Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case- control study

Background: NF-kappa B essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B). Animal studies suggest NEMO is required for NF-kappa B mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations. Method: We studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; mu-CT and histomorphometry of trans iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-kappa B activity was quantitated in BM-MSCs using a luciferase NF-kappa B reporter assay. Results: Seven Caucasian women with IP (age: 24-67 years and BMI: 20.0-35.2 kg/m(2)) and IKBKG mutation (del exon 4-10 (n = 4); c.460C > T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation ( > 90:10%) in blood, but not in BM-MSCs. NF-kappa B activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 +/- 679 vs. 5422 +/- 1038/mu g protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, mu-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7-fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0-fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01). Conclusion: Unlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.