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Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.

ABSTRACT: BACKGROUND AND AIMS:Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension. METHODS:Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing were performed. Patients were stratified based on the spleen length/patient height ratio as a marker of splenomegaly, used as a surrogate for probable portal hypertension. RESULTS:Forty-three patients (43%) had liver involvement based on elevated liver enzymes and/or liver hyperechogenicity and/or splenomegaly. None of the patients had macroscopic liver cysts or bile duct dilatation. Based on the spleen length/patient height ratio, 13 patients were stratified into a probable portal hypertension group. We observed significant elevations in alkaline phosphatase (269 vs 169?U/L, P???0.001), alanine aminotransferase (92 vs 42?U/L, P?=?0.004), aspartate aminotransferase (77 vs 40?U/L, P?=?0.002), and gamma-glutamyl transferase (226 vs 51?U/L, P???0.001) in the probable portal hypertension group. Platelets were lower in the probable portal hypertension cohort (229 vs 299?×?10 cells/?L, P?=?0.008), whereas synthetic function was intact in both groups. Probable portal hypertension was also more prevalent in patients with kidney disease (P?=?0.001) and colobomas (P?=?0.02), as well as mutations in the TMEM67 gene (P?=?0.001). CONCLUSIONS:In JS, probable portal hypertension is associated with abnormal hepatic enzymes, as well as presence of kidney disease, coloboma, and/or mutation in TMEM67. These findings may allow early identification of JS patients who have or are more likely to develop liver disease.

SUBMITTER: Strongin A

PROVIDER: S-EPMC5825259 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.

Strongin Anna A Heller Theo T Doherty Dan D Glass Ian A IA Parisi Melissa A MA Bryant Joy J Choyke Peter P Turkbey Baris B Daryanani Kailash K Yildirimli Deniz D Vemulapalli Meghana M Mullikin Jim C JC Malicdan May C MC Vilboux Thierry T Gahl William A WA Gunay-Aygun Meral M

Journal of pediatric gastroenterology and nutrition 20180301 3

<h4>Background and aims</h4>Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension.<h4>Methods</h4>Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing wer ...[more]

PMID: 29112083

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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.

Dataset Information

Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.

Publications

Characteristics of Liver Disease in 100 Individuals With Joubert Syndrome Prospectively Evaluated at a Single Center.

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