Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients

Figure 1. Schematic structure of titin: principal cardiac long isoform N2BA (NM_001256850.1) and schematic representation of the variants presented in our cohort. Patient 1, with very mild musculoskeletal phenotype, carries variants that are located beyond the second half of the I-band and the most distal part of the M-band. All other patients, with remarkable extracardiac involvement, show more proximally located variants.

Figure 2. Panel 1 shows skeletal muscular magnetic resonance imaging with diffuse fibrofatty infiltration of different degree. Minimal changes are observed in patient 1, while changes in almost each muscular segment are present in patient 4. Panel 2 includes major cardiac studies including cardiac magnetic resonance imaging in patients 2–5 with variable degree of late gadolinium enhancement of different intensity in three out of five patients, mainly in the subepicardial region. Specific histological specimens from extracted hearts of patients 1 and 3 are included: (A) in patient 1, the myocardium is characterized by polymetric and polymorphic nuclei of cardiomyocytes (HE, 10×). (B) Masson trichrome staining shows mild fibrotic expansion of the interstitium (10×), while in patient 3, (C) eccentric hypertrophy of the left ventricular free wall can be seen (HE, 1.25×). (D) In the insert, at higher magnification, large areas with loss of myocardium replaced by fibrosis (HE, 40×). The lower panel shows the ECG changes, including non-sustained ventricular tachycardia and premature ventricular contractions in patients 2, 3, and 4, respectively.

Figure 3. Wide phenotypic variability was noticed in the study cohort ranging from apparently no major skeletal or multisystemic involvement (patient 1) to major arthrogryposis, muscular rigidity, and craniofacial changes in patient 4. Moreover, in the latter, panoramic coronal curved multiplanar reconstructions (A,B) show diffuse, severe, end-stage fatty infiltration of all muscular groups, including intercostal ones (white arrows). Coronal and reformatted axial VIBE T1 DIXON of pelvis and thighs (C,D) revealed a less evident (moderate) bilateral fatty infiltration of adductor longus muscles (yellow arrows). Diffuse severe fatty infiltration of all muscular groups of the pelvis, thighs, and legs. Coronal and reformatted axial VIBE T1 DIXON (E,F) of the legs shows diffuse end-stage fatty infiltration of all muscular groups.

Figure 4. Family pedigrees of the study cohort showing phenotype-negative individuals with heterozygous variants and phenotype positive individuals with biallelic variants.