We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of
Camurati-Engelmann disease (CED) featuring histopathological changes of
osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg
pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had
deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with
knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively.
Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum
25-hydroxyvitamin D (25[
OH]D) levels. Pituitary
hypogonadism and low serum
insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite
vitamin D repletion, iliac crest histology revealed severe
osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent
mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific
alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5'11″ mother, also with low serum 25(
OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (
c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional
leucine residues in the latency-associated-
peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative
amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity.