Foetal achondroplasia: Prenatal diagnosis, outcome and perspectives

Achondroplasia, due to a specific pathogenic variant in FGFR3, is the most common viable skeletal dysplasia and the diagnosis is mostly done in the prenatal period. Since 2021, the use of Vosoritide, a specific treatment for achondroplasia, validated in phase 3 placebo-controlled trials, has been recommended to significantly increase the height of children and infants. In the light of these new therapeutic prospects, a complete understanding of the pathophysiology of skeletal damages occurring from foetal life is required.

To describe foetal imaging and the antenatal and postnatal management of pregnancies complicated by a diagnosis of foetal achondroplasia.

A retrospective and descriptive study, including all pregnant women with a prenatal diagnosis of achondroplasia, was conducted in the prenatal unit of Necker Hospital (Paris, France) between 2009 and 2022. Maternal and obstetric characteristics and foetal imaging (ultrasound and bone CT) were collected. Pregnancy outcomes, paediatric follow-up in the case of live births, and post-mortem examination (PME) data in the case of termination of pregnancy were reported. In addition, we have prospectively developed a specific research protocol using foetal brain MRI to assess the anatomy of the foramen magnum, following the same approach currently recommended in the postnatal period.

29 cases of achondroplasia were included. Median gestational age at referral was 31⁺² weeks', about 1 week after the suspected diagnosis on routine ultrasound. Shortening of the femoral length and of all the other long bones, macrocephaly, facial abnormalities, increased metaphyseal-diaphyseal angle and tapering of the proximal femoral bone were the five most prevalent ultrasound signs. Foetal diagnosis was done by the identification of the foetal FGFR3 mutation and/or by CT scans (n = 15) where specific abnormalities of the long bones, platyspondyly and abnormal profile have been described in 100 % of cases. PME revealed: i) on external examinations (n = 7) that all fetuses had very short long bones, moderate platyspondyly, small iliac wings with internal spines, macrocrania, and narrow thorax, ii) on internal examination (n = 5) all had severe abnormalities in the growth plate and particularities in the temporal cortex and hippocampal region. One foetal MRI was performed at 33 weeks' and revealed tight stenosis of the foramen magnum and compression of the spinal cord. Of the live-born infants for whom follow-up was known (n = 6), 2/6 (including the case who had a foetal MRI) required neurosurgical intervention in the first few months of life for spinal cord compression due to severe stenosis of the foramen magnum.

A complete mapping of the skeletal features present in foetuses with achondroplasia is reported here, providing a better understanding of the pathophysiology of this condition. New tools such as foetal MRI, to assess the risk of postnatal severe neurological complications, could help improve the care pathway of the affected neonates.