Laurence-Moon-Bardet-Biedl Syndrome Medical Booklet
Introduction
This booklet is aimed primarily at medical and health-care professionals involved in
the care of LMBBS patients, but is also for those with the syndrome, their parents
and carers who wish to know more about the syndrome and the implications for
those affected.
HISTORY
The earliest formal description of LMBBS was provided in a paper published by John
Zachariah Laurence (1829-1870), an eminent 19th century ophthalmic surgeon
based in London, and his then House-surgeon, Robert Moon (1845-1914), whose
own father, William, invented one of the first raised alphabets for the blind. In this
report they describe four out of eight siblings with retinitis pigmentosa (RP), short
stature for their age and hypogenitalism in the males.
There was no further mention of the syndrome until 1920, when George Bardet
submitted his MD thesis on hypothalamic obesity. Bardet was at that time working
with Louis Pasteur in Paris and recognised that a number of his cases had unusual
features, particular hexadactyly, retinitis pigmentosa and obesity.
In 1922 Artur Biedl, an Austrian professor of pathology and endocrinology published
a short independent account of 2 siblings with congenital deformations (retinitis
pigmentosa and polydactyly) and an ‘intellectual torpidity”.
Neither Bardet nor Biedl made any reference to Laurence and Moon’s paper
previously published in Ophthalmic Review, a publication which by then bad ceased
printing.
It was in 1925, when Solis-Cohen and Weiss ‘rediscovered’ the paper by Laurence
and Moon and went on to consider these conditions to be the same. They called it
the Laurence-Moon-Bardet-Biedl Syndrome (LMBBS). More recently, however, this
condition has been split once again on the basis of clinical features into the
Laurence-Moon and Bardet-Biedl Syndromes. Laurence-Moon Syndrome (LMS) is
characterised by retinitis pigmentosa (more accurately termed rod-cone dystrophy see later), mental retardation, hypogenitalism and spastic paraparesis. Bardet-Biedi
Syndrome (BBS) has as the main features RP (rod-cone dystrophy), obesity,
postaxial polydactyly, learning disabilities and hypogenitalism (males). This latter
subgroup represents by far the majority of published cases and is now the preferred
term amongst the medical and scientific community. As there are many cases of
overlap between them, we shall, for the purposes of this publication, make no
distinction and therefore refer to LMBBS throughout.
The hereditary nature of LMBBS was alluded to by Laurence and Moon but no
estimates of the prevalence of this disorder have been made until recently. In certain
regions, it is relatively common, such as amongst the Bedouins of Kuwait, where
LMBBS is present in 1 in 13,500 of the population. The reason for this lies with the
high frequency of interfamily marriages (consanguinity). Another common pocket is
Newfoundland where the prevalence is in the order of 1 in 17,500. As well as
consanguinity this may be the result of the founder effect’ of the original settlers who,
incidentally, can be traced back to a handful of families emigrating from the West
Country of England in the early 1800s. European studies from Switzerland and the
Netherlands put the prevalence nearer I in 160,000. Recently, a British study has
estimated 1 in 125,000 may have LMBBS. Whatever the true value is, there is
undoubtedly a major problem with under-diagnosis.
CLINICAL FEATURES AND PRESENTATION
Eye Signs
Although retinitis pigmentosa is commonly cited in LMBBS, the preferred term rodcone dystrophy should be used as it more accurately describes the pathological
process and, in early disease, there may be no pigmentary changes seen despite
significant visual disturbance. A recent study found rod-cone dystrophy in 96% and
also found the mean age at which night-blindness was first noted to be 9 years. The
mean age at registration of blindness was 15 years.
Other signs which may be present include; nystagmus (horizontal), myopia, optic
atrophy, macular dystrophy, strabismus, glaucoma and cataracts. Careful
assessment of acuity and visual fields should be made in all new or suspected cases
of LMBBS. Electroretinograms (ERG) with visually evoked responses (VER) should
be sought in aII suspected cases without clear fundoscopic evidence of rod-cone
dystrophy. ERG and VER abnormalities will be detectable in 90% of affected children
by the age of 10 years.
