Molar Tooth Sign Research Articles

Enlarged Intracranial Translucency, as a Potential Marker for Diagnosis of Joubert Syndrome during First-Trimester Screening: A Case Report

AbstractJoubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder that is usually diagnosed late in pregnancy or postnatally based on a pathognomonic midbrain–hindbrain malformation seen on magnetic resonance imaging brain, which consists of the hypoplasia of the cerebellar vermis, thickened superior cerebellar peduncles, and a deepened interpeduncular fossa described as molar tooth sign. The recurrence rate of JS in the same family is high (25%). In the era of first-trimester anomaly scan, early diagnosis of fetal anomaly is of utmost importance. First-trimester screening or first-trimester scan that is performed from 11 to 13 weeks, 6 days plays an important role in early diagnosis of posterior fossa abnormalities like Blake's pouch cyst, Vermian hypoplasia, Dandy-Walker malformation, and JS and related disorders based on increased intracranial translucency thickness. Our case also shows that early diagnosis of JS can be done by an enlarged intracranial translucency.

Exome Analysis Reveals Novel Missense and Deletion Variants in the CC2D2A Gene as Causative of Joubert Syndrome.

The CC2D2A gene is essential for primary cilia formation, and its disruption has been associated with Joubert Syndrome-9 (JBTS9), a ciliopathy with typical neurodevelopmental features. Here, we describe an Italian pediatric patient with typical features of Joubert Syndrome (JBTS): "Molar Tooth Sign", global developmental delay, nystagmus, mild hypotonia, and oculomotor apraxia. Whole exome sequencing and segregation analysis identified in our infant patient a novel heterozygous germline missense variant c.3626C > T; p.(Pro1209Leu) inherited from the father and a novel 7.16 kb deletion inherited from the mother. To the best of our knowledge, this is the first report showing a novel missense and deletion variant involving exon 30 of the CC2D2A gene.

Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome

BackgroundJoubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the ‘molar tooth sign’. Over 40 JS-associated genes are known, accounting for two-thirds of cases.MethodsWhile most variants...

A novel 1.38-kb deletion combined with a single nucleotide variant in KIAA0586 as a cause of Joubert syndrome

BackgroundKIAA0586, also known as Talpid3, plays critical roles in primary cilia formation and hedgehog signaling in humans. Variants in KIAA0586 could cause some different ciliopathies, including Joubert syndrome (JBTS), which is a clinically and genetically heterogeneous group of autosomal recessive neurological disorders.Methods and ResultsA 9-month-old girl was diagnosed as JBTS by the “molar tooth sign” of the mid-brain and global developmental delay. By whole-exome sequencing, we identified a single nucleotide variant c.3303G > A and a 1.38-kb deletion in KIAA0586 in the proband. These two variants of KIAA0586 were consistent with the mode of autosomal recessive inheritance in the family, which was verified using Sanger sequencing.ConclusionsThis finding of a compound heterozygote with a 1.38-kb deletion and c.3303G > A gave a precise genetic diagnosis for the patient, and the novel 1.38-kb deletion also expanded the pathogenic variation spectrum of JBTS caused by KIAA0586.

Clinical features and genetic analysis of two Chinese pedigrees affected with Joubert syndrome

To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.

Radiological Features of Joubert's Syndrome

AbstractJoubert syndrome (JS) is a rare autosomal recessive disorder. All patients affected by this syndrome presented a characteristic picture of cranial fossa malformations, called “molar tooth sign.” This sign is defined by the presence in axial section at the level of a deck/midbrain, of hypo/dysplasia of the cerebellar vermis, abnormally deep interpeduncular fossa and horizontalized thickened and elongated superior cerebellar peduncles. Although “molar tooth sign” is peculiar of JS, other radiological findings have been also reported in these patients. Here, the authors briefly assumed the principal magnetic resonance imaging findings of JS.

