Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-69) contains supplementary material, which is available to authorized users.

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.

We report a case of disseminated Scedosporium/Pseudallescheria infection due to Pseudallescheria boydii sensu stricto after lung transplantation in a patient with cystic fibrosis. Dissemination occurred under voriconazole. Despite surgery and combination therapy with voriconazole, caspofungin, and terbinafine, the patient died 8 months after transplantation. Previously reported cases are reviewed. CASE REPORTA 37-year-old woman suffering from cystic fibrosis (CF) was admitted to our institution in April 2008 for double-lung transplantation. Her medical history included diabetes mellitus since 2002 and more than 10 years of airway colonization with Aspergillus fumigatus and Scedosporium/Pseudallescheria. Starting in 2006, and while awaiting transplantation, she received oral voriconazole (250 mg, twice a day). Her postoperative course was relatively uncomplicated except for cytomegalovirus (CMV) infection due to a mismatch at the time of transplantation in spite of valganciclovir prophylactic treatment (900 mg/day). The immunosuppressive regimen included tacrolimus (therapeutic range, 12 to 13.5 ng/ml), mycophenolate mophetil (750 mg/day), and prednisone (37.5 mg/day). Oral voriconazole was continued as a long-term posttransplantation prophylaxis (250 mg twice a day). A fungal culture of a bronchial secretion obtained the day after transplantation was positive for a filamentous fungus routinely identified as Scedosporium apiospermum/P. boydii (isolate I), but several other respiratory specimens obtained over the following weeks were negative. The patient was discharged from the hospital on day 45 after transplantation, still taking voriconazole. The voriconazole serum levels, checked regularly (1.06, 1.96, and 1.69 mg/liter on days 26, 36, and 50, respectively) were within therapeutic limits (1 to 2.5 mg/liter) except for two occasions (0.16 and 0.35 mg/liter on days 18 and 64, respectively).In June (day 70), she presented at our hospital with nodules on her legs that had appeared 2 weeks previously. On examination, the nodules were fibrous, dermo-hypodermic, measuring 1 to 2 cm in diameter, and slightly pigmented on the surface. A biopsy was performed. Histopathological microscopic examination (Gomori-Grocott and periodic acid-Schiff stainings) revealed an inflammatory infiltrate along with several branched and septate hyaline hyphae (fungal cultures were not performed). Continuation of voriconazole in association with a reduced dose of corticosteroid was associated with clinical improvement. However, 3 weeks later, a new biopsy was performed and septate hyphae were again seen on direct examination. A fungal culture of this biopsy specimen was positive for S. apiospermum/P. boydii (isolate II). At this time, the results for chest computed tomography (CT) were unremarkable, no sign of dissemination was noted on brain CT, and the nodules disappeared over the following weeks.All the while, positive CMV DNAemia was still detected in spite of successive curative treatments with per os valganciclovir (1,800 mg/day fro...

Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.