Tumor-induced Osteomalacia Research Articles

Real-world efficacy and safety of Burosumab in tumor-induced Osteomalacia: case series from an early access program

Abstract Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces Fibroblast Growth Factor 23 (FGF23), causing hyperphosphaturia, hypophosphatemia, low 1,25(OH)2D and osteomalacia. Complete surgical resection is the standard of care, but some tumors cannot be found, and others cannot be removed. In such difficult situations, burosumab, a fully human monoclonal antibody that targets and inhibits excess circulating FGF23, is a treatment option. Early access program (EAP) to burosumab has been established for patients with TIO in France in July 2022. Before that, access to burosumab at no cost on compassionate grounds was provided for a few patients. Between July 21, 2022, and December 3, 2023, an EAP was initiated for burosumab across ten University Hospital Centers. The program included nine patients (3 pre-exposed and 6 burosumab-naïve patients). The EAP included assessments of phosphatemia, pain levels using the Visual Analogue Scale (VAS), and quality of life using the RAPID-3 (Routine Assessment of Patient Index Data 3) questionnaire. Patients’ ages ranged from 33 to 62 years, with various BMI categories. Seven patients had at least one follow-up visit (3 pre-exposed and 4 burosumab-naïve patients). In the burosumab-naïve group, phosphatemia levels improved in two patients, with one achieving levels >0.8 mmol/L. Pain reduction was reported in all four naïve patients with follow-up, while pain levels in pre-exposed patients remained stable or fluctuated. Quality of life scores indicated minimal impairment or remission in six patients at baseline. No serious adverse events were observed. These preliminary findings following burosumab EAP for patients with TIO in France support benefits in terms of efficacy, safety, and ease of treatment. Burosumab appears to be a promising option for patients who are ineligible or refractory to surgery.

Ga-68-DOTATATE PET/CT for Phosphaturic mesenchymal tumor localization in suspected tumor-induced Osteomalacia

Abstract Ga-68-DOTATATE PET/CT has recently been shown to have utility for the localization of phosphaturic mesenchymal tumors (PMT) that cause tumor-induced osteomalacia (TIO), a rare renal phosphate-wasting disorder. The aim of this study was to evaluate the accuracy of Ga-68-DOTATATE PET/CT in localizing PMTs causing TIO, and to compare its performance with other functional imaging modalities. Prospective recruitment and retrospective chart review of 30 patients with suspected TIO and evaluation with Ga-68-DOTATATE PET/CT between 2017 to 2023 were conducted at a tertiary medical center. True positive (TP) lesions were defined by histological confirmation of PMT. There were 22 TP lesions identified among 18 patients, with a mean SUVmax of 16.8 (±10.9). Sensitivity, specificity and accuracy of Ga-68-DOTATATE PET/CT was 85.7%, 77.8% and 83.3% on patient-based analysis, and 84.6%, 56.3% and 73.8% on lesion-based analysis. Lesions such as subacute fractures, parathyroid adenomas, thymus uptake, vertebral hemangiomas, bone enchondroma, liver hemangioma and avascular necrosis were some of the pitfalls in interpretation. Ga-68-DOTATATE PET/CT led to a significant impact in clinical management in 24 (80%) of patients. The presence of DOTATATE-avid fractures was significantly associate with a localizing scan on univariable (OR 15.0, 95%CI 2.80-110, p=.001) and multivariable analysis (OR 9.45, 95%CI 1.33-98.4, p=.003). Ga-68-DOTATATE PET/CT has good accuracy for the localization of TIO, with superior sensitivity compared to F-18-FDG PET/CT. This significantly impacted clinical treatment decisions. Although DOTATATE-avid fractures may be a source of false positives, they may also indicate a higher probability of a localizing study.

A rare tumor of the Brainstem: Phosphaturic mesenchymal tumor.

A rare tumor of the Brainstem: Phosphaturic mesenchymal tumor.

