro and in vivo methods have unveiled complex interactions between Arx and its binding partners and their effects on cell migration and maturation that can help explain the diversity of ARX phenotypes. New mutant mouse models of Arx-induced pathology, including a recent human triplet-repeat expansion mutation with a phenotype of infantile spasms and electrographic seizures, provide valuable tools for exploring the pathophysiology of Arx and substrates for testing novel therapies.

Laterality of brain and ocular lesions in Aicardi syndrome.

This study reports a large case series of children with Aicardi syndrome. A new severity scoring system is established to assess sidedness of ocular and brain lesions. Thirty-five children were recruited from Aicardi syndrome family conferences. All children received dilated ophthalmologic examinations, and brain magnetic resonance images (MRIs) were reviewed. Ocular and brain MRI Aicardi lesion severity scores were devised. A linear mixed model was used to compare each side for the ocular and brain MRI severity scores of Aicardi-associated disease. Twenty-six children met the inclusion criteria for the study. All subjects were female, ages 3 months to 19 years. Rates per child of optic nerve coloboma, severe lacunae, and microphthalmos in one or both eyes (among those with complete fundus examinations available) were 10/24 (42%), 8/22 (36%), and 7/26 (27%), respectively. Ocular and brain MRI asymmetry was found in 18% (4/22) and 58% (15/26) of subjects, respectively, with more right-sided brain lesions than left-sided ones (V = 52, P = 0.028). A significant correlation between sidedness of brain disease and microphthalmos was noted (T = 2.54, P = 0.02). This study substantiates the range and severity of Aicardi syndrome-associated ophthalmologic and brain MRI lesions from prior smaller case series.

[Aicardi syndrome associated with severe congenital ptosis]. / Un syndrome d'Aicardi associé à un ptosis congénital sévère.

Aicardi syndrome is a rare neurodevelopmental disorder characterized by corpus callosum agenesis, chorioretinal lacunae and early-onset infantile spasms. We report a particular case of Aicardi syndrome characterized by the association of the classical triad of severe bilateral ptosis, pontocerebellar hypoplasia, and perisylvian polymicrogyria in a girl born to non-consanguineous parents, but whose mother suffered from idiopathic generalized epilepsy.

Toriello-Carey syndrome with a 6Mb interstitial deletion at 22q12 detected by array CGH.

Toriello-Carey syndrome is a rare multiple congenital anomaly syndrome comprising agenesis of the corpus callosum, telecanthus, short palpebral fissures, abnormal ears, Pierre Robin sequence, and cardiac anomaly. Autosomal recessive inheritance has been hypothesized and chromosome abnormalities have been reported. The present case is a girl with agenesis of the corpus callosum, a large cleft palate, telecanthus, hypertelorism, atrial septal defect, ventricular septal defect, and patent ductus arteriosus. A routine karyotype and fluorescence in situ hybridization subtelomeric analysis were normal. Array comparative genomic hybridization (CGH) identified a de novo 6 Mb interstitial deletion at 22q12.1→22q12.2. These findings support recent findings of chromosomal abnormalities in patients with the Toriello-Carey phenotype. We suggest that the clinical features described in some cases with Toriello-Carey syndrome might be due to cryptic chromosomal rearrangements and that array CGH should be considered in any case presenting with clinical features of Toriello-Carey.

Connectivity and the corpus callosum in autism spectrum conditions: insights from comparison of autism and callosal agenesis.

Neural models of autism spectrum disorders (ASDs) have moved, in recent years, from a lesion model to a focus on abnormal connectivity. In this chapter, we review this work and summarize findings from our recent research comparing autism and agenesis of the corpus callosum (AgCC). We discuss our findings in the context of the "fractionable triad" account and highlight three main points. First, the social aspects of autism can be found in isolation, not accompanied by the nonsocial features of this disorder, supporting a view of autism as a "compound," rather than "monolithic," condition. Second, many young people with callosal agenesis show theory of mind- and emotion-processing deficits akin to those seen in autism. Diagnostic overshadowing may mean these people do not receive interventions that have proven beneficial in ASD. Last, study of AgCC shows that it is possible, in some cases, to develop good social cognitive skills in the absence of the corpus callosum, presenting a challenge to future connectivity models of autism.

Diffusion tensor imaging of Aicardi syndrome.

