Natural history and clinical management of patients with ASXL1 mutations and Bohring-Opitz Syndrome, including the first report of Wilms Tumor in two patients. B. Russell1, N. Kramer2, L. Biesecker3, J. Johnston3, W. Rhead4, A. Pickart4, A. Dobson5, L. Clarkson5, J. Graham2 1) Medical Genetics, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH; 2) Medical Genetics Institute, Cedars Sinai Medical Center, Dept of Pediatrics, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA; 3) National Human Genome Research Institute, National Institute of Health, Bethesda, MD; 4) Section of Medical Genetics, Childrens Hospital of Wisconsin, Milwaukee, WI; 5) Greenwood Genetic Center, Columbia, SC.
Introduction: Bohring-Opitz syndrome is a rare genetic condition (35 reported cases) characterized by distinct facial features (glabellar nevus flammeus, wide spaced eyes, depressed and wide nasal bridge, anteverted nares, palatal anomalies, micrognathia, low-set posteriorly angulated ears), typical posture (elbow flexion with ulnar deviation and flexion of the wrists and metacarpophalangeal joints), variable microcephaly, severe intellectual disability, hypertrichosis, and feeding problems. Nine published patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report natural history and clinical management of five previously unpublished patients with mutations in ASXL1. Natural History: The 5 patients we discuss range from 2-12 years of age with complicated medical histories that included feeding issues, cyclic vomiting, respiratory infections, insomnia and Wilms tumor. Severity of illness improved with age after the first 1-2 years of life. Dysmorphic features such as nevus flammeus also faded with age. Severe myopia was present in all patients. They also had distinctive personalities (interactive, happy, and curious), and excessive hair growth which were features not described in the literature. Clinical Management: Permanent feeding tubes due to gastric dysmotility, silent aspiration, chronic emesis and poor weight gain were required in 4 of the 5 patients. Two patients had cyclic vomiting that was managed with cyproheptadine, lorazapam, ondansetron and acetaminophen. Recurrent respiratory infections with components of reactive airway disease occurred in 3 patients and 1 patient required a tracheostomy. Insomnia was a significant challenge for 4 of the patients, 2 of which improved with treatment of their severe anemia and 3 patients had obstructive sleep apnea that improved with CPAP or mandibular distraction. With the occurrence of bilateral Wilms tumor in one of the patients, screening renal ultrasounds were recommended to the other patients. This led to the identification and treatment of bilateral Wilms tumor in a second patient. Given the known association between ASXL1 and myeloid malignancies along with the two patients presented here, consideration of Wilms tumor screening in patients with ASXL1 mutations will be discussed.
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