1149 Unveiling CDKN2A Copy Number Alterations as a Marker for Recurrence in Sinonasal Phosphaturic Mesenchymal Tumors

1149 Unveiling CDKN2A Copy Number Alterations as a Marker for Recurrence in Sinonasal Phosphaturic Mesenchymal Tumors

CT and MRI features of phosphaturic mesenchymal tumor

The aim of the study was to study the characteristic CT and MRI features of phosphaturic mesenchymal tumors.Material and methods. CT and MRI images of 13 patients with phosphaturic mesenchymal tumors were analyzed. The size, localization, shape, contours, structure of the tumor, accumulation of contrast agent, a position relative to the cortical layer, and size of the lymph nodes were assessed.Results. Eight bone tumors (average size 23 ± 9.6 mm) and 5 soft tissue tumors (36.2 ± 47.5 mm) were detected.In patients with soft tissue tumors, the oval shape was predominant. The contours of all tumors were smooth, the tumors were adjacent to the cortical bone layer according to CT data in 75% of cases. According to MRI data, in all cases the tumors were adjacent to the cortical bone layer. In half of cases, calcifications were determined in the tumor structure. The structure of the tumor according to CT data was homogeneous, while in half of the cases, septa were visualized on MRI images. Soft tissue tumors intensively enhanced on CT and MRI. In patients with bone tumor, rounded shapes predominated. In one case, a large sacral tumor (measuring about 40 mm) prolapsed into the spinal canal. The tumors were predominantly osteolytic with sclerotic contours and were located subcortically. Osteoid or chondroid matrix in the form of calcifications was determined in the structure. According to CT data, in 3 cases the tumors intensively enhanced, in 3 cases they did not enhance, and in 1 observation there was a weak enhancement. In MRI, all lesions intensively enhanced.Conclusion. Phosphaturic mesenchymal tumor can occur in bones and soft tissues. CT and MRI allow to identify them and determine the boundaries of surgical resection, but should be used as second-line diagnostic methods after radioisotope methods. The use of a new diagnostic feature: the adjacency of bone and soft tissue formations to the cortical layer, and focusing attention by radiologists on this area may reduce the risk of “missing” the tumor.

Intracranial phosphaturic mesenchymal tumor: A rare case report and systematic review.

Phosphaturic mesenchymal tumors (PMTs) are rare soft-tissue and bone tumors that can occur intracranially. Low incidence, nonspecific symptoms, and diverse histomorphology of PMTs contribute to a high rate of misdiagnosis. This report presents a rare case of an intracranial PMT located in the posterior cranial fossa. In addition, a systematic review of previously reported intracranial PMT cases was conducted and summarized. Incorporating clinical symptoms, laboratory findings, and imaging features, the definitive diagnosis of PMT was based on pathological examination. The patient underwent consultations in endocrinology, orthopedics, and neurosurgery, and ultimately had a surgical procedure to remove the intracranial tumor. After tumor resection, the patient's laboratory values returned to normal, his symptoms improved, and he could walk again. Due to the rarity and high misdiagnosis rate of PMTs, no unified diagnosis and treatment standards have been established. Early identification, accurate diagnosis, and timely treatment are essential for optimal management. Surgical resection remains the preferred treatment for PMTs, with total tumor resection strongly recommended. In case of incomplete resection, tumor recurrence and persistent symptoms may necessitate adjunctive drug therapy and radiation therapy.

The many faces of phosphaturic mesenchymal tumour: a case series

The many faces of phosphaturic mesenchymal tumour: a case series

Glucose Metabolic Abnormalities and Their Interaction With Defective Phosphate Homeostasis in Tumor-induced Osteomalacia.

Phosphate homeostasis was compromised in tumor-induced osteomalacia (TIO) due to increased fibroblast growth factor 23 (FGF23) secretion. Nevertheless, the glucose metabolic profile in TIO patients has not been investigated. This work aimed to clarify the glucose metabolic profiles in TIO patients and explore their interaction with impaired phosphate homeostasis. 20 TIO patients, 20 individuals with normal glucose tolerance, and 20 patients with type 2 diabetes mellitus (DM) were enrolled and underwent an oral glucose tolerance test (OGTT). Serum phosphate and FGF23 concentration were monitored during OGTT. In patients with TIO, 60% (12/20) exhibited impaired glucose tolerance (IGT) and 5% (1/20) had type 2 DM. Those with IGT or type 2 DM experienced more ambulatory difficulties (69.2% vs 42.9%), lower phosphate concentrations (0.43 ± 0.10 vs 0.53 ± 0.10, P = .042), and lower calcium concentrations (2.20 ± 0.08 vs 2.30 ± 0.40, P = .001) compared to TIO patients without these conditions. According to correlation analysis, serum phosphate levels were negatively correlated with plasma glucose levels at 60 minutes (P < .001), fasting plasma insulin levels (P < .05), and homeostasis model assessment for insulin resistance (P < .05). Those with high FGF23 levels had a higher glucose level at 60 minutes (10.5 [9.3, 12.3] vs 7.3 [6.4, 10.1], P = .048) than that of low group. After glucose loading, both FGF23 and phosphate levels exhibited a decreasing trend. The development of diabetes in TIO patients may be predisposed by ambulatory issues, low phosphate, and elevated FGF23 levels. Dysglycemia might further aggravate hypophosphatemia.

