Genetics and Clinical Characteristics of Bardet-Biedl Syndrome

Age Range:Any
Start Date:February 17, 2004
End Date:February 5, 2016

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Bardet-Biedl Syndrome: Phenotype and Metabolic Characteristics

This study will evaluate patients with a rare inherited condition called Bardet-Biedl
syndrome . The purpose of the study is to learn more about the genetics and clinical
characteristics of this disorder. Patients may have the following problems: polydactyly
(extra fingers and toes); retinal dystrophy (changes in the retina that may lead to vision
problems, including blindness); obesity and diabetes (overweight and high blood sugar due to
failure of body organs to respond to insulin); cognitive dysfunction (difficulties with
learning and understanding); hypogenitalism (decreased functioning of the ovaries in women
and the testes in men); kidney anomalies (changes in the structure or function of the
kidneys); heart disease; and hepatic fibrosis (liver disease).

Patients with Bardet-Biedl syndrome may be eligible for this study. First-degree relatives
will also be enrolled for certain tests and procedures. Candidates are screened with a review
of their medical records, laboratory tests, and x-rays.

Patients in this study undergo the following tests and procedures:

- Medical and family history and physical examination, including body measurements.

- Blood tests to evaluation kidney, liver, heart, and hormonal function, and for genetic
studies and other research purposes.

- Dual emission x-ray absorptiometry (DEXA) scan to measure the amount of total body fat.
For this test, the subject lies on a table for scanning with low-dose X-rays.

- Computed tomography (in adults) of the abdomen to measure abdominal fat. CT uses a small
amount of radiation to obtain images of internal body structures.

- Magnetic resonance imaging (in children) of the abdomen to measure abdominal fat. MRI
uses a magnetic field and radio waves to obtain images of internal body structures.

- Oral glucose tolerance tests to measure blood glucose and insulin levels. For this test,
the patient drinks a glucose (sugar) solution. Blood samples are drawn through an IV
catheter before the test begins and at 1, 2, and 3 hours after drinking the solution.

- Complete eye examination to look for retinal changes and to assess vision, and, if
medically needed, an examination of the ear, nose, and throat to check for hearing and
breathing abnormalities.

- Tests of learning ability in patients over 5 years of age. For younger patients, a
parent is asked about the child's development.

- Ultrasound study of the ovaries and uterus in females and of the testes in males.

- Photographs of the face, hands, feet, body, and genitalia, if the patient agrees.

- Meeting with investigators and a genetic counselor for review of test findings when the
studies are completed.

Relatives of patients have a complete medical and family history and physical examination.
Blood is drawn for assessment of kidney, liver, heart, and hormonal function and for genetic
study and other research purposes. Relatives over 5 years of age may have tests of learning
ability and cognition. For younger patients, a parent is asked about the child's development.
Relatives meet with investigators and a genetic counselor for review of test findings when
the studies are completed.

Although the Bardet-Biedl syndrome (BBS: severe obesity, polydactyly, learning disabilities,
retinopathy, renal disease and cardiac malformations) was described more than 80 years ago,
it is only over the past few years that extensive data on the natural history and molecular
pathogenesis of this complex disorder have been reported. We now know that BBS can be caused
by mutations in at least 12, genes and, although it is typically inherited in an autosomal
recessive pattern, BBS may occasionally exhibit more complex inheritance. In this study, we
are defining the physical (body mass, percent and distribution of body fat) and metabolic
(hyperglycemia, hyperinsulinemia, serum levels of lipids and adipokines) characteristics of
glucose and fat metabolism in a cohort of adult and pediatric patients with BBS. We are also
characterizing the hypogenitalism in BBS, and attempting to determine its relationship, if
any, to the incidence of obesity in BBS. In addition, we are studying the retinal dystrophy,
the renal dysfunction, and the nature of the reported mental retardation/learning disability
that is found in many patients. We plan to correlate the phenotypic manifestations in our
subjects with the results of our mutation analysis studies. Our objective is to learn more
about the genetic alterations that may underlie the obesity and associated organ dysfunction
that characterizes BBS.


We are using the previously published clinical diagnostic criteria for BBS(21) to determine
study eligibility of probands. As outlined in that report, we are including patients who
present with four of the five primary features or three primary features and two secondary
features. Parents are also enrolled for genetic studies. We are not enrolling unaffected
siblings or recruiting control subjects, instead, results of testing are being compared to
previously published data obtained from appropriate non-BBS control subjects.

The initial determination of eligibility is made by review of prior clinical records. Some
patients are not characterized in sufficient detail to know if the person meets the
clinical criteria, yet we may suspect the diagnosis. In those cases, the subjects are
brought to NIH and undergo clinically appropriate testing to make the diagnosis. If that
clinical testing does not confirm the diagnosis, the patient or parents are given
appropriate clinical counseling and returned to the care of their personal physician. If
features later develop that allow the diagnosis to be made, they may re-enroll and undergo
further evaluation.

Our study population includes patients of all ages and ethnic groups, and both genders. The
inclusion of children is essential to a research study that is correlating genotype with
phenotype, and is attempting an early identification of metabolic abnormalities that may be
best treated at an early age. Many of the age-dependent manifestations of BBS develop
during childhood and the average age of diagnosis is 9.2 years. Pregnant women and children
under the age of 5 yr do not undergo invasive research procedures (i.e. phlebotomy) or
procedures involving ionizing radiation (i.e. X-rays or DEXA scans) unless that procedure
would be performed as part of standard medical care.

Because cognitive dysfunction is known to be a component of BBS, some patients with
impaired cognition and understanding may be evaluated under this protocol. If the
investigators believe that an adult patient may not be competent to give informed consent
to participate, or does not understand the consent document and the procedures of the
study, that patient may be excluded from participation. We may request that the patient and
accompanying caregiver also be interviewed by an independent ethics panel to confirm that
he or she is competent to give consent and to participate if the team feels this would be


Neither healthy volunteers unrelated to an affected patient nor lab personnel will be

We will make efforts to obtain consent from all parents/guardians of minor subjects (i.e.
we would not allow a single parent to consent a child when both parents have parental
rights). If a single parent or guardian has sole custody/legal responsibility for a child
(e.g., a divorce with full custody to one parent or one parent is deceased), we will accept
consent from one parent.

Both mothers and fathers of children with BBS (who are also typically enrolled in our
protocol, as described above) are eligible to participate in the interview portion of the
study. We hypothesize that mothers and fathers will, as groups, have slightly different
experiences with coping with courtesy stigma, although a couple may have convergent
beliefs, coping mechanisms, and experiences. As such, we predict that we will initially
conduct interviews with both parents of the same proband (assuming both parents are
interested in participating), although we may target either mothers or fathers only
following interim analysis of the interview transcripts.
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, MD
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