Camurati-engelmann disease: Unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand

Abstract

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. © 2011 American Society for Bone and Mineral Research.

Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease (Chloride Channel 7 Deficiency Osteopetrosis) among the sclerosing bone disorders

“…Serum LDH levels were normal in 6 adult patients at Washington University representing skeletal fluorosis (26,27) (2), hepatitis C-associated osteosclerosis (28) (2), and LRP5 high bone mass (29) (1) and low (75 U/L; normal 100 to 190 U/L) in a man with a unique variant of Camurati-Engelmann disease (30) (1). The 41 Shriners patients and 6 adult patients had unremarkable serum AST and ALT levels.…”

Hearing loss in Camurati Engelmann disease: a case report

“….Mutations of this gene result in increased transforming growth factor activity and subsequent stimulation of osteoblastic bone formation. Also, although these mutations were originally thought to result in suppression of the osteoclastic bone resorption, newer evidence suggests that they may actually promote the formation and activity of osteoclasts 3,4 . CED is characterized by progressive expansion and sclerosis, especially along the shafts of the long bones,-and typically presents in childhood with generalized muscle weakness, lower limb pain, as well as a waddling gait 5 .…”

Identification of genetic modifiers of monogenic (bone) diseases: New tools available, but with limitations

“…Two other families previously were reported to have such a duplication, but interestingly, in this patient the duplication counts 12 nucleotides instead of the previously reported 9 nucleotides. (4) Whyte et al's report (1) shows many similarities to tandem duplications found in the signal peptide of the RANK protein. Closely related but clearly distinguishable phenotypes were associated with duplications of different size in that part of the gene encoding RANK.…”

“…I n the current issue, Whyte et al describe a mother and son diagnosed with Camurati-Engelmann disease (CED), (1) a sclerosing bone disease caused by mutations in the transforming growth factor b1 (TGF-b1) gene. (2,3) Interestingly, both patients show major differences in their phenotype.…”

“…However, the authors identified a genetic change in the gene encoding the RANKL protein and suggested this variant to be a genetic modifier of the disease. (1) With the advantage of major technological breakthroughs and data generated by the Human Genome Project, the diseasecausing genes for the majority of monogenic diseases have been identified in the last two decades. These achievements open the possibility to perform genetic counseling within the families involved.…”