Perinatal lethal hypophosphatasia

Perinatal lethal hypophosphatasia (PLH) is the most severe form of hypophosphatasia. If untreated, it is lethal in all cases.

The estimated incidence is at ~1:100,000 live births.

Genetics

As with all hypophosphatasia cases, this is due to a mutation in chromosome 1q36 for the tissue non-specific alkaline phosphatase (TNSALP) gene. It carries an autosomal recessive inheritance.

Markers
  • carriers may have low levels of serum alkaline phophatase (ALP)
  • fetal ALP isoenzymes are often low on chorionic villus sampling
  • urine phosphoethanolamine is elevated
Skeletal

Patients with this type tend to have short limb dwarfism (micromelia) with very soft calvaria

Other features include:

  • blue sclerae 
  • spurs (Bowdler spurs) in the mid-portion of the forearms and lower legs
  • marked variability in the amount of bone ossification
    • general underossification of the bones of the fetus
    • limb shortening
    • lack of ossification of groups of vertebral bodies: may sometimes give a pattern of three ossified and three unossified vertebral bodies
    • lack of ossification of the neural arches of the spine
    • lack of ossification of the hands
    • marked demineralisation of the fetal calvarium and absent segments of the spine
  • variability between patients as to which bones were most severely affected
  • unusually dense, round, flattened, butterfly shaped; and sagittally clefted vertebral bodies
  • variability in femoral shape including "chromosome" like, "campomelic" like, and shortening with or without metaphyseal cupping or irregularities 
  • osteochondral projections of the midshaft of the fibula and ulna
  • bifid diaphyses 1
Ancillary antenatal imaging features include
  • polyhydramnios on ultrasound
  • poor rib mineralisation seen as lack of normal bony reflectivity

Previously this subtype was thought lethal in all cases. However, since 2015 treatment has been available in the form of Asfotase alpha enzyme replacement therapy 8. This has been shown to induce bone mineralisation as well as improve related cognitive, respiratory and motor outcomes.

It radiologically difficult differentiate hypophosphaasia with conditions such as:

  • achondrogenesis type Ia
    • it is the bodies of the spine that are not ossified as opposed to the neural arches in hypophosphatasia
    • the calvarium will be ossified in achondrogenesis as opposed to hypophatasia where it will be absent.
  • osteogenesis imperfecta type II
    • in contrast to the thickened bones of osteogenesis type II, the long bones in hypophosphatasia tend to be thin or may be absent.
  • perinatal rickets
  • skeletal dysplasia
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Article information

rID: 13872
Tag: cases
Synonyms or Alternate Spellings:
  • Perinatal lethal hypophosphatasia (PLH)

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