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Perinatal lethal hypophosphatasia
A rare, genetic form of hypophosphatasia (HPP) characterized by markedly impaired bone mineralization in utero due to reduced activity of serum alkaline phosphatase (ALP) and causing stillbirth or respiratory failure within days of birth.
ORPHA:247623Classification level: Subtype of disorder
- Perinatal lethal Rathbun disease
- Perinatal lethal phosphoethanolaminuria
- Prevalence: Unknown
- Inheritance: Autosomal recessive
- Age of onset: Neonatal, Antenatal
- ICD-10: E83.3
- OMIM: 241500
- UMLS: C2673477
- MeSH: -
- GARD: -
- MedDRA: -
Incidence of Perinatal lethal hypophosphatasia (PL-HPP) is not known. However, the birth prevalence for severe HPP (both perinatal-lethal and infantile forms) is estimated at 1/300,000in North and West Europe.
Affected infants may have characteristic skin-covered osteochondral spurs protruding from the forearms or legs and often a small thoracic cavity. They may have hypercalcemia associated with apnea or seizures, and marked shortening of the long bones. Patients rarely survive for more than a few days due to inadequate chest size, hypoplastic lungs and rachitic deformities, leading to respiratory failure.
Loss of function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The specific mechanisms underlying PL-HPP have not been elucidated.
Diagnosis is suspected either on prenatal ultrasound findings or clinical presentation at birth, and confirmed by genetic testing (Sanger or next generetation sequencing of ALPL).
A benign form of HPP (prenatal benign HPP) has been described in which skeletal abnormalities resolve spontaneously and patients subsequently develop nonlethal HPP, often adult or childhood HPP. Osteogenesis Imperfecta is the most frequent differential diagnosis of this severe form of HPP. Other differential diagnoses include campomelic dysplasia, chondrodysplasia and Stuve Wiedemann syndrome.
Suspicious ultrasound findings include short and/or bowed limbs, skeletal hypomineralization, osteochondral spurs and, sometimes, the absence of certain bones (skull, ribs, vertebrae, pubis). Confirmation by genetic testing is indispensable, although correlation between the genotype and the prognosis remains a challenge. Genetic prenatal testing is also possible in at risk families with a previous index case and where at least one mutation has been identified.
The reported pattern of inheritance in this form of HPP is autosomal recessive but is not necessarily predictive of the lethal form of HPP.
Management and treatment
Ventilation support is initiated shortly after birth. Prompt diagnosis is essential in order to start targeted therapy. Asfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with improvement of the skeletal manifestations as well as respiratory and motor function.
Perinatal HPP is of poor prognosis when not treated with ERT; however, long term prognosis with ERT is currently unknown.
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