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Prenatal benign hypophosphatasia
A very rare form of hypophosphatasia characterized by prenatal skeletal manifestations (limb shortening and bowing) that slowly resolve spontaneously and later may develop into the moderate childhood or adult forms of the disease.
ORPHA:247638Classification level: Subtype of disorder
- Prenatal benign Rathbun disease
- Prenatal benign phosphoethanolaminuria
- Prevalence: Unknown
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: Antenatal, Neonatal
- ICD-10: E83.3
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence of prenatal benign hypophosphatasia (PB-HPP) is not known. About 50 cases have been reported to date.
PB-HPP may be identified on prenatal ultrasound examination. Patients manifest variable limb shortening and bowing and often have dimples overlaying long bones deformities. Postnatally, skeletal manifestations slowly resolve and patients eventually develop manifestations corresponding to other, non-lethal forms of HPP (either childhood-onset, adult hypophosphatasia or odontohypophosphatasia). Patients display progressive improvement of the skeletal anomalies and mineralization during the third trimester of pregnancy and after birth. Mothers of affected infants generally have biochemical evidence of hypophosphatasia but no clinical manifestations.
Mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PB-HPP have not been elucidated.
Diagnosis may be suspected pre- or postnatally on radiological and clinical presentation, respectively. However, it is likely that many patients go undiagnosed until later on when they present with another form of HPP (childhood, adult or odonto HPP). Genetic testing confirms the enzyme deficiency.
Antenatally, the main differential diagnoses include osteogenesis imperfect and perinatal lethal HPP. PB-HPP is differentiated from the perinatal lethal form by normal chest and abdominal circumference in utero and a benign post-clinical course.
The disorder may be suspected on prenatal ultrasound findings of limb bowing, limb shortening and/or skeletal hypomineralization. Chest and abdominal circumference are typically normal. A family history of hypophosphatasia and/or genetic testing support diagnosis.
Autosomal recessive and autosomal dominant patterns of inheritance have been reported, explaining the wide clinical spectrum. AD inheritance appears to be predictive of a benign course. A significant part of PB-HPP cases are dominantly inherited and seem to display a maternal bias of transmission, the fetus being affected only when the mutation is of maternal origin.
Management and treatment
Cesarean section may be indicated where diagnosis is not confirmed. Management is with observation. Enzyme replacement therapy with recombinant alkaline phosphatase may be indicated where skeletal manifestations persist.
The prognosis is generally good.
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