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a Department of
Medical and Molecular Genetics, 8th Floor Guy's Tower, Guy's
Hospital, London SE1 9RT, UK, b Genetics Department, Cerrahpasa Medical
School, Istanbul, Turkey, c Nephrourology Unit, Institute of Child Health,
University College London Medical School, London WC1N 1EH, UK, d Laurence-Moon-Bardet-Biedl
Society, Spring Grove, Loudhams Wood Lane, Chalfont St Giles, Bucks HP8
4AR, UK
Correspondence to: Dr Beales.
Received 17 July 1998;
Revised version accepted for publication 17 November 1998
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Abstract |
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 Abstract
 Introduction
Methods
Results
Discussion
Summary
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Bardet-Biedl syndrome (BBS) is an autosomal recessive condition
characterised by rod-cone dystrophy, postaxial polydactyly, central
obesity, mental retardation, hypogonadism, and renal dysfunction. BBS
expression varies both within and between families and diagnosis is
often difficult. We sought to define the condition more clearly by
studying 109 BBS patients and their families, the largest population surveyed to date. The average age at diagnosis was 9 years, which is
late for such a debilitating condition, but the slow development of the
clinical features of BBS probably accounts for this. Postaxial polydactyly had been present in 69% of patients at birth, but obesity
had only begun to develop at around 2-3 years, and retinal degeneration
had not become apparent until a mean age of 8.5 years. Our study
identified some novel clinical features, including neurological, speech, and language deficits, behavioural traits, facial dysmorphism, and dental anomalies. In the light of these features we propose a
revision of the diagnostic criteria, which may facilitate earlier diagnosis of this disorder. We present evidence for an overlapping phenotype with the Laurence-Moon syndrome and propose a unifying, descriptive label be adopted (polydactyly-obesity-kidney-eye syndrome).
We report an increased prevalence of renal malformations and
renal cell carcinoma in the unaffected relatives of BBS patients and
suggest that these may be a consequence of heterozygosity for BBS
genes. Our findings have important implications for the care of BBS
patients and their unaffected relatives.
(J Med Genet 1999;36:437-446)
Keywords:
Bardet-Biedl syndrome;
diagnosis;
renal
malformation;
heterozygotes
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Abstract
Introduction
Methods
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Bardet-Biedl syndrome (BBS) (MIM 209900) is an autosomal recessive condition with a wide spectrum of clinical features. The principal manifestations are rod-cone dystrophy (sometimes called atypical retinitis pigmentosa), postaxial polydactyly, central obesity, mental retardation, hypogonadism, and renal dysfunction.1 2 Other features, not always present, include hepatic fibrosis, diabetes mellitus, reproductive abnormalities, endocrinological disturbances, short stature, developmental delay, and speech deficits. BBS is distinguished from the much rarer Laurence-Moon syndrome, in which retinal pigmentary degeneration, mental retardation, and hypogonadism occur in conjunction with progressive spastic paraparesis and distal muscle weakness, but without polydactyly.3
BBS is genetically heterogeneous, with four loci mapped to date. These are BBS1 (11q13),4 BBS2 (16q22),5 BBS3 (3p13),6 and BBS4 (15q21).7 We have recently shown that the BBS1 locus is involved in ~45% of affected white families.8 The BBS4 locus appears to be the next most common,9 but there are several families of Middle Eastern and Asian origin which do not show linkage to any known locus. Genotype-phenotype correlations between the various loci do not show obvious differences, with the possible exception of minor effects on growth.8
We had noted certain, previously unreported clinical complications in a few BBS patients and were interested in establishing their prevalence. We undertook a survey of 109 BBS patients resident in the UK and their families, the largest such group reported to date. We present the results of this survey and discuss the findings and their implications for improved diagnosis and management of BBS.
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QUESTIONNAIRE
A seven page questionnaire, requesting details of the patient's
birth and delivery, age at diagnosis, and diagnosing clinician was
used. Information was sought regarding height, weight, presence or
absence of limb abnormalities (polydactyly or brachydactyly), presence
of rod/cone dystrophy (atypical retinitis pigmentosa) or other eye
conditions, renal abnormalities, developmental delay, and involvement
of other organs. We also enquired whether any other, apparently
unaffected, family members exhibited any manifestations associated with
BBS. This questionnaire was sent out together with one from the
Laurence-Moon-Bardet-Biedl Society of Great Britain (LMBBS), designed
to obtain practical information regarding the level of education
received and the social interests of patients and their families,
together with details of financial support, involvement with support
groups, use of special aids or clothing, and careers advice. The
information obtained by the LMBBS in this way has been of great
assistance to newly diagnosed patients and their families seeking
advice and support from the Society.
