Imaging features and differential diagnosis of multiple diaphyseal sclerosis: A case report and review of literature.

RATIONALE: Multiple diaphyseal sclerosis (MDS), known as Ribbing disease, is a rare congenital bone disease resulting from autosomal recessive inheritance. The case study involved a 22-year-old female patient who had been diagnosed with chronic sclerosing osteomyelitis due to lack of knowledge about MDS. Previous studies reported rarely on this condition. PATIENT CONCERNS: A 22-year-old female with MDS was analyzed. DIAGNOSES: MDS is characterized radiographically by a fusiform widening of the diaphyseal portion of the long bones, which is caused by a thickening of the cortex with obstruction of the medullary cavity. The pathologies are observed utilizing diagnostic imagery and are often difficult to identify. INTERVENTION: The patient was following a suggested regimen of oral celecoxib capsules at 200 mg/day for 6 days. OUTCOMES: The patient's diagnosis was revised to the rare condition of Ribbing disease by reviewing the clinical history and distinctive radiography images and because the symptoms were alleviated by celecoxib capsule. We also present a review of the literature on the diagnosis and differential diagnosis of MDS based on clinical and imaging features. LESSONS: MDS is rare and may often be initially misdiagnosed as another type of sclerosing bone dysplasia, thus, it is important to be aware of the existence of MDS. Once MDS is suspected, differential diagnosis should be performed to exclude other sclerosing bone dysplasias, taking into account clinical history, distinctive radiographic appearance, distribution, and laboratory and histopathologic findings. Laboratory evaluation and pathologic findings are nonspecific but assist in excluding other diagnoses. More evidence is needed to illustrate the effectiveness of medical or surgical treatments for patients with MDS.

Bone-targeted delivery of TGF-ß type 1 receptor inhibitor rescues uncoupled bone remodeling in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) is a genetic bone-modeling disorder mainly caused by mutations in the gene that encodes transforming growth factor-ß1 (TGF-ß1). Symptoms of CED include bone pain, fractures, and dysplasia. Currently, effective therapies for bone fracture and dysplasia in CED are urgently needed. We have demonstrated that TGF-ß1 is a coupling factor for bone remodeling and is aberrantly activated in CED. Daily injection of TGF-ß type 1 receptor inhibitor (TßR1I) attenuated CED symptoms, but this systemic administration caused serious side effects. In this study, we created a conjugate linking TßR1I and alendronate, which delivered TßR1I specifically to bone. After weekly injection of the conjugate for 8 weeks, normal bone morphology and remodeling in CED mice was maintained with a minimum effective dose 700 times lower than TßR1I injection. Additionally, we found that the conjugate restored normal bone turnover by reducing the number of osteoblasts and osteoclasts, maintained a regular osteogenic microenvironment by regulating the formation of CD31 and Endomucin double-positive vessels, and preserved ordinary bone formation via inhibition of the migration of leptin-receptor-positive cells. Thus, targeting delivery of TßR1I to bone is a promising therapy for CED and other uncoupled bone remodeling disorders.

Bilateral papilloedema in Camurati-Engelmann disease.

A 23-year-old woman presented with bilateral papilloedema in a setting of Camurati-Engelmann disease (CED). She was investigated with neuroimaging showing no optic nerve canal stenosis or jugular vein canal compromise. Her MRI venogram was normal. Her opening pressure at lumbar puncture and serum alkaline phosphatase were raised. Her papilloedema resolved with long-term use of acetazolamide. We believe that our patient suffered from raised intracranial pressure directly as a result of decreasing intracranial volume secondary to CED.

Transforming growth factor-ß1 gene mutations and phenotypes in pediatric patients with Camurati­Engelmann disease.

The aim of the present study was to investigate the clinical characteristics and major causative gene in pediatric patients with Camurati­Engelmann disease (CED). Biochemical and radiographic examinations, bone scintigraphy and genetic analyses were performed in two affected males and their parents. The two patients experienced waddling gait, muscular weakness and growth developmental delay. X-ray radiography revealed typical fusiform thickening of the diaphyseal portions of the long bones. The abnormal uptake of tracer Tc-99m was visualized in the skull and both sides of the upper humeri, ulnas, radii, femurs and tibias using bone scintigraphy. Serum levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) and the bone resorption marker ß­isomerized C-terminal cross-linked telopeptide of type I collagen (ß-CTX) in the 6-year-old patient were significantly increased compared with the normal value range, while only the ß-CTX levels were elevated in the 16-year-old patient. A heterozygous missense mutation p.Arg218Cys in exon 4 of the transforming growth factor ß1 (TGFß1) gene was detected in the two patients, while their parents had normal wild­type genotypes. In conclusion, the p.Arg218Cys mutation was shown to contribute to the clinical phenotypes in two pediatric patients with CED. The results of this study suggest that abnormal bone turnover marker levels, typical radiological findings and mutations in the TGFß1 gene are three important factors in the diagnosis of sporadic CED cases.

Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFß1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand.

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 TGFß1 and TNFSF11 encoding TGFß1 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 TGFß1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFß1, 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.