Aicardi syndrome is a congenital neurodevelopmental disorder associated with significant cognitive and motor impairment. Diffusion tensor imaging was performed on two subjects with Aicardi syndrome, as well as on two matched subjects with callosal agenesis and cortical malformations but not a clinical diagnosis of Aicardi syndrome. Whole-brain three-dimensional fiber tractography was performed, and major white matter tracts were isolated using standard tracking protocols. One Aicardi subject demonstrated an almost complete lack of normal corticocortical connectivity, with only the left inferior fronto-occipital fasciculus recovered by diffusion tensor tractography. A second Aicardi subject exhibited evidence of bilateral cingulum bundles and left uncinate fasciculus, but other corticocortical tracts were not recovered. Major subcortical white matter tracts, including corticospinal, pontocerebellar, and anterior thalamic radiation tracts, were recovered in both Aicardi subjects. In contrast, diffusion tensor tractography analysis on the two matched control subjects with callosal agenesis and cortical malformations recovered all major intrahemispheric cortical and subcortical white matter tracts. These findings reveal a widespread disruption in the corticocortical white matter organization of individuals with Aicardi syndrome. Furthermore, such disruption in white matter organization appears to be a feature specific to Aicardi syndrome, and not shared by other neurodevelopmental disorders with similar anatomic manifestations.

Brain abnormalities on MR imaging in patients with retinoblastoma.

BACKGROUND AND PURPOSE: Although pineoblastoma is the main brain abnormality associated with hereditary retinoblastoma, recent studies suggest an association with pineal cysts. This association is important because some pineoblastomas mimic pineal cysts. If there is a relationship, then radiologists should be aware of it because diagnostic confusion is possible. Mental retardation and congenital brain anomalies are also reported in patients with retinoblastoma, mostly in combination with 13q deletion syndrome. In this retrospective study, the presence of brain abnormalities on MR images in a large group of consecutive patients with retinoblastoma is evaluated. MATERIALS AND METHODS: Brain MR images of 168 patients with retinoblastoma from 1989 to 2009 were evaluated by 2 radiologists for tumors, structural anomalies, myelinization, and coincidental findings. Clinical records were reviewed for laterality, heredity, and the presence of the 13q deletion syndrome. RESULTS: The hereditary group (patients with bilateral and unilateral proved RB1-germline mutation) included 90 (54%) of 168 patients. Seven patients had 13q deletion syndrome. Normal findings on brain MR images were seen in 150 (89%) patients. Five pineoblastomas were detected, all in patients with hereditary retinoblastoma (5.5% in the hereditary subgroup). Nine pineal cysts were detected (2.2% in the hereditary subgroup). Corpus callosum agenesis was found in 1 patient and a Dandy-Walker variant in 1 patient, both in combination with 13q deletion syndrome. CONCLUSIONS: Pineoblastoma is associated with hereditary retinoblastoma, and structural brain abnormalities are restricted to patients with the 13q deletion syndrome. The incidence of pineal cysts in patients with retinoblastomas is similar to that in healthy children and is not associated with hereditary retinoblastoma.

Cerebral anomalies and Chiari type 1 malformation.

OBJECTIVE: To analyze the association of diverse cerebral anomalies in a series of pediatric patients with cerebellar tonsillar ectopia. METHODS: We reviewed the medical records of 60 children diagnosed with Chiari type 1 malformation (CM1), of these, 20 patients (11 boys and 9 girls; mean age 7.2 years, range 2-16 years) had an associated cerebral anomaly. Symptoms of tonsillar ectopia evolved over a mean of 12 months (range 3 months to 4 years). Syringomyelia was present in 5 cases. All patients underwent a posterior fossa decompression. RESULTS: Disclosed anomalies included: congenital hydrocephalus (n = 11), cervicomedullary kinking (n = 5), focal cerebral heterotopia with epilepsy (n = 4), partial agenesis of the corpus callosum (n = 4), hypoplastic brain stem (n = 2), holoprosencephaly (n = 1), and subcortical dysplasia in the context of neurofibromatosis type 1 (n = 1). Other malformations included: subcortical hamartoma associated with neurofibromatosis type 1, craniofacial dysmorphism secondary to Noonan syndrome, congenital occipital plagiocephaly, os odontoideum, craniofacial cleft, juvenile rheumathoid arthritis with platybasia, and osteogenesis imperfecta with bathrocephaly and scoliosis. CONCLUSION: Craniocerebral anomalies in children treated for CM1 may be found consistently. The association of hydrocephalus, which was the most common anomaly in this cohort, with cerebellar tonsillar ectopia may contribute to a poor outcome in regard to tonsillar herniation symptoms.