PATIENTS
Patients were identified either through the LMBBS or through the
Guy's Hospital Bardet-Biedl Register. One hundred and twenty five
prepaid reply questionnaires were sent out directly to patients and
their relatives and 112 replies (90%) were received. Patients were
offered telephone help in completing the form if they had a specific
query or if they were unable to enlist the help of a sighted person. In
all cases where there were ambiguities or points of interest on the
completed form, the patient (or a relevant relative) was contacted
directly; 44 cases were visited at home or seen in the Genetics Clinic.
Using the diagnostic criteria proposed by Schachat and Maumenee,10 which require the presence of four out of five principal features (retinal degeneration, mental retardation, obesity, polydactyly, hypogonadism), the BBS status of the respondent (affected versus unaffected) was determined. Only those respondents clearly satisfying these diagnostic criteria (109 of the 112 who replied, or 97%) were included in the analysis.
STATISTICS
The mean, standard deviation, and range were calculated where
appropriate. Student's t test was used for
comparison of means and a significance level of 5% (p=0.05) set.
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PATIENTS
One hundred and nine BBS patients, 47 females and 62 males, met
the diagnostic criteria, a female:male ratio of 1:1.3; 95% were of
northern European (white) origin, 5% originated from the Indian
subcontinent, and 8% were the offspring of consanguineous unions.
Table 1 summarises the principal findings in this population. Table 2
illustrates the distribution of ages at the time of survey. The paucity
of patients beyond 40 years of age may reflect underdiagnosis in past
years or an increased mortality rate.
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The mean birth weight was 3370 g (range 2050-5400 g). Most pregnancies were uncomplicated, and there was no significant increase in pre- or postmaturity.
AGE AT DIAGNOSIS
The average age at diagnosis was 9 years, lower than that found in
our pilot study, where it averaged 15 years8; however, the
average age at which parents first noted abnormalities in their
children was 3 years (n=77) giving a mean interval of 6 years between
first clinical signs and diagnosis.
MAJOR CRITERIA
Visual disorders
Rod-cone dystrophy (atypical retinitis pigmentosa) had been
diagnosed by an ophthalmologist in 102 (93%) patients, while the remaining seven patients were all aged less than 8 years. Parents reported that they first noted night blindness in their children at a
mean age of 8.5 years (range 1-34 years). The mean age at which
patients were "registered" blind was 15.5 years (range 8-43 years).
The onset in BBS patients is therefore earlier than in isolated typical
retinitis pigmentosa, and progression is rapid, with a mean of seven
years from diagnosis to blindness. Other ocular abnormalities noted
included astigmatism, strabismus, cataracts, colour blindness, macular
oedema and degeneration, and optic atrophy.
Limb defects
Seventy five subjects (69%) were born with at least one accessory
digit; in the majority of cases this was fully formed and bony and
situated on the lateral border of the hand or foot. Postaxial polydactyly was present in all four limbs in 23 patients (21%). In
nine patients (8%) the extra digit was only present on the hands and
in 23 (21%) only on the feet. The 34 patients who did not exhibit
polydactyly fulfilled other diagnostic criteria; 16 of these had
affected sibs with polydactyly.
Height and weight
The mean height in affected males was 1.73 m (SD 0.1) (n=30, range
1.57-1.90 m). This differed significantly from the general population
mean of 1.76 m (p<0.001). The postpubertal mean height in affected
females was 1.62 m (SD 0.13) (n=26, range 1.27-1.91 m); however, this
did not differ significantly from the general population mean of 1.63 m
(p>0.05).
height2). Fifty two percent had a BMI >30
kg/m2 (defined as obese) and 16% >40 kg/m2
(defined as morbidly obese). The mean BMI in affected males was 31.5 kg/m2 (SD 5.7) (n=25, median 30.6 kg/m2, range
21.5-46.4 kg/m2), while in affected females it was 36.6 kg/m2 (SD 8.1) (n=23, median 34.8 kg/m2, range
24.2-52.3 kg/m2). We examined 32 of these patients, all of
whom had a truncal and rhizomelic distribution of adipose tissue.