A novel mutation of TGF beta1 in a Chinese family with Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) [OMIM 131300] is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. It has been previously reported that CED is caused by mutations of the transforming growth factor beta 1 (TGF beta1) gene on chromosome 19q13.1-q13.3. Until now, seven mutations (LLL12-13ins, Y81H, R156C, R218C, R218H, H222D, C225R) in Australian, French, Belgian, Japanese, and European families have been reported and these data showed that there was no correlation between the nature of the mutations and the variability of the clinical manifestations. In this study, we found a Chinese family with CED and observed some intra-familial clinical variability and symptoms that became more severe with the age. A new TGF beta1 mutation (E169K) in exon 2 was identified in the Chinese family using polymerase chain reaction, direct sequencing analysis of PCR products and single-strand conformation polymorphism analysis. This mutation has not been previously reported in other countries in the world.

Bone biopsy and densitometry findings in a child with Camurati-Engelmann disease.

Progressive diaphyseal dysplasia (MIM 131300), also known as Camurati-Engelmann disease (CED), is a rare autosomal dominant craniotubular dysplasia caused by mutations in the transforming growth factor beta1 (TGF-beta1) gene. Radiographs of the long bones of a 9-year-old boy presenting with waddling gait, muscular weakness, underweight, and severe skeletal pain showed symmetric diaphyseal cortical thickening pathognomonic for CED. The diagnosis was verified by detecting a mutation in exon 4 of the TGF-beta1 gene. Full body bone mineral densitometry studies performed before treatment with prednisolone were indicative for osteoporosis (Z-scores for the lumbar spine and femoral neck -2.3 and -3.2, respectively). A transiliac bone biopsy showed markedly reduced trabecular bone volume. Oral prednisolone was initiated, and subsequently, pamidronate infusions were commenced in an attempt to prevent progression of osteoporosis. To our knowledge, this is the first time bone biopsy and bone mineral densitometry studies have been performed and bisphosphonate treatment evaluated in a child with CED.

Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment.

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.

Situs inversus totalis with accompanying craniodiaphysial dysplasia: a new syndrome?

A 20-year-old man with craniofacial anomalies of craniodiaphysial dysplasia (CDD), facial paralysis, mental retardation, and situs inversus totalis is described. Similar features except situs inversus totalis are also present in two of his sisters. The authors believe this to be the first reported case of CDD with accompanying situs inversus totalis.

Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati-Engelmann disease): report of a four-generation pedigree, identification of a mutation in TGFB1, and review.

Progressive diaphyseal dysplasia (PDD) (Camurati-Engelmann disease) is an autosomal dominant craniotubular dysplasia characterized by hyperostosis and sclerosis of the diaphyses of the long bones and the skull. Mutations in transforming growth factor beta-1 (TGFB1) were recently found in patients with PDD. We report on a four-generation pedigree with seven individuals affected by PDD, linkage and mutational analysis results, and review the literature. This pedigree demonstrates the autosomal dominant inheritance pattern, remarkable variation in expressivity, and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. We genotyped 7 markers from chromosome region 19q13.1-13.3 in 15 relatives and confirmed linkage to this region in this family. We screened the TGFB1 gene for mutations and identified a missense mutation resulting in an R218H substitution in the affected individuals, the asymptomatic obligate carrier, and another unaffected relative. We genotyped the family for seven known TGFB1 polymorphisms and a novel TAAA tetranucleotide repeat in intron 1. These polymorphisms did not appear to account for the variability in disease severity in this family. Our review illustrates how the disorder can significantly compromise health. Cranial involvement, which occurs in 61% of patients, can be severe, entrapping cranial nerves or causing increased intracranial pressure. Therapy with corticosteroids should be attempted in all symptomatic patients.

In vitro proteoglycan sulfation derived from sulfhydryl compounds in sulfate transporter chondrodysplasias.

Mutations in a sulfate-chloride antiporter gene, the diastrophic dysplasia sulfate transporter (DTDST), have been associated with a family of skeletal dysplasias including recessive multiple epiphyseal dysplasia, diastrophic dysplasia (DTD), atelosteogenesis type 2, and achondrogenesis type 1B (ACG1B). DTDST function is crucial for uptake of extracellular sulfate required for proteoglycan (PG) sulfation; the tissue-specific expression of the clinical phenotype may be the consequence of the high rate of PG synthesis in chondrocytes and the ensuing high sulfate requirement. We have studied the contribution of cysteine and its derivatives to PG sulfation in fibroblast and chondrocyte cultures from sulfate transporter dysplasia patients. Incubation of ACG1B fibroblasts in medium containing different concentrations of cystine indicated partial recovery of PG sulfation as measured by HPLC disaccharide analysis of chondroitin sulfate PGs; similar results were observed after incubation with N-acetylcysteine. When both compounds were tested in primary chondrocytes from a DTD patient, partial rescue of PG sulfation was observed, suggesting that the metabolic pathways producing cytoplasmic sulfate from thiols are also active in this cell type.

Van Buchem disease: lifetime evolution of radioclinical features.

