Familial presentation and variability in TRPV4 Brachyolmia Type 3
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical Genetics
-
Secondary Categories:
- Clinical Genetics
Introduction
Pathogenic variants in TRPV4 are associated with ~10 autosomal dominant conditions. Some of these conditions are more commonly described, while others represent more isolated presentations. Autosomal Dominant (AD) Brachyolmia Type 3 is a more rarely described skeletal dysplasia associated TRPV4. Only around 50 pathogenic gain-of-function variants have been identified as a cause of Brachyolmia Type 3. Characteristic features of Brachyolmia Type 3 include a short neck, kyphosis/scoliosis, short femoral neck, brachydactyly and platyspondyly. The spine differences result in pain, body stiffness, and limited flexion and extension of the spine.
Case Presentation
A female proband presented at 11 years of age with short stature, short neck, short trunk, brachydactyly, kyphosis, and increased pain and fatigue with sports and daily activities.
Diagnostic Workup
Spine MRI imaging showed vertebral body height shortening with irregular endplates throughout the lumbosacral spine. Spine X-rays revealed platyspondylia of the cervical spine with the exception of C2. Our patient was identified to have a pathogenic variant c.1847G>A (p.Arg616Gln) in TRPV4. Additional work-up showed normal bone density on DEXA, normal calcium and phosphorus and slightly low magnesium and Vitamin D 25 OH.
Outcome and Follow-Up
On obtaining the maternal family history, there was a long history of short stature and similar complaints of early childhood back pain. Multiple family members were tested and identified to have the c.1847G>A (p.Arg616Gln) variant in TRPV4.
The proband’s presentation is similar to cases described in the medical literature; however, she appears to have a more severe phenotype than her other family members who carry the same variant. Our proband’s mother underwent X-rays of her spine which did not show obvious characteristic findings aside from scoliosis, although an MRI was not obtained. Short stature, childhood back pain, and scoliosis appeared to coincide with family members who carried the pathogenic variant.
Discussion
Our proband was noted to have 3 additional variants of uncertain significance (VUS) identified on her skeletal dysplasia panel. Two uncertain variants were identified in two different preliminary evidence autosomal recessive (AR) genes that did not match the patient’s phenotype. The other VUS was also in the TRPV4 gene. The uncertain variant TRPV4 c.2456G>A (p.Arg819Lys) (not maternally inherited) is not present in the medical literature, but has been identified as an uncertain variant by 3 different labs.
While the TRPV4 c.1847G>A (p.Arg616Gln) variant is a known cause of Brachyolmia Type 3, our patient has a more severe presentation than other family members with the variant raising the question of an additive effect from the uncertain variant versus overall phenotypic variability among family members.
Conclusion
As more patients present with variants in TRPV4 we may learn more about the phenotypic variability in Brachyolmia Type 3. Brachyolmia Type 3 is likely under diagnosed due to its milder presentation which may not lead to genetic testing. Brachyolmia Type 3 should be considered in the differential of familial early childhood back pain, short stature, scoliosis and abnormal spine imaging such as features of platyspondyly. At this time, treatments are largely focused on maintaining bone health.
Pathogenic variants in TRPV4 are associated with ~10 autosomal dominant conditions. Some of these conditions are more commonly described, while others represent more isolated presentations. Autosomal Dominant (AD) Brachyolmia Type 3 is a more rarely described skeletal dysplasia associated TRPV4. Only around 50 pathogenic gain-of-function variants have been identified as a cause of Brachyolmia Type 3. Characteristic features of Brachyolmia Type 3 include a short neck, kyphosis/scoliosis, short femoral neck, brachydactyly and platyspondyly. The spine differences result in pain, body stiffness, and limited flexion and extension of the spine.
Case Presentation
A female proband presented at 11 years of age with short stature, short neck, short trunk, brachydactyly, kyphosis, and increased pain and fatigue with sports and daily activities.
Diagnostic Workup
Spine MRI imaging showed vertebral body height shortening with irregular endplates throughout the lumbosacral spine. Spine X-rays revealed platyspondylia of the cervical spine with the exception of C2. Our patient was identified to have a pathogenic variant c.1847G>A (p.Arg616Gln) in TRPV4. Additional work-up showed normal bone density on DEXA, normal calcium and phosphorus and slightly low magnesium and Vitamin D 25 OH.
Outcome and Follow-Up
On obtaining the maternal family history, there was a long history of short stature and similar complaints of early childhood back pain. Multiple family members were tested and identified to have the c.1847G>A (p.Arg616Gln) variant in TRPV4.
The proband’s presentation is similar to cases described in the medical literature; however, she appears to have a more severe phenotype than her other family members who carry the same variant. Our proband’s mother underwent X-rays of her spine which did not show obvious characteristic findings aside from scoliosis, although an MRI was not obtained. Short stature, childhood back pain, and scoliosis appeared to coincide with family members who carried the pathogenic variant.
Discussion
Our proband was noted to have 3 additional variants of uncertain significance (VUS) identified on her skeletal dysplasia panel. Two uncertain variants were identified in two different preliminary evidence autosomal recessive (AR) genes that did not match the patient’s phenotype. The other VUS was also in the TRPV4 gene. The uncertain variant TRPV4 c.2456G>A (p.Arg819Lys) (not maternally inherited) is not present in the medical literature, but has been identified as an uncertain variant by 3 different labs.
While the TRPV4 c.1847G>A (p.Arg616Gln) variant is a known cause of Brachyolmia Type 3, our patient has a more severe presentation than other family members with the variant raising the question of an additive effect from the uncertain variant versus overall phenotypic variability among family members.
Conclusion
As more patients present with variants in TRPV4 we may learn more about the phenotypic variability in Brachyolmia Type 3. Brachyolmia Type 3 is likely under diagnosed due to its milder presentation which may not lead to genetic testing. Brachyolmia Type 3 should be considered in the differential of familial early childhood back pain, short stature, scoliosis and abnormal spine imaging such as features of platyspondyly. At this time, treatments are largely focused on maintaining bone health.