Bardet-Biedl syndrome

Bardet-Biedl syndrome
ICD-10	Q87.8
ICD-9	759.89
OMIM	209900
DiseasesDB	7286
MeSH	D020788

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Synonyms and keywords: Laurence-Moon-Biedl syndrome; Laurence-Moon-Biedl-Bardet; LMBBS; LMBS;BBS

Overview

The Bardet-Biedl syndrome is a genetic disorder characterized mainly by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, renal dysplasia and renal failure in some cases.

Historical Perspective

The syndrome is named after Georges Bardet and Arthur Biedl. The first known case was reported by Laurence and Moon in 1866 at the Ophthalmic Hospital in South London. Laurence-Moon-Biedl-Bardet syndrome are no longer considered as valid terms in that patients of Laurence and Moon had paraplegia but no polydactyly and obesity which are the key elements of the Bardet-Biedl the syndrome. Laurence-Moon syndrome is usually considered a separate entity. However, some recent research suggests that the two conditions may not be distinct.

Classification

Two forms have been identified:

• Bardet-Biedl syndrome 1 (BBS1) has no linkage to chromosome 16
• Bardet-Biedl syndrome 2 (BBS2) is mapped to markers on chromosome 16.

Pathophysiology

• Even though the detailed biochemical mechanism that leads to BBS is unclear, the syndrome is thought to result largely from a defect in basal body of ciliated cells.
• The gene products encoded by these BBS genes (BBS1 to BBS8, called BBS proteins, are located in the basal body and cilia of the cell.
• Using the round worm C. elegans as a model system, biologists found that BBS proteins are involved in a process called Intraflagellar transport (IFT), a bi-directional transportation activity within the cilia along the long axis of the ciliary shaft that is essential for ciliogenesis and the maintenance of cilia. Recent biochemical analysis of human BBS proteins revealed that BBS proteins are assembled into a multiple protein complex, called "BBSome". BBSome is proposed to be responsible for transporting intracellular vesicles to the base of the cilia and to play an important role in the ciliary function.
• The syndrome is familial and is transmitted as an autosomal recessive trait. chromosome 3 locus appears to be linked to polydactyly of all four limbs, whereas chromosome 15 is associated with early-onset morbid obesity and is mostly confined to the hands, and chromosome 16 represents the "leanest" form.
• Since abnormalities of cilia are known to be related to a wide range of disease symptoms including those commonly seen in BBS patients, it is now widely accepted that mutated BBS genes affect normal cilia functions, which, in turns, causes BBS.
• Genes involved include:
  • BBsome: BBS1, BBS2, BBS4, BBS5, BBS7, TTC8/BBS8, BBS9
  • chaperone: BBS6, BBS10, BBS12
  • Other: ARL6/BBS3, TRIM32/BBS11

Relation to other rare genetic disorders

• Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely-varying, phenotypically-observed disorders.
• BBS is one such syndrome that has now been identified to be caused by defects in the cellular ciliary structure. Thus, BBS is a ciliopathy.
• Other known ciliopathies include primary ciliary dyskinesia, polycystic kidney and liver disease, nephronophthisis, Alstrom syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.

Differentiating Bardet-Biedl syndrome from other Diseases

• Bardet–Biedl syndrome (BBS) and Laurence–Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism.
• They are differentiated by the presence of spasticity and the absence of polydactyly in LMS.
• The overlapping features of these cases suggested that the two disorders represented variable expression of a single condition.
• The findings of neurological manifestations in BBS patients has prompted hypotheses that LMS and BBS are allelic.

Epidemiology and Demographics

• Bardet-Biedl syndrome has a prevalence of 1 in 125,000- 160,000 in Europe, whereas in Arab countries, it is about 1 in 165,000 population.

Diagnosis

Symptoms

• Poor visual acuity,
• Low vision, and/or
• Blindness.
• Loss of, or reduced sense of, smell. (anosmia)
• Polydactyly or
• Syndactyly (webbing of fingers and toes).
• Systemic hypertension from hypertrophy of interventricular septum and left ventricle and dilated cardiomyopathy
• Menstrual irregularities e.g: amenorrhea may occur from low estrogen levels or hypogonadotropism.
• Small testes and genitalia Hypogonadism
• Mental retardation: a wide variety of socialization and social interaction problems have been identified with BBS. Some refer to it as a kind of "mild-Autism." Many children who are later (explicitly and formally) diagnosed with the syndrome have gone through an extended period of time where school and medical professionals have struggled to find a name for the child's problems over several years.
• Growth retardation
• Obesity

Physical Examination

Appearance of the Patient

• The patient appears obese and has a short stature.

Vital Signs

• Blood pressure may be elevated.

Eyes

• Poor visual acuity
• Cataracts may be noted
• End gaze nystagmus
• Fundoscopy:
  • Retinitis pigmentosa
  • Retinal dystrophy

Nose

• Anosmia

Heart

• Precordial examination:
  • Thrill may be present.
• Auscultation:
  • Ejection systolic murmur may be present.
  • Machinery murmur from patent ductus arteriosus may be present.
  • S3 may be heard.

Extremities

• Polydactyly
• Syndactyly

Neurologic

• Mental retardation
• Learning disabilitites

Genitourinary examination

• Hypogonadism
• Cryptorchidism
• Microphallus
• Persistent urogenital sinus, ectopic urethra, hypoplasia of the uterus, ovaries, and fallopian tubes; uterus duplex; and septate vagina, vaginal atresia

Laboratory Findings

• Normocytic normochromic anemia or iron deficiency anemia
• Serum creatinine levels may be raised from chronic renal failure
• Similarly, increase in serum urea and BUN levels may be noted.
• Endocrine abnormalities:
  • Low ADH levels from diabetes insipidus
  • Low FSH and LH levels from hypogonadotropic hypogonadism
  • Low testosterone levels
  • Low estrogen levels

Ultrasound

• Bilateral renal cysts
• Medullary cystic kidney disease may be present in children
• Hepatic fibrosis
• Renal scarring

Echocardiogram

• Interventricular septum hypertrophy may be present.
• Aortic stenosis may be found.
• Tricuspid regurgitation and pulmonic valve may also be involved.

Other tests

• Gene mapping
• Renal biopsy may show interstitial nephritis

June 2006 Conference

• The LMBBS Association Family Meeting for non-medical-professionals was held in Houston, Texas, June 16-17, 2006.

The conference was sponsored by a steering committee of BBS folk and parents/grandparents of children with BBS. It was directed to a lay audience.

A primary purpose of the conference was to present the latest medical research results in an accessible fashion. This included one morning of presentations by leading BBS genetic researchers Dr. Richard Lewis (Baylor Medical Center, Houston) and Dr. Nicholas Katsanis (Johns Hopkins University, Baltimore, Maryland). Several additional doctors presented accessible information on growth and weight management; kidney issues; obesity & Syndrome X; pediatric bariatric surgery; and speech pathology & therapy.

Location: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas.

For additional information about the meeting, click here.

External links

• Laurence Moon Bardet Biedl Society (UK-based)
• LMBBS Association (US-based; newly formed in June at the Houston 2006 BBS conference)
• The Importance of Being Cilia Accessible article at Howard Hughes Medical Institute on the importance and extensive use of cilia and basal bodies in many organ systems of human physiology. Includes multiple specific mentions of BBS.
• BBS and loss of the sense of smell at Johns Hopkins University
• Overview at United States National Library of Medicine
• Foundation Fighting Blindness
• Bardet-Biedl Syndrome Association francaise (France-based; in French language) Syndrome de Bardet-Biedl (BBS)

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