Abstract
BackgroundLoeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability.Case presentationWe report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far.ConclusionsThis case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.
Highlights
Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability.Case presentation: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment)
This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring
Written informed consent was obtained from the patient’s parents for publication of this case report and all accompanying data. We report this family because patients with LDS are commonly at high risk for acute vascular events and less frequently known to be at risk for myocardial involvement and ventricular dysfunction
Summary
Additional case descriptions are needed to draw any conclusions regarding the phenotypic spectrum of patients with TGFBR1/2 mutations in mosaicism. Reporting on subtle vascular symptoms, as in our case, can help identifying mild forms. Further studies with large cohorts are warranted to correlate the phenotypic spectrum of heart muscle abnormalities with LDS. The long-term follow-up of the child’s mother included primary and secondary vascular. Jaw abnormalities imaging to exclude as early as possible any vascular and myocardial impairment. At present and with the methods used, we are unable to differentiate hemorrhagic events in the mother of index patient reflecting the consequences of a TGFBR1-related vascular malformation or resulting from another cause. Careful evaluation of myocardial imaging combined with assessment of the vascular territory is recommended for the early detection of progressive cardiovascular abnormalities in LDS patients.
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