RESUMEN
Joubert Syndrome, manifests in a spectrum of neurological symptoms. This case describes a 7-year-old girl with perinatal complications, and subsequent neurodevelopmental challenges. An MRI confirmed the diagnosis of Joubert syndrome, with the distinctive "molar tooth sign" being a key imaging characteristic. Approximately 25% of cases exhibit nephronophthisis, impacting kidney function, further complicating the clinical picture. Diagnosis relies on imaging and management necessitates a multidisciplinary approach, addressing symptoms and complications, with prognosis linked to the presence of organic disease. The case emphasizes the significance of a multidisciplinary strategy, including genetic counseling, and underscores the diverse manifestations of this syndrome. Prenatal identification through ultrasound and MRI plays a crucial role in diagnosing and treating this rare condition.
RESUMEN
The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.
Asunto(s)
Anomalías Múltiples , Encéfalo/anomalías , Vermis Cerebeloso , Cerebelo/anomalías , Colestasis , Coloboma , Enfermedades Genéticas Congénitas , Discapacidad Intelectual , Hepatopatías , Malformaciones del Sistema Nervioso , Riñón Poliquístico Autosómico Recesivo , Adulto Joven , Humanos , Coloboma/diagnóstico , Coloboma/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico , Riñón Poliquístico Autosómico Recesivo/genética , Diagnóstico Tardío , Genotipo , Cirrosis Hepática/genética , Ataxia/diagnóstico , Ataxia/genética , Discapacidad Intelectual/genética , Discapacidades del DesarrolloRESUMEN
We recently investigated the role of the cerebellum during development, reporting that children with genetic slow-progressive ataxia (SlowP) show worse postural control during quiet stance and gait initiation compared to healthy children (H). Instead, children with genetic non-progressive ataxia (NonP) recalled the behavior of H. This may derive from compensatory networks, which are hindered by disease progression in SlowP while free to develop in NonP. In the aim of extending our findings to intra-limb postural control, we recorded, in 10 NonP, 10 SlowP and 10 H young patients, Anticipatory Postural Adjustments (APAs) in the proximal muscles of the upper-limb and preceding brisk index finger flexions. No significant differences in APA timing occurred between NonP and H, while APAs in SlowP were delayed. Indeed, the excitatory APA in Triceps Brachii was always present but significantly delayed with respect to both H and NonP. Moreover, the inhibitory APAs in the Biceps Brachii and Anterior Deltoid, which are normally followed by a late excitation, could not be detected in most SlowP children, as if inhibition was delayed to the extent where there was overlap with a late excitation. In conclusion, disease progression seems to be detrimental for intra-limb posture, supporting the idea that inter- and intra-limb postures seemingly share the same control mechanism.
RESUMEN
Maternally inherited diabetes and deafness (MIDD) is a rare diabetic syndrome mainly caused by a point mutation in the mitochondrial DNA. It affects up to 1% of patients with diabetes but is often unrecognized by physicians. We report a case of MIDD in a 29-year-old man with coexisting imaging of cerebellar vermis hypoplasia and bilateral basal ganglia calcification.
Asunto(s)
Enfermedades de los Ganglios Basales , Vermis Cerebeloso , Sordera , Diabetes Mellitus Tipo 2 , Enfermedades Mitocondriales , Masculino , Humanos , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Sordera/diagnóstico por imagen , Sordera/genética , Sordera/complicaciones , Enfermedades Mitocondriales/complicaciones , ADN Mitocondrial/genética , Enfermedades de los Ganglios Basales/complicaciones , Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/genética , Ganglios Basales/diagnóstico por imagenRESUMEN
Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as chromosomal microarray. Deletions involving 6q21q22.1 region are associated with an extremely wide and heterogeneous clinical spectrum, thus genotype-phenotype correlation based on the size of the rearranged region and on the involved genes is complex, even among individuals with overlapping deletions. Here we describe the phenotypic and molecular characterization of a new 6q interstitial deletion in a girl with developmental delay, intellectual disability, cerebellar vermis hypoplasia, facial peculiar characteristics, ataxia and ocular abnormalities. Microarray analysis of the proposita revealed a 7.9 Mb interstitial de novo deletion at 6q21q22.1 chromosomal region, which spanned from nucleotides 108,337,770 to 116,279,453 (GRCh38/hg38). The present case, alongside with a systematic review of the literature, provides further evidence that could aid to the definition of the Smallest Region of Overlap and of the genomic traits that are associated with particular phenotypes, focusing on neurological findings and especially on cerebellar anomalies.
