Journal of Pediatric Ophthalmology and Strabismus

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Electroretinography and Diagnosis of the Laurence-Moon-Bardet-Biedl Syndrome in Childhood

L Prosperi, MD; M Cordella, MD; S Bernasconi, MD

Abstract

Laurence-Moon-Bardet-Biedl syndrome is an autosomal recessively inherited complex symptomatology, the main symptoms of which are obesity, polydactylism, mental retardation, hypogonadism, and tapeto-retinal degeneration.

These five salient features are not always simultaneously observed; more over, they are often associated with, or substituted by, other pathological changes of a congenital type,1'2 so that a rigid classification is not possible and the limits of the syndrome are still under discussion.3 At present, the syndrome, the exact pathogenesis of which is still unknown, is considered to be an expression of the pleiotropic effects of a partially recessive gene in homozygous subjects.4

Chromosomal abnormalities previously named in some patients (G-trisomy5 and aneuploidy6) are neither confirmed by recent reports nor by our observations. The whole pentad is observed in about 40-45 percent of cases.1-7 In Bell's statistics,1 the largest with its 273 reviewed cases, the most common symptom is tapeto-retinal degeneration (93%) followed by obesity (91%), retarded mentality (87%), polydactyfy (73%), and hypogonadism (74% in males and 53% in females).

The whole pentad is not easy to verify in early childhood. Obesity is present in a mild degree and is rarely recognized in children under three to four years. Adipose tissue is localized to the trunk, abdomen, pelvis, thighs, and less frequently, to the face; it is often associated with less than average height. Mental retardation is so variable in degree, that it frequently does not present itself until school age.

If genitalia show no abnormality (as is more frequent in females), hypogonadism is also not easy to assess before puberty.

Tapeto-retinal degeneration is the most common sign. Generalized chorioretinal atrophy, bone corpuscular pigmentary changes, and optic atrophy are not frequent7; ophthalmoscopy more often shows diffuse, widely scattered pigmentations of a pepper and salt appearance.

Night blindness is always present, but obviously difficult to ascertain at an early age. More over, fundus changes, which are commonly considered an early sign of the syndrome,8 are only evident some years after birth.

This is also confirmed in the two cases of Mazzantini and loli-Spada9 and in the case of Saraux et al,10 who presented no fundus pigmentary changes at the age of the first examination (respectively 8,11,6 years of age), but developed clear pigmentary alterations of the retina in successive years.

The only clearly manifest sign at birth is polydactyly (sometimes syndactyly, brachydactyly and partial or complete missing of a finger).

CASE REPORTS

Patient No. 1

M.C.A., a six-year-old male, was hospitalized in April 1976 because of mild obesity, mild mental retardation, strabismus, and bilateral visual deficit. The family history was noncontributory. He is the first and only child of a 35-year-old mother and 36-year-old father. He was born after an uncomplicated pregnancy and delivery with a birth weight of 3.200 g. The child pronounced his first babbled syllables and began assisted walking within the first year. His hands and feet were normal, his weight was 45,300 Kg (>97° perc.) and his height was 124 cm (97° perc.). Adipose tissue was uniformly distributed principally on trunk and thighs. Other clinical parameters were within normal limits. Radiological findings of skull, spine, chest, lower and upper limbs were normal. Blood glucose and glucose tolerance test, BUN, complete blood count, ESR, serum proteins and electrophoresis, serum lipid partition and standard urine were all within normal limits. OGTT and IVTT values indicated a mild hyperinsulinism as often observed in obesity. Pituitary supply of LH and FSH, evaluated by means of LH-RH stimulating test, showed normal values. Total serum thyroxine was normal. Urinary 17-KS and 11-deoxysteroids excretion was normal.

The ophthalmological consultation showed normal ocular adnexa, anterior segment, lens and vitreous. Ophthalmoscopy showed…

Laurence-Moon-Bardet-Biedl syndrome is an autosomal recessively inherited complex symptomatology, the main symptoms of which are obesity, polydactylism, mental retardation, hypogonadism, and tapeto-retinal degeneration.

