Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder arising from mutations in the TGF-β signaling pathway. It is characterized by vascular, skeletal, and craniofacial abnormalities, and presents a broad spectrum of clinical manifestations along with hypermobility. While these complications are well-documented, the co-occurrence of LDS with postural orthostatic tachycardia syndrome (POTS) has not been previously reported. POTS is known to occur in other connective tissue disorders, such as Hypermobile Ehlers-Danlos Syndrome (hEDS), but has not been explored in the context of LDS.

This case series presents two female patients with Loeys-Dietz syndrome (LDS). Case 1 involves a pathogenic variant of the TGFB2 gene, presenting as LDS type 4, while Case 2 has a monoallelic mutation of the TGFBR1 gene, presenting as LDS type 1. Autonomic testing revealed positive tilt-table test results, meeting the diagnostic criteria for postural orthostatic tachycardia with no evidence of orthostatic hypotension or cardiovagal and cardiovascular adrenergic abnormalities. Additionally, Case 1 had an abnormal QSART study, indicative of small fiber neuropathy. Both patients reported improvement of their symptoms after adhering to lifestyle modifications, Salt loading, hydration, thigh-high compression stockings, and regular exercise reduced significantly the clinical burden of POTS. The necessity of using renin-angiotensin-aldosterone system blockade for aortic aneurysm prophylaxis makes the management of these patients particularly challenging.

The coexistence of LDS and POTS suggests potential shared pathophysiological mechanisms with other connective tissue disorders. Further studies are warranted to explore the prevalence of dysautonomia in LDS and to examine the underlying pathophysiological pathways.