Recently described, Loeys-Dietz syndrome is phenotypically distinct from Marfan syndrome.Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disorder showing the involvement of cutaneous, cardiovascular, craniofacial, and skeletal systems. In particular, LDS patients show arterial tortuosity with widespread vascular aneurysm and dissection, and have a high risk of
aortic dissection or rupture at an early age and at aortic diameters that ordinarily are not predictive of these events. Recently, LDS has been subdivided in LDS type I (LDSI) and type II (LDSII) on the basis of the presence or the absence of cranio-facial involvement, respectively. Furthermore, LDSII patients display at least two of the major signs of vascular Ehlers-Danlos syndrome. LDS is caused by mutations in the transforming growth factor (TGF) beta-receptor I (TGFBR1) and II (TGFBR2) genes. The aim of this study was the clinical and molecular characterization of two LDS patients.
Methods
The exons and intronic flanking regions of TGFBR1 and TGFBR2 genes were amplified and sequence analysis was performed.
Results
Patient 1 was a boy showing dysmorphic signs, blue sclerae, high-arched palate, bifid uvula; skeletal system involvement, joint hypermobility, velvety and translucent skin, aortic root dilatation, tortuosity and elongation of the carotid arteries. These signs are consistent with an LDSI phenotype. The sequencing analysis disclosed the novel TGFBR1 p.Asp351Gly de novo mutation falling in the kinase domain of the receptor. Patient 2 was an adult woman showing ascending aorta aneurysm, with vascular complications following surgery intervention. Velvety and translucent skin, venous varicosities and wrist dislocation were present. These signs are consistent with an LDSII phenotype. In this patient and in her daughter, TGFBR2 genotyping disclosed in the kinase domain of the protein the novel p.Ile510Ser missense mutation.
Conclusion
We report two novel mutations in the TGFBR1 and TGFBR2 genes in two patients affected with LDS and showing marked phenotypic variability. Due to the difficulties in the clinical approach to a TGFBR-related disease, among patients with vascular involvement, with or without aortic root dilatation and LDS cardinal features, genotyping is mandatory to clarify the diagnosis, and to assess the management, prognosis, and counselling issues.
IN THIS PICTURE:
Clinical and radiographic features of the two LDS Patients. A) Phenotype of Patient 1, showing facial dysmorphisms: dolichocephaly, hypoplastic alae nasi, and micro/retrognathia; marfanoid habitus, muscular hypotrophy, mild thoracic scoliosis, and pes planus. B) Patient 2: Ascending aorta dilatation (i) and MRI axial T1 spin-echo images of the ascending aorta at the level of re-implanted coronary arteries, before (ii) and after (iii) gadolinium: a periaortic collection is visible (arrows), with contrast medium outside the aortic graft, due to detachment of re-implanted left coronary artery. C) Translucent skin with subcutaneous visible veins and flat feet in Patient 2.
Methods
The exons and intronic flanking regions of TGFBR1 and TGFBR2 genes were amplified and sequence analysis was performed.
Results
Patient 1 was a boy showing dysmorphic signs, blue sclerae, high-arched palate, bifid uvula; skeletal system involvement, joint hypermobility, velvety and translucent skin, aortic root dilatation, tortuosity and elongation of the carotid arteries. These signs are consistent with an LDSI phenotype. The sequencing analysis disclosed the novel TGFBR1 p.Asp351Gly de novo mutation falling in the kinase domain of the receptor. Patient 2 was an adult woman showing ascending aorta aneurysm, with vascular complications following surgery intervention. Velvety and translucent skin, venous varicosities and wrist dislocation were present. These signs are consistent with an LDSII phenotype. In this patient and in her daughter, TGFBR2 genotyping disclosed in the kinase domain of the protein the novel p.Ile510Ser missense mutation.
Conclusion
We report two novel mutations in the TGFBR1 and TGFBR2 genes in two patients affected with LDS and showing marked phenotypic variability. Due to the difficulties in the clinical approach to a TGFBR-related disease, among patients with vascular involvement, with or without aortic root dilatation and LDS cardinal features, genotyping is mandatory to clarify the diagnosis, and to assess the management, prognosis, and counselling issues.
IN THIS PICTURE:
Clinical and radiographic features of the two LDS Patients. A) Phenotype of Patient 1, showing facial dysmorphisms: dolichocephaly, hypoplastic alae nasi, and micro/retrognathia; marfanoid habitus, muscular hypotrophy, mild thoracic scoliosis, and pes planus. B) Patient 2: Ascending aorta dilatation (i) and MRI axial T1 spin-echo images of the ascending aorta at the level of re-implanted coronary arteries, before (ii) and after (iii) gadolinium: a periaortic collection is visible (arrows), with contrast medium outside the aortic graft, due to detachment of re-implanted left coronary artery. C) Translucent skin with subcutaneous visible veins and flat feet in Patient 2.
