A c t a P a t h . Jap. 21(3): 435443,1971

AN AUTOPSY CASE OF LAURENCE-MOON-BIEDL SYNDROME WITH PITUITARY EOSINOPHILIC ADENOMA

Shunkichi H~RAKI*, Akira TSUTSUMI* and Shuhei TSUROI**

Depzrtments of Path,ology and Intwnal Medicine, Oka!yama Uniiwsdty Mpdical School, Okaynm

(Recsived on Oct. 28, 1970)

A report was made on a 21-year-old girl who had Laurence-Moon- Biedl syndrome (retinitis pigmentosa, obesity, hypogenitalism, mental retardation and hereditary nature), pituitary eosinophilic adenoma, acromegaly and diabetes mellltus and died of delayed radionecrosis of the brain. The authors discussed on the complication of Laurence- Moon-Biedl syndrome and pituitary eosinophilic adenoma and their relation. ACTA PATH. JAP. 21: 435-443, 1971.

Introduction

In 1866, LAURENCE and MOON'O reported four cases of retinitis pigmentosa, occuring in the same family, associated with obesity, hypogenitalism and mental retardation. Suhseqnently, in 1920, RARDET~ and in 1923, BIEDI,~ described the same symptom-complex associated with polydactyly. Since then, occurrence of retinal pigment abnormalities, obesity, mental retardation, genital hypoplasia and polydactyly, often in siblings with normal parenh of consanguineous marriages, has been designated as Laurence-Moon-Biedl syndrome. This syndrome, while composing a distinct disease entity, is relatively rare, but there are numerous clinical reports in Japang and in other countries. 5,6,17 However, as the prognosis is not grave, only 20 autopsy caseq2J2.14 have been published up to the present. This autopsy case is the third in Japan. Of these, some are incomplete.

Clinical Record

The patient was a 21-year-old girl. 8he was born of parents who were cousins and her father had retinitis pigmentosa. Her paternal grandparents were also cousins (Fig. 1). She had been in good health until lkyear-old, but her intelligence was very low. She then began to complain of visual disturbance and

Department of Pathology, Okayama University, Medical School * Director: Prof. K. OQAWA

** Director: Prof. K. K O ~ A K A Y* @S> % B, ##F @F

435

436 LAURENCE-MOON-BIEDL SYNDROME

;5 retinitis pigmantosa t patient

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Fig. 1. The patient’s parents and paternal grandparents are consanguineous marriages and her father has retinitis pigmentosa.

her weight gradually increased. At the age of 17, she complained of polydipsia, which became prominent. In April, 1968, a t the age of 20, she wash ospitalized and treated with cobalt irradiation (4,100 roentgens113 times/l5 days) and insulin injection under the diagnosis of diabetes mellitus due to pituitary adenoma. Subjective symptoms were improved for a while, but again thirsty feeling changed for the worse. In September, 1968, she was admitted to the Okayama University Hospital and diagnosed as pituitary adenoma, acromegaly, diabetes mellitus and Laurence-Moon-Biedl syndrome after careful examination and treated with cobalt irradiation (12,250 roentgens169 times1201 days), insulin and a-chymotrypsin injection.

From about 35 weeks after admission her character changed, and from about 45 weeks agnosic, convulsive seizure and pathologic reflex appeared. High fever began from the 55th week and she finally died on December 8, 1969, 45 weeks after admission.

Clinical Examination

The blood count was normal. The total serum protein was 7.5 mg per 100 ml. The level of fasting blood sugar was 250 mg. per 100 ml. and that of serum choles- terol 367 mg per 100 ml. The 24- hour excretion of 17-ketosteroids and 17-hydroxycorticoids was 2.3 mg/day and 1.8 mglday, respectively. WasRermann reaction was negative. The count

The basal metabolic rate was + 20.5 per cent.

The level of growth hormone was 60 m,ug/ml. Intelligence quotient waN less than 60 (Wais).

8. IiIRAEI, A. TSUTSWMI AND 8. TSWBOI 437

of sexchromatin masses in the nuclei of the epidermis was normal. The roentgen0 gram of the skull Rhowed that the sella turcica was large in size and the frontal sinus was dilatated. The roentgenogram of the stomach and the chest was normal. The electrocardiogram was within normal limit. The visual fields were markedly contracted and the ophthalmoscopy showed deposition of abnormal pigments in the retina (Fig. 2). Menstruation was irregular.