Education
Learning difficulties were reported for 68 (62%) BBS patients.
Fifty four (50%) attended a special school because of learning difficulties, visual impairment, or both. Before entering a special school, the majority of pupils were placed in mainstream
establishments, where only 35 (32%) were receiving any additional
classroom help.
Renal tract abnormalities
Only 26 patients (24%) (of whom 11 (42%) were under 16 years at
time of diagnosis) were definitely known to have a renal defect, but
this may be explained by the fact that only 57 of the patients surveyed
(52%) had undergone any radiological investigation of the renal tract
(35% had an ultrasound scan, 40% had isotope renography, and 14% an
intravenous pyelogram). Of the 57 patients who had been investigated,
26 (46%) were found to have renal abnormalities. Structural
abnormalities included renal parenchymal cysts/communicating calyceal
cysts (6/57, 10%), calyceal clubbing and blunting (6/57, 10%), fetal
lobulation (7/26, 12%), scarring (7/57, 12%), dysplastic kidneys
(3/57, 5%), unilateral agenesis (2/57, 4%), renal calculi (1/57,
2%), vesicoureteric reflux with pyelonephritis (5/57, 9%), bladder
obstruction (2/57, 4%), hydronephrosis (without bladder involvement)
(2/57, 4%), horseshoe kidney (1/57, 2%), and ectopic kidney (1/57,
2%). Six patients (5%) (four of them children, 66%) had chronic
renal failure (based on raised plasma urea and creatinine levels) and
four (4%) (two of them children) received a kidney transplant.
Detrusor/bladder instability, requiring either continuous or
intermittent self-catherisation to drain residual bladder urine, was
reported in 11 patients (10%).
OTHER FEATURES
Developmental delay
Fifty five patients (50%) were developmentally delayed and late
in reaching milestones. More specifically, 46 (42%) showed a delay in
walking of up to one year and speech was delayed by up to two years in
47%. Thirty four patients (31%), all males, were slow in passing
through puberty.
Neurological and motor defects
Neurological examination of four patients from two families showed
moderate hypotonia, with ligamentous laxity, genu valgum, and joint
pain. Two further patients had a slowly progressive spastic
paraparesis, but polydactyly was present, thereby excluding the
diagnosis of Laurence-Moon syndrome.
Behaviour
One third of parents/relatives commented on difficult behaviour in
young BBS patients, with certain traits continuing into adulthood.
These included emotional immaturity, frequent volatile outbursts, and
poor reasoning. We have observed inappropriate affect in approximately
half the patients and some appear disinhibited. Two patients (2%) in
this survey displayed obsessive or obsessive-compulsive behaviour, with
frequent hand washing or panic attacks, while five patients (5%) had a
history of depression and two (2%) had been diagnosed with
schizophrenia. We have noted some BBS children (no figures available)
had a tendency to avoid direct gaze and many had difficulty in
appreciating abstract thought. All BBS children preferred fixed
routines and disliked any deviation from them.
Speech deficit
Speech delay/deficit, requiring speech
therapy, was reported in 59 patients (54%). From survey responses
and from a specialist speech and
language assessment of four BBS children, vocal and speech defects are
the main components of this deficit. The voice is high pitched, of
breathy quality, and shows poor volume control, while oral and palatal
movements appear uncoordinated. Speech is hypernasal and slow, with
multiple misarticulations, substitutions (particularly of the first
consonant of a word), and omissions of the last syllable of a word.
Language and comprehension difficulties are also apparent; these BBS
children were unable to repeat sentences accurately and had difficulty
interpreting language subtleties correctly.
Hearing
Hearing loss was reported in 23 patients (21%). In 20 cases this
was conductive, and associated with chronic otitis media ("glue
ear"), but had largely resolved by puberty. However, three patients
had unexplained sensorineural hearing loss.
Dental anomalies
Dental problems appear to be common; 29 patients (27%) reported
malocclusion, or crowding of the teeth, or had required dental extractions. We observed enamel hypoplasia with yellow discoloration, crowding of teeth, and mild micrognathia. Forty out of 45 patients examined by us (89%) had a high arched palate.
