A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4

Abstract

The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal defects of the pelvis and lower limbs. We report here a fetus with a novel multiple malformation syndrome associated with sacrococcygeal agenesis, bilateral lower limb aplasia, hypoplastic left heart, bilateral lung hypoplasia, hydroureteronephrosis, and nonimmune fetal hydrops, found to have a homozygous nonsense variant in the TBX4 gene. We propose that biallelic variants in the TBX4 gene are associated with a severe syndromic phenotype of sacrococcygeal agenesis and lower limb reduction defects.

Fig. 1. Fetal images following termination of pregnancy.

a Whole body radiograph (anteroposterior view) showing absence of sacrum, pelvic bones, and lower limb bones. b Autopsy findings suggestive of  craniofacial dysmorphism, hydropic features, normal upper limbs, normal chest and abdomen, a triangular pelvis, and bilateral lower limb aplasia.

Fig. 2. Three generation pedigree of the family showing the three consecutive affected pregnancies of the third-degree consanguineous couple.

Sanger sequence chromatograms of the TBX4 gene showing the c.402G>A variant (highlighted by the rectangle) in the homozygous form in the third affected fetus (the index case) and in the heterozygous form in both carrier parents.

Fig. 3. Clinical photograph and skeletal radiographs of the father.

a Close-up of the father’s feet showing the proximally placed fourth and fifth toes bilaterally. b Anteroposterior radiograph of the right foot showing the short fourth and fifth metatarsals. c Anteroposterior radiograph of the hip joints and femora showing the hypoplastic lesser trochanter of the femur bilaterally (marked with red arrows). d Anteroposterior radiograph of the knee joints showing the hypoplastic patellae bilaterally (marked with red arrows). e Lateral radiographs of the knee joints showing the hypoplastic patellae bilaterally (color figure online).