The Rathbun syndrome, also known as hypophosphatasia, is a congenital, autosomal recessive disease caused by defective encoding of tissue-nonspecific alkaline phosphatase leading to peripheral (serum and tissue) deficiency of this enzyme. The illness has several degrees of severity, causing symptoms at various ages. The most serious form manifests during the newborn period and leads to death.
Rathbun syndrome has six forms: odontohypophosphatasia, adult monophasic and biphasic, childhood, infantile and perinatal [1]. The more early clinical signs appear, the more severe the disease is. Thus, an adult suffering from this condition may have no complaints other than a pathologic fracture, whereas a fetus with severe hypophosphatasia may be stillborn, with no mineralized bone tissue. Children with less severe forms lose their deciduous teeth earlier than normal, therefore a dentist may be the first to diagnose the disease. Infantile Rathbun syndrome cases present with complaints during the first six months of life, consisting of failure to thrive, rachitic chest, hypotonia, seizures, vomiting, constipation, poor feeding, weakness, respiratory complications, waddling gait or irritability [2]. Seizures may progress to severe epileptic encephalopathy but respond to vitamin B6 administration [3]. Bone deformities like metaphyseal cupping, craniosynostosis, brachycephaly or bowed and short limbs may be noticed and the child may learn how to walk later than his healthy peers. Intracranial hypertension follows head deformities and causes headaches, papilledema, and proptosis. The bone tissue has an increased risk of fracture and skeletal ossification is delayed. Rib deformities and fractures predispose to pulmonary disease, potentially progressing to life-threatening respiratory distress, especially in cases where the lungs are underdeveloped. Bone pain in affected children is often noticed [4].
In adults, the ailment may have a biphasic course, with mild symptoms during childhood that remain unnoticed and more severe signs during middle age or a monophasic pattern, with complaints appearing later in life. Patients have osteomalacia, metatarsal or femoral fractures due to decreased mineralization may lose their permanent teeth early. Spine fractures, as well as calcific periarthritis, chondrocalcinosis, pseudogout, and sterile osteomyelitis, have also been documented [5].
Blood workup is especially important in Rathbun syndrome. Typical findings include decreased alkaline phosphatase level and increased phosphoethanolamine (now considered to be a non-specific finding) and inorganic pyrophosphate blood and urinary levels, as well as hypercalcemia [6]. The alkaline phosphatase value must be interpreted according to the patient's age; keeping in mind that decreased values can be encountered in other diseases too. Serum level of vitamin B6 must also be measured and will found to be elevated. Additional useful tests include magnesium, phosphorus, creatinine, vitamin D, and parathyroid hormone determinations.
Radiographic features of Rathbun syndrome can include premature closure of skull sutures, hyperostosis, calcific periarthritis and chondrocalcinosis [7]. Mineralization is often found to be diminished, in addition to pathological fractures, pseudofractures, stress fractures and rachitic changes. A renal ultrasound may reveal the presence of nephrocalcinosis. A bone biopsy, although seldom needed, can differentiate this disease from osteomalacia.
The diagnosis can be suspected before birth by ultrasonography and confirmed using ALPL gene analysis. Alkaline phosphatase can also be measured in the amniotic fluid and cultured amniotic cells.