Case Report: Atypical Silver-Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum

The amount of IGF2 (Insulin Growth Factor 2) accounts for regular embryonal and postnatal growth. Due to an imprinting control by H19:IGF2:IG-DMRs (IC1) in the 11p15.5, the maternal IGF2 allele is silenced. Dysregulation consequent to IC1 Loss of Methylation or Gain of Methylation causes Silver-Russell (SRS) or Beckwith-Wiedemann syndrome (BWS), opposite disorders associated with growth retardation or overgrowth. Specific clinical features define each of the two syndromes, but if isolated asymmetry, a common cardinal feature, occurs the diagnosis may be tricky. Here we report the case of a girl, with a height of 171 cm, appropriate growth parameters at birth and right body asymmetry, so classified in the BWS spectrum. Later, BWS/RSS MS-MLPA identified proper methylation at IC2 and an IC1_LoM disclosing an apparent discrepant diagnosis of SRS. A clinical re-evaluation revealed a relative macrocephaly at birth, feeding difficulties, asymmetry, and familiarity with tall stature, which fit with SRS diagnosis. Interestingly and never described in IC1_LoM SRS patients, since 16 years old she developed hand-writer’s cramps, depression and bipolar disorder. Trio-WES disclosed a VPS16 gene heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity. IGF2 involvement in the lysosomial pathway led us to speculate that the neurological phenotype of the proband might triggered by the concurrent IGF2 deficit and VPS16 alteration.