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.
As with all hypophosphatasia cases, this is due to a mutation in chromosome 1q36 for the tissue non-specific alkaline phosphatase (TNSALP) gene. It has an autosomal recessive inheritance.
- carriers may have low levels of serum alkaline phosphatase (ALP)
- fetal ALP isoenzymes are often low on chorionic villus sampling
- urine phosphoethanolamine is elevated
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 under-ossification 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 demineralization 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 mineralization is seen as lack of normal bony reflectivity
Treatment and prognosis
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 mineralization as well as improve related cognitive, respiratory and motor outcomes.
It is radiologically difficult differentiate hypophosphatasia 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 hypophosphatasia 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
- 1. Sinico M, Levaillant JM, Vergnaud A et-al. Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images. Prenat. Diagn. 2007;27 (3): 222-7. doi:10.1002/pd.1648 - Pubmed citation
- 2. Kritsaneepaiboon S, Jaruratanasirikul S, Dissaneevate S. Clinics in diagnostic imaging (112). Perinatal lethal hypophosphatasia (PLH). Singapore Med J. 2006;47 (11): 987-92. Singapore Med J (link) - Pubmed citation
- 3. Simon-bouy B, Taillandier A, Fauvert D et-al. Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling. Prenat. Diagn. 2008;28 (11): 993-8. doi:10.1002/pd.2088 - Pubmed citation
- 4. Sawai H, Kanazawa N, Tsukahara Y et-al. Severe perinatal hypophosphatasia due to homozygous deletion of T at nucleotide 1559 in the tissue nonspecific alkaline phosphatase gene. Prenat. Diagn. 2003;23 (9): 743-6. doi:10.1002/pd.696 - Pubmed citation
- 5. Daldrup-Link HE, Gooding CA. Essentials of Pediatric Radiology, A Multimodality Approach. Cambridge Univ Pr. (2010) ISBN:0521515211. Read it at Google Books - Find it at Amazon
- 6. Sumner TE, Volberg FM, Karstaedt N et-al. Hypophosphatasia and nephrocalcinosis demonstrated by ultrasound and CT. Clin. Nephrol. 1984;22 (6): 317-9. - Pubmed citation
- 7. Van dongen PW, Hamel BC, Nijhuis JG et-al. Prenatal follow-up of hypophosphatasia by ultrasound: case report. Eur. J. Obstet. Gynecol. Reprod. Biol. 1990;34 (3): 283-8. - Pubmed citation
- 8. Scott Lesley J. "Asfotase Alfa: A Review in Paediatric-Onset Hypophosphatasia". Drugs 76, no. 2 (2016): 255-262. Pubmed citation