Rare association of Hirschsprung’s disease and Joubert syndrome

Özyürek, Hamìt; Kayacik, Özlem Eroğlu; Güngör, Olcay; Karagöz, Filiz

doi:10.1007/s00431-007-0504-1

Cited by 11 publications

(8 citation statements)

References 11 publications

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“…Due to the young median age of the present patient cohort renal and/or liver involvement may still develop and no firm conclusions can be drawn at present. Interestingly, one patient of our cohort had Hirschsprung disease, which has also been described in one patient with "pure" JS [45] and in one patient with Bardet-Biedl syndrome, another ciliopathy [46]. This association does not seem to be coincidental and cilia have been implicated recently in neural crest development [47].…”

Section: Discussionmentioning

confidence: 55%

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Poretti

Vitiello

Hennekam

et al. 2012

Orphanet J Rare Dis

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Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

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Section: Discussionmentioning

confidence: 55%

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Poretti

Vitiello

Hennekam

et al. 2012

Orphanet J Rare Dis

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“…Treatments can involve positioning, oral‐motor therapy, oral medications, and injected botulinum toxin. While a few individuals have been reported with JS and Hirschsprung disease (manifested by intractable constipation), this appears to be a rare or chance association (Brancati et al, ; Ozyurek, Kayacik, Gungor, & Karagoz, ). On the other hand, constipation unrelated to Hirschsprung disease is common in JS.…”

Section: Methodsmentioning

confidence: 99%

Healthcare recommendations for Joubert syndrome

Bachmann‐Gagescu

Dempsey

Bulgheroni

et al. 2019

American J of Med Genetics Pt A

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Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

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“…Importantly, our data also illuminate interrelated roles for these BBS loci and RET in buffering the effects of genetic variation during ENS development, and between their mutant alleles in the copresentation of BBS and HSCR phenotypes. Interestingly, HSCR has been recurrently reported in association with other ciliopathies, namely Jeune and Joubert syndromes (23,24).…”

Section: Discussionmentioning

confidence: 99%

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

Pontual

Zaghloul²,

Thomas

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.Bardet-Biedl ͉ neural crest cells ͉ genetic interaction ͉ zebrafish H irschsprung disease (HSCR, MIM 164761) is the most common (1/5,000 live births) form of structural intestinal obstruction. It is defined by the absence of neural crest (NC)-derived enteric ganglia along a variable length of the bowel, invariably involving the recto-anal junction. This phenotype has been attributed to defects in migration, proliferation, and/or survival of the NC cells (NCC) that normally give rise to all neurons and supporting cells of the enteric nervous system (ENS), defining HSCR as a neurocristopathy. HSCR is also a useful model oligogenic disorder; it displays non-Mendelian modes of inheritance with low, sex-dependant penetrance in isolated HSCR cases. Although oligogenic multiplicative models have been proposed, mutations in the RET proto-oncogene have emerged as pivotal (1-4). Almost all HSCR patients harbor either a heterozygous mutation in the RET coding sequence or, more frequently, a hypomorphic allele in a conserved noncoding element in intron 1 that acts as a spatially restricted transcriptional enhancer (4-6).In addition to HCSR, some 30% of patients also exhibit other congenital anomalies as the result of chromosomal rearrangements [mostly Down syndrome (DS)], monogenic Mendelian disorders regardless of the mode of inheritance, or undiagnosed associations (6). In such cases, penetrance for the HSCR trait is 5 to 70%, suggesting additional predisposing genetic factor(s). Interestingly, alleles at the RET locus can have a role in modifying the risk of HSCR to be associated with several HSCR predisposing syndromes [congenital central hypoventilation, DS, Waardenburg (WS) type IV due to EDNRB mutations, and Bardet-Biedl (BBS)], but not all (Mowat-Wilson and Waardenburg type IV due to SOX10 mutations) (6-8). These observations are suggestive of RET-dependent and RET-independent HSCR cases (9); consistent with RET acting as a modifier gene in some HSCR predisposing syndromes, no correlation between the genotype for the syndrome disease causing gene and the HSCR trait could be drawn in monogenic HSCR syndromes (9,10). Surprisingly, the greatest RET ...

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Rare association of Hirschsprung’s disease and Joubert syndrome

Cited by 11 publications

References 11 publications

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Healthcare recommendations for Joubert syndrome

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease

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