Excess fibroblast growth factor 23 in alcoholic osteomalacia is derived from the bone.

Excess fibroblast growth factor 23 (FGF23), a mature osteocyte-derived phosphaturic hormone, causes chronic hypophosphatemic osteomalacia in adults. This rare condition was recently reported in 2 alcoholic patients, with marked improvement upon cessation of alcohol consumption, suggesting a link between alcohol and FGF23-related hypophosphatemia within the highly limited cases. This study aimed to investigate whether the source of excess FGF23 in alcohol-induced FGF23-related hypophosphatemic osteomalacia is the bone or the other organs. To achieve this goal, an immunohistochemical approach for the bone obtained from a patient was employed. Initial attempts at quantifying FGF23 in the bone using conventional immunohistochemistry (IHC) faced issues in quantifiability and sensitivity for low FGF23 expression levels. Therefore, next-generation IHC with phosphor-integrated dots (PIDs) was applied, which enabled the quantification of FGF23 expression in the bone across a broad range. Preliminary analyses using IHC with PIDs on normal bone samples (n = 12) provided a reference level (154.5 PID particles per cell). IHC with PIDs quantified suppressed physiological FGF23 expression in the bone samples from 3 patients with tumor-induced osteomalacia, where FGF23 is oversecreted from a tumor (13.6 PID particles per cell). Subsequently, bone samples obtained from a 70-yr-old male with alcohol-induced FGF23-related hypophosphatemic osteomalacia were analyzed, showing a higher number of PID particles per cell (199.4 PID particles per cell) than the reference level. This study suggests that orthotopic, bone-derived FGF23 is implicated in alcohol-induced FGF23-related hypophosphatemic osteomalacia. Furthermore, the study also demonstrated that highly sensitive IHC with PIDs could aid in the differential diagnosis of FGF23-related hypophosphatemia of unknown origin. Specifically, a bone sample with a low number of PID particles per cell indicates an excess ectopic secretion of FGF23; a bone sample with a normal to high number of PID particles per cell indicates an excess orthotopic secretion of FGF23.

Primary Hyperparathyroidism-Phosphaturic Mesenchymal Tumour: An Unusual Association and a Probable Syndrome

Phosphaturic Mesenchymal Tumour (PMT) is a rare and underdiagnosed tumour that causes Tumour-Induced Osteomalacia (TIO). These tumours produce Fibroblast Growth Factor-23 (FGF23), which inhibits renal tubular phosphate reabsorption, leading to hyperphosphaturia and oncogenic osteomalacia. The association of primary Hyperparathyroidism (pHPT) with PMT is extremely rare, with only two cases reported in the literature to date. A 51-year-old male presented in a bedridden state with multiple episodes of fractures throughout his skeleton over six years. Investigations revealed mild hypocalcaemia, marked hypophosphatemia, elevated serum Alkaline Phosphatase (ALP), low 25-Hydroxy Vitamin D, and persistently raised Parathormone (PTH) levels. A 68-Ga-DOTANOC 3D PET (Positron Emission Tomography) scan revealed a 4.1×3.2×2.5 cm DOTA avid mass in the right thigh. FGF23 levels were found to be 1466 pg/mL. A diagnosis of hypophosphatemic osteomalacia with pHPT was made, and the mass was subsequently excised. The thigh mass measured 3.5×2.5 cm and had a tan-brown cut surface. Microscopy revealed a benign spindle cell tumour with a vasoformative pattern and areas of grungy calcification. Immunohistochemistry demonstrated strong positivity for Vimentin, while CD34, CD68, CK, and Desmin were negative. A diagnosis of PMT, Mixed Connective Tissue type, was established. Normal phosphate, calcium, and FGF23 levels were restored after surgery, and the patient was able to walk again. This unusual case of a patient with pHPT and PMT, and the possible existence of a “pHPT-PMT syndrome, “was reported in the Times of India on November 20, 2022, as “Rare phosphorus-guzzling tumour left Dongri man bedridden for three years.” The exact aetiology for the association of PMT and pHPT is not known, and the hypothesis of aberrant gene expression has been implicated.

