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Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

ABSTRACT: Joubert syndrome (JS) is a neurodevelopmental disorder characterized by hypotonia and developmental delay, as well as the obligatory molar tooth sign on brain imaging. Since hypotonia and developmental delay are nonspecific features, there must be a high level of clinical suspicion of JS so that the diagnostic brain imaging and/or molecular testing for the >38 genes associated with JS is/are obtained. The goal of this study was to analyze clinical photographs of a cohort of patients with JS to define a list of physical examination features that should prompt investigation for JS. Analysis of photographs from 94 individuals with JS revealed that there is a recognizable pattern of facial features in JS that changes over time as individuals age. Macrocephaly, head tilting even when looking straight ahead, eye movement abnormalities (oculomotor apraxia, nystagmus, strabismus), and ptosis are common in those with JS. Distinctive features in younger children include triangular-shaped open mouth with tongue protrusion; in older children and adults, mandibular prognathia and prominent nasal bridge are common.

SUBMITTER: Forsyth R

PROVIDER: S-EPMC9117497 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

Forsyth RaeLynn R Parisi Melissa A MA Altintas Burak B Malicdan May Christine MC Vilboux Thierry T Knoll Jasmine J Brooks Brian P BP Zein Wadih M WM Gahl William A WA Toro Camilo C Gunay-Aygun Meral M

American journal of medical genetics. Part C, Seminars in medical genetics 20220321 1

Joubert syndrome (JS) is a neurodevelopmental disorder characterized by hypotonia and developmental delay, as well as the obligatory molar tooth sign on brain imaging. Since hypotonia and developmental delay are nonspecific features, there must be a high level of clinical suspicion of JS so that the diagnostic brain imaging and/or molecular testing for the >38 genes associated with JS is/are obtained. The goal of this study was to analyze clinical photographs of a cohort of patients with JS to d ...[more]

PMID: 35312150

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Project description:Background and aimsJoubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes. However, long-term follow-up data are scarce, and further research is needed to determine the abundant phenotypes and genetics of this disorder. The study aimed to summarize clinical manifestations, particular appearance on cranial imaging, genetic data, and prognostic features of patients with JBTS.MethodsA retrospective case review of 36 cases of JBTS from May 1986 to December 2021 was performed. Clinical data of JBTS patients with development retardation and molar tooth sign on cranial imaging as the main features were analyzed. Genetic testing was performed according to consent obtained from patients and their families. The Gesell Developmental Scale was used to evaluate the intelligence level before and after treatment. The children were divided into a purely neurological JBTS (pure JBTS) group and JBTS with multi-organ system involvement group and then followed up every 3-6 months.ResultsWe enrolled 18 males and 18 females. Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. There was one case co-morbid with Lesch-Nyhan syndrome. Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment. JBTS could also involve the skin. Thirty-one cases (86.11%) showed a typical molar tooth sign, and five cases showed a bat wing sign on cranial imaging. Abnormal video electroencephalogram (VEEG) result was obtained in 7.69% of cases. We found six JBTS-related novel gene loci variants: CPLANE1: c.4189 + 1G > A, c.3101T > C(p.Ile1034Thr), c.3733T > C (p.Cys1245Arg), c.4080G > A(p.Lys1360=); RPGRIP1l: c.1351-11A > G; CEP120: c.214 C > T(p.Arg72Cys). The CHD7 gene may be potentially related to the occurrence of JBTS. Analysis showed that the prognosis of pure JBTS was better than that of JBTS with neurological and non-neurological involvement after the formal rehabilitation treatment (P < 0.05). Of the three children with seizures, two cases had epilepsy with a poor prognosis, and another case had breath-holding spells.ConclusionOur findings indicate that early cranial imaging is helpful for the etiological diagnosis of children with unexplained developmental delay and multiple malformations. Patients with JBTS may have coexisting skin abnormalities. The novel gene loci of CPLANE1, RPGRIP1l, and CEP120 were associated with JBTS in our study and provided significant information to enrich the related genetic data. Future works investigating several aspects of the association between CHD7 gene and JBTS merit further investigation. The prognosis of children with pure JBTS is better than that of children with JBTS with non-neurological involvement.

Project description:Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.

Project description:Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.

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Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

Publications

Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

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