Isolated Lateralized Overgrowth - Phenotypic Spectrum and Molecular Alterations

To evaluate the molecular aberrations at 11p15.5 locus in thirty-two patients with isolated lateralized overgrowth (ILO).

Among selected 32 cases of ILO, methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) was performed initially followed by short tandem repeats (STR) marker analysis to confirm uniparental disomy (UPD). In those patients with normal MLPA reports, cyclin dependent kinase inhibitor 1C (CDKN1C) gene and whole exome sequencing was performed.

Molecular analysis by MS-MLPA showed methylation aberrations in 28% (9/32) of patients. Gain of methylation at IC1 imprinting center (H4, H7) and loss of methylation at IC2 (H6, H9) was observed in 2 patients each. Uniparental disomy was observed in 9% cases. Except one, all patients with methylation aberration had more than one limb hypertrophy. Two patients (H22/H29) also had loss of methylation at IC1. Though this molecular alteration is specifically associated with Silver Russel syndrome (SRS), but the affected children did not completely fulfill the diagnostic criteria for SRS. In a recent study, a discrepancy was reported between the diagnosis of Beckwith-Wiedemann syndrome (BWS)/SRS and the molecular findings in the patients. Many times, it is very difficult to differentiate between hemi hypertrophy/hemi hypotrophy. Patients, in whom no aberrations were detected on MS-MLPA, whole exome sequencing (WES) was performed and no pathogenic variant was identified.

Thus, ILO may be considered as a mild presentation on the extreme edge of BWS spectrum with methylation aberration and UPD in one third of cases which has implications in follow up.