Bardet-Biedl syndrome diagnosis

Diagnosing the rare genetic disorder Bardet-Biedl syndrome (BBS) can be challenging, but early diagnosis enables initiation of a multidisciplinary management plan that may delay or prevent serious complications.

In BBS, genetic mutations impair tiny cellular structures called cilia. Because cilia help cells perform many vital processes, their disruption can lead to a wide range of symptoms, including vision loss, obesity, and learning disabilities.

A BBS diagnosis usually involves identifying these characteristic signs and symptoms, then confirming with BBS genetic testing when available.

Signs and symptoms leading to a diagnosis

Reaching a BBS diagnosis is largely based on recognizing the clinical features of BBS, which vary between individuals and evolve throughout life. A BBS diagnosis can be made at any age.

For diagnostic purposes, doctors often divide the signs of BBS into primary and secondary features. Having four primary features, or three primary plus two secondary features, can support a BBS diagnosis under traditional diagnostic frameworks. Newer recommendations integrate age-specific thresholds and incorporate genetic testing.

Primary features

The primary features of BBS include:

• obesity: carrying excessive weight, often in the middle of the body (truncal obesity)
• retinal dystrophy: vision problems caused by degeneration of the light-sensitive area at the back of the eye (retina)
• polydactyly: extra fingers or toes
• learning disabilities: challenges with learning or cognitive impairment
• renal abnormalities: problems with kidney structure and function
• genital and reproductive abnormalities: low sex hormone production (hypogonadism) and altered structure or function of the reproductive tract

In some cases, polydactyly, kidney enlargement, or genital abnormalities due to hypogonadism in BBS can be identified from an ultrasound before birth.

Obesity and metabolic dysfunction — changes in how the body uses energy — as well as eye and kidney problems, often develop in infancy or early childhood and worsen over time. Learning disabilities and cognitive impairment symptoms vary, but usually emerge during childhood.

Not everyone with BBS experiences every primary disease feature, but a cluster of these signs can raise clinical suspicion of the disease.

Secondary features

Secondary symptoms that may also support a BBS diagnosis include:

• metabolic dysfunction, including diabetes
• hormonal imbalances, including thyroid issues or polycystic ovary syndrome
• other eye issues, including crossed eyes or fogging of the eye’s lens (cataracts)
• fused or short fingers or toes
• dental abnormalities
• loss of smell or smell dysfunction (anosmia or hyposmia)
• developmental delays
• poor coordination or balance
• behavioral problems
• speech delays
• liver disease or gastrointestinal problems
• abnormal heart structure at birth
• abnormalities in facial structure

Many people with BBS have some of these secondary features, but the combination and severity vary widely.

Diagnostic approaches

In addition to collecting a thorough medical history and evaluating symptoms, doctors may also order diagnostic tests to detect key disease features and support a BBS diagnosis. These include:

• genetic testing: to identify BBS-causing genetic mutations
• electroretinogram (ERG): to identify retina problems
• imaging tests: to visualize structural anomalies with internal organs
• blood and urine tests: to assess organ function and metabolic issues

Depending on individual circumstances, neurological tests, developmental assessments, sleep studies, or orthopedic evaluations may also be performed.

Diagnostic criteria for rare diseases such as BBS often evolve over time as researchers learn more and develop new tools. While a BBS diagnosis historically relied solely on symptoms, recent guidelines may allow a diagnosis with fewer characteristic symptoms if genetic testing confirms a disease-causing mutation.

Genetic testing

Genetic testing is increasingly important for diagnosing BBS and can confirm the diagnosis in up to around 80% of cases. It also helps differentiate between BBS and other genetic conditions with overlapping symptoms.

BBS molecular genetic screening usually involves analyzing cells from a blood sample or cheek swab to look for mutations in BBS-associated genes, such as BBS1 and BBS10 mutations, which are among the most common causes of BBS.

A family history of BBS or related symptoms may prompt genetic testing, but many people with BBS don’t have a family history of it. This is because the disease typically follows an autosomal recessive inheritance pattern, meaning an individual must inherit mutated gene copies from both biological parents for BBS to develop. Each parent of a person with BBS is usually a carrier, meaning they have only one mutated gene copy and no symptoms.

ERG

An ERG uses a small electrical sensor to measure retinal activity. Eye specialists perform the test by numbing the eye, placing the sensor, and showing a series of flashing lights to measure retinal cell responses.

ERG findings in people with BBS often show lower than normal activity of light-sensing retinal cells. The test may detect retinal problems before vision issues become obvious.

A comprehensive eye exam, including various tests of visual function, is also usually performed.

Imaging tests

Imaging tests, such as MRIs, CT scans, or ultrasounds, can be used to identify structural abnormalities in various organs.

In some cases, ultrasounds performed before birth can reveal early signs of BBS, including polydactyly, enlarged kidneys, genital abnormalities, or heart defects.

Blood and urine tests

Some signs of BBS, including certain liver and kidney problems, may not cause clear symptoms. Blood and urine tests may help identify such abnormalities, and can also reveal BBS symptoms such as diabetes or hormone imbalances.

Challenges in diagnosis

Diagnosing BBS can be challenging because symptoms vary greatly and overlap considerably with other conditions, particularly ones that also affect cilia (ciliopathy disorders), including:

• Alström syndrome
• Joubert syndrome
• Leber congenital amaurosis
• Meckel syndrome
• McKusick-Kaufman syndrome
• Senior-Løken syndrome

Limited awareness of the rare disease among clinicians might also affect diagnosis. If doctors don’t connect symptoms across body systems, there is a risk they won’t recognize the full multisystemic condition.

Close collaboration between a multidisciplinary team of healthcare professionals can help ensure a prompt and accurate diagnosis.

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