The pathophysiology of generalized essential telangiectasia is not well understood. Generalized essential telangiectasia is an uncommon disorder in which widespread telangiectasias of unknown cause develop without associated systemic or antecedent dermatologic disease. We report a case of generalized essential telangiectasia in an otherwise healthy 49-year-old man.

Cutaneous collagenous vasculopathy (CCV) is a rare benign microangiopathy of the superficial dermal vessels. Clinically, it is characterized by widespread, asymptomatic development of cutaneous telangiectasia in the absence of systemic symptoms. Morphologically, it most resembles generalized essential telangiectasia and other telangiectatic syndromes such as telangiectasia macularis eruptiva perstans (TMEP), ataxia telangiectasia, and hereditary hemorrhagic telangiectasia. It is distinctive in its histology, showing characteristic dilated thick-walled blood vessels in the superficial dermis. The thickened walls of these superficial dermal blood vessels demonstrate reduplication of the basement membrane on PAS staining. We report a 63-year-old man with CCV with this condition for 20 years, starting in 1996. He was diagnosed in the past as having essential telangiectasia. The development of the telangectasias occurred after coronary artery bypass grafting, also performed in 1996. This case not only demonstrates the characteristic clinical and histologic findings, but also suggests a possible mechanism. Moreover, it illustrates that cases of generalized essential telangiectasia may in fact be CCV that are misclassified.

Cutaneous collagenous vasculopathy (CCV) is a rare idiopathic microangiopathy affecting superficial dermal blood vessels. It is characterized by asymptomatic, disseminated, telangiectatic macules that typically involve the extremities. We report the case of a 58-year-old woman who presented with widespread telangiectasias of three years' duration on the upper extremities and abdomen. Cutaneous collagenous vasculopathy may be underdiagnosed as it is often mistaken for disorders that are morphologically very similar, including generalized essential telangiectasia, hereditary hemorrhagic telangiectasia, and pigmented purpuric dermatosis. The diagnosis of CCV is made histologically and findings feature dilated superficial dermal vessels with thickened walls containing periodic acid-Schiff-positive eosinophilic hyaline material. Effective treatment options for CCV have yet to be established and given its benign disease course, treatment may not be necessary. Pulsed dye laser can be offered to patients for cosmetic improvement but the extent of the disease makes complete lesion clearance challenging in most cases. Given the lesions were asymptomatic our patient declined all offered treatment modalities.

Ataxia-telangiectasia confers a significant increase in the development of several cancer types, most commonly leukemia and lymphoma. However, as the natural history for these patients is evolving and their lifespan is increasing, there is the potential for the development of additional uncommon tumors in an already rare patient population. We report the first case, to our knowledge, of an incidental retroperitoneal tumor in a 26-year-old woman undergoing evaluation for hepatic dysfunction. The mass was suspicious for retroperitoneal sarcoma, but proved to be an extramedullary hematopoietic pseudotumor after extensive pathologic evaluation. The changing landscape of neoplasms associated with ataxia-telangiectasia is discussed with emphasis on previously underreported benign and malignant tumors.

BACKGROUND: Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor-like kinase 1 (Alk1) are linked to hemorrhagic telangiectasia type 2. METHODS: Endothelial-specific deletion of Alk1, endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific Alk1 deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro-computed tomography, with other molecular and cell biological tools were also performed. RESULTS: We performed endothelial-specific deletion of Alk1 in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after Alk1 deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after Alk1 deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after Alk1 deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model. CONCLUSIONS: Together, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.

Purpose of review

The TGFβ (transforming growth factor β) superfamily - a large group of structurally related and evolutionarily conserved proteins - profoundly shapes and organizes the vasculature during normal development and adult homeostasis. Mutations inactivating several of its ligands, receptors, or signal transducers set off hereditary hemorrhagic telangiectasia (HHT), a disorder that causes capillary networks to form incorrectly. Drosha, an essential microRNA-processing enzyme, also interfaces with TGFβ signal transducers, but its involvement in vascular conditions had not been tested until recently. This review summarizes current evidence that links mutations of Drosha to HHT.

Recent findings

Genetic studies have revealed that rare missense mutations in the Drosha gene occur more commonly among HHT patients than in healthy people. Molecular analyses also indicated that Drosha enzymes with HHT-associated mutations generate microRNAs less efficiently than their wild-type counterpart when stimulated by TGFβ ligands. In zebrafish or mouse, mutant Drosha proteins cause the formation of dilated, leaky blood vessels deprived of capillaries, similar to those typically found in patients with HHT.

Summary

Recent evidence suggests that Drosha-mediated microRNA biogenesis contributes significantly to the control of vascular development and homeostasis by TGFβ. Loss or reduction of Drosha function may predispose carriers to HHT and possibly other vascular diseases.

Blepharospasm is rarely due to an identifiable etiology. In the majority of cases, imaging fails to reveal any structural lesion. Here we describe an otherwise healthy patient with blepharospasm who was found to have pontine capillary telangiectasia. We propose a potential association between blepharospasm and pontine capillary telangiectasia.

The transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an overrepresentation of rare nonsynonymous variants of DROSHA Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino-directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.