Acral Mesenchymal Tumor Leading to Tumor-Induced Osteomalacia: Case Report and Literature Review

Acral Mesenchymal Tumor Leading to Tumor-Induced Osteomalacia: Case Report and Literature Review

A case and review of FGF23-mediated hypophosphatemic osteomalacia in the absence of pathogenic PHEX variants

Abstract We report an atypical case of fibroblast growth factor-23 (FGF23)-mediated hypophosphatemic osteomalacia without a pathogenic variant (PV) of PHEX, who improved biochemically, clinically and radiologically post burosumab treatment. We present a narrative review of FGF23-mediated hypophosphatemic osteomalacia and propose a roadmap for investigating the etiology of hypophosphatemia to guide therapy. A 29-year-old female with FGF23-mediated hypophosphatemic osteomalacia experienced multiple insufficiency fractures, including bilateral femoral diaphyseal fractures and delayed healing. This occurred on a background of juvenile enthesitis-related arthritis, narcolepsy and brittle dentition since her early teens. Whole-body magnetic resonance imaging and Gallium-68 DOTATATE positron emission tomography scans were unremarkable, making tumor-induced osteomalacia highly unlikely. No hypophosphatemic PVs were found using massively parallel sequencing. Despite phosphate and calcitriol therapy, mild hypophosphatemia persisted with minimal improvement in fracture healing or pain. One dose of 60 mg burosumab, an anti-FGF23 antibody, led to hyperphosphatemia requiring dose titration and three doses of burosumab normalized renal tubular maximum reabsorption rate of phosphate relative to glomerular filtration rate. Burosumab led to fracture healing with callus formation corresponding with improved pain at fracture sites. Hypophosphatemic osteomalacia manifests with varus deformity of the lower limbs, gait disturbance, muscle weakness, enthesopathy, and dental necrosis. Evaluation of the etiology is crucial and requires an algorithmic approach to determine whether hypophosphatemia is renally-mediated, FGF23-mediated, acquired or inherited. The most common inherited cause of FGF23-mediated hypophosphatemic osteomalacia is X-linked hypophosphatemia (XLH) secondary to a PV of the PHEX gene. However, the absence of a PHEX PVs does not exclude a diagnosis of hereditary FGF23-mediated hypophosphatemic osteomalacia. Other inherited causes of this disorder include autosomal dominant and autosomal recessive hypophosphatemic rickets, fibrous dysplasia-McCune-Albright syndrome, cutaneous skeletal hypophosphatemia syndrome and osteoglophonic dysplasia. Burosumab significantly improves serum phosphate and fracture healing in XLH and may effectively treat other forms of FGF23-mediated hypophosphatemia.

Phosphaturic mesenchymal tumor of the popliteal fossa: a case report and literature review

Phosphaturic mesenchymal tumor of the popliteal fossa: a case report and literature review

Basics of Management of Calcium and Bone Disorders

Calcium homeostasis is maintained by three hormones (parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3, and calcitonin. PTH acts on the kidneys to increase calcium reabsorption and secretion of Vitamin D3 by activating 25 (OH) Vit D3 to 1,25-dihydroxyvitamin D3, and on bones it stimulates osteoclasts leading to bone reabsorption and release of free calcium. Vitamin D3 stimulates calcium absorption from the gut. Calcitonin on the other side do the opposite to PTH and Vitamin D3, it is released from the thyroid parafollicular cells and acts on the bones to deposit calcium in case of hypercalcaemia, Calcitonin increases urinary calcium excretion and inhibits absorption in the intestines. Hypomagnesemia will reduce parathyroid hormone leading to calcium deficiency, common scenario with Proton pump inhibitor. FGF23 causes renal phosphate wasting and low 1,25(OH)2D3 in normal kidney function but its effect is lost in advanced kidney disease. Elevated FGF23 from bones occurs in X-linked hypophosphatemia rickets, hypophosphatemia rickets type 1, and tumour-induced osteomalacia due to FGF23-producing tumours.

