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].

• Poor Feeding

  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 [symptoma.com]

  Infantile hypophosphatasia [ edit ] Infantile hypophosphatasia 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. [en.wikipedia.org]

  Hypercalcemia can cause vomiting, constipation, weakness, and poor feeding. Increased excretion of calcium may lead to kidney (renal) damage. In rare cases, vitamin B6-dependent seizures may occur. [rarediseases.org]

• Severe Pain

  Others have sudden, severe pain in a joint (pseudogout). Affected adults may experience loss of adult teeth. Odontohypophosphatasia is characterized by the premature loss of deciduous teeth in childhood, or loss of teeth in adulthood. [rarediseases.org]

• Anosmia

  Battle\'s sign may be the only outward sign of basilar skull fracture, or it may be accompanied by periorbital ecchymosis (raccoon eyes), conjunctival hemorrhage, nystagmus, ocular deviation, epistaxis, anosmia, a bulging tympanic membrane (from CSF or [checkorphan.org]

• Failure to Thrive

  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 [symptoma.com]

  The initial symptom may be the failure to gain weight and grow at the expected rate for age and gender referred to as “failure to thrive.” [rarediseases.org]

• Tinnitus

  […] may be accompanied by periorbital ecchymosis (raccoon eyes), conjunctival hemorrhage, nystagmus, ocular deviation, epistaxis, anosmia, a bulging tympanic membrane (from CSF or blood accumulation), visible fracture lines on the external auditory canal, tinnitus [checkorphan.org]

• Osteoporosis

  This is not the same as osteoporosis, another bone disorder that also can lead to bone fractures. [softbonescanada.ca]

  Antibodies that act against sclerostin have been shown to increase bone mass in osteoporosis. For additional information regarding HPP, contact: Michael P. [rarediseases.org]

  Factors influencing fracture risk, T score, and management of osteoporosis in patients with rheumatoid arthritis in the Consortium of Rheumatology Researchers of North America (CORRONA) registry. J Clin Rheumatol. 2009 Jun; 15(4):155-60. [profiles.umassmed.edu]

• Long Bone Deformity

  Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement. J Clin Endocrinol Metab. 2008;93:3443-3448. Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. [rarediseases.org]

• Epistaxis

  Battle\'s sign may be the only outward sign of basilar skull fracture, or it may be accompanied by periorbital ecchymosis (raccoon eyes), conjunctival hemorrhage, nystagmus, ocular deviation, epistaxis, anosmia, a bulging tympanic membrane (from CSF or [checkorphan.org]

• Irritability

  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 [symptoma.com]

  May have trouble changing activities, resist redirection (disregulation, state rigidity), show irritability, stubbornness or repetitive speech or behavior (perseveration) as signs of distress. [come-over.to]

• Papilledema

  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. [symptoma.com]

  This complication can cause headaches, swelling of the optic disk (papilledema), and bulging of the eyes (proptosis). Affected infants have softened, weakened bones that lead to the skeletal malformations of rickets. [rarediseases.org]

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.

1. Fraser D. Hypophosphatasia. Am J Med. 1957;22:730–746.
2. Gurenlian JR. Hypophosphatasia. Access. 2001;15:38-41.
3. Balasubramaniam S, Bowling F, Carpenter K, et al. Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5'-phosphate availability. J Inherit Metab Dis. 2010;33(3):S25-33.
4. Jenny C. Evaluating infants and young children with multiple fractures. Pediatrics. 2006;118(3):1299-303.
5. Girschick HJ, Mornet E, Beer M, et al. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr. 2007;7:3.
6. Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev. 1994;15:439–61.
7. Krohn-Grimberghe B, Ludwig B, Furkert D. Rathbun syndrome (hypophosphatasia). Clinical aspects: dwarfism and Bechterew symptoms. Z Rheumatol. 1991;50(6):387-91.