association of osteomalacia or rickets with neurofibromatosis has been documented only rarely . as a rule , osteomalacia in neurofibromatosis
is characterized by later onset in adulthood , renal phosphate loss with hypophosphatemia , and multiple pseudofractures in the typical cases .
the hypophosphatemic conditions that interfere in bone mineralization comprise of many hereditary or acquired diseases , all of them sharing the same pathophysiological mechanism - reduction in the phosphate reabsorption by the renal tubuli .
this process leads to chronic hyperphosphaturia and hypophosphatemia , associated with inappropriately normal or low levels of calcitriol , causing rickets in children and osteomalacia in adults .
a 43-year - old woman presented to the orthopedic department of our institute with progressive bone pain and difficulty in walking since two years .
the patient was a known case of neurofibromatosis-1 , with multiple cutaneous nodules , from her early childhood .
she was otherwise healthy until the age of 40 years , when she started experiencing progressive bone pain affecting her thighs , pelvis , and left forearm . in recent times
, she could walk only with the help of crutches . on examination , tenderness and deformity
were present in the regions of her left forearm , bilateral thigh , left knee , and leg .
multiple skin nodules were present all over her face , back , and abdomen [ figure 1 ] .
43 yrs old , female known case of von recklinghausen neurofibromatosis with multiple skin nodules all over her face and legs her skeletal survey revealed generalized osteopenia , coarse trabeculations , and nodular shadows in the soft tissue .
in addition , a radiograph of her left forearm with elbow revealed fractures of the upper shafts of the radius and ulna [ figure 2 ] .
a radiograph of her left knee revealed pseudofractures ( looser 's zone ) in the distal femur , upper shafts of the tibia / fibula and mid shaft of the fibula [ figure 3 ] .
a radiograph of the pelvis with bilateral hips showed a deformed , triradiate pelvis , with bilateral symmetrical fractures of the upper shaft of the femur and pseudofractures of the inferior pubic rami [ figure 4 ] .
and lateral revealed diffuse osteopenia with fractures of upper shafts of radius and ulna ( arrows ) radiograph of left knee with leg a.p and lateral revealed generalized decrease in bony density with pseudo fractures ( looser 's zone ) in the distal femur , upper shafts of tibia / fibula and mid shaft of fibula ( white arrows ) .
note nodular shadows in soft tissue ( black arrows ) radiograph of pelvis - a.p . view .
triradiate pelvis with osteopenia and bilateral , symmetrical fracture of upper shafts of femur ( white arrows ) with bilateral , symmetrical pseudo fracture of inferior pubic ramii ( black arrows ) the laboratory data in our institute were as follows : serum calcium was 8.7 mg / dl ( normal 8.5 - 10.5 mg / dl ) .
serum phosphorus was 1.5 mg / dl ( normal : 2.5 - 4.5 mg / dl ) .
alkaline phosphatase was 650 lu / l ( normal 44 - 147iu / l ) .
the 24-hour urinary excretions of calcium and phosphorus were 98 mg/24 hours ( normal : 0 - 300 ) and 440 nmol/24 hours ( normal : 13 - 42 ) , respectively .
her serum parathyroid hormone ( pth ) and 25-(oh ) vitamin d were within normal range . on the basis of the radiological and laboratory findings , a final diagnosis of hypophosphatemic osteomalacia in a patient of von recklinghausen disease was made .
she has been prescribed a high dose of calcitriol and oral phosphate and in view of innumerable neurofibromas , surgical resection was not advised .
her constitutional symptoms have improved , but the fractures have shown no radiological signs of healing in the last three months of follow - up .
oncogenic hypophosphatemic osteomalacia ( oho ) is a rare endocrinological paraneoplastic syndrome , characterized by defective bone mineralization from renal phosphate loss .
it is an unusual condition , but probably still is the most common cause of acquired hypophosphatemic osteomalacia in adult males .
the affected age group range is between seven and seventy - seven years with a male : female ratio of 1.2:1 .
patients characteristically present with joint deformities , waddling gait , bone pain , muscle weakness , anorexia , fatigue , and occasionally long - bone fractures .
the initial clinical presentation may be mistaken for rheumatoid arthritis , muscular dystrophy or primary neurological disorder in some cases .
