Isolated Hypophosphatemia-Induced Proximal Weakness

Sir, When a patient presents with features suggestive of an endocrine myopathy, the focus of the treating physician is usually on disorders of calcium homeostasis, thyroid, or adrenal syndromes.[1] We present a case to highlight that disorders of phosphorus metabolism can also present with a similar depiction. Our report describes a young woman presenting with diffuse myalgia and progressive proximal predominant weakness of all four limbs and who was eventually diagnosed with tumor-induced hypophosphatemia. After management of the condition, her symptoms improved. This case highlights the necessity of one to be cognizant about this amendable cause. A 29-year-old woman with no prior comorbidities presented with generalized pain and weakness for the last one-and-a-half years. The dull, aching pain started in the lower back and progressed to the limbs and the entire trunk. There was also joint pain that increased on movement. Four months later, she developed insidious, onset, gradually progressive proximal predominant weakness of her lower limbs, which then progressed over the next one year to involve the upper limbs and trunk to a point where she could not walk. There was no family history and no history of fever, drug or toxin exposure, or skin rashes. Examination confirmed the weakness: 2/5 around the shoulders (deltoid, latissimus dorsi, teres major, supraspinatus, infraspinatus, and pectoralis major) and hips (iliopsoas, gluteus maximus, and medius, adductor magnus); 3/5 at the elbow and knee; and 4+/5 at the wrist and ankles), adding 3+ reflexes and flexor plantar to the clinical picture. Other neurological examinations were unremarkable. She presented to the outpatient department with a normal set of initial investigations, including calcium, magnesium, vitamin D, parathyroid, thyroid, and serum creatinine kinase (23 U/L). Having a strong suspicion of endocrine myopathy, we re-sent the endocrine profile which then showed low phosphorus levels (1.2 mg/dl) with other tests being normal. After an endocrine consultation, 24-hour urine phosphorus analysis was done, which was very high. We considered hypophosphatemic osteomalacia with the triad of phosphaturia, increased alkaline phosphatase, and muscle symptoms; we initiated simultaneous evaluation for the presence of phosphatonins and tumor. Fibroblast growth factor (FGF 23) level was elevated and Ga-68 DOTANOC positron emission tomography computed tomography (PET-CT) showed an fluorodeoxyglucose (FDG)-avid tumor in the lateral epicondyle of the right humerus [Figure 1]. Histopathology confirmed the SATB2-, FL1-, and vimentin-positive, phosphaturic mesenchymal tumor, and it was subsequently avulsed and curetted [Figure 2].Figure 1: Patient’s Ga-88 DOTANOC report. Ga-68 DOTANOC avid sclerotic lesion measuring 13 × 11 mm in the lateral epicondyle of the right humerusFigure 2: Pathology slides microscopy report. (a) Bony trabeculae enclosing the spindle cell lesion composed of bland-looking, spindled cells arranged in fascicles. (b) Tumor cells positive for SATB2. (c) Tumor cells positive for FL1One month after the procedure and after the initiation of oral phosphorus supplements, the patient’s pain and weakness improved by 75%. She could walk with support. The proximal power at the hips improved to 4−/5, at the shoulder to 4+/5, and at the elbow and knee to 4+/5. The causative basis for this case lies in elevated levels of FGF 23. It is a protein secreted by osteocytes in response to an impetus such as elevated calcitriol, parathyroid hormone (PTH), or low levels of iron, and its primary function is to maintain normal body phosphorus levels by modifying phosphorus excretion or absorption.[2] Increased levels of FGF 23 can be seen due to decreased clearance or increased production, as in our case. Other causes of hypophosphatemia are detailed in Table 1.[3]Table 1: Causes of hypophosphatemiaThe reason why hypophosphatemia causes muscle manifestations can be explained at two levels. At the cellular level, mitochondrial oxidative phosphorylation is affected. Hypophosphatemia leads to reduced inorganic phosphorus (Pi) levels present in the circulation and this directly determines the amount of Pi entry into muscle cells via the Na/Pi cotransporters, which then participate in ATP synthesis or ATP synthetic flux.[4] Its depletion also would affect phosphorylation and de-phosphorylation of the contracting muscle.[5] Decreased muscle ATP synthesis, in part, may explain muscle weakness associated with hypophosphatemia. These cellular events also translate macroscopically into lower muscle density and power but of normal size.[6] Schubert and DeLuca[5] in their study, reported that slow-twitch muscle fibers were preferentially affected in hypophosphatemia and further stated that the muscle weakness noted in rachitic patients was the consequence of the hypophosphatemia of vitamin D deficiency, independent of hypocalcemia and the weakness reversed after phosphorus supplementation. Of note is that when replenishing phosphorus levels, the oral route is preferred over the intravenous route as the latter can cause arrhythmias, hypocalcemia, and acute kidney injury due to rapid correction and especially if the levels are more than 1 mg/dl. The dosage is to be up-titrated slowly to avoid diarrhea. The role for a neurologist, as a take-home message from this case, is to additionally make sure that phosphorus assay is included in the early screening endocrine and metabolic bloodwork. Early identification of the endocrine defect, as in this case, hastens the involvement of the multidisciplinary team and leads to enhanced and holistic care. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.