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A rare, severe, genetic form of hypophosphatasia (HPP) characterized by infantile rickets without elevated serum alkaline phosphatase (ALP) activity and a wide range of clinical manifestations due to hypomineralization.
ORPHA:247651Classification level: Subtype of disorder
- Infantile Rathbun disease
- Infantile phosphoethanolaminuria
- Prevalence: Unknown
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: E83.3
- OMIM: 241500
- UMLS: C0268412
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence is not known. About 160 cases have been reported to date.
Individuals with infantile-HPP may be normal at birth. Clinical signs resembling rickets are generally found between birth and six months of age. Initial manifestations may include irritability, poor feeding, failure to thrive, hypotonia, and more rarely seizures. Other clinical features include growth failure, short stature, blue sclerae, bone hypomineralization (softening or thinning of the skull, rachitic ribs, scoliosis, thickening of wrists and ankles and bowing of long bones), craniosynostosis (possibly with increased intracranial pressure), lax ligaments, and hypercalciuria/hypercalcemia. Some patients have premature loss of deciduous teeth. Kidney damage (nephrocalcinosis due to hypercalciuria) is reported in some older infants. Severity is variable but many affected patients are at risk of respiratory failure due to rachitic deformities of the chest within the first year of life. There may be some clinical overlap with the moderate form, classed as childhood-onset HPP.
Loss-of-function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. Most patients with the infantile form have two ALPL mutations.
Diagnosis is based on clinical examination, alkaline phosphatase assay and genetic testing.
The main differential diagnosis is osteogenesis imperfecta.
Although not typically picked up in ultrasound, there is evidence to suggest affected individuals may present prenatally with radiographic findings of limb bowing, limb shortening and/or skeletal hypomineralization. Genetic prenatal diagnosis may be offered to at risk pregnancies where the genetic mutation has been previously identified in an affected family member.
An autosomal recessive pattern of inheritance is mostly reported. Few cases may be dominantly inherited. Genetic counseling should be offered to affected families. Currently, there is no identified geno-phenotype relationship and individuals inheriting a pathogenic mutation may express any form of HPP (perinatal lethal to odontoHPP).
Management and treatment
Asfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with healing of the skeletal manifestations of hypophosphatasia as well as improved respiratory and motor function.
Prognosis depends on the organs affected and timely intervention. Currently there is no data on the long term prognosis when treated with ERT.
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