Macrocephaly associated with the DICER1 syndrome

BACKGROUND: Germline mutations in DICER1 increase the risk of various tumors, including pleuropulmonary blastoma. Macrocephaly and symmetric overgrowth has been reported in some, but not all, patients with mosaic DICER1 RNase IIIb mutations; the prevalence of these features in individuals with constitutional germline DICER1 mutations is unknown. METHODS: We analyzed prospectively collected auxology data from 67 DICER1 mutation carriers and 43 family controls. We assessed differences between groups using an exact test for proportions and generalized estimating equations for continuous dependent variables. RESULTS: Twenty-eight DICER1 mutation carriers (42%) were macrocephalic, and none had an occipital-frontal circumference (OFC) below the 3(rd) centile, which significantly differed from family controls, of whom five were macrocephalic (12%) and two had OFC below the 3(rd) centile (5%) (P<0.001). DICER1 mutation carriers were taller than familial controls after controlling for gender (P=0.048), but similar proportions of both groups were above the 97(th) centile of population norms. Head circumference remained increased after adjusting for differences in height. CONCLUSIONS: For the first time, we establish macrocephaly as a common finding in the DICER1 syndrome. Like some of the other tumor-predisposition disorders, macrocephaly may be a useful, albeit a subtle, clinical clue to the DICER1 syndrome diagnosis.