Another face of RASA1: Report of familial germline variant in RASA1 with dysmorphic features.

RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS-MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation-arteriovenous malformation type 1 (CM-AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast-flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM-AVM type 1 and propose a new RASA1 variant as likely pathogenic.

Misdiagnosis of capillary malformations in darker skin phototypes.

In the dermatologic medical literature, there is an underrepresentation of conditions in individuals of color. Due to the lack of representation, it may be harder for clinicians to recognize certain diagnoses in patients with darker skin phototypes leading to misdiagnosis and affecting overall patient management, outcomes, and satisfaction. Here, we present four Black or Indigenous People of Color who were initially referred for hyperpigmentation, hemihyperplasia, or café au lait spots and found to have syndromic capillary malformations.

Good response to pulsed dye laser in patients with capillary malformation-arteriovenous malformation syndrome (CM-AVM).

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by heterozygous mutations in RASA1 and EPHB4. Capillary stains in CM-AVM are compatible with Schöbinger's phase I AVMs. Vascular laser has been classically contraindicated for the treatment of AVMs, as there is a fear of accelerating their progression. In this study, we have treated capillary stains in five CM-AVM patients with pulsed dye laser, with improvement and without worsening or recurrence of the lesions after 1 year of clinical and ultrasound follow-up.

RASA1 mutation in a family with capillary malformation-arteriovenous malformation syndrome: A discussion of the differential diagnosis.

We describe a family who presented with several scattered, vascular, cutaneous lesions and was found to have a novel mutation in RASA1, diagnostic of capillary malformation-arteriovenous malformation syndrome. Our patient was initially given a presumptive clinical diagnosis of hereditary hemorrhagic telangiectasia. Capillary malformation-arteriovenous malformation syndrome shares several features with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but it can be distinguished clinically according to its morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast-flow lesions, and genetic analysis.

A spectrum of intracranial vascular high-flow arteriovenous shunts in RASA1 mutations.

PURPOSE AND BACKGROUND: We describe three paediatric cases with different intracranial fast-flow shunts presenting early in life, all with capillary malformation-arteriovenous malformation syndrome and RASA1 verified mutations. Intracranial arteriovenous fast-flow shunts are rare vascular malformations typically presenting early in life and have been associated with cutaneous capillary malformations, characterized as capillary malformation-arteriovenous malformation syndrome. Heterozygous RASA1 gene mutations have been found to be disease causing with high penetrance for the typical cutaneous findings, but only some individuals with the syndrome have intracranial lesions. CASES: One infant presented with a vein of Galen malformation responsible for hydrodynamic disorders, one neonate suffered from severe cardiac insufficiency related to a superior sagittal sinus dural malformation with high-flow fistulas, and one baby was treated at infant age of a choroidal arteriovenous fistula discovered antenatally. RESULTS AND CONCLUSIONS: We report the follow-up of these three cases with RASA1 gene mutation and comment on the possible role of evaluation for vascular lesions and capillary malformation-arteriovenous malformation syndrome in patients and their families, with intracranial fast-flow shunts.

Multifocal vascular lesions.

Multifocal vascular lesions are important to recognize and appropriately diagnose. Generally first noticed on the skin, multifocal vascular lesions may have systemic involvement. Distinguishing among the different types of multifocal vascular lesions is often based on clinical features; however, radiological imaging and/or biopsy are frequently needed to identify distinct features and guide treatment. Knowledge of the systemic associations that can occur with different vascular anomalies may reduce life-threatening complications, such as coagulopathy, bleeding, cardiac compromise, and neurologic sequelae. This review provides a synopsis of the epidemiology, pathogenesis, presentation, workup, and treatment of several well-recognized multifocal vascular tumors and malformations.

RASopathies: Dermatologists' viewpoints.

Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well-recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.

RASopathies: The musculoskeletal consequences and their etiology and pathogenesis.

The RASopathies comprise an ever-growing number of clinical syndromes resulting from germline mutations in components of the RAS/MAPK signaling pathway. While multiple organs and tissues may be affected by these mutations, this review will focus on how these mutations specifically impact the musculoskeletal system. Herein, we review the genetics and musculoskeletal phenotypes of these syndromes in humans. We discuss how mutations in the RASopathy syndromes have been studied in translational mouse models. Finally, we discuss how signaling molecules within the RAS/MAPK pathway are involved in normal and abnormal bone biology in the context of osteoblasts, osteoclasts and chondrocytes.