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JORDAN ORANGE, MD. PhD. |
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| Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine Department of Pediatrics Visit Orange Lab. here. |
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| Ectodermal Dysplasia with Immunodeficiency
and Lymphedema, but not Osteopetrosis, is Associated with a Unique NF-Kb
Essential Modulator (NEMO) Mutation. K. A. Risma,1 R. Deering, L. Monaco-Shawver,
M. Heltzer, J. Burnham, J. Niemela, T. A. Fleisher, J. J. Bleesing, P. E.
Putnam, A. Jain, J. S. Orange. 1Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH.
Recent studies of NF-nB signaling in patients with ectodermal dysplasia (ED) and immunodeficiency (ID) have revealed the diverse impact of hypomorphic NEMO mutations on tumor necrosis factor receptor (TNFR) superfamily signaling. We describe a male patient with a newly identified mutation in NEMO leading to a previously undescribed clinical phenotype: ED with ID and lymphedema, but no osteopetrosis. This child presented in the neonatal period with feeding intolerance, diarrhea, and failure to thrive, largely unresponsive to elemental formula. He exhibited lower extremity and scrotal edema. At 5 months of age, he began to experience recurrent bacterial infections including cellulitis and adenitis, as well as bacteremia with Streptococcus spp., Staphylococcus spp., and Hemophilus influenza. Family history reveals two other affected males (maternal uncle and cousin) who died in childhood from presumed immunodeficiency syndromes. Our patients’ physical characteristics were notable for fine sparse hair, oligodontia, conical incisors, and dramatic lower extremity and scrotal edema. Unlike other patients with osteopetrosis, lymphedema and ED-ID, he had lymphedema without osteopetrosis. Instead, radiographic and biochemical assessments demonstrated osteopenia. Biopsy of the gastrointestinal tract revealed chronic esophagitis with lymphocytic infiltrates, and acute colitis with ulceration. Stool cultures grew Mycobacterium avium intracellulare. Immune studies revealed abnormal B cell function characterized by elevated IgA, poor response to vaccination, and low memory B cells. Toll like receptor (TLR) signaling was variably affected with normal TNF production following TLR 2, 3, 4, and 5 ligation, but impaired response after exposure to TLR7 and TLR9 ligands. Genomic sequencing revealed a donor splice site mutation predicted to cause Abstracts 300 abnormal splicing of exon 6 (IVS6 + 5G > A). Consistent with this prediction, Western blot analysis revealed a smaller NEMO protein detectable only with a polyclonal antibody directed at the carboxy terminus. The association of this mutation with lymphedema suggests an impairment of signaling via the lymphatic development receptor, vascular endothelial growth factor receptor 3, with preserved function of the osteoclast activating receptor, receptor activator of NF-nB. This novel mutation, therefore, will likely provide biochemical insight as to which protein interactions lead to signaling via one TNFR superfamily member but not another.
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| The
presentation and natural history of immunodeficiency caused Finding Nemo: genetic disorders of NFkB
activation. Deficient natural killer cells cytoxicity
in patients with |
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