RESUMEN
Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.
Asunto(s)
Cerebelo/anomalías , Síndrome de Dandy-Walker/embriología , Síndrome de Dandy-Walker/patología , Desarrollo Fetal/fisiología , Feto/patología , Malformaciones del Sistema Nervioso/embriología , Malformaciones del Sistema Nervioso/patología , Estudios de Casos y Controles , Cerebelo/embriología , Cerebelo/patología , Discapacidades del Desarrollo/patología , Humanos , Recién NacidoRESUMEN
BACKGROUND: Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. CASE PRESENTATION: A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. CONCLUSION: In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.
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Anomalías Múltiples/genética , Cerebelo/anomalías , Secuenciación del Exoma/métodos , Anomalías del Ojo/genética , Predisposición Genética a la Enfermedad/genética , Enfermedades Renales Quísticas/genética , Mutación , Proteínas Gestacionales/genética , Retina/anomalías , Factores Supresores Inmunológicos/genética , Anomalías Múltiples/diagnóstico , Preescolar , Anomalías del Ojo/diagnóstico , Genes Recesivos , Humanos , Enfermedades Renales Quísticas/diagnóstico , MasculinoRESUMEN
BACKGROUND: Joubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid-hindbrain malformation called the "molar tooth sign" on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS. METHODS: Whole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT-PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690). RESULTS: We identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode. CONCLUSION: Our study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anomalías , Secuenciación del Exoma/métodos , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Mutación , Retina/anomalías , Preescolar , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Análisis de Secuencia de ADNRESUMEN
Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
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Duplicación Cromosómica , Cromosomas Humanos X , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteínas de Unión al GTP rab/genética , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Facies , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Adulto JovenRESUMEN
We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense (c.770T>C, p.[Leu257Pro]) variant in the hedgehog acyl-transferase gene (HHAT), encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling. There is a report of one family with Nivelon-Nivelon-Mabille syndrome in which HHAT was proposed as the likely candidate gene. The phenotypic overlap with the family we report herein provides further evidence implicating HHAT in cerebellar development and the pathogenesis of this rare spectrum.
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Aciltransferasas/genética , Alelos , Vermis Cerebeloso/anomalías , Microcefalia/diagnóstico , Microcefalia/genética , Mutación Missense , Fenotipo , Niño , Preescolar , Análisis Mutacional de ADN , Facies , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Imagen por Resonancia MagnéticaRESUMEN
Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.
Asunto(s)
Discapacidad Intelectual/genética , Mutación , Proteínas Represoras/genética , Anomalías Múltiples/genética , Adulto , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Exoma , Femenino , Haploinsuficiencia , Humanos , Imagen por Resonancia Magnética , Masculino , Microcefalia/genética , Mutación Missense , EmbarazoRESUMEN
In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7.
Asunto(s)
Síndrome de Williams/etiología , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 7 , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/genética , Cara/anomalías , Femenino , Humanos , Lactante , Masculino , Megalencefalia , Embarazo , Complicaciones del Embarazo/genética , Síndrome de Williams/genética , Adulto JovenRESUMEN
We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis.