Polydactyly and Brachydactyly
The presence of extra digits is by no means universal (66%). The most common
form is post-axial hexadactyly ranging from a single skin tag to a fully formed digit on
all four limbs. The position of the extra digit tends to be placed on the lateral aspect
of the hand or foot.
Brachydactyly (short, stubby fingers/toes) is common and more frequent in the feet
than in the hands. When present in the hands, it can considerably affect dexterity
and the ability to use keyboards or Braille raised types.
Syndactyly (webbing) is much less frequently seen but usually is partial and confined
to the feet (2nd and 3rd toes).
Obesity
Many studies have cited a high frequency of obesity in LMBBS but a recent UK
survey shows this to be present in just over 75% of patients. One possible reason for
the over-estimates may lie in the definition of obesity. A useful key is the WHO
classification in which the body mass index (BMI) is the ratio of the weight in
kilograms to the square of the height in metres.
Excess weight gain does not usually begin until 1 - 2 years of age and occasionally
may not present until puberty. Nevertheless, children are often described as having a
stocky build when compared to other unaffected siblings. The cause is unknown but
the mechanism of obesity appears to be a complex combination of hyperphagia
(although less pronounced than in the Prader Willi Syndrome) and altered disposal of
calories.
Recent studies show the mean affected adult BMI to be 33 kg/m 2 with females being
considerably heavier.
The multiple health problems that can arise from obesity are some of the most
challenging for those with LMBBS and their carers.
Learning Difficulties
Many case reports describe mental retardation as a major feature of LMBBS. This is
inaccurate as more often patients have mild to moderate learning disabilities. Many
early studies used controversial 10 tests which were not tailored to visual
impairment. In general, those with LMBBS achieve much better at performance skills
than at verbal skills.
Often patients, and parents alike, report a deficit in short term memory which is
counterbalanced by excellent long term memory. A few patients also have
extraordinary mathematical ability, usually in the form of rapid mental arithmetic.
A recent UK study has shown that the majority of children with LMBBS were able to
remain in mainstream education provided adequate classroom assistance and/or low
vision aids were available. Just over a quarter required placement in special schools
(see educational needs later).
Developmental delay is common in LMBBS children. Several components of general
motor skills and, to a lesser extent, fine motor skills are often delayed. In particular
sitting, standing and walking may be delayed by up to one year. Later on, parents
often note clumsiness and poor coordination (53%). Speech delay is also common
and may not be seen until 3 or 4 years of age, but is eventually attained with
appropriate speech therapy (see treatments).
Speech Deficit
Apart from speech delay, continued speech deficit has recently been noted to be
present in over half of those with LMBBS. The quality of the voice is breathy and
often high-pitched nasal. Speech itself often comprises substitution of the first
consonant of a word, leading to incomprehension. The last consonant may also be
dropped resulting in incomplete word formation. Language use is occasionally a
problem, although vocabulary may be limited by learning difficulties.
Hearing
There is conductive hearing loss (‘glue ear’) in 21% of children with LMBBS. This
often resolves spontaneously or with treatment by adulthood. A minority have
sensori-neural deafness (3%).
Behaviour
Parents often report behavioral difficulties in childhood with labile emotional
outbursts, frustration and inflexibility commonplace. Many prefer a fixed routine and
don’t tolerate deviation from it. A few demonstrate compulsive/obsessive tendencies.
Some children are hyperactive with attention deficit, while others are docile with
unwaivering attention towards subjects that interest them. In adulthood, patients are
often quite chatty almost to the point of appearing disinhibited and over-familiar.
Renal
Only in the last 20 years has a significant renal component been noted. The
abnormalities can be divided loosely into structural and functional.
