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.

Shprintzen-Goldberg-syndrome (SGS) is caused by pathogenic exon 1 variants of SKI. Symptoms include dysmorphic features, skeletal and cardiovascular comorbidities, and cognitive and developmental impairments. We delineated the neurodevelopmental and behavioral features of SGS, as they are not well-documented. We collected physician-reported data of people with molecularly confirmed SGS through an international collaboration. We identified and deep-phenotyped the neurodevelopmental and behavioral features in four patients. Within our cohort, all exhibited developmental delays in motor skills and/or speech, with the average age of first words at 2 years and 6 months and independent walking at 3 years and 5 months. All four had learning disabilities and difficulties regulating emotions and behavior. Intellectual disability, ranging from borderline to moderate, was present in all four participants. Moreover, we reviewed the literature and identified 52 additional people with SGS, and summarized the features across both datasets. Mean age was 23 years (9-48 years). When combining our cohort and reported cases, we found that 80% (45/56) had developmental and/or cognitive impairment, with the remainder having normal intelligence. Our study elucidates the developmental, cognitive, and behavioral features in participants with SGS and contributes to a better understanding of this rare condition.

Shprintzen-Goldberg syndrome (SGS) shares skeletal features with Marfan syndrome (MFS), but differs in its craniofacial and neurodevelopmental features. Cardiovascular features have been specifically investigated in few of the 57 known patients with SGS described in the literature, making it difficult to determine their prevalence and characteristics. We reviewed the medical records of an international cohort of 29 patients, with a particular focus on cardiovascular features. Data were compared with those of MFS. The sex ratio was 1.9 and median age was 23 years (range: 4-54). 13 patients (44.8%) had mitral regurgitation (MR), 11 (37.9%) had a thoracic aortic aneurysm (TAA) and 9 (31.1%) had aortic regurgitation (AR). No cases of aortic dissection were reported. None had beta-blockers as a primary prevention of aortic events. The Kaplan-Meier method revealed a 30 years risk of 47%, 33% and 22% for occurrence of MR, TAA and AR, respectively. A statistically significant association was found between variants in the Dachshund Homology Domain and the risk of aortic aneurysm (11/20 vs 0/9, p=0.036). Patients with SGS also significantly have cardiovascular manifestations, encouraging the implementation of a follow-up and preventive cardiovascular treatment identical to that of MFS.

Shprintzen-Goldberg syndrome is a rare systemic connective tissue disorder caused by heterozygous mutations in the Sloan-Kettering Institute (SKI) gene. The clinical presentation is reminiscent of Marfan and Loeys-Dietz syndromes, making differential diagnosis challenging. Shprintzen-Goldberg syndrome's distinctive features are craniosynostosis and learning disabilities. The pathophysiology of these three conditions is similar as they all result in the deregulation of the transforming growth factor beta (TGF-β) signaling pathway and thus an altered expression of TGF-β responsive genes. We report a family of two patients: one with initial suspicion of hypermobile Ehlers-Danlos syndrome and the second with suspicion of Marfan syndrome, as the Marfan systemic score was positive and no craniosynostosis or learning disabilities were described. They were diagnosed with Shprintzen-Goldberg syndrome after a heterozygous probably pathogenic variant in the second mutational hotspot of SKI Dachshund homology domain was identified. We reviewed the genotype-phenotype correlation among the three mutational hotspots in SKI: the amino acids 20 to 35 of the receptor-regulated small mothers against decapentaplegic domain (group 1, n = 32), amino acids 94 to 117 of Dachshund homology domain (group 2, n = 12), and threonine 180 of Dachshund homology domain (group 3, n = 11 including our patients). As the main differential diagnoses of Shprintzen-Goldberg syndrome are Marfan and Loeys-Dietz syndromes, we completed the comparison already made by Loeys and Dietz. (2008) of Shprintzen-Goldberg syndrome clinical features among the different mutational hotspots with Marfan syndrome and the different types of Loeys-Dietz syndrome. In addition to the already described absence of learning disabilities in Shprintzen-Goldberg patients with a pathogenic variant in the threonine 180 of Dachshund homology domain, facial features also appeared to be less severe. The clinical overlap with Marfan and Loeys-Dietz patients requires genetic testing in order to establish an accurate molecular diagnosis at the variant level, and to adapt genetic counseling and clinical management.

Loeys-Dietz syndrome (LDS) is a very rare connective tissue disorder with autosomal dominant inheritance, characterized by the involvement of the cardiovascular, musculoskeletal, and cutaneous systems, along with dysmorphic facial features. Currently, there are limited data regarding this disease. This case presents a clinical observation of a 17-year-old boy with acute onset of sensorimotor paraparesis and genetically confirmed LDS. The predominant symptoms of LDS include arterial aneurysms, arterial tortuosity, hypertelorism, and bifid uvula. However, this constellation of symptoms is not found in all patients with the disease. Genetic confirmation is essential for an accurate diagnosis. The prognosis for LDS differs from its mimics, such as Marfan syndrome, Beals syndrome, Ehlers-Danlos syndrome, and Shprintzen-Goldberg syndrome. Management of the disease warrants a multidisciplinary approach to address its various manifestations. Such an approach can help increase the life expectancy and improve the quality of life for these patients.