if the biochemical profile of the patient is that seen in hypophosphatemia , namely low phosphate in the serum and high phosphate excretion in the urine , and the patient is not responding adequately to oral calcium and vitamin d therapy , then the possibility of an underlying cause of either renal or oncogenic or hereditary x - linked hypophosphatasia must be entertained .
the most common tumor described is hemangiopericytoma , but other tumor types described include fibrous dysplasia , osteosarcoma , chondroblastoma , chondromyxoid fibroma , malignant fibrous histiocytoma , giant - cell tumor , hemangioma , paraganglioma , prostate cancer , and oat - cell carcinoma of the lung .
hypothesize that putative melatonin deficiency in cases of neurofibromatosis-1 may play a role in the pathogenesis of hyperphosphaturia , by decreasing the sodium - phosphate cotransport , increasing the level of cyclic adenosine monophosphate ( camp ) and the un - antagonized effect of dopamine on phosphate reabsorption , and increasing the glucocorticoid levels .
parathyroid overactivity that may occur secondary to osteomalacia may have synergistic effects with dopamine and further exaggerate the phosphate loss in urine . on the other hand
moreover , in the presence of hypophosphatemia , hypercortisolism may further inhibit melatonin secretion that may lead to progression of bony deformities in these cases . in recent times
, it has been suggested that in the epidermal nevus syndrome and type-1 neurofibromatosis , hypophosphatemic rickets / osteomalacia is probably due to increased secretion of fibroblast growth factor 23 ( fgf-23 ) by cells from the nevus or neurofibromas .
x - linked hypophosphatemic rickets , autosomal dominant hypophosphatemic rickets , tumor - induced osteomalacia ( tio ) , fibrous dysplasia , and the mccune albright syndrome share a common underlying pathophysiological condition : increased phosphorus renal loss secondary to augmented fgf-23 plasma levels and activity .
( a gene on the x chromosome that codes for a zn - metaloendopeptidase proteolytic enzyme , which regulates the phosphate ) .
fgf-23 , the largest member of the fibroblast growth factor family ( fgf ) , contains 251 amino acids and is encoded by a gene in 12p13 .
the metabolic abnormalities in oncogenic osteomalacia are hypophosphatemia , hyperphosphaturia , low or normal serum calcium , raised alkaline phosphatase , low concentrations of 1,25 dihydroxy vitamin d , decreased tubular resorption of phosphates , normal paratharmone levels , and normal urinary calcium .
these are believed to be the result of mesodermal dysplasia , intrinsic to the disease and they appear early in life .
they cause bone deformities , and are not associated with disturbances in calcium and phosphate metabolism . in contrast , osteomalacia of neurofibromatosis is very rare , presents in middle age , and is associated with marked disturbance of phosphate metabolism .
the presence of multiple symmetrical pseudofractures ( looser 's zone ) , high alkaline phosphatase , low serum phosphate , and generalized demineralization of the bones pointed to the diagnosis of hypophosphatemic osteomalacia .
if complete excision of the tumor is achieved , it can lead to improvement in the clinical course of the disease as well as the biochemical markers , and may be curative . in patients with neurofibromatosis and osteomalacia , although innumerable neurofibromas are present , it is probably the largest ones or those with recent growth that cause oho and their surgical removal should be tried , to achieve permanent cure .
high doses of calcitriol and oral phosphate salts are indicated , similar to those used in the treatment of x - linked hypophosphatemia .
osteomalacia in neurofibromatosis is a very rare entity and distinct from the more common dysplastic skeletal affections of this disease , as a rule , being characterized by later onset in adulthood , with renal phosphate loss , and with hypophosphatemia and multiple pseudofractures in typical cases . in patients with neurofibromatosis , although innumerable neurofibromas are present , it is probably the largest ones or those with recent growth that cause oho , and their surgical removal should be tried , to achieve permanent cure , along with high doses of calcitriol and oral phosphate .
 osteomalacia in neurofibromatosis is a rare entity and distinct from more common dysplastic skeletal affections of this disease . as a rule 
 , it is characterized by later onset in adulthood . 
 there is renal phosphate loss with hypophosphatemia and multiple pseudofractures in the typical cases . 
 the hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases , all of them sharing the same pathophysiological mechanism - reduction in phosphate reabsorption by the renal tubuli . 
 this process leads to chronic hyperphosphaturia and hypophosphatemia , associated with inappropriately normal or low levels of calcitriol , causing rickets in children and osteomalacia in adults . 