Cortical Hyperostosis Research Articles

378 - A rare case of prenatal onset cortical hyperostosis with favorable outcome

378 - A rare case of prenatal onset cortical hyperostosis with favorable outcome

Hyperphosphatemic Familial Tumoral Calcinosis with Hyperphosphatemic Hyperostosis Due to a Novel Mutation: Severe Presentation of a Rare Disorder

Tumoral calcinosisis (TC) is a rare disorder characterized by abnormal deposition of calcium in subcutaneous tissues. It can be primary or secondary to systemic diseases. The primary familial form with hyperphosphatemia has been described to be due to underlying biallelic variants in GALNT3, KLOTHO, or FGF23 gene which lead to the inactivation of FGF23 resulting in hyperphosphatemia and its effects thereof. These patients usually present only with TC or diaphysitis with cortical hyperostosis, known as hyperphosphatemic-hyperostosis syndrome (HHS), and rarely present with both. We present a 13-year-old boy with a history of painful swelling of the right hip joint for the last 4 years who was found to have hyperphosphatemic familial TC on evaluation with HHS of the left tibia due to an underlying novel homozygous missense variant in GALNT3 gene. Further, in silico analysis was carried out to identify the impact of this missense variant on the structure and function of protein coded by GALNT3.

Cortical hyperostosis secondary to chronic treatment with prostaglandins

Cortical hyperostosis secondary to chronic treatment with prostaglandins

CASE REPORT OF A RARE DISEASE : MELORHEOSTOSIS

Introduction: Melorheostosis is a rare, non-genetic, non-developmental, sclerosing developmental dysplasia of bone and adjacent soft tissue. The characteristic radiographic appearance is that of candle wax dripping. Diagnosis is usually based on classical radiographic appearance rather than clinical picture. A 26 year old female with Case report: dull aching pain over upper third left leg and knee with limitation in movements and associated swelling. On examination tenderness and limitation of movements were present. Plain radiograph showed extensive, dense, undulating or irregular cortical hyperostosis, resembling candle wax dripping along length of left tibia suggestive of Melorheostosis and MRI showed features of Osteopathica striata of left femur and Osteopoikilosis of left hip joint. Inj. Zolindronic acid given. Physiotherapy was started to avoid contractures. Lab investigations in Melorheostosis is usua Conclusion: lly normal. Exact pathophysiology of the disease remains uncertain. No curative treatment options are available. Bisphosphonates, Denosumab and physiotherapy are the available options for treatment.

John P. Caffey, 1895–1978

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of Dr. John Caffey, whose name is associated with infantile cortical hyperostosis, also known as Caffey's disease.

Scapular Caffey’s disease: A masquerading swelling in an infant, a case report and review of literature

Caffey’s disease was characterized by a triad of symptoms, irritability, soft tissue swelling, and underlying cortical bone thickening. It mostly occurs before the first 5 months of life in infancy. The knowledge of this pathology was essential as it masquerades as wide range diseases including acute osteomyelitis, bone tumors, trauma, battered baby syndrome (child abuse), hypervitaminosis a, scurvy, infantile malignant osteopetrosis, neonatal tuberculosis, congenital syphilis, pseudoparalyis of infancy which was more common and require specific management including extensive surgery. Classically, infantile cortical hyperostosis disease occurs in the early part of the first year of life. Infantile cortical hyperostosis was characterized by a clinical triad (fever, soft-tissue swelling, hyperirritability) and a clinching radiographic picture of underlying cortical hyperostosis (thickening or bony expansion). We reported a case of scapular swelling in a 2 -month-old infant where a retrospective diagnosis of caffey’s disease was made. We proposed a high clinical suspicion for early diagnosis of Caffey’s disease and hence appropriate management.

Irritable Infant with Bilateral Leg Swelling.

Irritable Infant with Bilateral Leg Swelling.