Asthma
We have previously noted childhood onset asthma in a high
proportion of BBS patients,8 and in this survey it was
reported in 28 patients (25%). Asthma was diagnosed if bronchodilators were used regularly, with benefit. Although the asthma was nearly always of early onset, there was no clear evidence for atopy when patients/respondents were questioned further.
Facial features
Photographs of 70% of the participants in the survey were
received. There was considerable, inconsistent, dysmorphism, but a
subgroup of patients showed facial similarities comprising deep set
eyes, hypertelorism with downward slanting palpebral fissures, a flat
nasal bridge with anteverted nares and prominent nasolabial folds, a
long philtrum, and a thin upper lip (fig 1). Many BBS patients have a
prominent forehead, while adult males show early balding, giving them
the appearance of being much older than their chronological age (fig
2).
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Hypogonadism
All adults examined showed secondary sexual characteristics. In
males, hypogonadism was almost universal (being present in 60 of 62 respondents), while maldescended testes were reported by eight patients
(13%). The penis was small and often buried in adipose tissue. In
females, the mean age of menarche was 13.8 years. Following the onset
of menstruation, irregular cycles were reported for the majority of
females. Three affected women (2.7%) have given birth to normal,
healthy children.
Heart defects
Congenital heart defects were recorded in eight patients (7%).
These included, in order of frequency, aortic stenosis (3), patent
ductus arteriosus (3), and unspecified cardiomyopathy (2).
Diabetes mellitus
Seven patients (6%) had non-insulin dependent diabetes (NIDDM).
Since only a minority of patients surveyed had undergone a fasting
glucose measurement or glucose tolerance test, many BBS patients may
have undetected NIDDM or impaired glucose tolerance.
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RELATIVES
Obesity
It has been suggested previously that obesity is an indication of
obligate carrier status in BBS.11 12 We found no excess of obesity among carrier parents (fig 3).
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Renal anomalies
We found that five of 123 sibs (4.1%) of the 109 BBS patients
surveyed had one or more congenital renal malformations. Two (1.6%)
had unilateral renal agenesis and one also had a complex malformation
of the solitary urinary tract. In addition, three (2.4%) showed
vesicoureteric reflux. One parent of a BBS patient had unilateral renal
agenesis, with a solitary kidney in end stage renal failure, and a
second parent (a 37 year old male) had a duplicated renal pelvis and
ureter. This man, a second male aged 52 years, and a female aged 40 years, all white parents of affected subjects, had renal cell
adenocarcinomas of the same clear cell histopathological type.
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Introduction
Methods
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A Medline search showed that since 1966, 325 articles specifically
about the Laurence-Moon and Bardet-Biedl syndromes have been published.
Before this, some 400 cases had been published. These syndromes have
been reviewed by Green et al,1
Schachat and Maumenee,10 and Klein and
Ammann.13 Bell14 reviewed a large population
based on 273 published pedigrees. We present the largest and most
comprehensive survey of living patients with Bardet-Biedl syndrome. A
comparison of the cardinal features in each of these reviews is
presented in table 4.
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SEX RATIO
In this study, the male to female ratio was 1.3:1. A similar ratio
was found in other studies,13-15 except for that of Green et al1 who found a small excess
of females. Of the 462 BBS subjects detailed in these studies (table
4), 264 were male and 198 female giving a male excess of 1.3. Although
all these studies point to an autosomal recessive mode of inheritance
there does appear to be an imbalance in the sex ratio which is not
entirely attributable to ascertainment bias.
CONSANGUINITY
The consanguinity rate in our study is low (8%) compared with
that in other studies,1 13 14 but not surprising given the social structure of the UK population. However, it may also be the
result, in part, of a reluctance to admit to, or a lack of awareness
of, intrafamily marriage. Bell14 (39%), Klein and Ammann13 (48%), and Green et
al1 (35%) recorded much higher rates. The latter
two studies, from Switzerland and Newfoundland, were confined to
isolated populations in which consanguinity was more common and the
founder effect plays a major role.
DIAGNOSIS
There is clearly a major delay in diagnosing BBS in young
patients. This is probably because of both a lack of medical awareness of the condition and the difficulty of making a firm diagnosis owing to
the slow emergence of features such as retinitis pigmentosa and renal dysfunction.
EYE DISEASE
The presence of rod-cone dystrophy is the clinical finding most
likely to lead to a successful diagnosis. Previous reviews (table 4)
all cite a high frequency of retinal dystrophy, thus weighting this
sign disproportionately and many cases of BBS remain undiagnosed in its
absence, a diagnostic problem which will only be resolved by the
development of a biochemical or a direct molecular test.