Structural - An irregular kidney contour (fetal lobulation) is commonly seen on renal
imaging but may have no bearing on function.
The presence of communicating cysts and cystic dilatation of collecting ducts and
calyces (with blunting and clubbing) is thought to be a consequence of failure of the
fetal kidney to develop normally.
Functional - Two-thirds of patients report excessive thirst and urine production
(polydipsia & polyuria). This probably reflects the well-documented underlying
inability to concentrate the urine, (nephrogenic diabetes insipidus).
A significant number of patients (30%) develop symptoms or signs of renal disease
ranging from recurrent urinary tract infections (associated with reflux) to chronic renal
failure. A minority (5%) develop end-stage renal failure and require dialysis or
transplantation.
Liver
An occasional but specific finding is hepatic fibrosis which can present with jaundice,
elevated liver enzymes and, occasionally, fulminant hepatic failure.
Heart
Congenital heart disease has been reported but is rare in LMBBS. However,
hypertension is much more common and, along with left ventricular hypertrophy, may
be a consequence of obesity.
Endocrine/Fertility/Genitalia
Diabetes mellitus (NIDDM) is present in 15% of patients with LMBBS but a previous
study has shown an additional 30% were discovered to have mild NIDDM when a
glucose tolerance test was performed. A small proportion have hypothyroidism
responsive to therapy.
Hypogonadism is common amongst the affected males, A small buried penis with
reduced volume testes is usual. 10% have undescended testes at birth. The
underlying pathology appears to be partial gonadal failure rather than secondary to
pituitary dysfunction. This is reflected in low testosterone and raised LH/FSH levels
in males. However, the small amount of testosterone produced appears to be
enough for normal secondary sexual characteristics to develop. There is usually no
significant pubertal delay. Although males are highly unlikely to be fertile, in reality at
least two are known to have fathered children.
The assessment of hypogonadism in females is much more difficult, but does not
appear to be prevalent. High LH levels may be seen but equally may be a reflection
of obesity and lead to reduced fertility in that way. Structural anomalies of the female
genitourinary tract are documented including vaginal atresia, hydrometrocolpos,
persistent urogenital sinus, ectopic urethra, hypoplasia of the uterus, ovaries and
fallopian tubes, duplex uterus and septate vagina. Several females with L.MBBS
have given birth successfully to healthy children.
Joints
A large number of those with LMBBS complain of pain in weight-bearing joints,
probably due to osteoarthritis. However, a small proportion also have abnormally
hypermobile or lax joints, the cause of which is unknown, but may be associated with
mild hypotonia.
Dental
Several people with LMBBS have unusually short tooth roots, especially of the front
lower teeth. Crowding of the teeth necessitating prophylactic removal is common.
The majority of patients have a high-arched palate. Occasionally enamel dysplasia is
evident. Both of these abnormalities can increase susceptibility to tooth decay and
loss and regular dental supervision is advisable.
Stature
Short stature has commonly been reported. A recent study of 18 affected families in
which clinical features were matched with genetic linkage to the four known
locations, has shown an excess of tall patients in one category (11q13). There are
some case reports of growth hormone deficiency, but this is by no means
commonplace.
Neurological Features
It is becoming evident that a number of patients have ataxic gaits and signs of
cerebellar involvement . These probably contribute to the clumsiness and poor
coordination.
Spasticity, particularly in the legs, is apparent in a minority.
CT and MR1 scanning has failed to show any consistent underlying structural
abnormalities.
Asthma
A recent survey has pointed out a higher than expected rate (27% compared with
7%) of asthma, allergy and hayfever amongst people with LMBBS residing in the UK.
The implications of this are as yet unknown.
Relatives
There have been suggestions that some relatives who carry a single gene for
LMBBS may be predisposed to some of the features associated with the syndrome.
These are: high blood pressure, diabetes, obesity and renal disease. It is worth
obtaining renal ultrasound scans on all close relations. However, there do not appear
to be any signs of retinal eye disease or learning difficulties amongst these relatives.