Epilepsy in Joubert Syndrome: A Still Few Explored Matter

AbstractEpilepsy is rarely associated with Joubert's syndrome and related disorders (JSRD), being reported only in 3% of cases. Few patients have been described, moreover, with poor evidences of specific seizures' semiology or standard of practice for pharmacological treatment. Epilepsy is likely to be related to brain malformations in ciliopathies. Beyond the typical hindbrain malformation, the molar tooth sign, other cerebral anomalies variably reported in JSRD, such as generalized polymicrogyria, hamartomas, periventricular nodular heterotopia, and hippocampal defects, have been described. Herein, we aimed to revise the main clinical and etiopathogenetic characteristics of epilepsy associated with JSRD.

A Brief Focus on Joubert Syndrome and Related Acute Complications

AbstractJoubert syndrome (JS) and related disorders are a group of congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign, a complex midbrain–hindbrain malformation. Moreover, JS may be associated with multiorgan involvement, mainly nephronophthisis, hepatic fibrosis, retinal dystrophy, and other abnormalities with both inter- and intra-familial variability. Therefore, these patients should be followed by both diagnostic protocol and multidisciplinary approach to assess multiorgan involvement. Here, we briefly summarize the possible complications in patients with JS.

Joubert Syndrome with Renal and Cerebral Manifestations: A Case Series of Three Siblings

Joubert syndrome is a rare genetic disorder. Marie Joubert made the first official diagnosis of the syndrome in 1969. It is characterised by aberrant neurodevelopment and a complex midbrain-hindbrain malformation which can be seen on the Magnetic Resonance Imaging (MRI) as molar tooth sign. The present case series reports three siblings from a consanguineous marriage. The first child had delayed developmental milestones, ataxia, mental retardation and presented with advanced renal failure and succumbed to uremic complications. The second and third siblings also had similar clinical findings and the diagnosis of Joubert syndrome was confirmed by the presence of molar tooth sign on MRI. The presence of renal failure in them was detected earlier than the first sibling with favourable outcome in both. The characteristic symptoms of Joubert syndrome include developmental delay, intellectual disability, ocular abnormalities, and lack of control over voluntary movements. Each sibling of an affected individual has a 25% chance of developing the disease, a 50% chance of being an asymptomatic carrier, and a 25% chance of being not affected and not being a carrier. Renal involvement occurs in approximately one third of patients. In the present case series, all the siblings were affected by the syndrome and developed renal failure which is extremely rare. Failure to evaluate the renal function in these patients can result in delayed presentation with adverse outcome as seen in the first sibling. The case series highlights the importance of considering this disorder in the differential diagnosis of chronic kidney disease, especially in cases with a family history and other suggestive symptoms and the need for early recognition and management of the disorder, as early intervention and supportive care can improve the patient’s quality of life and prognosis.

Endocrine manifestations in Joubert syndrome—literature review

<abstract> <p>Joubert syndrome (JS) is a heterogeneously inherited, rare, autosomal recessive disorder characterised by neonatal breathing dysregulation, developmental delay, hypotonia, abnormal eye movements and a distinctive cerebellar and brainstem malformation called the molar tooth sign (MTS). Patients with JS may develop hypothalamic-pituitary dysfunction, leading to growth hormone deficiency, hypothyroidism, adrenal insufficiency and hypogonadism. This review summarizes the screening, diagnosis, and management of these conditions in JS.</p> </abstract>

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome

ObjectiveJoubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. MethodsWe retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. ResultsThe most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber’s congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. ConclusionSome rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Age-Related Neurodevelopmental Features in Children with Joubert Syndrome

AbstractJoubert syndrome (JS) is a rare inherited disorder of central nervous system with neonatal/infantile onset, mainly affecting cerebellum and brainstem, and clinically characterized by agenesis or dysgenesis of the cerebellar vermis with accompanying brainstem malformations. More than 20 disease-causing genes have been associated with JS but a clear genotype–phenotype correlation has not been assessed yet. Diagnosis is usually confirmed by detection of the JS neuroradiological hallmark, the molar tooth sign. Patients with JS typically present with neurological manifestations, moreover, a heterogeneous spectrum of multisystemic anomalies may be observed. Signs and symptoms onset varies according to the age range and clinical diagnosis might become complicated. Moreover, specific neurodevelopmental disorders can be associated with JS such as autism spectrum disorders, attention deficit with hyperactivity, and a wide range of behavioral disturbances. Here, we examined the main neurological and neurodevelopmental features of JS according to an age-dependent mode of presentation. Furthermore, differential diagnosis with other neurological syndromes was closely reviewed.

