Browsing by Subject "encephalocele"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations
    (Elsevier, 2020-01-12) Hughes, Joel J.; Alkhunaizi, Ebba; Kruszka, Paul; Pyle, Louise C.; Grange, Dorothy K.; Berger, Seth I.; Payne, Katelyn K.; Masser-Frye, Diane; Hu, Tommy; Christie, Michelle R.; Clegg, Nancy J.; Everson, Joshua L.; Martinez, Ariel F.; Walsh, Laurence E.; Bedoukian, Emma; Jones, Marilyn C.; Harris, Catharine Jean; Riedhammer, Korbinian M.; Choukair, Daniela; Fechner, Patricia Y.; Rutter, Meilan M.; Hufnagel, Sophia B.; Roifman, Maian; Kletter, Gad B.; Delot, Emmanuele; Vilain, Eric; Lipinski, Robert J.; Vezina, Chad M.; Muenke, Maximilian; Chitayat, David; Pediatrics, School of Medicine
    In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
  • Thumbnail Image
    Item
    Middle Cranial Fossa Repair of Temporal Bone Spontaneous CSF Leaks With Hydroxyapatite Bone Cement
    (Wiley, 2021-03) Alwani, Mohamedkazim M.; Saltagi, Mohamad Z.; MacPhail, Margaret E.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Objectives To determine the safety and effectiveness of the middle cranial fossa (MCF) approach in repairing spontaneous cerebrospinal fluid (sCSF) leaks. Study Design Retrospective cohort study. Methods Patient with sCSF leaks repaired by MCF approach between January 1, 2014 and August 31, 2019 were included. Demographic information, clinical and surgical findings, and postoperative outcomes were recorded. Results The cohort (n = 45) included 24 tegmen repairs by multilayer reconstruction using hydroxyapatite cement and 21 cases of multilayer repair without hydroxyapatite cement. Ten MCF repairs were performed on patients ≥65 years old. Twenty (53%) ears had multiple tegmen defects (range, 1–9 tegmen defects) and 78% of patients had ≥1 encephaloceles. All sCSF leaks were resolved with one surgical intervention. There were no major intracranial complications. Transient expressive aphasia occurred in 2 patients. Medical complications occurred in four patients. There were no short-term postoperative CSF leaks with bone cement reconstruction and two postoperative leaks without bone cement. One resolved with lumbar drain (LD) and the other resolved without treatment. The average (SD) length of stay (LOS) with bone cement was shorter than in patients without bone cement (2.54 [0.83] days vs. 3.52 [1.99] days, P < .05). There have been no long-term CSF leak recurrences with an average (SD) follow-up of 13.5 (12.9) months (range 0.25–46 months). Conclusions MCF approach for sCSF repairs demonstrate efficacious outcomes, particularly with tegmen reconstruction using hydroxyapatite cement. The approach exhibited no serious adverse events and few complications requiring intervention. Therefore, MCF is a safe and effective approach to resolve sCSF leaks.