A Bone to Pick: A Case of Infantile Cortical Hyperostosis

A Bone to Pick: A Case of Infantile Cortical Hyperostosis

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Parosteal lipoma of humerus with a medical history of 24 years: a case report

: Parosteal lipoma is an extremely rare benign tumor, responsible for less than 0.1% of primary bone neoplasms and 0.3% of all lipomas, which mainly constitutes of mature adipose tissue with a bony component. Bony lesions are often discovered in patients with this tumor (59.2%), creating the significance of differential diagnosis of malignant tumors. The tumor is known to be related with underlying bony changes including focal cortical hyperostosis, pressure erosion of the underlying bone, and bowing malformation. Here we state a case of a parosteal lipoma appearing in the humerus with a bony excrescence in a 70-year-old male patient, which had the longest medical history (24 years) in documents of the last 50 years. Twenty-four years after the mass was found, he presented with complaints of night pain. MRI presented a large 11 cm ×6 cm ×5 cm well defined, lobulated mainly fat intensity lesion with a small part of chondroid component measuring 2.7 mm ×1.9 mm ×0.9 mm in proximal left humerus. The mass was excised, and the pathology demonstrated ossifying parosteal lipoma without features of malignancy. The patient had no recurrence and no complaints for 2 years after the operation. In conclusion, orthopedic surgeons should bear the diagnosis of parosteal lipoma in mind, thus providing appropriate treatment. Surgery is usually ideal treatment, which requires that any periosteal involvement is removed completely.

A CHALLENGING DIAGNOSIS OF IDIOPATHIC VOLUMETRIC GROWTH IN THE SUBMANDIBULAR REGION

A 2-year-old white girl, accompanied by her mother, presented with a swelling in her face and 4 days of the same asymptomatic spontaneous volumetric growth. The mother denied comorbidities or weight loss. The extra-oral exam showed a 4-cm node in the right jaw angle progressing to the submandibular region, steady and painless during palpation. The intra-oral exam revealed normal features. The patient was referred to the hospital with hypothetical diagnosis of infantile cortical hyperostosis, lymphoma, and osteosarcoma. The hemogram showed neutrophilia and thrombocytopenia. Magnetic resonance imaging revealed hyperintensity in the submandibular lymph nodes of the jaw angle and normal aspects of the bones. The fine-needle aspiration of the submandibular region showed bacteria, neutrophils, and simple cuboidal and columnar epithelium-like salivary gland duct. The final diagnosis was lymphadenomegaly secondary to acute sialadenitis. The patient was treated with 7 days’ of oral amoxicillin/clavulanate. On the 14th day, we observed a complete tumoral remission. A 2-year-old white girl, accompanied by her mother, presented with a swelling in her face and 4 days of the same asymptomatic spontaneous volumetric growth. The mother denied comorbidities or weight loss. The extra-oral exam showed a 4-cm node in the right jaw angle progressing to the submandibular region, steady and painless during palpation. The intra-oral exam revealed normal features. The patient was referred to the hospital with hypothetical diagnosis of infantile cortical hyperostosis, lymphoma, and osteosarcoma. The hemogram showed neutrophilia and thrombocytopenia. Magnetic resonance imaging revealed hyperintensity in the submandibular lymph nodes of the jaw angle and normal aspects of the bones. The fine-needle aspiration of the submandibular region showed bacteria, neutrophils, and simple cuboidal and columnar epithelium-like salivary gland duct. The final diagnosis was lymphadenomegaly secondary to acute sialadenitis. The patient was treated with 7 days’ of oral amoxicillin/clavulanate. On the 14th day, we observed a complete tumoral remission.

A Rare Case of Melorheostosis in the Hand of a Saudi Woman

Melorheostosis is a very rare bone dysplasia, especially in the hand. Most cases were diagnosed incidentally, with the lower limbs being the most affected. This is the first Saudi woman with hand melorheostosis.A 33-year-old Saudi female had mild to moderate right-hand pain that started six years ago. Hand examination showed a full range of motion and full hand grip, and there was no tenderness upon palpation. Plain X-ray, unenhanced CT scan, and MRI of the hand showed an appearance resembling dripping candle wax as melorheostosis. The bone scan showed a nonvascular and nonacute lesion. An unenhanced CT scan demonstrated cortical and endosteal hyperostosis involving the proximal, middle, and distal third and fourth phalanges. Multi-sequential MRI of the hand demonstrated cortical hyperostosis involving the ulnar and radial aspect of the right fourth proximal, middle, and distal phalanges.Features in the X-ray, CT scan, bone scan, and MRI confirmed a diagnosis of melorheostosis with associated flexor tenosynovitis.

