A long way to syndromic short stature

Background: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine-Harbison clinical scoring system (NH-CSS).

Case presentation: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort.

Conclusions: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems.