EDS was misdiagnosed as Larsen syndrome for 40 years: Case report

Study recommends genetic testing to get correct diagnosis, timely treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A woman with kyphoscoliotic Ehlers-Danlos syndrome (EDS), a rare disease form that causes an abnormally curved spine, went misdiagnosed with Larsen syndrome, which can also cause the spine to curve, for more than 40 years, according to a report.

This case in the U.S. highlights the value of genetic testing to confirm a diagnosis or rule out genetic diseases with similar symptoms. Getting the right diagnosis early means it’s possible to start adequate intervention when it is likely most effective.

The report, “FKBP14 kyphoscoliotic Ehlers–Danlos syndrome misdiagnosed as Larsen syndrome: a case report,” was published in Cold Spring Harbor Molecular Case Studies.

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Genetic diseases of connective tissues are difficult to diagnose

Some genetic diseases of the body’s connective tissues have similar symptoms, especially in the muscles and bones, making it difficult to diagnose them based on clinical observations alone.

However, some of these diseases can also cause specific symptoms, such as heart and blood vessel problems, that require close attention and early intervention.

Kyphoscoliotic EDS is characterized by kyphoscoliosis, a sideways curvature of the spine combined with a hunched back that worsens over time and can make breathing difficult.

Other symptoms include low muscle tone (hypotonia) at birth, fragile arteries that are prone to tears, and an unusually large range of joint movement (hypermobility) that is common to all types of EDS.

It is caused by mutations in the PLOD1 gene, and in rarer cases, in the FKBP14 gene. A diagnosis usually starts with a physical examination and is ultimately confirmed with genetic testing.

In the report, researchers describe the case of a 42-year-old woman with kyphoscoliotic EDS “who carried an incorrect clinical diagnosis of Larsen syndrome from birth.”

Larsen syndrome is a rare genetic disease that also affects the bones and joints, causing them to be dislocated or take on an abnormal shape from birth.

We recommend that patients with a clinical diagnosis of Larsen syndrome consider undergoing broad-based sequencing for multiple hereditary connective tissue disorders.

Woman’s Larsen syndrome diagnosis never confirmed with genetic testing

The woman went to the hospital because of her recent diagnosis of invasive ductal carcinoma (the most common type of breast cancer) in her right breast.

When she was born, the patient was diagnosed with Larsen syndrome because she had hypotonia and an abnormally curved spine (kyphosis). However, the diagnosis was never confirmed with genetic testing.

She experienced a first tear (dissection) in one carotid artery at age 27, and a second dissection in the opposite one about five years later at age 32. The carotid arteries are the blood vessels that supply blood to the brain, face, and neck.

At age 27, she also had an ischemic stroke (loss of blood flow supply) to the left side of her brain. Then, at age 40, she had another stroke, likely caused by either a narrowing of a blood vessel (stenosis) or a clot (thrombus) related to one of the carotid dissections.

Because such carotid dissections are not typical of Larsen syndrome, doctors suspected a different genetic disease of the body’s connective tissues, so they ordered a genetic test.

The test revealed no mutations in the FLNB gene, the cause of Larsen syndrome. However, it revealed a mutation (variant) known as c.362dupC (p.Glu122fs) in both copies of the FKBP14 gene.

This particular mutation “has been reported multiple times and is one of the most frequently reported pathogenic [disease-causing] variants in FKBP14,” the researchers wrote.

A physical examination revealed wide-set eyes (hypertelorism), low-set ears, a high-arched roof of the mouth (palate), a “sunken” chest (pectus excavatum), and overly flexible wrists and lower back joints.

However, she had no history of hearing loss, a symptom that is common to both kyphoscoliotic EDS and Larsen syndrome.

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The doctors prescribed bisoprolol, a beta-blocker used to treat high blood pressure (hypertension) and heart failure. The patient also continued on warfarin, an anticoagulant medication she was taking since her second stroke.

A CT scan of the chest and abdomen was recommended to check for any abnormalities in the aorta, a large artery that carries blood from the heart to the rest of the body.

The findings suggest that people with a diagnosis of Larsen syndrome should get broad genetic testing for other connective tissue diseases, especially if they have a history of blood vessel problems.

“We recommend that patients with a clinical diagnosis of Larsen syndrome consider undergoing broad-based sequencing for multiple hereditary connective tissue disorders,” the researchers wrote.