Hypophosphatasia

Inherited inborn error of metabolism characterized by severe bone disease (similar to vitamin D-resistant rickets), failure to thrive, movement disorders, and low plasma levels of alkaline phosphatase.

Hypophosphatasia perinatal type (neonatal hypophosphatasia)

Hypophosphatasia infantile type (phosphoethanolaminuria)

Hypophosphatasia childhood type

Hypophosphatasia adult type (mild hypophosphatasia)

Odontohypophosphatasia

Inborn error of metabolism initially identified by Rathbun in 1948.

Estimated at 1:100,000 live births (and 1 carrier per 200 individuals in the United States). Some ethnic or religious groups have a higher incidence of the disease (1:2500 among Canadian Mennonites). No sex predilection.

Autosomal recessive. However, mild adult hypophosphatasia and odontohypophosphatasia cases seem to be inherited as an autosomal dominant trait. Prenatal diagnosis is possible by measuring alkaline phosphatase activity in chorionic villus samples from amniocentesis, and the perinatal (severe) form of the disease can be detected by ultrasonography. The defective gene, called ALPL, is located at 1p36.1-34.

Deficient activity of tissue-nonspecific alkaline phosphatase, one of the four isomers of alkaline phosphatase (each of which has its own gene locus). This results in accumulation of several metabolites including phosphoethanolamine, pyridoxal-5′-phosphate (a form of vitamin B6), and inorganic pyrophosphate, which are found in large amounts in the blood and urine. The characteristic defective calcification of bones in children (rickets) and adults (osteomalacia) is caused by the accumulation of inorganic pyrophosphate.

Clinical features. Radiologic appearance: epiphyseal and metaphyseal abnormalities of long bones, vertebrae, and ribs. Elevated plasma and urine levels of phosphoethanolamine. Elevated plasma inorganic pyrophosphate and pyridoxal-5′-phosphate.

Hypophosphatasia varies widely in clinical presentation. It has been subdivided into five categories: perinatal, infantile, childhood, adult, and odontohypophosphatasia. The earlier the symptoms occur, the more severe the disease. Perinatal form presents with a history of poor feeding, failure to thrive, hypotonia, and skin-covered spurs extending from the forearms or legs; it is lethal in 50% of cases. Childhood form often presents as delayed walking, early loss of deciduous teeth, and bone pain. Adult form has mild symptoms (foot pain as a result of spontaneous fractures of metatarsal bones). Odontohypophosphatasia is limited to dental problems (premature loss of adult teeth). Severe forms are characterized by widespread failure of ossification of the skeleton and marked shortening of long bones. Multiple rib fractures may lead to flail chest and predispose to pneumonia. There may be failure of ossification of the cranial vault. Hypercalcemia may lead to nephrocalcinosis and renal failure. In milder childhood forms, the skeletal abnormalities are less severe, but frequent fractures and bone pain are typical. There is defective development of the teeth leading to premature loss. There is no effective treatment, but some spontaneous improvement may occur as the child ages.

Check serum calcium level and renal function. Assess extent of skeletal abnormalities.

Care should be taken with positioning for surgery to avoid fracturing bones. The teeth are fragile and should be protected during direct laryngoscopy and tracheal intubation. Infants may have hypercalcemia, which leads to systemic vasoconstriction with contraction of the intravascular space. Intravenous fluid should be administered before induction of anesthesia to prevent hypotension.

Presence of renal failure necessitates care with renally excreted drugs; cis-atracurium is the muscle relaxant of choice.

Coffin-Lowry Syndrome: X-linked polymalformative syndrome equally affecting males and females (but more severe in males). Characterized by craniofacial and skeletal abnormalities, short stature, hypotonia, and mental retardation. Caused by a mutation of RSK2 gene (Xp22.2-p22.1) that codes for a protein kinase.

Osteogenesis Imperfecta: Disorder caused by a mutation causing abnormal type I collagen, mainly characterized by fragility of bones. Four types of osteogenesis imperfecta exist, each presenting different characteristics.

Rickets and Hereditary Vitamin D-Resistant Rickets (HVDRR): Metabolic disorder of calcium and/or phosphate metabolism primarily caused by lack of vitamin D and mainly involving weakening of the bones. Hereditary forms are usually a result of kidney disorder (when kidneys are unable to retain phosphate or when renal tubular acidosis is present).