Figure 1. Germline mutations in CBL can be inherited in an autosomal dominant fashion and are associated with a phenotype, GM-CSF hypersensitivity and vasculitis.

Panel (a) demonstrates the angiograms from the aorta and left subclavian artery from patient D048 nine months after the diagnosis of Takayasu arteritis type III. Panel (b) The family tree of UPN1333 is shown in panel a, where the diseased bone marrow of UPN1333 displayed a homozygous CBL c.1111T>C (red) mutation as well as a heterozygous lesion from his buccal swab (black). Only women appear to be heterozygote carriers, and only boys appear to be affected by JMML in this family. Panel (c) The bone marrow of UPN1125 demonstrated a homozygous CBL mutation—her mother (III:5) is a known carrier, and she had two male cousins dying from JMML (III:6, III:7). Panel (d) demonstrates a classic GM-CSF hypersensitivity response on a colony assay for patients with CBL mutations (n=3) versus normal (n=13). Error bars represent standard error of the mean (s.e.m.) Panel (e) shows one toddler (D703) diagnosed with JMML and a homozygous mutation at p.C384R. She displays frontal bossing, downslanting palpebral fissues, hypertelorism, and a low nasal bridge. Photographs of her father, who harbors a heterozygous mutation at p.C384R, are included in Figures S1, panel d. Of note, both father and daughter also display bilateral ptosis.