Laurence-Moon-Bardet-Biedl Syndrome Medical Booklet Introduction
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- CLINICAL FEATURES AND PRESENTATION
- Polydactyly and Brachydactyly
- Liver An occasional but specific finding is hepatic fibrosis which can present with jaundice, elevated liver enzymes and, occasionally, fulminant hepatic failure. Heart
- Endocrine/Fertility/Genitalia
- Development The local child development team (CDT) can aid in regular assessments and provide a programme to improve on deficient skills. Speech Therapy
| 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. HISTORYThe 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 PRESENTATIONEye SignsAlthough retinitis pigmentosa is commonly cited in LMBBS, the preferred term rod-cone 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 BrachydactylyThe 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). ObesityMany 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/m2 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 DifficultiesMany 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. HearingThere 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%). BehaviourParents 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. RenalOnly 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. LiverAn occasional but specific finding is hepatic fibrosis which can present with jaundice, elevated liver enzymes and, occasionally, fulminant hepatic failure. HeartCongenital 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/GenitaliaDiabetes 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. JointsA 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. DentalSeveral 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. StatureShort 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 FeaturesIt 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. AsthmaA 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 FeaturesThere 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. rod-cone 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 featuresRod-cone dystrophy Polydactyly Obesity Learning disabilities Hypogonadism in males Renal anomalies Secondary featuresSpeech disorder Brachydactyly Developmental delay Polyuria/polydipsia Ataxia Poor coordination/clumsiness Diabetes mellitus Left ventricular hypertrophy Hepatic fibrosis Spasticity Hearing loss
GENETICSLMBBS 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.
Diseases where there are problems with cilia are called ciliopathies. LMBBS has been classified as one such ciliopathy; others include Alstrom syndrome, Meckel-Gruber syndrome and nephronophthisis. Scientists are still trying to find out exactly how problems with the cilia lead to the symptoms of the disease.
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.
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 DystrophyAlthough 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. PolydactylyRudimentary 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. ObesityThis 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 DifficultiesThese 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’. DevelopmentThe local child development team (CDT) can aid in regular assessments and provide a programme to improve on deficient skills. Speech TherapyThis is a valuable aid in the early years and referral should be prompt. Parents are taught exercises to help their children with communication skills. RenalIntervention 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 MellitusThis 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. HypogonadismSome 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 StatureThis 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-Moon-Bardet-Biedl Society web page, lmbbs.org.uk. Download 37.81 Kb. Share with your friends:
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