medwireNews: Sequencing selected genes of patients referred for genetic testing for Silver Russell Syndrome (SRS) can identify those with diagnoses requiring a markedly different management strategy, report researchers.

Targeted sequencing allowed Thomas Eggermann (Technical University Aachen, Germany) and study co-authors to make differential diagnoses including Bloom syndrome and Mulibrey nanism. They stress that growth hormone treatment is contraindicated for patients with either of these conditions.

“Because of its molecular and clinical heterogeneity, patients with a positive clinical score for SRS are often un- or misdiagnosed”, the team writes in The Journal of Pediatrics.

“However, this study shows that the molecular diagnosis is a prerequisite for a well-directed therapy.”

All 47 patients in the study had been referred for testing, but none had the genetic variants commonly associated with SRS, so the researchers assessed a further 25 genes that are either proposed SRS candidate genes or associated with its differential diagnoses. This approach detected 15 genetic variants (in 14 patients), of which six were definitely or likely pathogenic, four were of unknown significance and the remainder were heterozygous for a recessive disorder and therefore of unknown significance.

Ultimately, four patients who had scored at least 4 out of 6 points on the Netchine-Harbison clinical scoring system had a pathogenic mutation identified that was a definite cause of their symptoms, but was not consistent with a diagnosis of SRS. The pathogenic mutations in these four patients were associated with Bloom syndrome, Mulibrey nanism, KBG syndrome or insulin-like growth factors receptor-1-associated short stature.

The researchers stress that being diagnosed with Bloom syndrome or Mulibrey nanism has a “major impact on the medical management.” Bloom syndrome is associated with a very high risk of neoplasms, requiring monitoring and efforts to minimise risks such as sun exposure, and Mulibrey nanism carries a high risk of restrictive pericardial heart disease, as well as an increased risk of Wilms tumour and ovarian fibrothecomas.

“We suggest focusing on differential diagnoses with the most severe complications first when examining SRS differential diagnoses”, say Eggermann and team.

“In the case of cancer predisposition mutations, this strategy avoids patients carrying mutations in these genes remaining without a molecular diagnosis and can be treated.”

By Eleanor McDermid

J Pediatr 2017; Advance online publication

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