Comment on “Retinitis Pigmentosa and Molar Tooth Sign Caused by Novel AHI1 Compound Heterozygote Pathogenic Variants: A Case Report”

Joubert syndrome (JS) is a rare congenital neurodevelopmental disease which is basically a primary Ciliopathy. It’s characteristic manifestation on imaging is so called ‘molar tooth sign’ in the brainstem and cerebellum. JS can involve multiple organs, mainly including retina, kidney, bone and liver.

Long-Surviving Adult Siblings With Joubert Syndrome Harboring a Novel Compound Heterozygous CPLANE1 Variant.

Background and ObjectivesWe describe 2 long-surviving siblings with a mild phenotype of Joubert syndrome (JBTS) harboring a novel compound heterozygous missense variant in the CPLANE1 gene.MethodsTargeted sequencing data of 2 middle-aged siblings (sister and brother) with JBTS were analyzed.ResultsThe patients were older than 60 years and presented with an inborn facial anomaly and ataxia, accompanied by a molar tooth sign on brain MRI. The male patient showed mild intellectual disability, abnormal eye movements, and progressive gait disturbance. Targeted sequencing revealed a compound heterozygous missense variant of CPLANE1 p.Arg1193Cys_Gln1223Pro; c.3577C>T_3668A>C. Multiple in silico assays predicted that the missense sites were pathogenic.DiscussionThe phenotype-genotype correlation of CPLANE1 remains controversial, although many cases have been previously reported in children and young adults. Our study revealed a novel pathogenic variant of CPLANE1 in patients, confirming the role of this gene in JBTS, thus providing an opportunity for neurologists to recognize JBTS as a differential diagnosis for chronic progressive ataxia in an aging society.

The Molar Tooth Sign of Brain Mri: A Case Report of Joubert Syndrome

Joubert syndrome is a rare genetic disorder of autosomal recessive inheritance characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis resulting in respiratory disorders, nystagmus, hypotonia, ataxia and delayed motor development. Magnetic resonance imaging allows the diagnosis to be made by demonstrating the "molar tooth sign". We report the observation of an infant aged 1 year 4 months, from a 2nd degree consanguineous marriage, hospitalized for seizures. On examination, she presented with hypotonia. She had abnormal eye movements such as nystagmus. The cerebral magnetic resonance image revealed hypoplasia of the cerebellar vermis and enlargement of the superior cerebellar peduncles with a "molar tooth" aspect in favor of a Joubert syndrome. The evolution was marked by the installation of a delay in psychomotor development.

Prenatal Diagnosis of Joubert Syndrome With Whole Exome Sequencing

Joubert syndrome(JS), was first discovered by Marie Joubert, which is a rare autosomal recessive inherited disease belonging to ciliopathy with the causative mutation of genes. A 27-years-old woman was referred to our clinic for advanced research over the detection of fetal renal cyst.We observed policycstic kidney in detailed examination.INPP5E mutation was detected on chorion villus sampling.We were thought may be this findings will be associated with the syndrome, primarily joubert syndorme (JS),upon detection the vermis hypoplasia, policyctic kidney and molar teeth sign was observed on USG in the 23rd week of pregnancy.The vermis hypoplasia, posterior fossa expansion and bilateral polycystic kidney was seen on MRI and radiologist was reported as Dandy-Walker depend on this findings.They did not pay attention to the molar tooth finding.We were explanied prognosis and suggeted termination to the family.The family was accepted and fetus was terminated. The most common characteristic brain image of JS is the molar tooth sign(MTS) on the axial plane, cerebellar vermis (CV) hypoplasia, and a deepened interpeduncular fossa.The MTS is the key diagnostic feature for this disease. So far, more than 30 causative genes have been found for the various subtypes of JSRD.One of them is INPP5E. Defects of additional extra-nervous systems involve polycystic kidney disease, retinal degeneration, skeletal defects (such as polydactyly), and liver disorder.
 Joubert Syndrome can be diagnosed in prenatally period.MTS can be seen easily with usg during prenatal period.The vermian hypoplasia and additional organ anomalies must be brought to mind JS and MTS should be searched.