When compared with hereditary retinitis pigmentosa, the visual impairment in BBS is consistently early in onset; almost all patients (98%) have suffered visual loss before the third decade. Klein and Ammann13 also observed this age relationship; 73% of their population were totally blind by 20 years and 86% by 30 years, while all cases had a visual deficit by this age. We have previously suggested a genetic locus effect on the rate of progression of retinal dystrophy.8
Up to 5 years of age, electroretinograms (ERG) and visually evoked responses (VER) are often normal, but 90% of children will have an attenuated ERG response by 10 years (D Calver, personal communication). Many children develop myopia or strabismus well before retinal changes are apparent, and these should alert the clinician to the possible diagnosis, in conjunction with the other cardinal signs.
LIMB DEFECTS
Polydactyly was observed in 69% of BBS patients and is a useful
diagnostic sign, but it may not be present in every case, even within
the same family. We observed polydactylous toes three times as often as
polydactylous fingers, as did Green et
al1 and Klein and Ammann.13 Riise
et al16 found polydactyly to be
present at birth in 20 of 44 BBS patients (45%). Interestingly, we
have observed monozygous male twins with BBS, where one twin was born
with postaxial polydactyly of three limbs, while the other had no
polydactyly. This suggests that complex influences operate on limb
differentiation, despite an identical genotype and a similar
intrauterine environment. The presence of brachydactyly is largely a
subjective assessment, and its true frequency can only be determined by
anthropometric measurements.17
OBESITY
The lower incidence of obesity in our study compared with other
reviews (table 4) can probably be explained by the use of different
measurement parameters. We used the WHO classification based on body
mass index (BMI), where the height is incorporated into the
calculation. According to this formula, the BMI of a normal female on
the 50th centile for height will be 26 kg/m2 at the 91st
centile and 29 kg/m2at the 98th centile. Females above the
91st centile are classed as overweight and above the 98th as obese.
Klein and Ammann13 based their obesity estimates on weight
alone, and plotted them on age related normal population charts, while
classifying any patient over the 50th centile as obese. Green
et al1 used height adjusted
weight charts in a study of 25 BBS subjects, and defined all those
above the 90th centile as overweight and all above the 95th as grossly obese.
HEIGHT
Although the mean height of subjects did not differ significantly
from the population mean, the range was very wide. We have previously
suggested a gene locus effect on height which might account for the
variation seen in this cohort.8
EDUCATION
Of those subjects with learning difficulties (62%), half received
educational support at a "special school". The severity of learning
disability is usually mild to moderate, with a minority having severe
mental retardation.8 Several subjects went on to further
education and three completed university degrees. This is similar to
findings by Green et al,1 where
formal IQ assessments were made, and Riise et
al.16 Unusually, several of the respondents reported a talent for mathematics and mental arithmetic while many are
reported to have very poor short term memory but excellent long term
recall particularly for minutiae.
RENAL AND URINARY TRACT ABNORMALITIES
Renal failure is the major cause of morbidity and early mortality
in BBS subjects.18 A wide range of renal abnormalities has
been described, with one study2 showing 100% of subjects affected. These were the same patients as described by Green
et al,1 and the high frequency
may perhaps represent a sampling bias, since they were ascertained
through a nephrology department. Characteristic cystic tubular disease,
lower urinary tract malformations, chronic glomerulonephritis, and
defects of tubular concentrating ability are among the commonest causes
of renal impairment.18 Our study highlights the fact that
renal abnormalities are diagnosed in relatively few cases (46%),
partly because of the limited investigations performed. In our survey,
18% of subjects investigated had an ultrasound scan (which will not
detect the commonest calyceal malformations). We recommend a
combination of renal ultrasound scanning and intravenous urography.
Despite the presence of underlying renal malformations, only a small
number of BBS patients were symptomatic at the time of the survey. It
would be of interest to follow a cohort with structural changes present
at birth.
