BARDET-BIEDL SYNDROME

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1 Australian Journal of Ophthalmology 1984; 12: BARDET-BIEDL SYNDROME C. G. KEITH FRACS Royal Children's Hospital, Melbourne. VIC Abstract The Bardet-hedl syndrome is characterized by five main features: obesity, polydactyly, pigmentary retinopathy, mental deficiency and hypogonadism; recently a sixth feature, renal disease, has been described. It was formerly known as the Laurence-Moon-Biedl syndrome, but Laurence and Moon described a drfferent entity in which the main feature was paraplegia. Fourteen cases have been seen: all had pigmentary retinopathy which. in most cases, was severe and tended to affect central vision early in life. All had subnormal intelligence, twelve were obese, ten had polydactyly, eight hypogonadism, and two had renal disease. The condition was thought to be rare, but this may have been due to the failure to diagnose incomplete or partial cases. It is suggested that the prevalence is 1: of the population. Key words: Bardet-Biedl syndrome, obesity, polydactyly, pigmentary retinopathy, mental deficiency, hypogonadism, renal disease. The Bardet-Biedl syndrome is characterized by five main features: obesity, polydactyly, pigmentary retinopathy, hypogonadism and subnormal intelligence. It was formerly known as the Laurence-Moon-Biedl syndrome, but Franceschetti and Klein' drew attention to the fact that Laurence and Moon described a condition in which there was paraplegia, hypogenitalism, tapetoretinal degeneration, and subnormal intelligence, which is a different entity from the Bardet-Biedl syndrome. More recently it has become apparent that renal abnormalities are frequently present; these can be fatal and they should be considered as a sixth feature of the syndrome.2 The condition seems to be less uncommon than is usually thought and an incidence of 1: of the population was found in a study carried out in S~itzerland.~ It is inherited as an autosomal recessive trait, but the affected members in a kindred may not show all the features of the disorder, and in the absence of a family history the recognition of incomplete or partial cases may be particularly difficult. The purpose of this paper is to draw attention to the relative frequency of the disorder, the severity of the retina! degeneration, which usually causes blindness by the age of 30 years, and to the problem of diagnosing the incomplete syndrome. PATIENTS At the Royal Children's Hospital, Melbourne, in the Eye Clinic, and Genetics and Ophthalmology Clinic, 14 cases have been seen which fall into the category of Bardet-Biedl syndrome. The features found are shown in Table 1. A full physical examination was made in all cases, but renal and gonadal functions were not assessed. Ophthalmological examination included testing the visual acuity, ophthalmoscopy, and in most cases an examination under anaesthesia, performed in order to carry out full fundus examination, electroretinography, fundus Reprint requests: C. G. Keith, 231 Flemington Road, North Melbourne, Victoria BARDET-BIEDL SYNDROME 143

TABLE 1 Clinical Features in 14 Patients with the Bardet-Biedl Syndrome Feature Number of patients Males Females (n=9) (n = 5) Pigmentary retinopathy 9 5 Obesity I 5 Mental deficiency 9 5 Polydactyly

2 TABLE 1 Clinical Features in 14 Patients with the Bardet-Biedl Syndrome Feature Number of patients Males Females (n=9) (n = 5) Pigmentary retinopathy 9 5 Obesity I 5 Mental deficiency 9 5 Polydactyly 6 4 HypogQnadism 8 - photography and fluorescein angiography. Charting of the visual fields was not usually at tempted. RESULTS AND DISCUSSION The five classical features can be very variable, and the fully expressed syndrome occurred in only three of the 14 patients; nine exhibited four of the main features, and in two patients only three of the features were seen. The most difficult feature to establish was hypogonadism in the female and in the very young male, and this feature was absent or undetected in six patients. Polydactyly was absent in four, and obesity in two. The findings in two large ~eries~,~ are shown in Table 2. Most of the features are present in 80 to 90% of the cases; however, polydactyly seems to be less common in males, and hypogonadism less common in females. Obesity This was found in 12 of the subjects. It varied from gross (Figure 1) to slight, and two children were normal in build (Figure 2). The obesity may TABLE 2 Clinical Features of Bardet-Biedl Syndrome Found in Two Large Se~ies~,~ Number of Number of males females Feature Retinitis pigmentosa Obesity Mental retardation I0 Polydact yly Hypogonadism be present in infancy (Figure 3), but in some it only became obvious after puberty. It has been reported that some cases may lose the obesity in adult life.3 The absence of obesity in one child (Figure 2), who had only slight mental retardation, but had the other three features of the syndrome, caused considerable delay in the diagnosis. Polydacty iy Post-axial polydactyly was present in ten cases, and brachydactyly in two. The polydactyly can be very variable, and in one report3 it was found to affect all four extremities in only 26%, while in the remainder only three, two, or one limb was affected. Brachydactyly can be quite marked, and is considered to be equivalent to the polydactyly. The extra digits are usually removed very early in life, so direct questioning may be necessary, as the event may have been forgotten. Mental Deficiency This feature is also very variable, and some children may be just dull, or finding school a, struggle, while others are more severely retarded requiring institutional care. Emotional immaturity is often quite marked and there hav! been reports of some cases with normal intelligence. Hypogonadotrophic Hypogonadism This is easier to diagnose in the male than the female, and in this series was mainly manifested by undescended testicles and micropenis. One, female patient, not included in this series, was referred by an endocrinologist querying the advisability of administering hormones to make her fertile, for her marriage to a man with dystrophia myotonica and testicular atrophy. Pigmentary Retinopathy This was present in all our cases; the high prevalence may be due to most of them being referred for visual problems, but a few were referred to the Genetic Clinic for assessment of obesity. In other ~eries~,~ the prevalence of retinopathy has been between 85% and 100% of 144 AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