No longer to be ignored: Hypophosphatemia following intravenous iron administration.

Intravenous iron supplementation is increasingly used to safely and effectively correct iron deficiency anemia, but some formulations are linked to a renal phosphate wasting syndrome which is mediated by fibroblast growth factor 23. Unawareness among prescribers and the nonspecific clinical symptoms of hypophosphatemia result in underreporting of this complication. Even though it is often an asymptomatic and self-limiting condition, accumulating evidence from case reports and dedicated randomized controlled trials show that IV iron induced hypophosphatemia may be associated with clinical symptoms. If hypophosphatemia is not recognized and treated, a metabolic bone disease phenotype may develop, pathophysiologically reminiscent of hypophosphatemic rickets as seen in X-linked hypophosphatemic rickets or oncogenic osteomalacia. This syndrome is particularly, but not uniquely, associated with formulations containing ferric carboxymaltose, probably due to specific chemical characteristics of its carbohydrate moiety. Risk factors include repeated infusion, severity of iron deficiency, as well as normal kidney function. Coexisting vitamin D deficiency or hyperparathyroidism increase the risk of metabolic bone disease. Complications can be easily prevented by an early diagnosis and switching to another IV iron formulation. In this review, we describe the epidemiology and pathophysiology of this condition, to raise awareness among prescribing clinicians.

Clinical management of hypophosphatemic osteomalacia induced by adefovir and tenofovir: Insights from a case report.

Hypophosphatemic osteomalacia is a rare chronic metabolic bone disease characterized by low serum phosphate levels owing to genetic or acquired causes. This article presents a case report of the clinical management, challenges encountered, and prognosis of secondary hypophosphatemic osteomalacia induced by defovir and tenofovir. A 55-year-old male patient had been experiencing persistent dull chest pain and fatigue for more than a year. The patient had chronic hepatitis B infection for over 10 years, with regular use of adefovir dipivoxil capsules for more than 10 years. Five months before admission, the patient was switched to tenofovir alafenamide fumarate tablets. After obtaining clinical manifestations, medical history, and examination results, tumor-induced osteomalacia was excluded, and the final diagnosis was drug-induced hypophosphatemic osteomalacia. Adefovir dipivoxil and tenofovir alafenamide were discontinued, and the patient was switched to entecavir disintegration tablets for antiviral therapy. He was advised to follow a high-phosphate diet, receive phosphorus supplementation and calcitriol capsules to promote calcium absorption, obtain moderate sun exposure, and take measures to prevent falls and fractures. Serum phosphate levels showed a gradual upward trend, with the most recent measurement being 0.85 mmol/L. The bone density gradually improved and reached normal levels in the most recent assessment. The symptoms of fatigue and chest pain were resolved. Accurate diagnosis requires a combination of clinical presentation, medical history, biochemical and radiological findings, and, if available, measurement of fibroblast growth factor 23 (FGF 23). The role of national, provincial, or regional centers for rare diseases is crucial for conducting unconventional tests and providing access to rare medications.

Acquired hypophosphatemic osteomalacia: case series from a Peruvian referral center (1999-2023).

Acquired hypophosphatemic osteomalacia (AHO) is a rare metabolic bone disorder characterized by hypophosphatemia and impaired bone mineralization. Tumor-induced osteomalacia (TIO) is the most common cause of AHO, caused by phosphaturic tumors that overproduce fibroblast growth factor 23 (FGF-23). To present the clinical characteristics, diagnostic challenges, and outcomes of seven cases of AHO in Peruvian patients between 1999 and 2023. A retrospective review of seven patients diagnosed with AHO was conducted. Clinical data, including diagnostic procedures, treatments, and outcomes, were collected. Seven cases of AHO were reviewed. In case one, osteomalacia did not improve despite supraphysiological doses of vitamin D (ergocalciferol/cholecalciferol), and no tumor was detected with available tests, resulting in the patient's death. Cases two and three involved tumors located in the right leg and right hemithorax, respectively, with symptom resolution following total resection. In cases four, five, and seven, exhaustive exams failed to locate tumors. Cases four, six, and seven showed elevated FGF-23 levels, while case five had inappropriately normal FGF-23 levels. Case seven was the first patient in Peru to receive burosumab treatment. In case six, a tumor in the head of the femur was identified, but the patient opted for nonsurgical management. The diagnosis of AHO is challenging, requiring a high index of clinical suspicion and biochemical confirmation. TIO is the most common cause of AHO, emphasizing the importance of locating the phosphaturic tumor. However, in some cases, the tumor remains elusive despite exhaustive diagnostic workups. This is particularly challenging in developing countries like Peru, where resources are limited.

