First evidence of maternally inherited mosaicism in TGFBR1 and subtle primary myocardial changes in Loeys-Dietz syndrome: a case report

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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0661-2) contains supplementary material, which is available to authorized users.

Involvement of MAP3K7 in FMD2 and CSCF, delineation of genotype/phenotype correlations.

“…Regarding the occurrence of left sided heart lesions and the potential progressive aspect in our patient of aortic dilatation, these features go along with previous reports that genes which belong to TGFβ cascade are potentially prone to this subcategory of cardiac involvement (Baban et al, 2018). It might be wise to establish a specific screening program through serial electrocardiography and echocardiography detect progressive aortic dilatation or arrhythmias.…”

The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations

“…Both our FMD2 patients showed phenotypes compatible with previously reported patients (Wade et al, 2017). Interestingly, our adult male FMD2 Regarding the occurrence of left-sided heart lesions and the potential progressive aspect in our patients of aortic dilatation, these features go along with previous reports that genes which belong to the TGF-β cascade are potentially prone to this subcategory of cardiac involvement (Baban et al, 2018;Caulfield et al, 2018;Cheng et al, 2017;Engwerda et al, 2021;Hanson et al, 2022;Yin et al, 2022). It might be wise to establish a specific screening program through serial electrocardiography and echocardiography detect progressive aortic dilatation or arrhythmias.…”

Multi‐exon COL5A1 deletion in a child with classical Ehlers–Danlos syndrome: A case report expanding the allelic spectrum and showing evidence of parental gonosomal mosaicism

“…4 Gonosomal mosaicism occurs in several heritable connective tissue disorders, for example Loeys-Dietz syndrome and Marfan syndrome. 5,6 In a study on 333 individuals with Marfan syndrome, around 5% of assumed de novo cases were caused by parental gonosomal mosaicism. 7 In the same study, a case with low-level parental mosaicism for a COL5A1 variant was reported for the first time.…”