Autopsy Findings

Gross

She was 150 om tall, and weighed 63 kg. The body was generally obese and The occipital protuberance was hyperostotic and

The sella turoica was extended, but was showed acromegaly (Fig. 3). the frontal sinuses were overdeveloped.

Figr2. The patient’s face and fingers show acromegaly (at left) and her sister is normal (at

Fig. 3. Abnormal deposition of pigments in the retina. Fig. 4. Enlarged pituitary gland in the extended sella turcica.

right).

438 LATJRENCE-MOON-BIEDL SYNDROME

Fig. 5.

Fig. 6. Right temporal lobe. Kliivcr-Barrera stain x l . Fig. 7.

Symmetric and large necrosis with small hemorrhage in both temporal lobeg due to cobalt irradiation.

Delayed radionecrosis with calcification of the pons. H.E. stain, x 100.

9. HIRbRI, A. TSUTSUMI AND 9. TSUBOI 439

not destroyed. The pituitary gland was enlarged to thumb’s tip size (weight: 3.0 g) (Fig. 4). The brain was slightly edematous. Both temporal lobes, hypothalamus, anterior half part of pons and optic chiasm had symmetric, large, relatively clearly demarcated and yellow-gray necrotic part, especially in the white matter (Fig. 5). The external genitals showed no remarkable changes, but the breasts were hypoplastic and the uterus was slightly small. The ovaries had several cysts. The heart was hypoplastic (weight: 175g) and the foramen ovale was patent (0.2 cm in diameter). The liver and spleen showed no remarkable changes. The left kidney was hyperemic and there were numerous abscesses. In the left kidney, the corticomedullary junction was indistinct and the pelvic mucosa was hyperemic. The alimentary tract, pancreas, adrenal glands and thyroid gland revealed no remarkable changes. The bone showed a red marrow in general.

The lung was edematous and hyperemic.

Microscopic

Central nervous system : The most noteworthy change is the symmetric, large coagulation necrosis, mainly in the white matter, with partial calcification of both temporal lobes, hypothalamus and pons due to cobalt irradiation (Pigs. 6 , 7). In the necrotic part, hemorrhage and lymphocyte and plasma cell infiltration around the blood vessel, of which the wall shows fibrinoid degeneration (so-called angionecrosis) are noted (Fig. 8). Around the necrotic area, gliosis and narrowing of vascular channels are found. The nuclei of the hypothalamus and corpus mammillare show largely slight degeneration and partially necrosis (Fig. 9). The infundibulum shows gliosis and optic chiasm reveals localized necrosis.

Reticuloendothelial system : The spleen qhows chronic congestion and slight hemosiderosis.

Cardiovascular system : The heart muscle fibers are slightly hypoplastic and there are a few muscle fibers with basophilic degeneration.

Respiratory system: The lung is hyperemic, edematous and infiltrated by a great number of neutrophils and lymphocytes, especially in the right upper lobe.

Digestive system: Fatty degeneration of liver cells in the central zone of the lobules is noted, and there are several liver cells with hydropic nuclei. The islets of pancreas, in general, are atrophic and show paucity in number. The alimentary tract reveals no remarkahle change.

Urinary system: In the left kidney, there are numerous abscesses with the surrounding parenchymatous tissue showing degeneration and diffuse neutrophilic and lymphocytic infiltration.

The breasts show atrophy of the acini and lobes (Pig. 10). Ovaries have several folliciilar cysts and few follicles. The endometrial glands

The lymph nodes reveal no particular change.

Slight degeneration of proximal tubules is noted, Sexual organs:

440 LAVRENOE-MOON-BIEDL SMDROME

9. HIRAKI, A. TSUTSUMI AND 5. TSUBOI 441

of the uterus are atrophic. Endocrine organs: The pituitary gland is mostly occupied by the eosinophilic

adenoma and compressed (Fig. 11). The eosinophilic adenoma, being composed of well differentiated columnar cells, shows a papillary arrangement. The cytoplasm is abundant and eosinophilic (Pig. 12). The supporting tissue consists of a few strands of connective tissue around a small blood vessel or capillary. The adrenal cortex shows the exhaustion of lipid. In the thyroid gland, retention of colloid is noted.