In a smaller study (n=41), we found that 33% of subjects had polyuria and polydipsia in the absence of diabetes mellitus.8 This probably represents an underlying nephrogenic diabetes insipidus, which has been well documented.2 This is a useful diagnostic question, particularly when directed at parents. Ten percent of BBS subjects reported problems of incomplete bladder emptying and overflow incontinence, probably owing to bladder instability. This might, however, be neurogenic in origin, secondary to a spinal canal lesion, as these subjects all exhibit gait abnormalities, with varying degrees of lower limb spasticity.19 Further spinal cord imaging studies in this subgroup are warranted. Conversely, bladder anomalies may reflect a more generalised primary defect in the urinary tract.
NEUROLOGICAL ABNORMALITIES
The overlap between Bardet-Biedl syndrome and Laurence-Moon
syndrome has been described before.19-22 We believe that
the two clinical entities may represent allelic forms of the same
condition and that perhaps the older term, Laurence-Moon-Bardet-Biedl
syndrome should be reinstated. Moreover, perhaps a more descriptive
term such as the polydactyly-obesity-kidney-eye syndrome could be adopted.
Ataxia
Ataxia has been documented rarely in Bardet-Biedl syndrome but is
associated with the Laurence-Moon syndrome along with long tract
signs.3 23 Many subjects (and their relatives) complain of clumsiness, incoordination, and poor balance and cite the latter as
their main mobility problem, far outweighing the inconveniences of
blindness. The lower limbs appear to be more severely affected than the
upper limbs, which may in part be because of the weight on the lower
limbs exaggerating the signs or a structural deformation of the
spinocerebellar tracts. Ten patients who have had CT/MRI of the
brain failed to show an isolated structural abnormality of the
cerebellum which might account for these findings.
BEHAVIOUR
Parents often report behavioural difficulties in childhood with
labile emotional outbursts, frustration, and inflexibility, traits
which have been documented twice.1 13 Many prefer a fixed
routine and tolerate poorly any deviation from it. A few show
compulsive/obsessive tendencies. Some children are hyperactive with
attention deficit, while others are docile with unwavering attention
toward subjects that interest them. Adult patients are often
disinhibited and appear unable to recognise social cues.
SPEECH DEFICIT
We have previously reported a high frequency of speech deficit
which has been poorly characterised to date.8 The quality of the voice is breathy and often high pitched and nasal. Substitution of the first consonant of a word often leads to incomprehension. The
last consonant may also be dropped resulting in incomplete word
formation. Language use is occasionally a problem and vocabulary may be
limited by learning difficulties. While the pattern of speech, voice,
and language disorder is not specific to BBS, it does appear to be
consistent and this may be helpful diagnostically, especially in children.
DENTAL ANOMALIES
Dental anomalies in BBS were first documented in
1960.24 More recently they have been described by Kobrin
et al,25 Lofterod et al,26 and Borgstrom
et al.27 The most significant
findings were hypodontia, small teeth, enamel hypoplasia, short roots, and a thickened mandibular body. Our finding of high arched palate has
not been noted to be a significant feature of BBS before, but is a
useful minor sign.
ASTHMA
We have reported asthma previously in 24% of subjects, all of
whom were linked to the BBS1 locus (chromosome 11q13).8
This is confirmed in the current study (25%) representing a three fold increase on the national prevalence rates (7%), but is unlikely to be
the result of a direct association with the 
subunit of the high
affinity IgE receptor gene mapping nearby, as it is some 6-8 cM
away.28 The finding may be because of coinheritance of the
two genes, a further asthma locus, or perhaps BBS1 itself plays a role
in bronchial hypersensitivity.
FERTILITY
This is more difficult to determine in females than males, and
thorough radiological and endocrinological investigations may be
indicated. In addition, several genitourinary malformations have been
reported.29 30 Males are usually infertile owing to
primary gonadal failure; however, we know two males who are fertile and
have children. Endocrinological assessments and semen analysis may be helpful.
DIABETES MELLITUS
Non-insulin dependent diabetes mellitus has been described in 45%
of patients with BBS,1 but more particularly in Alstrom syndrome (recently mapped to 2p12) in which there is cone-rod dystrophy, obesity, sensorineural deafness, acanthosis nigricans, and
diabetes but no polydactyly.31 This should be considered as a differential diagnosis. NIDDM in BBS is a consequence of severe
insulin resistance (unpublished data).
MISCELLANEOUS FINDINGS (TABLE 3)
Ten patients, of whom eight were female, had multiple widespread
pigmented naevi. Hirschsprung's aganglionosis has been reported elsewhere.32-34 Several patients had marked joint laxity
resulting in multiple dislocations of the shoulder or patella. Two
families each had two affected sibs with joint laxity and early onset, lower limb osteoarthritis.
