First and second branchial arch involvement in mandibulofacial dysostosis Guion-Almeida type.

BACKGROUND: Mandibulofacial dysostosis Guion-Almeida Type (MFDGA; OMIM#610536) is a rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the EFTUD2 gene. Mandibulofacial dysostoses are characterised by the core triad malar hypoplasia, maxillary hypoplasia and dysplastic ears, all derived by the impaired development of the first and second branchial arches. Differential diagnosis is often challenging. The early genetic diagnosis is extremely useful, not only for the correct management of cranial malformations, but also for the early diagnosis and treatment of the comorbidities associated to the disease, which greatly benefit from early treatment.

Improved clinical utility of preimplantation genetic testing through the integration of ploidy and common pathogenic microdeletions analyses.

STUDY QUESTION: Can chromosomal abnormalities beyond copy-number aneuploidies (i.e. ploidy level and microdeletions (MDs)) be detected using a preimplantation genetic testing (PGT) platform? SUMMARY ANSWER: The proposed integrated approach accurately assesses ploidy level and the most common pathogenic microdeletions causative of genomic disorders, expanding the clinical utility of PGT. WHAT IS KNOWN ALREADY: Standard methodologies employed in preimplantation genetic testing for aneuploidy (PGT-A) identify chromosomal aneuploidies but cannot determine ploidy level nor the presence of recurrent pathogenic MDs responsible for genomic disorders. Transferring embryos carrying these abnormalities can result in miscarriage, molar pregnancy, and intellectual disabilities and developmental delay in offspring. The development of a testing strategy that integrates their assessment can resolve current limitations and add valuable information regarding the genetic constitution of embryos, which is not evaluated in PGT providing new level of clinical utility and valuable knowledge for further understanding of the genomic causes of implantation failure and early pregnancy loss. To the best of our knowledge, MDs have never been studied in preimplantation human embryos up to date. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort analysis including blastocyst biopsies collected between February 2018 and November 2021 at multiple collaborating IVF clinics from prospective parents of European ancestry below the age of 45, using autologous gametes and undergoing ICSI for all oocytes. Ploidy level determination was validated using 164 embryonic samples of known ploidy status (147 diploids, 9 triploids, and 8 haploids). Detection of nine common MD syndromes (-4p=Wolf-Hirschhorn, -8q=Langer-Giedion, -1p=1p36 deletion, -22q=DiGeorge, -5p=Cri-du-Chat, -15q=Prader-Willi/Angelman, -11q=Jacobsen, -17p=Smith-Magenis) was developed and tested using 28 positive controls and 97 negative controls. Later, the methodology was blindly applied in the analysis of: (i) 100 two pronuclei (2PN)-derived blastocysts that were previously defined as uniformly euploid by standard PGT-A; (ii) 99 euploid embryos whose transfer resulted in pregnancy loss. PARTICIPANTS/MATERIALS, SETTING, METHODS: The methodology is based on targeted next-generation sequencing of selected polymorphisms across the genome and enriched within critical regions of included MD syndromes. Sequencing data (i.e. allelic frequencies) were analyzed by a probabilistic model which estimated the likelihood of ploidy level and MD presence, accounting for both sequencing noise and population genetics patterns (i.e. linkage disequilibrium, LD, correlations) observed in 2504 whole-genome sequencing data from the 1000 Genome Project database. Analysis of phased parental haplotypes obtained by single-nucleotide polymorphism (SNP)-array genotyping was performed to confirm the presence of MD. MAIN RESULTS AND THE ROLE OF CHANCE: In the analytical validation phase, this strategy showed extremely high accuracy both in ploidy classification (100%, CI: 98.1-100%) and in the identification of six out of eight MDs (99.2%, CI: 98.5-99.8%). To improve MD detection based on loss of heterozygosity (LOH), common haploblocks were analyzed based on haplotype frequency and LOH occurrence in a reference population, thus developing two further mathematical models. As a result, chr1p36 and chr4p16.3 regions were excluded from MD identification due to their poor reliability, whilst a clinical workflow which incorporated parental DNA information was developed to enhance the identification of MDs. During the clinical application phase, one case of triploidy was detected among 2PN-derived blastocysts (i) and one pathogenic MD (-22q11.21) was retrospectively identified among the biopsy specimens of transferred embryos that resulted in miscarriage (ii). For the latter case, family-based analysis revealed the same MD in different sibling embryos (n = 2/5) from non-carrier parents, suggesting the presence of germline mosaicism in the female partner. When embryos are selected for transfer based on their genetic constitution, this strategy can identify embryos with ploidy abnormalities and/or MDs beyond aneuploidies, with an estimated incidence of 1.5% (n = 3/202, 95% CI: 0.5-4.5%) among euploid embryos. LIMITATIONS, REASONS FOR CAUTION: Epidemiological studies will be required to accurately assess the incidence of ploidy alterations and MDs in preimplantation embryos and particularly in euploid miscarriages. Despite the high accuracy of the assay developed, the use of parental DNA to support diagnostic calling can further increase the precision of the assay. WIDER IMPLICATIONS OF THE FINDINGS: This novel assay significantly expands the clinical utility of PGT-A by integrating the most common pathogenic MDs (both de novo and inherited ones) responsible for genomic disorders, which are usually evaluated at a later stage through invasive prenatal testing. From a basic research standpoint, this approach will help to elucidate fundamental biological and clinical questions related to the genetics of implantation failure and pregnancy loss of otherwise euploid embryos. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. S.C., M.F., F.C., P.Z., I.P., L.G., C.P., M.P., D.B., J.J.-A., D.B.-J., J.M.-V., and C.R. are employees of Igenomix and C.S. is the head of the scientific board of Igenomix. A.C. and L.P. are employees of JUNO GENETICS. Igenomix and JUNO GENETICS are companies providing reproductive genetic services. TRIAL REGISTRATION NUMBER: N/A.

Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1.

OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

Hyperglycemia is associated with relatively lower lean body mass in older adults.

BACKGROUND/OBJECTIVES: Older adults with known diabetes are vulnerable to accelerated loss of lean body mass. However, the relationship of hyperglycemia per se with lean body mass is not fully understood. We sought to examine the independent relationship of hyperglycemia with relative lean body mass in older persons without a reported history of diabetes. DESIGN: Cross-sectional nationally representative survey. SETTING: United States. PARTICIPANTS: We studied U.S. adults >50 years without known diabetes (n=5434) in the National Health and Nutrition Examination Survey (1999-2004). MEASUREMENTS: In linear regression models, we studied the relationship of measured HbA1c (<5.0%, 5.0-5.4%, 5.5-5.9%, 6.0-6.4%, ≥6.5%) with percent lean body mass, measured by dual-energy x-ray absorptiometry, after accounting for potential confounders. RESULTS: Among older U.S. men and women, progressively higher HbA1c was associated with relatively lower total, appendicular, and trunk percent lean mass, independent of demographics and height (all p<0.05). Accounting for physical activity, C-reactive protein, and diabetes-related comorbidities (heart disease, peripheral arterial disease, arthritis, neuropathy, hip fracture, amputation, cancer, pulmonary disease), undiagnosed diabetes (i.e. HbA1c ≥6.5%) versus reference (<5.0%) in both men and women was associated with lower total (-3.5±0.8% and -2.9±0.8%), appendicular (-1.8±0.5% and -1.2±0.4%), and trunk percent lean mass (-1.2±0.4% and -1.3±0.5%), respectively (all p<0.05). Persons at increased risk for diabetes (i.e. HbA1c 6.0-6.4%) also had significant decrements at these sites versus reference. CONCLUSIONS: Hyperglycemia is associated with relatively lower lean mass in a nationally representative population of older adults without history of diabetes. Future longitudinal studies are needed to investigate the relationship of hyperglycemia with the accelerated decline of skeletal muscle mass in older persons.

Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.

Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.

Unbiased next generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases.