Facial Features
There is no clear-cut facial characteristic described with LMBBS other than ‘moon
face’. Nevertheless, different parents often remark on the similarities of their
unrelated children. Often the eyes may be deep-set (enophthalmos) and premature
frontal balding appears to be common in adult males.
DIAGNOSIS
It is fair to say that the diagnosis of LMBBS is at times very difficult. In particular, this
is so in the young where many features have yet to present themselves (e.g. rodcone dystrophy, renal disease). The reason for this is largely attributable to the
variation in expression of the syndrome, not only between families but within them as
well,
Primary features
Rod-cone dystrophy
Polydactyly
Obesity
Learning disabilities
Hypogonadism in males
Renal anomalies
Secondary features
Speech disorder
Brachydactyly
Developmental delay
Polyuria/polydipsia
Ataxia
Poor coordination/clumsiness
Diabetes mellitus
Left ventricular hypertrophy
Hepatic fibrosis
Spasticity
Hearing loss
For diagnosis, four primary features are required to be present or three primary plus two
secondary features.
GENETICS
LMBBS is recessively inherited where both parents are phenotypically normal. When
a new case is seen, a careful family history should be taken and other possibly
affected relatives also examined. In the clinic, fundoscopic examination of the eyes
should be performed through dilated pupils as well as blood pressure measurement
and urinalysis for glucose, protein and leukocytes. Baseline investigations should
include ERG/VER, ECG, echocardiogram, ultrasound of the kidneys and urinary tract
and either an IVP or DMSA/DPTA scan.
12 LMBBS genes have, so far, been identified and scientists know that there are still more
genes to find. Not all patients have an identified mutation in any of those 12 LMBBS genes,
implying that these patients must have mutations in other genes.
Until all genes are located and cloned and mutations in them found, we will not be
able to provide an accurate diagnostic test pre- or post -natally. Undoubtedly when
they are eventually cloned and their functions determined, a great deal of insight will
be gained into the normal and abnormal development of the retina, kidneys, limb
buds, control of weight etc.
Parents who already have an affected child run a risk of further affected children and
should be counselled as such (the child from each pregnancy has a I in 4 chance of
being affected). There is a 2 in 3 chance that the child from any subsequent
pregnancy, if not affected, will be a carrier of the gene for LMBBS. As the syndrome
is rare (1 in 125,000 - see earlier), then the frequency with which the gene is being
silently carried in the population is unknown but estimated to be approximately 1 in
160 (according to the HardyWeinburg equation). Therefore, a gene carrier is unlikely
to have children with another carrier unless they are to marry within their own family.
Cilia
Diseases where there are problems with cilia are called ciliopathies. LMBBS has
been classified as one such ciliopathy; others include Alstrom syndrome, MeckelGruber syndrome and nephronophthisis. Scientists are still trying to find out exactly
how problems with the cilia lead to the symptoms of the disease.
Cilia are structures found on almost every cell in our bodies and are thin, tail-like projections
extending approximately 0.1mm outwards from the cells. A single cilia is a cilium. There are
two types of cilia, motile cilia and non-motile cilia
Motile Cilia
Motile cilia constantly beat in a single direction and help a cell move around. They
also move other ‘things’ along (e.g. fluid). An example of motile cilia can be found in
humans in the lining of the windpipe, where they sweep mucus and dirt out of the
lungs.
Non-Motile Cilia
Normally a cell has only one non-motile cilium. Non-motile cilia are often referred to
as ‘primary’ cilia. There are some cells in the body that have a specialized primary
cilium that plays a very important part in the cell’s function.
For example, in the human eye, there is a primary cilium that connects the outer
segment of the rod photoreceptor cell to its cell body. Problems with it can result in
Retinitis Pigmentosa. Some kidney cells can also be affected.