5 The visual acuity was below normal (6/6) in all measurable cases, and in four it was 6/36 or less. Night blindness was a feature in eight, and five showed restricted visual fields.

3 Figure i: Case 12. Gross obesity and hypoplastic genitalia. Figure 2.- Case 3. Normal build in child with partial Bardet-Biedl syndrome. cases (Table 2), but more recently it has been suggested that without this feature the diagnosis should not be made.5 The visual acuity was below normal (6/6) in all measurable cases, and in four it was 6/36 or less. Night blindness was a feature in eight, and five showed restricted visual fields. Ametropia was common with a tendency to hypermetropia and astigmatism which was found in six patients; three children also had squints. The electroretinogram (ERG) was abnormal in all cases, being either very reduced or absent. Both scotopic and photopic responses were involved. The fundal appearances were very characteristic (Figure 4). All showed narrowed arteries, and all except two showed marked disc pallor. Macular changes were prominent in seven, but pigmentary deposits tended to be very sparse, being found in eight patients, and they consisted mainly of a few spots of pigment in the equatorial regions, while bone corpuscle type pigment was rare. Pigment epithelial atrophy was marked in ten patients, and ten also showed a dystrophic sheen. The retinal degeneration is usually rapidly progressive, as 73% are socially blind by the age of 20 years, and 86% by the age of 30. This is in contrast to the visual retention in typical autosomal recessive retinitis pigmentosa. The central vision is usually affected very early in the course of the disease, and this was evident in most of our cases. The severity of the disease is often a clue to the diagnosis, as other BARDET-BIEDL SYNDROME 145

night blindness is often an early feature. Other authors6 have found that the rods are usually more severely involved than the cones.

4 Figure 3; Case 9. Obesity in infancy. types of pigmentary retinopathy do not usually cause such severe visual handicap at such an early age. It has been suggested that this is primarily a cone-rod degeneration, rather than a rod-cone degeneration, but on electrophysiological testing both rods and cones are severely affected (Figure 9, and night blindness is often an early feature. Other authors6 have found that the rods are usually more severely involved than the cones. One case in this series had manifest pigmentary retinopathy at birth (Leber s congenital amaurosis) and his ERG was nearly extinguished (Figure 6). His obesity was also extreme (Figure 3), he had hexadactyly on all four extremities, severe mental deficiency, hypogonadism, and polycystic kidneys. Renal Disease Renal disease in the Bardet-Biedl syndrome has been reported by many a~thors.~. -~ The pathological changes found varied greatly, and included renal dysplasia, focal interstitial fibrosis, mesangial proliferation, sclerosis with cystic dilatation of the tubules and cortical and 146 medullary periglomerular fibrosis. Renal abnormalities were found in only two of our cases: Case 9 had polycystic kidneys when investigated in infancy, and Case 10 died from uraemia at the age of 27 years. Routine renal investigations were not carried out in the other cases, but in view of its obvious importance, this will be done in the future. The relationship between the Bardet-Biedl syndrome and familial nephronophthisis with retinitis pigmentosa,i0 either congenital or of later onset, * with no other features of the Bardet-Biedl syndrome, has yet to be elucidated, but in both conditions congenital nerve deafness may occur. A further feature, hepatic fibrosis, in addition to renal and testicular fibrosis in a child who had many of the features of the Bardet-Biedl syndrome, has also been reported. Differential Diagnosis There are a few other syndromes that have overlapping features with the Bardet-Biedl syndrome, and the exact relationships are not yet completely clear. Alstrom s syndrome comprises deafness, diabetes mellitus, obesity and pigrnen- AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

~ LIGHT -L 20ms Figure 6: Case 9. Virtually extinguished ERG in case with congenital onset of retinopathy (Leber s disease). LIGHT Figure 4: Case 3. Right fundus.

