Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

Keywords: Ehlers-Danlos syndrome; Loeys-Dietz syndrome; SMAD2; SMAD3; TGFB2; TGFB3.; TGFBR1; TGFBR2; arterial aneurysms; hereditary connective tissue disorders.

Figure 1

Clinical and instrumental findings observed in our Loeys-Dietz syndrome (LDS) patients. (a–c) Proband of family 1 (p.Asp400Gly,TGFBR1), aged 7 years manifesting dolichocephaly (a), milia (b) and enamel defect of permanent dentition. (d,e) Family 4 (p.Gly271Asp, TGFBR1), proband (d) and his brother (e) outlining intrafamilial variability of palpebral fissures, horizontal in the proband (d) and downslanted in his brother (e) in the presence of severe milia in both. (f) CT-angiography of the abdomen in the proband of family 7 (p.Gly353Arg, TGFBR1), aged 23 years, showing aneurysm of the abdominal aorta (asterisk) with intimal blister flap (arrow head). (g) Proband of family 15 (p.Asp522Asn, TGFBR2), aged 36 years: CT-angiography of head and neck showing fusiform aneurysm of the left subclavian artery (asterisk), middle cerebral artery stenosis (arrow heads), diffuse tortuosity of vertebral arteries (area within the circle). (h–k) Proband of family 16 (p.Asp446Asn, TGFBR2), aged 7 years, displays asymmetry of iliac crest, thin and translucent skin with highly visible subcutaneous venous reticulum (h); Limited function of the feet after corrective surgery for bilateral clubfoot (i); hind foot deformity with bilateral pronated valgus pes planus (j); X-ray frontal view performed at 6 years shows the displaced heart in the left thorax due to severe pectus excavatum and scoliosis with lumbar left rotation and asymmetric iliac wings (k). (l–n), Proband of family 24 (p.Phe160Leufs*14, TGFB2), aged 48 years featuring facial asymmetry and dysmorphism (highly arched eyebrows, hypertelorism, bilateral exophthalmos, bifid nasal tip, long philtrum with thin upper lip, micrognathia) in addition to premature aging appearance (l); Joint laxity of the thumb (m) and the knee (n); Note the thin and translucent skin with visible subcutaneous veins.