Though the primary cilium has historically been ignored by scientists, research has
now shown that this structure is involved in many important cell processes such as
sensing its environment, cell growth and also cell development. These recent
findings have led scientists to re-evaluate the importance of this structure.
TREATMENT
As the basic biochemical aetiology of LMBBS is unknown, there is, of course, no
cure. Owing to the diversity of features involved in the syndrome, it would be more
realistic to concentrate approaches to treatment on specific organs or systems.
Rod-Cone Dystrophy
Although many treatments have come and gone, there are none proven to either
prevent or alleviate the deterioration in vision. However, there is much that can be
done to prepare for a life with low vision. Ophthalmological advice is crucial as a first
point of contact from whence referral to appropriate specialist units will be made.
Polydactyly
Rudimentary skin tags can be tied off at birth after documentation by a discharging
paediatrician or general practitioner. Larger accessory digits are often nonfunctional
and excised within the first year of life by either orthopaedic or plastic surgeons.
Occasionally ‘phantom’ pain can be felt over the residual scar. Bony deformation in
already wide feet can lead to ill-fitting shoes and it is important to seek podiatric
advice and special fitting.
Obesity
This is a major source of stress for both patients and parents alike. If left untreated,
obesity will lead to multiple health problems. Unfortunately, as with obesity in
general, there is no satisfactory single treatment.
Those with LMBBS can successfully lose weight given an appropriate diet regimen
and so early referral to a dietician is important. However, there is a perceived
resistance to traditional weight-losing measures, although there is no published
evidence for this.
Given the complex aetiology to weight gain in LMBBS, a multidisciplinary approach
to weight loss is advocated. This might include a combination of careful dietary
assessment, diet, behavioural therapy and exercise. Such programmes exist only at
a handful of Obesity clinics in the UK and referral to such centres would be entirely
appropriate. As a last resort, the use of appetite suppressants may be advocated,
but only when other methods have failed.
Learning Difficulties
These should be assessed early, if possible before visual impairment interferes. A
formal statement of educational needs is advised in order that help can be provided
by the appropriate authorities. Educational needs are covered in another of the
Society’s booklets entitled ‘The LMBBS Child at School’.
Development
The local child development team (CDT) can aid in regular assessments and provide
a programme to improve on deficient skills.
Speech Therapy
This is a valuable aid in the early years and referral should be prompt. Parents are
taught exercises to help their children with communication skills.
Renal
Intervention is dependent on the type of renal dysfunction. If reflux is a problem
leading to recurrent infections, then prophylactic antibiotics should be taken. If
structural changes have been identified, then half-yearly urinalysis, blood pressure
and urea and creatinine levels should be sought. Rising urea levels should prompt
referral to a nephrologist. A small proportion of patients will require dialysis either in
the form of chronic ambulatory peritoneal dialysis (CARD) or haemodialysis. The
former is often not possible when visual impairment is severe as this usually involves
self-administration. Finally, a handful of patients have had renal transplantation
(some in early childhood) to good effect.
Diabetes Mellitus
This is usually of the non-insulin dependent type (Type 2) although some patients
are insulin-requiring in order to maintain control. If dietary measures are insufficient
in the first instance, the use of oral hypoglycaemics is advocated. Regular diabetic
assessments are important and should be carried out at least annually. Preventable
diabetic retinopathy can lead to rapid deterioration of vision already compromised by
rod-cone dystrophy.
Hypogonadism
Some endocrinologists will prescribe testosterone supplements to male patients.
Unless there is a very low level of this hormone which might interfere with normal
sexual development, there is no evidence to suggest benefit. Supplements will not
increase the size of the penis or testes. Puberty is a particularly stressful time for
those with LMBBS, regardless of their sex and referral to a counsellor with
experience in this field can be of immense help.
Short Stature
This may be slightly improved by growth hormone therapy but in general the results
are poor.
References
A full reference list and further information is available on the Laurence-MoonBardet-Biedl Society web page, lmbbs.org.uk.