5 ~ LIGHT -L 20ms Figure 6: Case 9. Virtually extinguished ERG in case with congenital onset of retinopathy (Leber s disease). LIGHT Figure 4: Case 3. Right fundus. Marked arterial narrowing but no abnormal pigmentation. tary retinopathy. The extremely rare Biemond syndrome has all the features of the Bardet-Biedl syndrome, except that an iris coloboma replaces the pigmentary retinopathy. The Prader-Willi syndrome is manifested by obesity, mental retardation, hypotonia and hypogonadism, but without retinopathy; and the Laurence-Moon syndrome has already been discussed. In a recent a further variant was described in which cataracts but no retinopathy were present in an infant with a normal ERG; however, we have found in many of our cases that the ERG is normal at the onset of this condition, but later becomes reduced as the retinal dystrophy advances. FLICKER 50uv L 20rns Figure 5: Case 8. ERG, showing severely reduced photopic and scotopic waves and absent flicker response. Inheritance and Prevalence Autosomal recessive inheritance was apparent in this series, as there were three pairs of siblings (Cases 5 and 6, 7 and 8, 13 and 14) and in one family the maternal aunt of the propositus was also affected. The parents were not consanguineous, and there was no evidence of incest. The approximate odds of this occurring by chance are one in 800. No other cases of consanguinity have been detected in this series, but in the Swiss survey3 it was found in 20 out of 38 families. The relatively large number of cases collected over a short period indicates that the syndrome is not as rare as formerly thought, and the prevalence of one in , as found in S~itzerland,~ would mean that in Victoria there should be approximately 20 cases; we have ascertained 14 without making a deliberate search. A number may go unrecognized because BARDET-BIEDL SYNDROME 147

6 of the lack of obesity or polydactyly. Two cases were identified when referred for visual assessment associated with poor school performance, and this was caused by a combination of the reduced vision and the subnormal intelligence. It is important to make the diagnosis because of the poor visual prognosis, and the need for parental counselling and guidance. Any infant born with polydactyly should be considered as a possible bardet-biedl syndrome, and if obesity develops, then referral for electrophysiological studies is recommended. Effective counselling may reduce the number of siblings affected, but there is no known method of prenatal diagnosis at present. References 1. Franceschetti A, Klein D, Forni S, Babel J. Bardet-Biedl syndrome. Acta XVIth Concil Ophthal Britain 1950: Hurley RM, Dery P, Nogrady MB, Drummond KN. The renal lesion of the Laurence-Moon-Biedl syndrome. J Pediatr 1975;87: Ammann F. Investigations clinique et genetiques sur le syndrome de Bardet-Biedl en Suisse. J Genet Hum 1970; 18 (SUPPI): Bell J. The Laurence Moon syndrome. In: Penrose LS, ed. The treasury of human inheritance, vol5. Cambridge: Cambridge University Press, Schachat AP, Maumenee IH. Bardet-Biedl syndrome and related disorders. Arch Ophthalmol 1982; 100: CamDo RV. Aubere TM. Ocular and svstemic manifestation; of the BardecBiedl syndrome. Am J Ophthalmol 1982; 94: Nadjmi B, Flanagan MJ, Christian JR. Laurence-Moon- Biedl syndrome associated with multiple genitourinary tract anomalies. Am J Dis Child 1969; 117: Tieder M, Levy M, Gubler MC, Gagnadoux MF, Broyer M. Renal abnormalities in the Bardet-Biedl syndrome. Int J Pediatr Nephrol 1982; 3: Churchill DN, McManamon P, Hurley RM. Renal disease: a sixth cardinal feature of the Laurence-Moon- Biedl Syndrome. Clin Nephrol 1981; 16: Senior B, Friedmann At, Braudo JL. Juvenile familial nephropathy with tapetoretinal degeneration. Am J Ophthalmol 1961; 52: Dekaban AS. Hereditary syndrome of congenital retinal blindness (Leber) polycystic kidneys and maldevelopment of the brain. Am J Ophthalmol 1969; 68: Senior B. Familial renal-retinal dystrophy. Am J Dis Child 1973; 125: Pagon RA, Haas JE, Bunt AH, Rodaway KA. Hepatic involvement in the Bardet-Biedl syndrome. Am J Med Genet 1982; 13: The encouraging results obtained in the treatment of foveal membranes have prompted us to examine more eyes for photocoagulation to establish the exact criteria for successful treatment. The advent of krypton red and, recently, of krypton yellow has opened new horizons in the treatment of choroidal neovascular membranes in the foveal area. The benefits of treatment with each type of laser-blue-green argon, monochromatic green argon, krypton yellow, and krypton red-are now under investigation as part of a collaborative study involving several treatment centres in the United States and abroad. Alex E. Jalkh, et at. Arch Ophthalmol 1983; 101: AUSTRALIAN JOURNAL OF OPHTHALMOLOGY

Impaired Visual Function in Childhood

Arch. Dis. Childh., 1968, 43, 658. Role of Electroretinography in Investigation of Impaired Visual Function in Childhood KENNETH WYBAR and BRIAN HARCOURT From The Hospital for Sick Children, Great Ormond