The mode of inheritance of Alport syndrome (ATS) has long been controversial. In 1927, the disease was hypothesized as a dominant condition in which males were more severely affected than females. In 1990, it was considered an X-linked (XL) semidominant condition, due to COL4A5 mutations. Later on, a rare autosomal recessive (AR) form due to COL4A3/COL4A4 mutations was identified. An autosomal dominant (AD) form was testified more recently by the description of some large pedigrees but the real existence of this form is still questioned by many and its exact prevalence is unknown. The introduction of next generation sequencing (NGS) allowed us to perform an unbiased simultaneous COL4A3-COL4A4-COL4A5 analysis in 87 Italian families (273 individuals) with clinical suspicion of ATS. In 48 of them (55%), a mutation in one of the three genes was identified: the inheritance was XL semidominant in 65%, recessive in 4% and most interestingly AD in 31% (15 families). The AD form must therefore be seriously taken into account in all pedigrees with affected individuals in each generation. Furthermore, a high frequency of mutations (>50%) was shown in patients with only 1 or 2 clinical criteria, suggesting NGS as first-level analysis in cases with a clinical suspicion of ATS.

Meta-analysis: vitamin D and non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition. Emerging evidence suggests that vitamin D may play a role in the pathogenesis of NAFLD. AIM: To review systematically the association between vitamin D levels, measured as serum 25-hydroxy vitamin D [25(OH)D], and NAFLD. METHODS: We used PubMed and EMBASE databases to identify all studies that assessed the association between vitamin D and NAFLD up until 22 April 2013, without language restrictions. We included studies that compared vitamin D levels between NAFLD cases and controls and also those that compared the odds of vitamin D deficiency by NAFLD status. Pooled standardised differences and odds ratios were calculated using an inverse variance method. RESULTS: Seventeen cross-sectional and case-control studies have evaluated the association between vitamin D and NAFLD. NAFLD was diagnosed using biopsy (4 studies), ultrasound or CT (10 studies) and liver enzymes (3 studies). Nine studies provided data for a quantitative meta-analysis. Compared to controls, NAFLD patients had 0.36 ng/mL (95% CI: 0.32, 0.40 ng/mL) lower levels of 25(OH)D and were 1.26 times more likely to be vitamin D deficient (OR 1.26, 95% CI: 1.17, 1.35). CONCLUSIONS: NAFLD patients have decreased serum 25(OH)D concentrations, suggesting that vitamin D may play a role in the development of NAFLD. The directionality of this association cannot be determined from cross-sectional studies. Demonstration of a causal role of hypovitaminosis D in NAFLD development in future studies could have important therapeutic implications.

Nectinopathies: an emerging group of ectodermal dysplasia syndromes.

Cleft Lip/Palate-Ectodermal Dysplasia and Ectodermal Dysplasia-Syndactyly Syndrome are rare congenital disorders caused by recessive mutations in the PVRL1 and PVRL4 genes, respectively. These genes encode nectins 1 and 4, an emerging class of molecules acting in cooperation with cadherins to form cell-cell adhesion especially at adherens junctions. Their role in skin, hair and teeth biology and in the fine-tuning morphogenesis of craniofacial (lip/palate) and limbs is yet to be outlined prompting future research. We propose refer to these entities (nectin 1-ED and nectin 4-ED) as "nectinopathies", which are likely to be underestimated/underdiagnosed ED syndomes.

Potassium intake and risk of incident type 2 diabetes mellitus: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

AIMS/HYPOTHESIS: Serum potassium has been found to be a significant predictor of diabetes risk, but the effect of dietary potassium on diabetes risk is not clear. We sought to determine if dietary potassium is associated with risk of incident type 2 diabetes in young adults. METHODS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Potassium intake was measured by (1) an average of three 24 h urinary potassium collections at the 5-year study visit, and (2) the CARDIA dietary assessment instrument at baseline. Incident type 2 diabetes cases were ascertained on the basis of use of diabetes medication and laboratory measurements. Analyses were adjusted for relevant confounders including intake of fruit and vegetables and other dietary factors. RESULTS: Of 1,066 participants with urinary potassium measurements, 99 (9.3%) developed diabetes over 15 years of follow-up. In multivariate models, adults in the lowest urinary potassium quintile were more than twice as likely to develop diabetes as their counterparts in the highest quintile (HR 2.45; 95% CI 1.08, 5.59). Of 4,754 participants with dietary history measurements, 373 (7.8%) developed diabetes over 20 years of follow-up. In multivariate models, African-Americans had a significantly increased risk of diabetes with lower potassium intake, which was not found in whites. CONCLUSIONS/INTERPRETATION: Low dietary potassium is associated with increased risk of incident diabetes in African-Americans. Randomised clinical trials are needed to determine if potassium supplementation, from either dietary or pharmacological sources, could reduce the risk of diabetes, particularly in higher-risk populations.

