Amy Wiegand1, Rama Kastury2, Arpita Neogi3, Arya Mani3, Allen Bale4 and Allison Cox4,5 1Smilow Cancer Genetics and Prevention Program, Yale New Haven Health, New Haven, Connecticut 06510, USA; 2Department of Pediatric and Adolescent Gynecology, National Institutes of Health, Bethesda, Maryland 20892, USA; 3Department of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut 06510, USA; 4Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA; 5Department of Pathology and Laboratory Medicine at University of Rochester Medical Center, Rochester, New York 14642, USA Corresponding author: amy.wiegandynhh.org Abstract

Hereditary connective tissue disorders have overlapping phenotypes, particularly in regard to musculoskeletal features. This contributes to the challenge of phenotype-based clinical diagnoses. However, some hereditary connective tissue disorders have distinct cardiovascular manifestations that require early intervention and specific management. Molecular testing has increased the ability to categorize and diagnose distinct hereditary connective tissue disorders. A 42-yr-old female with a clinical diagnosis of Larsen syndrome from birth presented for genetic testing based on her recent diagnosis of premenopausal breast cancer. She had a past medical history of multiple carotid dissections. As she never had confirmatory molecular genetic testing for Larsen syndrome, whole-exome sequencing was utilized to assess both hereditary cancer predisposition syndromes and connective tissue disorders. A homozygous pathogenic variant in the FKBP14 gene was identified associated with FKBP14 kyphoscoliotic Ehlers–Danlos syndrome. We recommend that patients with a clinical diagnosis of Larsen syndrome undergo broad-based molecular sequencing for multiple hereditary connective tissue disorders. Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only. Early diagnosis of a hereditary connective tissue disorder with vascular features allows for screening and subsequent prevention of cardiovascular events.

Received February 17, 2023. Accepted May 10, 2023.

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