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.

A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis.

Melorheostosis is a very rare sclerosing bone dysplasia characterized by asymmetrical and progressive cortical hyperostosis, usually with involvement of soft tissues surrounding the lesions. Recently Kang et al. identified somatic mosaicism for variants (p.Gln56Pro, p.Lys57Asn, or p.Lys57Glu) in the negative regulatory domain of MAP2K1, resulting in increased ERK1/2 signalling in affected tissues. In our study, we employed several sequencing technologies to unravel genetic variants (only present in affected tissues) from four sporadic melorheostosis patients. In the exome of two patients, we identified the same variants (p.K57N and p.K57E) as previously described by Kang et al. WGS and RNAseq analysis in a third patient demonstrated the presence of a novel variant (p.Cys121Ser) in the catalytic domain of MAP2K1. In addition, gene set enrichment analysis of the transcriptome data demonstrated upregulation of proliferative pathways. Interestingly, increased proliferation of MAP2K1 p.Lys57Asn-positive osteoblasts has been reported by Kang et al. The variants located in the hotspot region of the negative regulatory domain as well as this newly identified p.Cys121Ser variant have all been classified as MAP2K1 variants that can constitutively activate the downstream effector Erk. Finally, in a fourth patient with classical radiographic features of melorheostosis, no pathogenic variants could be identified in MAP2K1 or the other candidate genes for melorheostosis (SMAD3; LEMD3; KRAS). In conclusion, our study strongly suggests that not only somatic variants in the regulatory domain of MAP2K1 but also in the catalytic domain can cause melorheostosis. Our observations confirm that mutations in MAP2K1 are a major cause of melorheostosis and also suggest further locus heterogeneity for this disorder.

Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs.

Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.

Radiographic overlap of recurrent Caffey disease and chronic recurrent multifocal osteomyelitis (CRMO) with considerations of molecular origins.

Caffey disease, or infantile cortical hyperostosis, classically describes a self-limited inflammatory disorder that presents in the infant with fussiness, focal swelling and sometimes fever. Imaging is conventionally limited to radiography, which shows mild to profound subperiosteal bone formation and sometimes deformity. This disease was not uncommonly diagnosed in the late 20th century. Interestingly, the disease may not just occur in the infant, and it may be due to a genetic mutation in the alpha-one chain of type 1 collagen (COL1A1). Recurrent or delayed onset in the older child or adolescent also occurs. In more recent years, another type of inflammatory bone disorder, chronic sterile osteomyelitis, has been frequently recognized and, depending on the radiographic stage or the diagnostic modality used, may have characteristics overlapping with Caffey disease. In this review, we discuss the demographics, imaging and known etiologies for Caffey disease and chronic recurrent multifocal osteomyelitis and raise the possibility of similar molecular origins.

Microcomputed tomography and genetic analysis of a rare case of Caffey's disease in a 5–7‐month‐old girl

AbstractAncient human remains provided precious information about the health and disease of individuals from the past. Usually, diagnosis and assessment of the paleopathological remains were performed using RX analysis, tomography, and histology. However, thanks to the progress in ancient DNA recovery and sequencing, genetic information can used to support the diagnoses performed using classical approach. Here, we described the paleopathological remains of a 5 to 7‐month infant, excavated from Saint‐Jacques church (Douai, France), dated from 16th to 18th century. The skeleton displayed bone lesions, consisting in a massive corticoperiosteal thickening with subperiosteal new bone formation. To investigate the pathological condition of the remains, we applied a combined approach using both microcomputed tomography and paleogenetic analysis. Among several pathologies, we proposed a potential diagnosis of Caffey's disease (Infantile Cortical Hyperostosis, ICH), a rare genetic infantile pathology that causes a massive subperiosteal new bone formation in some diagnostic skeletal districts. Association of the disease with the COL1A1 gene on chromosome 17q21 has been highlighted in several familial cases, whereas other evidences suggest genetic heterogeneity of ICH. Although the osteological clinical picture was compatible with Caffey's disease, we did not find evidence of the mutated allele in COL1A1 gene, suggesting a diagnosis of ICH caused by a different genetic mutation. Our study represents one of the first documented historical case of Caffey's disease and highlights the contribution of paleopathological studies for a better knowledge of human diseases.