These five salient features are not always simultaneously observed; more over, they are often associated with, or substituted by, other pathological changes of a congenital type,1'2 so that a rigid classification is not possible and the limits of the syndrome are still under discussion.3 At present, the syndrome, the exact pathogenesis of which is still unknown, is considered to be an expression of the pleiotropic effects of a partially recessive gene in homozygous subjects.4

Chromosomal abnormalities previously named in some patients (G-trisomy5 and aneuploidy6) are neither confirmed by recent reports nor by our observations. The whole pentad is observed in about 40-45 percent of cases.1-7 In Bell's statistics,1 the largest with its 273 reviewed cases, the most common symptom is tapeto-retinal degeneration (93%) followed by obesity (91%), retarded mentality (87%), polydactyfy (73%), and hypogonadism (74% in males and 53% in females).

The whole pentad is not easy to verify in early childhood. Obesity is present in a mild degree and is rarely recognized in children under three to four years. Adipose tissue is localized to the trunk, abdomen, pelvis, thighs, and less frequently, to the face; it is often associated with less than average height. Mental retardation is so variable in degree, that it frequently does not present itself until school age.

If genitalia show no abnormality (as is more frequent in females), hypogonadism is also not easy to assess before puberty.

Tapeto-retinal degeneration is the most common sign. Generalized chorioretinal atrophy, bone corpuscular pigmentary changes, and optic atrophy are not frequent7; ophthalmoscopy more often shows diffuse, widely scattered pigmentations of a pepper and salt appearance.

Night blindness is always present, but obviously difficult to ascertain at an early age. More over, fundus changes, which are commonly considered an early sign of the syndrome,8 are only evident some years after birth.

This is also confirmed in the two cases of Mazzantini and loli-Spada9 and in the case of Saraux et al,10 who presented no fundus pigmentary changes at the age of the first examination (respectively 8,11,6 years of age), but developed clear pigmentary alterations of the retina in successive years.

The only clearly manifest sign at birth is polydactyly (sometimes syndactyly, brachydactyly and partial or complete missing of a finger).

CASE REPORTS

Patient No. 1

M.C.A., a six-year-old male, was hospitalized in April 1976 because of mild obesity, mild mental retardation, strabismus, and bilateral visual deficit. The family history was noncontributory. He is the first and only child of a 35-year-old mother and 36-year-old father. He was born after an uncomplicated pregnancy and delivery with a birth weight of 3.200 g. The child pronounced his first babbled syllables and began assisted walking within the first year. His hands and feet were normal, his weight was 45,300 Kg (>97° perc.) and his height was 124 cm (97° perc.). Adipose tissue was uniformly distributed principally on trunk and thighs. Other clinical parameters were within normal limits. Radiological findings of skull, spine, chest, lower and upper limbs were normal. Blood glucose and glucose tolerance test, BUN, complete blood count, ESR, serum proteins and electrophoresis, serum lipid partition and standard urine were all within normal limits. OGTT and IVTT values indicated a mild hyperinsulinism as often observed in obesity. Pituitary supply of LH and FSH, evaluated by means of LH-RH stimulating test, showed normal values. Total serum thyroxine was normal. Urinary 17-KS and 11-deoxysteroids excretion was normal.

The ophthalmological consultation showed normal ocular adnexa, anterior segment, lens and vitreous. Ophthalmoscopy showed normal optic disk and vessels on a scarcely pigmented retina in both eyes. Refraction, measured under tropamide cycloplegia, was that of a myopic compound astigmatism, symmetrical in both eyes, with vision OD -5 sph = -3 cyl a 180° = 2/10 and vision OS -5 sph = -3 cyl a 180° = 2/10 (scarcely). Little angle esotropia of OS was present.

The electroretinogram (ERG), symmetrical in both eyes at the fifteenth minute of DA, showed alterations typically present in the cone-rod dystrophy:

- a wave with slightly anticipated culmination time (16 msec) and normal amplitude (OD: pV. 37; OS p V. 38).