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Trastornos de los Cromosomas/genética , Síndrome de Dandy-Walker/genética , Holoprosencefalia/genética , Encéfalo/patología , Deleción Cromosómica , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 13/genética , Proteínas de Unión al ADN , Síndrome de Dandy-Walker/complicaciones , Síndrome de Dandy-Walker/patología , Femenino , Eliminación de Gen , Holoprosencefalia/complicaciones , Holoprosencefalia/patología , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Proteínas Nucleares/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Joubert Syndrome (JS) is a rare genetic developmental disorder, first identified in 1969. In patients with JS, certain regions of the brain (mainly cerebellar vermis and brainstem) are underdeveloped or malformed. This can lead to impaired attention, visual, spatial, motor, language and social functional skills. JS is characterized by a host of features, many of which do not occur in every patient. AIM OF THE STUDY: To spotlight and increase awareness of clinical profile and neuroimaging findings of children with Joubert syndrome. METHODS: This is a retrospective case series study of patients with JS who attended the Pediatric Neurology Clinic in Aladan and Alfarawanya Hospitals in Kuwait, from September 2007 to September 2012. Clinical and radiological data were obtained from the patient medical records. RESULTS: Cerebellar vermis hypoplasia/aplasia and apnea were present in all patients, polydactly in 3 of 16, renal problems with cysts in 5 patients and 11 of 16 had abnormal electroretinograms (ERGs). Blood investigations of organic acids, amino acids and very-long-chain fatty acid, were normal in the all the nine patients. CONCLUSION: JS is a rare genetic brain malformation with association of retinal dystrophy and renal abnormalities. The retinal dystrophy may be progressive. The prognosis of patients depends mainly on the degree of brain malformation.
RESUMEN
PURPOSE: To report the incidence and new findings of abnormal brain imaging studies associated with patients initially diagnosed with Leber's congenital amaurosis (LCA) without definite systemic abnormalities and to determine the need for brain imaging studies in these patients. METHODS: A retrospective review of medical records was performed in 83 patients initially diagnosed as LCA and without definite systemic abnormalities before the age of 6 months in 2 tertiary referral centers. Brain magnetic resonance imaging was performed in 31 of 83 patients (37.3%). RESULTS: Six of 31 patients (19%) had radiologically documented brain abnormalities. Two patients had cerebellar vermis hypoplasia, 1 patient showed an absence of septum pellucidum, 2 subjects showed mild external hydrocephalus, and 1 patient was found to have a small cerebellum. CONCLUSIONS: Approximately one fifth of the LCA patients in whom brain imaging was performed were associated with brain abnormalities, including the absence of septum pellucidum, which has not been documented in the literature. Brain imaging is mandatory in patients primarily diagnosed with LCA, even without definite neurologic or systemic abnormalities.
Asunto(s)
Encéfalo/patología , Amaurosis Congénita de Leber/diagnóstico , Imagen por Resonancia Magnética , Cerebelo/patología , Femenino , Humanos , Hidrocefalia/patología , Técnicas In Vitro , Lactante , Estudios Retrospectivos , Tabique Pelúcido/patologíaRESUMEN
PURPOSE: To report the incidence and new findings of abnormal brain imaging studies associated with patients initially diagnosed with Leber's congenital amaurosis (LCA) without definite systemic abnormalities and to determine the need for brain imaging studies in these patients. METHODS: A retrospective review of medical records was performed in 83 patients initially diagnosed as LCA and without definite systemic abnormalities before the age of 6 months in 2 tertiary referral centers. Brain magnetic resonance imaging was performed in 31 of 83 patients (37.3%). RESULTS: Six of 31 patients (19%) had radiologically documented brain abnormalities. Two patients had cerebellar vermis hypoplasia, 1 patient showed an absence of septum pellucidum, 2 subjects showed mild external hydrocephalus, and 1 patient was found to have a small cerebellum. CONCLUSIONS: Approximately one fifth of the LCA patients in whom brain imaging was performed were associated with brain abnormalities, including the absence of septum pellucidum, which has not been documented in the literature. Brain imaging is mandatory in patients primarily diagnosed with LCA, even without definite neurologic or systemic abnormalities.