A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy.

OBJECTIVES: Homozygous mutations in HPGD gene, encoding 15-hydroxyprostaglandin dehydrogenase, have recently been associated with primary hypertrophic osteoarthropathy (PHO). So far, only 7 HPGD alterations are known. In order to expand this mutational spectrum and better delineate the HPGD-related phenotype, we report the clinical and molecular characterisation of a 13-year-old boy and compare his features to known mutated patients. METHODS: The HPGD gene exons 1-7 and exon-intron junctions were analysed by direct sequencing. Previously published HPGD-mutated patients were systematically reviewed based on the original clinical description. RESULTS: A novel homozygous c.217+1G>A mutation affecting the obligatory donor splice site of HPGD exon 2 was identified in our proband who showed a mild form of PHO. Review of HPGD-mutated patients outlined all patients manifested digital clubbing, periostosis and acro-osteolysis. Hyperhidrosis (92%), arthralgia (65%) and eczema (33%) were variably associated features. Pachydermia (54%) was mild and mostly limited to palms and sole; cutis vertigis gyrata, blepharoptosis and severe skin thickening were never observed. Besides digital clubbing, PHO infants often presented patent ductus arteriosus (PDA) (32%) and delayed cranial sutures closure (55%). CONCLUSIONS: The present findings broaden the allelic spectrum of HPGD gene to include a novel c.217+1G>A mutation. Mutated patients display a homogeneous phenotype mainly consisting in digital clubbing, periostosis, acro-osteolysis, hyperhidrosis and mild pachydermia. Earliest manifestations include delayed closure of the cranial sutures and PDA. In conclusion, the information reported herein would facilitate the diagnosis of PHO due to HPGD mutations.

Does pre-existing diabetes affect prostate cancer prognosis? A systematic review.

To summarize the influence of pre-existing diabetes on mortality and morbidity in men with prostate cancer. We searched MEDLINE and EMBASE from inception through 1 October 2008. Search terms were related to diabetes, cancer and prognosis. Studies were included if they reported an original data analysis of prostate cancer prognosis, compared outcomes between men with and without diabetes and were in English. Titles, abstracts and articles were reviewed independently by two authors. Conflicts were settled by consensus or third review. We abstracted data on study design, analytic methods, outcomes and quality. We summarized mortality and morbidity outcomes qualitatively and conducted a preliminary meta-analysis to quantify the risk of long-term (>3 months), overall mortality. In total, 11 articles were included in the review. Overall, one of four studies found increased prostate cancer mortality, one of two studies found increased nonprostate cancer mortality and one study found increased 30-day mortality. Data from four studies could be included in a preliminary meta-analysis for long-term, overall mortality and produced a pooled hazard ratio of 1.57 (95% CI: 1.12-2.20). Diabetes was also associated with receiving radiation therapy, complication rates, recurrence and treatment failure. Our analysis suggests that pre-existing diabetes affects the treatment and outcomes of men with prostate cancer.

Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers.

Joubert syndrome (JS) is characterized by hypotonia, ataxia, developmental delay, and a typical neuroimaging finding, the so-called "molar tooth sign" (MTS). The association of MTS and polymicrogyria (PMG) has been reported as a distinct JS-related disorder (JSRD). So far, five patients have been reported with this phenotype, only two of them being siblings. We report on one additional family, describing a living child with JS and PMG, and the corresponding neuropathological picture in the aborted brother. No mutations were detected in the AHI1 gene, the only so far associated with the JS + PMG phenotype. Moreover, linkage analysis allowed excluding all known gene loci, suggesting further genetic heterogeneity.

Normal cognitive functions in joubert syndrome.

Developmental delay and subsequent impaired cognitive functions are present in almost all patients with Joubert syndrome (JS). We report on a 20-year-old woman with mild clinical signs of JS (minimal truncal ataxia and oculomotor apraxia) but typical molar tooth sign on neuroimaging, normal full scale (IQ=93), verbal (IQ=93), and performance intelligence quotient (IQ=94). Only minor difficulties in visual-spatial organization and in some executive functions could be detected. This pattern of deficits is partly reminiscent of the cerebellar cognitive affective syndrome. Her diagnosis was only reached following the diagnosis of JS in two brothers with severe cognitive impairment. Molecular investigations demonstrated a homozygous mutation in the INPP5E gene. This exceptional observation confirms that normal cognitive functions are possible in JS and corroborates the well known intrafamilial variability.

RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders.

Joubert syndrome-related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign' (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel-Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello-renal presentation ( approximately 12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (<2%).

Birth weight is not related to risk of diabetic retinopathy in type 2 diabetes: the Atherosclerosis Risk in Communities Study.

PURPOSE: Low birth weight has been suggested as a risk factor for diabetes. Whether it is related to diabetic retinopathy is unclear and is examined in this study. MATERIALS AND METHODS: We examined 609 adults with type 2 diabetes from the population-based Atherosclerosis Risk in Communities Study. Retinal photographs were graded for diabetic retinopathy. Birth weight was assessed by self-report. RESULTS: Retinopathy was present in 116 (19%) participants (113 non-proliferative and 3 proliferative). After adjusting for age, sex, race, education level, body mass index, fasting glucose, duration of diabetes, glycosylated hemoglobin A1c, family history of diabetes, serum total cholesterol, and blood pressure, there was no evidence of either a linear or non-linear relationship between birthweight and diabetic retinopathy. CONCLUSIONS: Birth weight was not associated with diabetic retinopathy.

Quantitative comparison and evaluation of software packages for assessment of abdominal adipose tissue distribution by magnetic resonance imaging.

OBJECTIVE: To examine five available software packages for the assessment of abdominal adipose tissue with magnetic resonance imaging, compare their features and assess the reliability of measurement results. DESIGN: Feature evaluation and test-retest reliability of softwares (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision) used in manual, semi-automated or automated segmentation of abdominal adipose tissue. SUBJECTS: A random sample of 15 obese adults with type 2 diabetes. MEASUREMENTS: Axial T1-weighted spin echo images centered at vertebral bodies of L2-L3 were acquired at 1.5 T. Five software packages were evaluated (NIHImage, SliceOmatic, Analyze, HippoFat and EasyVision), comparing manual, semi-automated and automated segmentation approaches. Images were segmented into cross-sectional area (CSA), and the areas of visceral (VAT) and subcutaneous adipose tissue (SAT). Ease of learning and use and the design of the graphical user interface (GUI) were rated. Intra-observer accuracy and agreement between the software packages were calculated using intra-class correlation. Intra-class correlation coefficient was used to obtain test-retest reliability. RESULTS: Three of the five evaluated programs offered a semi-automated technique to segment the images based on histogram values or a user-defined threshold. One software package allowed manual delineation only. One fully automated program demonstrated the drawbacks of uncritical automated processing. The semi-automated approaches reduced variability and measurement error, and improved reproducibility. There was no significant difference in the intra-observer agreement in SAT and CSA. The VAT measurements showed significantly lower test-retest reliability. There were some differences between the software packages in qualitative aspects, such as user friendliness. CONCLUSION: Four out of five packages provided essentially the same results with respect to the inter- and intra-rater reproducibility. Our results using SliceOmatic, Analyze or NIHImage were comparable and could be used interchangeably. Newly developed fully automated approaches should be compared to one of the examined software packages.

Diffusion tensor imaging in Joubert syndrome.

BACKGROUND AND PURPOSE: Neuropathologic findings and preliminary imaging studies demonstrated the absence of pyramidal tract and superior cerebellar peduncular decussation in individual patients with Joubert syndrome (JS). We hypothesized that functional-structural neuroimaging findings do not differ between the genetic forms of JS. MATERIALS AND METHODS: MR imaging was performed with a 3T MR imaging-unit. Multiplanar T2- and T1-weighted imaging was followed by diffusion tensor imaging (DTI). Isotropic diffusion-weighted images, apparent diffusion coefficient maps, and color-coded fractional anisotropy maps, including tractography, were subsequently calculated. RESULTS: In all 6 patients studied, DTI showed that the fibers of the superior cerebellar peduncles did not decussate in the mesencephalon and the corticospinal tract failed to cross in the caudal medulla. The patients represented various genetic forms of JS. CONCLUSION: In JS, the fibers of the pyramidal tract and the superior cerebellar peduncles do not cross, irrespective of the underlying mutation.