Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic Variant

Abstract

TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in TRPV4 are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to TRPV4 pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a TRPV4 pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that TRPV4-related skeletal dysplasias and TRPV4-related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any TRPV4-related disorder include assessment for both skeletal and neurological findings.

Keywords: CMT2C; Charcot-Marie-Tooth; SMD-K; Spondlyometaphyseal dysplasia Kozlowski; TRPV4.

Fig. 1

Lateral spine radiograph at 5 years of age demonstrating generalized platyspondyly and anterior vertebral abnormalities consistent with spondylometaphyseal dysplasia-Kozlowski type.

Fig. 2

Radiograph of the pelvis and lower spine at 5 years of age. There is moderate to marked metaphyseal irregularity at the proximal femurs and of the greater trochanters, very short femoral necks, and asymmetric neck shaft femoral angles. The ilia are mildly broad.

Fig. 3

Hand radiograph at 10 years of age. There is moderate to marked brachydactyly with shortening particularly of the distal phalanges. Metaphyseal cupping as is seen in spondylometaphyseal dysplasia-Kozlowski type is also evident.

Fig. 4

A, B Patient's hands at age 27 showing characteristics consistent with Charcot-Marie-Tooth disease type 2. Note decreased muscle bulk and clawing. C Patient's feet at age 27. Note residual pes cavus and metatarsus adductus. D Frontal view of patient at age 27. Note relatively short trunk and distal extremity muscle wasting.