RELATIVES
Obesity
The frequency of obese and severely obese parents did not differ
significantly from that of the general population in contrast with
Croft et al,12 who found an
excess of severely overweight fathers (BMI >31 kg/m2) in
their study of 33 patients. They also went on to propose that 2.9% of
severely overweight white males might carry a BBS gene.
Renal anomalies
Renal cell carcinoma is an uncommon tumour especially in the age
group we have documented (37-52 years). The cumulative risk of
developing RCC under 55 years in the general population is 1 in
1041.35 Three cases out of 180 (1 in 60) represents a 17 fold increased risk. Each case was a parent (by definition an obligate
carrier of a BBS gene) with the same histopathological picture and one
had an accompanying ureteral duplication. Heterozygous carrier effects
have been suggested for autosomal recessive conditions such as ataxia
telangiectasia where there appears to be a 3-4 fold risk of breast
cancer in gene carriers.36 Croft and Swift11 have suggested that carriers of a Bardet-Biedl gene have an increased incidence of obesity, hypertension, and renal disease. The high incidence of renal dysgenesis/agenesis is intriguing. The population incidence of unilateral renal agenesis is 0.1%,37 so our
finding of 1.6% represents a 16 fold increase; however, the aetiology and incidence of these anomalies are complex and only the emergence of
further cases, or identification of gene mutations, will unravel the
processes. On the basis of these findings we suggest obligate gene
carriers and sibs could be screened for kidney tumours and an
ultrasound scan or intravenous urography could be offered to possible
carriers to exclude congenital renal tract abnormalities. These renal
anomalies and cancer are the subject of further genetic analysis.
NEW DIAGNOSTIC CRITERIA
A new scheme (table 5) for diagnosing BBS is proposed, which
should be helpful particularly in children. We are mindful of the
difficulty in differentiating between Laurence-Moon syndrome and
Bardet-Biedl syndrome using these criteria, but we feel it is important
to identify the many overlapping cases highlighted by this study.
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CLINICAL SURVEILLANCE
We recommend the scheme in table 6 for initial investigation and
follow up of BBS patients. In addition, partners and sibs could be
screened for renal malformations and carcinoma.
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Summary |
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Abstract
Introduction
Methods
Results
Discussion
Summary
References
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The results of this comprehensive study show a wide range of previously undescribed features. Not all patients are obese at the time of measurement (72% obese) and polydactyly is present in 69%, so its absence should not exclude diagnosis. In contrast, rod-cone dystrophy is a universal finding among all adults diagnosed with BBS, but symptoms do not begin until about 8 years and signs are often not visible until the early teens. The diagnosis remains difficult in young patients. There are several other ocular associations such as myopia, strabismus, and cataracts which may help to suggest the diagnosis.
Neurodevelopmental delay is common and features such as hypotonia, dyspraxia, poor balance, and ataxic gait are not infrequent. Speech and behaviour is characteristic but more work is required to define their pattern accurately. Learning difficulties, while present in the majority, are in general mild to moderate.
The characteristic renal tract abnormalities in BBS are helpful diagnostically, but are not very frequent.
Dental anomalies, reported in a third of respondents, such as crowding of the teeth, hypodontia, and high arched palate should also be sought.
The presence of a typical facies with "moon face", frontal premature balding, enophthalmos, and downward slanting palpebral fissures is not necessarily helpful in all cases but when present is characteristic.
Finally, the relatively high incidence of renal developmental anomalies and renal cell carcinoma in relatives of BBS patients may be manifestations of the heterozygous state. Furthermore, these genes may be involved in renal development and disruption of one allele may be enough to increase susceptibility to renal dysgenesis or predispose to malignant transformation or both.
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Acknowledgments |
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We are grateful to Ms Elizabeth Manners for help with the manuscript, Dr Sheena Reilly for advice on speech and language, Dr Lucinda Carr and Ms Alison Wisbeach for developmental assessments, and the LMBBS Society for their help and encouragement. PLB is a Medical Research Council Clinical Training Fellow. ASW is supported by a grant from Action Research (S/P/8178). Finally, we thank the patients and relatives who participated in this study.
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Top
Abstract
Introduction
Methods
Results
Discussion
Summary
References
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