The patient presented with ostium secundum-type atrial septal defect, muscular ventricular septal defect, and pulmonary hypertension that worsened when she was 6 months old. Due to this worsening, she was placed under pediatric critical care again. The computerized tomography scan showed diffuse cerebral edema with a partial collapse of the ventricular system without other focal lesions such as embolism and bleeding. Magnetic resonance imaging of the brain revealed restriction of generalized diffusion predominantly in the posterior and right areas without ventricular collapse and subdural efflux without compressive effect associated with adjacent cortical changes ascribable to necrosis. The electroencephalogram showed the absence of deep rhythms, severe slowing of the wave registers, and high-voltage bursts. Surgical intervention was provided to close the aortopulmonary and the pulmonary cerclage. After the first surgery, she presented with cerebral edema with encephalopathy due to axonal sprouting after the cortical lesion and generalized hypertonia as a consequence of the motor descending tract lesion, which was treated with clonazepam and phenobarbital without new episodes.
At 14 months of age, she presented with oropharyngeal dysphagia with moderate oral motor skills. For that reason, she received enteral feeding by gastrostomy. An intestinal transit study showed a duodenal corkscrew sign in the second intestinal portion at the Treitz angle level on the right side close to the right pedicle (L1). The image showed that the first jejunal handles were at the right center. All of these findings were related to intestinal malrotation changes. These changes included normal cecum position and gastroesophageal reflux grade III, which reached the barium column up to the proximal region of the esophagus. The follow-up electrocardiogram showed increased signs of sinus rhythm and right ventricular function. In addition, there was evidence of successful modification of the aortopulmonary window and pulmonary cerclage, muscular restrictive interventricular communication with a few left to right shunts, properly biventricular function without overflow, and pulmonary hypertension signs without clots and vegetations.
Radiological studies of the upper limbs revealed absence of bilateral metacarpal bones and phalanges of the first finger, bilateral radioulnar hypoplasia, absence of the ulna in the left arm (Figure 2), hip dysplasia, and femoral-tibial varum angle (genu varum). No radiological changes in the spinal column X-ray were detected.
She was referred for genetic consultation at 2 years of age with a weight of 11.8 kg (50th-75th percentile), height 88 cm (75th-90th percentile). She presented with forehead hemangioma and hypoplasia of the nasal bones without appropriate visual follow-up, cephalic support was not successful, trunk and upper limbs were hypotonic, superior limbs with spasticity were more notable on the left side, and nipple hypertelorism.
A complete sequence of the TBX5 gene was generated and compared to the NG_007373.1 (GeneBank) reference sequence which identified a novel potentially pathogenic variant in the heterozygous status NM_181486.2:c.243-1G>C. This splice-site mutation alters the acceptor site of the third intron, which is predicted to affect the splicing and lead to a nonfunctional protein. Using Sanger sequencing, this novel variant was confirmed using an ABI 3500 sequencer (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA). A carrier study in the parents was negative for this mutation (Figure 3). For that reason, this mutation was considered to be a novel de novo mutation, which has not been previously reported.