Abnormal pigment deposition is almost exclusively in the form of large pigment clumps in the inner layer of the retina (Fig. 13). The inner and outer nuclear layers show marked atrophy.

The parenchyma of the thymus is replaced by fatty tissue. Eyes:

1.

2. 3. 4. 5. 6. 7.

Main Pathological Diagnosis ( A N . 4795)

Laurence-Moon-Biedl syndrome (retinitis pigmentosa, obesity, hypogenitalism and mental retardation). Delayed radionecrosis due to cobalt irradiation, brain. Eosinophilic adenoma, pituitary gland (3.0 a). Acromegaly. Diabetes mellitus. Purulent pyelonephritis, left. Hypoplasia and patent foramen ovale, heart (175 g).

Disczt ssion

The Laurence-Moon-Biedl syndrome is recognized as the symptom complex of retinitis pigmentosa, obesity, mental retardation, polydactylism, hypogenitalism and familial occurrence. In relation to the number of clinical reports of this syndrome, autopsies have been very scarce with only 20 cases having been reported.

BARD9T3 suggested that the syndrome might be caused by the disease of the pituitary gland. LOEPP~' reported that the pituitary tissue was partially replaced by a cyst, and GRIFPITHS,~ ANDERSON,~ BISLAND, MCLOUCHIN~~ and ASANO~

The pathognesis of the syndrome remains still obscure.

Fig. 8. Hemorrhage and lymphocytic infiltration around the blood vessel of which the wall shows fibrinoid degeneration in the delayed radionecrotic part of the temporal lobe. H.E. stain, x 260.

Fig. 9. Slight gliosis in the supraoptic nucleus. Fig. 10. Hypoplasia of the breast. H.E. stain, ~ 4 0 . Fig. 11. Papillary type of eosinophilic adenoma compressing normal pituitary gland.

Fig. 12. Pituitary adenoma cells having acidophilic cytoplasm. Azan-Mallory stain, x 400. Fig. 13. Abnormal pigment deposition in the inner layer and striking atrophy of the

H.E. stain, x 250.

H.E. stain, x 22.50.

nuclear layers of the retina. H.E. stain, x 100.

442 LAURENOE-MOON-BIEDL SYNDROME

described that the ratio of cellular conlponents of the pituitary gland was abnormal.

BIEDL,~ finding the sella turcica normal, rejected the hypophysical theory and postulated that the syndrome was due to a diencephalic lesion. Though the brainin all reported autopsy cases reveals no consistent pattern, minor changes are evident in many cases. For instance, Ross" and GRIFFITHS~ reported slight atrophy of the frontal lobes of the brain, GRIFFITHS,* ANDERSON,' BRATTEGARD' and ASANO~ found slight paucity in number of nerve cells in diencephalon and R I G G S ~ ~ demonstrated the defects in the media of the blood vessels supplying the region of the hypothalamus.

R A A B ~ ~ supposed that a high or massive dorsum sellae was causing pressure on the infundibular stalk, thus disturbing the comunication between the brain and pituitary gland. VAN BOCAENT and BORREMANS~ 6 described some hyalinosis of the pituitary stalk, but these findings have not been described in other autopsy studies.

As mentioned above, all alteration of the diencephalon and telencephalon are not conclusive factors to explain the pathogenesis of the syndrome. Familial occurrence, consanguinity in parents and frequent complication of multiple mal- formations seem to reveal that the syndrome is a hereditary disease. The genetics of the syndrome have been studied by several authors, but their opinions differ as to whether the gene is single or multiple. The high rate consanguinity in parents suggests a single recessive gene and frequent complication of multiple malformations suggests that a single recessive gene acts very early in embryonic life.

In the present case, the hypothalamus was partially necrotic due to delayed radionecrosis, so that the authors could not study it in detail, but the most interesting finding is the complication of this syndrome and pituitary eosinophilic adenoma. The patient's parents and paternal grandparents were consanguineous marriages and her father had retinitis pigmentosa, so thot she had retinitis pigmentosa and mental retardation inherently. Furthermore, pituitary eosino- philic adenoma began to develop from the age of 14 years or before. Consequently, her breasts, uterus and ovaries were disturbed to grow normally and her weight increased gradually. For this reason, the authors believe that the pathogenesis of Laurence-Moon-Biedl syndrome in the present case consists of two factors, namely, a hereditary factor and pituitary eosinophilic adenoma.