Phosphaturic Mesenchymal Tumor and Tumor-Induced Osteomalacia: A Report of 5 Cases, Including 2 Skull Base Cases With Arterial Spin Label Perfusion.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting and impaired bone mineralization secondary to secretion of fibroblast growth factor 23 (FGF23) from mesenchymal tumors (phosphaturic mesenchymal tumors, PMTs). PMTs have wide anatomical distribution but typically affect extremities and craniofacial bones. Diagnosis of TIO/PMT is often delayed, and a high index of suspicion is essential in patients with unexplained fractures, but many physicians lack familiarity with TIO/PMT and simply attribute fractures to the more common diagnosis of osteoporosis. We present 5 cases of TIO, with 4 having long histories of multiple insufficiency fractures prior to recognition of TIO and localization of a PMT. Four patients were treated surgically, while 1 preferred medical management. Two patients had lesions localized to the skull base, both of which showed marked hypervascularity on arterial spin label perfusion imaging. Thus, arterial spin label may not only help to localize these tumors, but may also be a helpful supplemental imaging finding in supporting this diagnosis. PMT should be considered in the differential diagnosis for hypervascular skull base masses, especially if the patient has any history of insufficiency fracture or imaging evidence of osteopenia, as early diagnosis of TIO can help prevent disabling complications.

Malignant Bone-Forming Neoplasm With NIPBL::BEND2 Fusion.

Conventional high-grade osteosarcomas are characterized by aggressive radiologic features, cytologic pleomorphism, and complex genomics. However, rare examples of osteosarcomas remain challenging due to unusual histology, such as sclerosing or osteoblastoma-like features, which may require molecular confirmation of their complex genetic alterations. We have encountered such a case in a 17-year-old man, who presented with a third metatarsal sclerotic bone lesion, found incidentally in the work-up of a foot trauma. The initial imaging revealed a lesion with sclerotic/blastic features proximally and lucent/lytic portion distally, findings interpreted consistent with osteoblastoma. The lesion was managed intra-lesionally with curettings and cryoablation; however, the microscopic findings were non-specific, showing a bland osteoblastic proliferation embedded in a densely sclerotic matrix. Subsequently, the patient developed two rapid recurrences; the first recurrence was treated similarly despite its associated soft tissue extension radiographically, and the histologic findings remained non-specific. The 2nd recurrence showed a large mass, with bone destruction and soft tissue extension and an open biopsy revealed features of osteosarcoma with lace-like osteoid deposition, albeit with uniform cytomorphology. The subsequent below knee amputation showed features compatible with high-grade osteosarcoma, including solid growth of uniform epithelioid cells, with vesicular nuclei and scant cytoplasm, set in a lace-like meshwork of osteoid matrix. There was significant mitotic activity and tumor necrosis. Tumor cells were positive for SATB2. Further molecular work-up was performed showing an unexpected NIPBL::BEND2 fusion, which has been previously reported in two cases of phosphaturic mesenchymal tumor (PMT). FGF23 (ISH) was performed and was negative. By DNA methylation profiling, unsupervised clustering and UMAP dimensionality reduction revealed grouping with high-grade osteosarcomas and not with the PMT group. The patient received chemotherapy post-amputation and is alive without evidence of disease, with 10-month follow-up. We report an aggressive, overtly malignant acral bone-forming tumor, harboring a NIPBL::BEND2 fusion. Further studies are needed to evaluate the recurrent potential of this fusion in osteosarcomas and its relationship with PMT.

Tumour-induced Osteomalacia: A Case Report

Tumour-induced Osteomalacia: A Case Report