- bi wave (phototopic b component) with slightly anticipated culmination time (46 msec) and markedly decreased amplitude (OD p V. 15 and OS p V. 18; i.e., 10 percent of normal values).

- b2 wave (scotopic b component) with normal culmination time (msec 100) and subnormal amplitude (OD and OS p V. 57).

- oscillatory potentials within normal limits.

Similar recordings, typical of a cone-rod progressive dystrophy, have already been reported in association with a LMBB syndrome."'12

Patient No. 2

G.G., a one-year and nine-month-old male, was hospitalized in December 1974 because of obesity and polydactyly. His paternal grandfather was healthy who had three diabetic brothers and one healthy sister. He is the first and only child of a 24-year-old mother and 24-year-old father and was born after normal pregnancy and uncomplicated delivery with a birth weight of 2.700 g. The child pronounced his first babbled syllables and began assisted walking within the first year. A hexadactyly at birth was noticed, which, in the absence of other clinical signs, was considered as monosymptomatic so that the baby underwent plastic surgery on both hands at six months. The physical examination put in evidence an hexadactyly of the feet and scars on both hands, as a consequence of the previous amputation of the sixth finger. His weight was 20,400 Kg (> 97° perc.) and his height was 95.5 cm (> 97° perc.). Adipose tissue was normally distributed. Radiological findings of skull, spine, and thorax were normal; a large exostosis was present on the lateral side of the fifth methacarpal bone. Blood glucose, BUN, complete blood count, ESR, serum proteins and electrophoresis, serum lipid partition, and standard urine were within normal limits. GH release after insulin and arginin, LH and FSH release after LH-RH, and TSH release after TRH were normal as were values of Ti-Tj in blood and of 17-KS in 24-hours urine.

Ophthalmological consultation showed normal ocular adnexa, anterior segment, lens and vitreous. Ophthalmoscopy showed normal optic disk and vessels on a retina diffusely covered with fine pigment, in both eyes. Refraction, measured under tropamide cycloplegia, was that of a myopic compound astigmatism in both eyes, (OD -1,5 sph = -1 cyl a 180° and OS -2,0 sph = -1 cyl a 180°). Alternating exotropia of about 30A (corneal reflexes) was present. On March 1975, the patient was hospitalized again to obtain an electroretinogram. The ERG, symmetrical in both eyes, presented the typical changes of a tapeto-retinal degeneration: markedly decreased a and bi waves, extinct b2 wave and oscillatory potentials. On December 1976, the child, four years old, was examined again, after atropine cycloplegia. After the total correction of the refractive error he had vision OD -3 sph = - 1 a 180° = 1 /10 and vision OS -4,5 sph = -1 a 180° = 1 /10, with 30A alternating exotropia.

Ophthalmoscopy showed mildly pale optic disks with a temporal crescent of chorio-retinal atrophy, diffusely spread fine pigmentation and normal vessels in both eyes.

Patient No. 3

G.U., a one year and two-month-old male, is G.G.'s younger brother. He was examined the first time in December 1976 because he was present by chance during G.G.'s last ophthalmological control. He was born nine months after the diagnosis of LMBB syndrome was made on G.G., even though the parents had been advised that it would be better not to have other children. He seemed to be physically and mentally normal and showed normal refraction and ocular motility; however, the ophthalmoscopic examination revealed in both eyes a pale disk, normal vessels and a diffuse atypical pigmentation of the retina. The ERG, registered in January 1977, supported the diagnosis of a heredo-dystrophy of the retina (subnormal a wave, bi wave with mrcrovoited amplitude retarded culmination time and extinct b; wave). Hospitalization was recommended to evaluate the endocrine function.

METHODS

Usefulness of electrophysiology in evaluating the visual function in childhood, the method to register, to analyze and to interpret recordings, have been discussed in previous papers.13'17

In Patient No. 1, exactly similar electroretinographic responses were registered atfirst while awake (Valium guttae XXX) and later under deep sedation with Ketamine; in Patients 2 and 3, the electrophysiological examination was performed in narcosis by halothane.

