Several autosomal-dominant monogenic disorders have been conclusively associated with mutations in TGFBR1 and TGFBR2, key receptors of the Transforming Growth Factor-β (TGFβ) signaling pathway. Although these disorders share a common cardiovascular connective tissue manifestation, different mutations present with strikingly distinctive clinical presentations leading to distinct disorders, including Loeys-Dietz syndrome Marfan syndrome type 2 (MFS2), and Thoracic Aortic Aneurysms and Dissections (TAAD). In addition, some mutations lead to Shprintzen-Goldberg syndrome which is characterized by skeletal deformities and intellectual disabilities in addition to the cardiovascular involvement, or vascular Ehlers-Danlos Syndrome (vEDS) that is associated with spontaneous rupture of the main arteries and internal organs. Furthermore, Multiple Self-healing Squamous Epithelioma (MSSE), a rare familial skin cancer, is linked to mutations in these genes. This significant phenotypic variability observed in these disorders could be attributed to various factors, ranging from the nature of the mutation including its location within the protein, the variable functional impact of the mutations (hypomorphicity), the level of disruption to the intricate interactions between signaling pathways, and the influence of modifier genes or environmental factors. In addition to haploinsufficiency, the impairment of TGFβ signaling could be exacerbated in other scenarios, such as the dominant-negative effects, in which a mutant allele disrupts the normal activity of the wild-type protein by forming non-functional receptor oligomers, hindering their trafficking. This review sheds light on these hereditary disorders, highlighting the broad spectrum of their clinical presentations associated with mutations in the same gene, their pathophysiology, and underlying molecular mechanisms. Most crucially, it underscores the critical gaps in our current understanding while proposing compelling directions for future research. This review also emphasizes the pressing need to unravel the complex genotype-phenotype correlations, which could pave the way for more precise diagnostic and therapeutic strategies.

Multiple Self-Healing Squamous Epithelioma of Ferguson-Smith (OMIM 132800) is a syndrome increasing the risk of developing keratoacanthomas, which are locally aggressive skin tumours. Loeys-Dietz syndrome is a connective tissue disease characterised by arterial fragility. There is no increased risk of skin tumours classically described.Both phenotypes have been associated with a different pathogenic variant of the TGFBR1 gene involved in the TGFbeta signalling pathway. We present the case of a patient with both phenotypes. This appears to be caused by a single likely pathogenic variant within TGFBR1: c.1421G>A (p.Cyst474Tyr) in the protein domain of the serine-threonine protein kinase.This is the fourth reported case exhibiting this dual clinical presentation with a single genetic variant in this same region.

Keratoacanthoma (KA) is a fast-growing skin tumor subtype that can be observed as a solitary lesion or rarely as multiple lesions in the context of rare genetic syndromes. Syndromes with multiple keratoacanthoma-like lesions have been documented as multiple self-healing squamous epithelioma (Ferguson-Smith syndrome), eruptive keratoacanthoma of Grzybowski, multiple familial keratoacanthoma of Witten and Zak Muir-Torre syndrome, and incontinentia pigmenti. The treatment approach of those entities is challenging due to the numerous lesions, the lesions' undefined nature, and the co-existence of other malignant skin tumors. Herein, we report a case of a 40-year-old woman who developed multiple treatment-resistant Ferguson-Smith-like keratoacanthomas with a co-existing large and ulcerated invasive squamous cell carcinoma and microcystic adnexal carcinoma on the scalp. Multiple keratoacanthomas on her extremities were successfully treated with oral acitretin (0.5 mg/kg/day) in combination with topical Fluorouracil (5-FU) 5%, while excision and plastic surgery restoration were performed to treat the ulcerated cancer lesion on her scalp. Due to the interesting nature of this rare syndrome, we performed a literature review including case reports and case series on multiple-KA-like lesions syndromes and focusing on diagnosis and therapy approaches. We also conducted a comparison of patient reports, which included assessing the clinical appearance of the lesions and evaluating the success and progress or the failure of various treatment approaches that were implemented.

Pathogenic variants in TGFBR1 are a common cause of Loeys-Dietz syndrome (LDS) characterized by life-threatening aortic and arterial disease. Generally, these are missense changes in highly conserved amino acids in the serine-threonine kinase domain. Conversely, nonsense, frameshift, or specific missense changes in the ligand-binding extracellular domain cause multiple self-healing squamous epithelioma (MSSE) lacking the cardiovascular phenotype. Here, we report on two novel variants in the penultimate exon 8 of TGFBR1 were identified in 3 patients from two unrelated LDS families: both were predicted to cause frameshift and premature stop codons (Gln448Profs*15 and Cys446Asnfs*4) resulting in truncated TGFBR1 proteins lacking the last 43 and 56 amino acid residues, respectively. These were classified as variants of uncertain significance based on current criteria. Transcript expression analyses revealed both mutant alleles escaped nonsense-mediated mRNA decay. Functional characterization in patient's dermal fibroblasts showed paradoxically enhanced TGFβ signaling, as observed for pathogenic missense TGFBR1 changes causative of LDS. In summary, we expanded the allelic repertoire of LDS-associated TGFBR1 variants to include truncating variants escaping nonsense-mediated mRNA decay. Our data highlight the importance of functional studies in variants interpretation for correct clinical diagnosis.