No au topey case of Laurence-Moon-Biedl syndrome with pituitary eosinophilic adenoma has been reported up to the present.

Acknowledgement: The authors wish to thank Prof. K. OQAWA snd Prof. K. KOSAKA for their generous support and criticism.

9. HIRAKI, A. TSUTSUMI AND 9. TSUBOI 443

Reference 1. ANDERSON, N.L. : Laurence-Moon-Biedl syndrome ; case report with complete autopsy.

J. Clin. Endocr. 1: 905-911, 1941. 2. ASANO, M., CHINO, F. and KARASAWA, M. : An autopsy case of Laurence-Moon-Biedl

syndrome with renal rickets. Med. J. Shinshu Univ. 8: 3347, 1963. 3. BARDET, G.: Sur un syndrome d’obesite infantile avec polydactylie et. retinitis

pigmentaire. Univ. Paris Thesis 470: 107, 1920. Quoted by Blumel et aE. 4. BIEDL, A. : Geschwisterpaar mit adiposa-genitaler Dystrophie. Dtsch. med. Wschr. 48:

1630, 1922. Quoted by Raab. 5. BISLAND, T.: The Laurence-Moon-Biedl syndrome; report of a typical case with

complete necropsy. 6. BLUMEL, J. and KNIKER, W.T: Laurence-Moon-Biedl syndrome; review of the

literature and a report of five cases including a family group with three affected males. Texas Rep. Biol. Med. 17: 391410, 1959.

7. BRATTQARD, S.O. : The pathology of Laurence-Moon-Biedl syndrome. Acta path. microbiol. scand. 26: 525-537, 1949.

8. GRIFFITHS, G.M. : The Laurence-Moon-Biedl syndrome. A pathologic report. J. Neurol. and Psychiat. 1: 1-6, 1938.

9. KARINO, M. and MATSUOPA, J.: Five cases of Laurence-Moon-Biedl syndrome. Ann. Pediet. Jap. 7: 69-84, 1961.

10. LAURENCE, F.A. and MOON, R.C.: Four cases of “retinitis pigmentosa” occurring in the same family and accompanied by general imperfections of development. Ophthal. Rev. 2: 3241, 1866.

11. LOEPP, W.: Genenseitige Auswertungen der Augen und Rontgensymptome bei der Tumordiagnostik in Sellabereich. Abhandl. a.d. Augenheilk. 23 : 1936. Quoted by Ross et al.

12. MCLOUQHLIN, T.G. and SHANKLIN, D.R. : Pathology of Laurence-Moon-Bardet-Biedl syndrome. J. Path. Bact. 93: 65-79, 1967.

13. OETTLE, A.G., Rabinowitz, D. and Seftel, H.C. : The Laurence-Moon-Biedl Syndrome with germinal aplasia of the testis: report of a case and review. J. Clin. Endocr. 20:

14. OHTSU, S., INOUE, K., WATANABE, T. and TOKOROZAWA, T.: An autopsy case of Laurence-Moon-Biedl syndrome with renal insufficiency. Tr. SOC. Path. Jap. 57 : 78-79, 1968.

15. RAAB, W. : Klinische und rontgenologische Beitriige zur hypophyshren und zerebralen Fettsucht und Genitalatrophie.

16. RIQQS, H.E.: The Laurence-Biedl syndrome occurring in a brother and sister. Arch. Neurol. and Psychiat. 39: 1033-1042, 1938. Quoted by Oettle et al.

17. ROSS, C.F., CROME, L. and MACRENZIE, D.Y. : The Laurence-Moon-Biedl syndrome. J. Path. Bact,. 72: 161-172, 1956.

18. VAN BOQAERT, L. and BORREMAN, P. : La forme familiare de la r6tinite pigmentaire avec c6cit6 et ob6sit,6 dite c8r6bmle. Ann. de m6d. 39: 54-74, 1936. Quoted by McLoughlin et al.

h e r . J. Ophthal. 34: 874-884, 1951.

683-699, 1960.

Wien. Arch. f. inn. Med. 7: 443-530, 19234.