DISCUSSION

At an initial stage, children suffering from LMBB syndrome may only show polydactyly and obesity, or either. To make a correct diagnosis it is necessary to exclude familiar polydactyly, Ellis-Van Creveld's chondroectodermal dysplasia and hypopituitarism associated with hypothalmic lesions. Electroretinography is indicated in order to assess early retinal dysfunction. In the first five or six months of life, an electroretinogram can be recorded from unanesthetized children. The value of electroretinography in making the diagnosis easier in such cases of LMBB syndrome in which retinopathy is not revealed by ophthalmoscopy was pointed out by Francois et al in 1954.18 Since then many papers have dealt with the topic.7'9'11'19'28

To find an extinct or altered ERG in young people with a normal fundus is not uncommon.2'26 On the contrary, cases of LMBB syndrome with normal fundus and normal ERG are very rare.9'25'26 Nevertheless, according to the literature, only nine children less than eight years old with normal or mildly atypical fundus oculi and suffering from LMBB syndrome were submitted to electroretinographic examination (which was altered in all of them).9'19'21'26 A tenth child, ten months old, with unexplored fundus because of bilateral cataract presented a very low amplitude ERG.26 It is very rare for the ERG to be normal in LMBB syndrome, while an altered ERG even in presence of a normal fundus verifies a diagnosis previously suspected on the basis of other symptoms.

Our first two observations are very illustrative and confirm the value of the ERG in an early diagnosis. In the first case the abnormality of the ERG in association with abnormal results of endocrinological tests immediately cleared the diagnosis. In the second case the marked changes in the ERG confirmed the diagnosis even in the presence of normal values of pituitary tests. An early diagnosis is necessary for practical and eugenic purposes. Educational methods and programs can be plannedkeeping in mind that a visual deficit will develop progressively and a mental retardation may also appear. The heterozigous condition of both parents makes it easier to explain to them the eugenic question, that is the inherent risk of successive pregnancies.

SUMMARY

The cases of two children affected from LMBB syndrome are reported. The first child was six years old, suffering from obesity and mild mental retardation; the other was two years old, suffering from hexadactyly and obesity. In both children the suspected diagnosis of LMBB syndrome was verified by the electroretinographic evidence of a tapetoretinal degeneration although the fundi were atypical. A third child, the younger brother of the second case, presented an atypical pigmentation of the retina and the electroretinographic changes of a tapeto-retinal degeneration.

Since tapeto-retinal degeneration, which is the most common of the main signs of the syndrome, is not always recognized by opthalmoscopy in early childhood, the clinical value of electroretinography in making an early diagnosis is emphasized.

REFERENCES

1. Bel) J: The Laurence-Moon-Biedl syndrome. In Penrose LS (ed): The Treasury of Human Inheritance, vol 5, pt 3. London, Cambridge University Press, 1958.

2. McLaughin TC, Korvetz LJ, Schiebler GL: Heart disease in the Laurence-Moon-Biedl-Bardet syndrome. J Ped 65:388, 1964.

3. Caldera R, Combourieux M: Les limites du syndrome de Laurence-Moon-Biedl-Bardet. Sem Hop Paris 54:2424, 1967.

4. Cockayne EA, Krestin D, Sorsby A: Obesity, hypogenitalism, mental retardation, polydactylism and retinal pigmentation: the Laurence- Moon-Biedl syndrome. Quart J Med 4:93,1935.

5. Stankovic I, Eskovic R, Dergnec S et al: Syndrome de Bardet-Biedl comme consequence de l'aberration chromosomique. Bull Mem Soc Franc Ophtal 79:226, 1966.

6. Bowen P, Ferguson-Smith MA, Moisier D et al: The Laurence-Moon syndrome association with hypogonadism and sex chromosome aneuploidy. Arch Inter Med 116:598, 1965.