A probable case of infantile cortical hyperostosis in 2nd–4th centuries AD Romania

ObjectiveThis study aims to discuss the differential diagnosis for the pathological alterations displayed on an infant skeleton from Romania. MaterialsOne infant skeleton retrieved form the bathhouse of an abandoned Roman fort and dated between the 2nd and the 4th centuries AD. MethodsAll available skeletal elements were analyzed macroscopically. In addition, the isotopic signatures (δ13C and δ15N) and the control region of the human mitochondrial genome for this archaeological sample were analyzed. ResultsBased on dental development and long bone length, the skeleton was aged between birth and 2 months of age. Pathological lesions were noted on the mandible and diaphyses of long bones, but spared the metaphyses. ConclusionsThe perinatal age of the individual, along with lesion morphology and location, suggests a diagnosis of infantile cortical hyperostosis. LimitationsThe analysis would benefit from further stable isotope and mitochondrial genome analyses, which was limited due to the absence of comparative human and faunal remains from the site. Suggestions for further researchFurther multidisciplinary research on human archaeological remains from Romania would provide a clearer image of past disease and life histories in this geographic area.

Infantile Cortical Hyperostosis (ICH) Secondary to Prostaglandin E1 Infusion in a Newborn with Complex Cyanotic Heart Disease: A Case Report

Infantile cortical hyperostosis (ICH), also known as Caffey’s disease, is a benign self-limiting condition affecting young infants. The initial symptom of the classical ICH is usually irritability, fever and soft tissue swelling affecting one or more bones. Diagnosis is usually delayed because its clinical presentation mimics many other clinical conditions such as osteomyelitis, scurvy, hypervitaminosis A, child abuse, bone tumor or even fracture. There are no laboratory tests to confirm the diagnosis. There are two types of ICH been described; the classical mild infantile form and the more severe prenatal form. Most of the cases of ICH are sporadic, but autosomal dominant and recessive patterns have been reported as well. It is linked with missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen and has raised some doubts whether it is a type of collagen disorder, like osteogenesis imperfect. In this case, the newborn developed ICH due to prolonged infusion with prostaglandin E1 which was given in view of congenital cyanotic heart disease. Prostaglandin E1 infusion is used for maintaining the patency of ductus arteriosus in ductus dependent congenital heart defects in neonates and is usually administered before corrective heart surgery. ICH is mostly self-limiting and resolves within 12-24 months and usually does not require any treatment. Anti-inflammatory drugs such as NSAIDS(indomethacin and naproxen) and steroids has been used in symptomatic cases with success. The outcome is generally good with symptoms resolution usually before the age of one year. Relapses are uncommon.

Clinical improvement in a patient with monostotic melorheostosis after treatment with denosumab: a case report

BackgroundA 20-year-old Danish woman with melorheostosis in her right femoral shaft and disabling pain in the affected area, whose symptoms did not in the long term respond to zoledronic acid, experienced continuous remission of pain after treatment with denosumab. To the best of our knowledge, this is the first case report on denosumab treatment for melorheostosis.Case presentationRadiologic findings and bone biopsy showed irregular cortical hyperostosis in the right femoral shaft with increased tracer uptake on Tc99-bone scan.The diagnosis of melorheostosis was made based on the radiological findings. There was a good initial response to zoledronic acid administration, but after relapse of pain, the second and third administrations had a poor effect. As a second line of treatment denosumab was administered at 8-week intervals, the frequency was based on our patient’s symptoms and on biochemical markers of bone turnover.ConclusionThis is the first report indicating that denosumab has a place in the treatment of melorheostosis when the effect of bisphosphonate treatment is insufficient.