Introduction
The TRPV4 gene (transient receptor potential cation channel,  subfamily V member 4) , encodes a calcium permeable ion channel expressed in many tissues, including bone and peripheral nervous system.  Pathogenic variants (PV) in the gene are associated with autosomal dominant  neuromuscular and/or skeletal dysplasia phenotypes.  Milder phenotypes are often inherited, while lethal phenotypes are typically de novo. The neuromuscular phenotypes include scapulopheroneal spinal muscular atrophy, congenital distal spinal muscular atrophy, and Charcot-Marie-Tooth type 2C.  Six skeletal dysplasia phenotypes have been reported, ranging from mild to severe/lethal, including lethal metatropic dysplasia. Some PV have been  associated predominantly with neuromuscular phenotypes, while others have been associated primarly with the skeletal dysplasia phenotype. It is important to note that there is phenotypic variability, including variability within families.  Mosaicism has also been reported, and also may contribute to clinical phenotype. 

The c.806A>G, p.Arg269His alteration in the TRPV4 gene has been associated predominantly with the neuromuscular phenotype; however, phenotypic variability with overlap between phenotypes has been reported (Jedrzejowska et al Muscle and Nerve, Janary 2019).  Importantly, this pathogenic alteration has not been previously associated with a severe prenatal phenotype. 

Case Presentation
Here we describe a prenatal case of a fetus with known TRPV c.806A>G alteration, and ultrasound findings concerning for pulmonary hypoplasia, not apparent until third trimester of pregnancy. 

The mother of the fetus is a 35yo G5P2113.  She has a history of two children, ages 17 and 15, with congenital distal spinal muscular atrophy (CDSMA) associated with the TRPV4 c.806A>G alteration.

Anatomy US of current pregnancy revealed  fetus with flexion at the hip and the knee joint with the fetal leg positioned lateral to the left thigh.  Additional anatomy ultrasound findings included bilateral renal pyelectasis with the renal pelvis measuring 5 mm bilaterally, 

Serial growth ultrasounds beginning at 28 weeks gestation revealed appropriated growth.  At 35 weeks, overal  fetal growth and abdominal circumference were within normal limits.  However, new and concerning findings included shortening of the proximal long bones with the HL and FL at less than 2nd percentile for gestational age, consistent with 

 rhizomelic shortening. Additionally, a skull abnormality with frontal scalloping concerning for fetal craniosynostosis was noted.

Skeletal dysplasia lethality assessment based on the 35 week ultrasound measurements demonstrated a cardiothoracic ratio of 58%, which is above the 50% cut off, and a thoracic ratio of less than 1%, which is less than the 5th percent cut off to predict lethality.   However, the thoracic to abdominal circumference ratio (TC/AC) was  0.7 and the femur length to abdominal circumference (FL/AC) ratio was 0.2, neither of these measurements fulfill lethality criteria.

 







 

Diagnostic Workup
Prior to this pregnancy, testing of affected siblings with a peripheral neuropathy panel revealed heterozygosity for the TRPV4 c.806A>G alteration.  An unaffected sibling was negative for this variant.  Parental testing revealed  maternal  mosacisim for the TRPV4 variant; the mother  is clinically asymptomatic for TRPV4 associated conditions.  Paternal testing was negative.  CVS of current pregnancy revealed heterozygosity for the TRPV4 variant.  

Treatment and Management
This pregnancy has been followed by serial growth ultrasounds beginning at 28 weeks. After the 35 week ultrasound findings, weekly antenatal assessment is ongoing. We are planning for delivery at 39 weeks gestation.  The patient is followed by a multidisciplinary team including genetics, maternal fetal medicine, obstetrics, neonatology, and our pediatric critical care team. 

Outcome and Follow-Up
At the time of this writing, weekly fetal assessment is onging, with induction of labor scheduled for 39 weeks. All teams, including obstetrical and pediatric critical care, have been apprised of the situation and prepared for delivery.  The parents have been thoroughly counseled regarding potential outcomes. 

Discussion
TRPV4 alterations have been associated with neuromuscular and skeletal dysplasia phenotypes.  Some alterations have been classified as having predominantly neuromuscular phenotypes, while others predominantly skeletal dysplasia phenotypes.  Additionally, phenotypic variability has been desribed.  The variant described for the family in this case report has been associated predominantly with neuromuscular phenotype, without previous report of findings concerning for lethal skeletal dysplasia. 

Conclusion
We await assessment of the infant at delivery.  This case further illustrates the spectrum of phenotypic variability associated with TRPV4 alterations. This case also potentially contributes to the list of variants  which may be associated with severe prenatal phenotype.