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome.

Cilia are quasi-ubiquitous microtubule-based sensory organelles, which play vital roles in signal transduction during development and cell homeostasis. Dysfunction of cilia leads to a group of Mendelian disorders called ciliopathies, divided into different diagnoses according to clinical phenotype constellation and genetic causes. Joubert syndrome (JBTS) is a prototypical ciliopathy defined by a diagnostic cerebellar and brain stem malformation termed the “Molar Tooth Sign” (MTS), in addition to which patients display variable combinations of typical ciliopathy phenotypes such as retinal dystrophy, fibrocystic renal disease, polydactyly or skeletal dystrophy. Like most ciliopathies, JBTS is genetically highly heterogeneous with ∼40 associated genes. Zebrafish are widely used to model ciliopathies given the high conservation of ciliary genes and the variety of specialized cilia types similar to humans. In this review, we compare different existing JBTS zebrafish models with each other and describe their contributions to our understanding of JBTS pathomechanism. We find that retinal dystrophy, which is the most investigated ciliopathy phenotype in zebrafish ciliopathy models, is caused by distinct mechanisms according to the affected gene. Beyond this, differences in phenotypes in other organs observed between different JBTS-mutant models suggest tissue-specific roles for proteins implicated in JBTS. Unfortunately, the lack of systematic assessment of ciliopathy phenotypes in the mutants described in the literature currently limits the conclusions that can be drawn from these comparisons. In the future, the numerous existing JBTS zebrafish models represent a valuable resource that can be leveraged in order to gain further insights into ciliary function, pathomechanisms underlying ciliopathy phenotypes and to develop treatment strategies using small molecules.

De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome.

Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.

Homozygous AHI1 gene mutation (c.1213A>C; Thr405Pro) leads to Joubert syndrome in a consanguineous Iranian family: A case report

Joubert syndrome (JS) is an autosomal recessive (AR) neurological disorder primarily characterized by aplasia/hypoplasia of the cerebellar vermis, retinal degeneration, and a molar tooth sign (MTS) can be seen on brain imaging. This study aimed to identify JS pathogenic variant in an Iranian consanguineous pedigree. We carried out whole-exome sequencing (WES) to identify likely causal pathogenic variant in the patient. The WES analysis identified a novel homozygous missense mutation (c.1213A>C; p.T405P) in the AHI1 gene (in exon 10). The Sanger sequencing data has validated the c.1213A>C mutation. We postulated that the disease in our patient was caused by a novel homozygous missense mutation in the AHI1 gene. To the best of our knowledge, this is the first report of the AHI1 pathogenic variant causing JS phenotype in an Iranian family. Our data expand the spectrum of mutations in the AHI1 gene in JS.

Neonatal Joubert Syndrome With Renal Involvement and Respiratory Distress

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder with characteristic clinical presentation of hyperpnea-apnea spells, hypotonia, dysmorphic facies, and nystagmus and imaging features of molar tooth sign and cerebellar vermian hypoplasia-dysplasia. Early diagnosis is needed for timely management and favorable outcome. We present a case of neonatal JS with renal involvement presenting with respiratory distress and highlight the characteristic clinical and imaging findings. On examination, the baby had low set ears, a large protruding tongue, hypertelorism, and a depressed nasal bridge. Ultrasonography (USG) abdomen showed echogenic kidneys with cortical and medullary cysts. Magnetic Resonance Imaging (MRI) brain showed classical molar tooth sign, vermian hypoplasia-dysplasia, and thinning of the corpus callosum.