Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans.

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A

Disseminated cryptococcosis initially presenting as cellulitis in a patient suffering from nephrotic syndrome

<p>Abstract</p> <p>Background</p> <p>Cryptococcosis is considered as an opportunistic infection because it mainly occurs in immunosuppressed hosts. C. neoformans is usually acquired by the respiratory route and then may disseminate hematogenously to other places, such as meninges, bone and skin. Cutaneous involvement is a rare but important feature of disseminated cryptococcosis with a poor outcome if misdiagnosis. We reported the first case of patients with nephrotic syndrome suffering from disseminated cryptococcosis initially presented as cellulitis.</p> <p>Case presentation</p> <p>A 34-year-old man developed severe cellulitis on his both lower extremities without any preceding injury and allergies. The patient had been treated with systemic corticosteroids nearly one year for nephrotic syndrome. According to the outcome of blood culture, the wound area was interpreted as bacterial cellulitis at first. However, the antimicrobial treatment made no response and the skin biopsy revealed the presence of Cryptococcus neoformans, which was subsequently confirmed by microbiological culture. Though the initiation of therapy with fluconazole 400 mg per day was immediately adopted, the patient’s conditions suddenly plummeted and he died in the end.</p> <p>Conclusion</p> <p>Since the poor outcome of disseminated cryptococcosis if unrecognized and untreated in time, it should be investigated rigorously as a differential diagnosis in patients with nephrotic syndrome suffering from cutaneous diseases.</p