We conducted this review to heighten the awareness and describe pathologic manifestations of hypophosphatemia. We present 3 cases of varied manifestations of hypophosphatemia where recognition was delayed. In certain settings, severe hypophosphatemia has significant morbidity and potential mortality. Appreciation of the pathophysiologic basis for organ dysfunction in severe hypophosphatemia should result in early recognition and treatment. We reviewed the English-language literature for reported cases and research studies dealing with pathophysiologic mechanisms subserving clinical manifestations. We observed that depletion of adenosine triphosphate (ATP) would explain most of the derangement noted in cellular functions. Phosphate plays a key role in the delivery of oxygen to the tissue. Lack of phosphate, therefore, leads to tissue hypoxia and hence disruption of cellular function. Severe hypophosphatemia becomes clinically significant when there is underlying phosphate depletion. Otherwise, short-term acute hypophosphatemia is not usually associated with any specific disorder. Chronic hypophosphatemia, on the other hand, results in hematologic, neuromuscular, and cardiovascular dysfunction, and unless corrected, the consequences can be grave. Most of the time hypophosphatemia results from renal loss of phosphate, diagnosed by a fractional secretion of phosphate > 5%. It is hard to provide precise estimates of how many patients are seen with hypophosphatemia annually at academic medical centers. This is complicated by use of chemistry panels that do not measure inorganic phosphate unless specifically ordered. This often leads to delay in correct diagnosis, and, therefore, additional delay in providing appropriate management. A high index of suspicion alone avoids the unnecessary withholding of treatment that can be life saving.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.

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