ABSTRACT
Camurati-Engelmann disease (CED) is a rare autosomal dominant bone disorder caused by a mutation in transforming growth factor ß1 (TGFß1). The present study aimed to identify a Chinese family with suspected CED based on the clinical symptoms, including pain in extremities, waddling gait, muscle weakness, cortical thickening of the diaphysis of the long bones, and sclerosis of the skull, facial bone, and pelvis. Molecular analysis revealed the presence of the p.Glu169Lys (E169K) mutation in exon 2 of TGFß1 in patients when compared with the controls. Therefore, the Chinese family was diagnosed with CED due to the presence of the E169K mutation. The present study emphasized the importance of clinical and genetic evidence for the diagnosis of CED. The data presented in the present study are of significance to clinicians, as well as genetic counselors, in the prenatal screening of CED.
Subject(s)
Camurati-Engelmann Syndrome/diagnosis , Camurati-Engelmann Syndrome/genetics , Point Mutation , Transforming Growth Factor beta1/genetics , Adolescent , Adult , Aged , Asian People/genetics , Base Sequence , Bone and Bones/pathology , Camurati-Engelmann Syndrome/epidemiology , China/epidemiology , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , PedigreeABSTRACT
Camurati-Engelmann disease (CAEND, OMIM 131300) is a rare autosomal dominant, progressive diaphyseal dysplasia, which is characterized by hyperosteosis and sclerosis of the diaphyses of long bones. Estimated number of patients with CAEND in Japan is approximately 50-60 by our epidemiological survey. We have reported that domain-specific mutations in transforming growth factor-ß1 gene(TGFB1) cause CAEND. Mutations in latency associated peptide(LAP) domain of TGF-ß1 destabilize the complex and may hyperactivate TGF signal pathway. We tried to establish CAEND model mice by gene-targeting, but could not because of spermatogenesis defects in chimera mice. We also failed using CRISPR/Cas9 system. Alternatively, we established CAEND patient-derived iPS cells, and are advancing research with them to develop novel therapeutic agents for CAEND.
Subject(s)
Camurati-Engelmann Syndrome/genetics , Animals , Camurati-Engelmann Syndrome/diagnosis , Camurati-Engelmann Syndrome/epidemiology , Camurati-Engelmann Syndrome/therapy , Diagnosis, Differential , Humans , Microsatellite Repeats , Mutation , Signal Transduction , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
34-year old patient had history of muscular wasting, easy fatigability, pain in extremities and waddling gait since age of four. During the time, neuromuscular disease was suspected, but not confirmed. Elevated bone alkaline phosphatase as well as other bone turnover markers (osteocalcin, procollagen, telopeptide) indicated further skeletal evaluation. Symmetrical enhanced uptake on technetium methylene diphosphonate [99mTc]MPD bone scintigraphy at diaphyses of longitudinal bones and scull matched cortical thickening of long bones and sclerosis of the scull seen at radiograms. Those findings pointed to Camurati-Engelmann disease misdiagnosed for the long time. This rare genetic autosomal dominant disorder was retrospectively diagnosed in asymptomatic father too on the basis of bone scans done long time ago. Old family member scans confirmed heredity pattern of the disease.
Subject(s)
Bone and Bones/diagnostic imaging , Camurati-Engelmann Syndrome/epidemiology , Genetic Predisposition to Disease , Camurati-Engelmann Syndrome/genetics , Croatia/epidemiology , Humans , Radionuclide ImagingSubject(s)
Anorexia/etiology , Camurati-Engelmann Syndrome/diagnosis , Gait , Adolescent , Age of Onset , Camurati-Engelmann Syndrome/drug therapy , Camurati-Engelmann Syndrome/epidemiology , Camurati-Engelmann Syndrome/genetics , Female , Gait/physiology , Glucocorticoids/administration & dosage , Humans , Mutation , Prednisolone/administration & dosage , Transforming Growth Factor beta1/geneticsABSTRACT
Moderate increases in "classical" biochemical markers of bone turnover have been described only in some patients with Camurati-Engelmann disease. However, the determination of the following "new" markers has not been previously performed: serum osteocalcin (BGP), bone alkaline phosphatase (BAP), carboxyterminal propeptide of type I procollagen (PICP), aminoterminal propeptide of type I procollagen (PINP), tartrate-resistant acid phosphatase (TRAP), telopeptide carboxyterminal of type I collagen (ICTP), urinary pyridinoline (PYR), crosslinked N-telopeptides of type I collagen (NTX), and Crosslaps (CL). Such a determination may improve the evaluation of the disease activity. To evaluate the usefulness of biochemical markers of bone turnover reflecting Camurati-Engelmann disease activity we measured the levels of all these markers in four affected patients. The results were compared with bone scintigraphic indices of disease activity. Except for PICP and TRAP, bone formation and resorption markers were abnormal in all patients and were related to bone scan indices of disease activity. Among the markers of bone formation PINP, BAP, and BGP showed the highest values, whereas NTX and CL were the most sensitive markers of bone resorption. These results suggest that the determination of NTX or CL, and PINP or either BAP and BGP, associated with bone scan evaluation, provides the best assessment of Camurati-Engelmann disease activity.
