There is a remarkable variety of symptoms that depends, largely, on the age of the patient at initial presentation, ranging from death in utero to relatively mild bone problems with or without dentition symptoms in adult life although neurological and extra-skeletal symptoms are also reported. Although several clinical sub-types of the disease have been characterized, based on the age at which skeletal lesions are discovered, the disease is best understood as a single continuous spectrum of severity. As the presentation of adult disease is highly variable, incorrect or missed diagnosis may occur. In one study, 19% of patients diagnosed with fibromyalgia had laboratory findings suggestive of possible<unk> . One case report details a 35-year old female with low serum ALP and mild pains but no history of rickets, fractures or dental problems. Subsequent evaluation showed osteopenia and renal microcalcifications and an elevation of PEA. The genetic mutations found in this case were previously reported in perinatal, infantile and childhood<unk> , but not adult<unk> . Perinatal<unk>  Perinatal<unk>  is the most lethal form. Profound hypomineralization results in caput membranaceum (a soft calvarium), deformed or shortened limbs during gestation and at birth, and rapid death due to respiratory failure. Stillbirth is not uncommon and long-term survival is rare. Neonates who manage to survive suffer increasing respiratory compromise due to softening of the bones (osteomalacia) and underdeveloped lungs (hypoplastic). Ultimately, this leads to respiratory failure. Epilepsy (seizures) can occur and can prove lethal. Regions of developing, unmineralized bone (osteoid) may expand and encroach on the marrow space, resulting in myelophthisic anemia. In radiographic examinations, perinatal<unk>  can be distinguished from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked undermineralization and severe osteomalacia. Occasionally, there can be a complete absence of ossification in one or more vertebrae. In the skull, individual bones may calcify only at their centers. Another unusual radiographic feature is bony spurs that protrude laterally from the shafts of the ulnae and fibulae. Despite the considerable patient-to-patient variability and the diversity of radiographic findings, the X-ray can be considered diagnostic. Infantile<unk>  Infantile<unk>  presents in the first 6 months of life, with the onset of poor feeding and inadequate weight gain. Clinical manifestations of rickets often appear at this time. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often “functional” craniosynostosis. If the patient survives infancy, these sutures can permanently fuse. Defects in the chest, such as flail chest resulting from rib fractures, lead to respiratory compromise and pneumonia. Elevated calcium in the blood (hypercalcemia) and urine (hypercalcenuria) are also common, and may explain the renal problems and recurrent vomiting seen is this disease. Radiographic features in infants are generally less severe than those seen in perinatal<unk> . In the long bones, there is an abrupt change from a normal appearance in the shaft (diaphysis) to uncalcified regions near the ends (metaphysis), which suggests the occurrence of an abrupt metabolic change. In addition, serial radiography studies suggest that defects in skeletal mineralization (i.e. rickets) persist and become more generalized. Mortality is estimated to be 50% in the first year of life. Childhood<unk> <unk>  in childhood has variable clinical expression. As a result of defects in the development of the dental cementum, the deciduous teeth (baby teeth) are often lost before the age of 5. Frequently, the incisors are lost first; occasionally all of the teeth are lost prematurely. Dental radiographs can show the enlarged pulp chambers and root canals that are characteristic of rickets. Patients may experience delayed walking, a characteristic waddling gait, stiffness and pain, and muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show defects in calcification and characteristic bony defects near the ends of major long bones. Growth retardation, frequent fractures, and low bone density (osteopenia) are common. In severely-affected infants and young children, cranial bones can fuse prematurely, despite the appearance of open fontanels on radiographic studies. The illusion of open fontanels results from hypomineralization of large areas of the calvarium. Premature bony fusion of the cranial sutures may elevate intracranial pressure. Adult<unk>  Adult<unk>  can be associated with rickets, premature loss of deciduous teeth, or early loss of adult dentation followed by relatively good health. Osteomalacia results in painful feet due to poor healing of metatarsal stress fractures. Discomfort in the thighs or hips due to femoral pseudofractures can be distinguished from other types of osteomalacia by their location in the lateral cortices of the femora. Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional attacks of arthritis (pseudogout), which appears to be the result of elevated endogenous inorganic pyrophosphate (PPi) levels. These patients may also suffer articular cartilage degeneration and pyrophosphate arthropathy. Radiographs reveal pseudofractures in the lateral cortices of the proximal femora and stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis. Odontohypophosphatasia Odontohypophosphatasia is present when dental disease is the only clinical abnormality, and radiographic and/or histologic studies reveal no evidence of rickets or osteomalacia. Although hereditary leukocyte abnormalities and other disorders usually account for this condition, odontohypophosphatasia may explain some “early-onset periodontitis” cases.
Hypophosphatasia
Hypoprolactinemia
Hypervalinemia
Osteomalacia
Hyperphosphatasia with mental retardation syndrome
Hyperprolinemia
Methaemalbuminaemia
Hypophosphatemia