OBJECTIVE: The purpose of this study was to evaluate the lifetime evolution of the radioclinical features in a large family with van Buchem disease. DESIGN AND PATIENTS: The study population included 13 patients, ranging between 6 and 69 years. The evolution of the clinical features has been assessed by retrospective analysis of the clinical records of the patients. The age-related evolution of the cortical hyperostosis and defective modeling at the tubular bones was evaluated by morphometric analysis of hand films in 9 patients, compared with 9 control individuals. Progression of sclerosis of the craniofacial bones was evaluated by analysis of the skull radiographs of eleven van Buchem patients, taken at different age. RESULTS AND CONCLUSIONS: Radioclinical features, including sclerosis of the cranial and tubular bones and cranial nerve deficit, become more prominent in older patients. Defective modeling of tubular bones, cortical thickness and medullary width progress with age. Radioclinical abnormalities of van Buchem patients become more prominent in older patients, which suggests that the van Buchem gene is very actively involved in bone metabolism throughout life. Morphometric analysis of the plain films supports the hypothesis that the physiological function of the van Buchem gene is to inhibit bone formation and possibly to regulate bone remodeling.

Macrocephaly and sclerosis of the tubular bones in an isolated patient: a mild case of craniodiaphyseal dysplasia?

We report a 56-year-old woman, mainly suffering from painful legs and the inability to run. Radiologically, marked sclerosis and hyperostosis of the skull bones is present resulting in macrocephaly. Most tubular bones of the limbs, as well as the clavicles, are affected by sclerosis. By mutation analysis of the TGFB1, SOST and LRP5 genes, we were able to exclude the diagnoses of Camurati-Engelmann disease, Van Buchem disease, sclerosteosis, high-bone-mass trait and endosteal hyperostosis (Worth type). We believe this patient represents one of the very few examples of adult craniodiaphyseal dysplasia with a mild form of the disease and moderate facial changes.

Early manifestation of Ghosal-type hemato-diaphyseal dysplasia.

Ghosal-type hemato-diaphyseal dysplasia is a rare autosomal recessive disorder with distinctive diaphyseal and metaphyseal dysplasia of long bones and steroid-dependant anemia. The authors describe a 20-month-old girl who had had a severe transfusion-dependent anemia since late infancy and marked locomotion difficulties as a toddler. The diagnosis was established by X-ray bone survey. The anemia was treated with oral prednisolone. Since then, the patient has been doing well on steroid-maintenance therapy and has no more walking difficulties. The incidence of hemato-diaphyseal dysplasia in the Indian subcontinent and Middle East is notable.

Gnathodiaphyseal dysplasia: a syndrome of fibro-osseous lesions of jawbones, bone fragility, and long bone bowing.

We report an unusual generalized skeletal syndrome characterized by fibro-osseous lesions of the jawbones with a prominent psammomatoid body component, bone fragility, and bowing/sclerosis of tubular bones. The case fits with the emerging profile of a distinct syndrome with similarities to previously reported cases, some with an autosomal dominant inheritance and others sporadic. We suggest that the syndrome be named gnathodiaphyseal dysplasia. The patient had been diagnosed previously with polyostotic fibrous dysplasia (PFD) elsewhere, but further clinical evaluation, histopathological study, and mutation analysis excluded this diagnosis. In addition to providing a novel observation of an as yet poorly characterized syndrome, the case illustrates the need for stringent diagnostic criteria for FD. The jaw lesions showed fibro-osseous features with the histopathological characteristics of cemento-ossifying fibroma, psammomatoid variant. This case emphasizes that the boundaries between genuine GNAS1 mutation-positive FD and other fibro-osseous lesions occurring in the jawbones should be kept sharply defined, contrary to a prevailing tendency in the literature. A detailed pathological study revealed previously unreported features of cemento-ossifying fibroma, including the participation of myofibroblasts and the occurrence of psammomatoid bodies and aberrant mineralization, within the walls of blood vessels. Transplantation of stromal cells grown from the lesion into immunocompromised mice resulted in a close mimicry of the native lesion, including the sporadic formation of psammomatoid bodies, suggesting an intrinsic abnormality of bone-forming cells.

Engelmann's disease: a 45-year follow-up.

We report a 45-year follow-up of a patient with Engelmann's disease previously described in 1950, showing progression of the disease with unique involvement of the femoral capital epiphyses. The case is compared with others to add some information about the later stages of a disease which is not fully understood.

[Otolaryngological aspects of Camurati-Engelmann disease (progressive diaphyseal dysplasia): review of literature and report of one case]. / Aspectos otorrinolaringológicos de la enfermedad de Camurati-Engelmann (displasia diafisaria progresiva): revisión de la literatura y descripción de un caso.

Camurati-Engelmann's disease (progressive diaphyseal dysplasia) is a rare hereditary condition characterized by symmetrical hyperostosis of the long bones and the skull-base, myopathies and neurological disturbances. So far, little more than one hundred cases have been reported. The diagnosis is based on radiological imaging (traditional X rays and CT scan) and family history. Our patient (a 15-year-old male) had high-grade skull-base hyperostosis producing audiological signs, such as progressive deafness, persistent otorrhea and otalgia with progressive stenosis of the external acoustic meatus.