7. Krill AE: The electroretinogram and electrooculogram: clinical applications. Invest Ophthal 9:600-617, 1970.

8. Amman F: Investigation cliniques etgenetiques sur la syndrome de Bardet-Biedl en Suisse. Suppl J Genet Huma 18:310, 1970.

9. Mazzantini L, loli Spáda G: L'elettroretinogramma nella síndrome di Laurence-MoonBardet-Biedl. Boll D'Ocul 43:786-802, 1964.

10. Saraux H, Laplane R, Lasfargue G et al: La syndrome de Bardet-Biedl. Ann Ocul 197:864879, 1964.

11. Franceschetti A, Francois J, Babel J: Les Heredo-Degenerescence Chorio-Retiniennes, vol I. Paris, Masson et Cie, 1963, p 1251.

12. Berson EL, Gouras P, Gunkel RD: Progressive cone-rod degeneration. Arch Ophthal 80:68, 1968.

13. Cordelia M, Prosperi L: Comportamento dell'elettroretinogramma in una famiglia affetta da malattia di Stargardt ad ereditarieta dominante. Minerva Oftal 15:78, 1973.

14. Cordelia M, Prosperi L, Borghi C et al: L'E.R.G. come esame funzionale visivo nell'infanzia, Atti del Simp Int di Oftal, Ped, Parma 1974, Maccari Ed, 1976, p 44.

15. Cordelia M, Prosperi L: Utilita delle metodiche elettrofisiologiche nella valutazione della funzione visiva nella prima infanzia e nei bambini con ipoevolutismo psichico. Ann Ottal, 101:217, 1975.

16. Borghi C, Cordelia M, Lettieri S et al: Some results on mathematical analysisof thedynamic ERG. XII ISCERG Symp, Clermont-Ferrand, 1974. (In press.)

17. Prosperi L, Cordelia M: Influenza della narcosi da fluotano sull'ERG dinámico. Atti Soc Oftalm Lombarda 30:113, 1975.

18. Francois J, Stefens R, Derouck A: Lelectroretino-encephalographie dans la retinopathie pigmentarie. Ann Ocul 187:908-937, 1954.

19. Bamatter F, Franceschetti A, Klein D: Aspects cliniques, ophtalmologiques et genetiques des abiotrophies neuro-retiniennes en pédiatrie. XVIII Congr Ass Ped Langue Franc li:67, 1961.

20. Ciccarelli EC, Vesell ES: Laurence-Moon-Biedl syndrome. Report of an unusual family. Amer J Dis Child 101:519, 1961.

21. Krill AE, Folk E, Rosenthal IM: Electroretinography in the Laurence-Moon-Bardet-Biedl syndrome: an aid in the diagnosis of the atypical case. Am J Dis Child 102:205, 1961.

22. Jayle G, Boyer R, Saracco J: L'electroretinographie. Paris, Masson et Cie Ed, 1965.

23. Berson EL, Gouras P, Gunkel RD: Progressive cone-rod degeneration. Arch Ophthal 80:68-76, 1968.

24. Gorgone G, Greco S: La síndrome di LaurenceMoon-Bardet-Biedl (contributo clínico e casuístico). Ann Ottal e Cl Ocul 94:770-786, 1968.

25. Ehrenfeld EN, Rowe H, Auerbach E: LaurenceMoon-Bardet-Biedl syndrome in Israel. Am J Ophthal 70:524-532, 1970.

26. Samson-Dolfus D, Levillaine: Visual evoked responses in cerebral diseases of children. Proceedings VIII Symp ISCERG, Pisa, 1970, p 63.

27. Stanescu B, Wawernia E: Electroretinogram and electro-encephalograms in Laurence-MoonBardet-Biedl syndrome. Confin Neurol 32:423, 1970.

28. Stanescu B, Nereantu F: Laurence-Moon-Bardet-Biedl syndrome with juvenile macular degenerescence of Stargardt. Ophthalmologica 162:76-81, 1971.

10.3928/0191-3913-19770901-13

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