274

CLAY: Laurence-Moon-Biedl Syndrome

The eighth case is that of an eye that in life was hard, whereas in most cases of intra-ocular tuberculosis the eyes become soft. The pupil is wide, and at its margin there is a pathologic ectropion of the uvea. Much of the ciliary body and choroid is replaced by a diffuse tuberculous process resembling diffuse sarcoma of the choroid. The ninth case, one of tuberculosis of the cornea, is exhibited in order to demonstrate that whereas tuberculosis of the cornea may appear clinically to be an independent disease, yet under the microscope it is almost always shown to be an extension from a focus in the ciliary body. The tenth case is an instance of conglomerate tuberculosis of the choroid that fills almost the entire vitreous cavity, and yet the anterior segment of the eyeball shows only the mildest inflammatory reaction. The damage done to the tissues of the eye by tuberculosis is not so much by the exertion of any great toxic action as it is by the power to erode and to replace tissues.

LAURENCE-MOON-BIEDL SYNDROME *
GRADY E. CLAY, M.D.
Atlanta, Georgia

In 1866 Laurence and Moon described a disease characterized by adiposity, genital dystrophy, retinitis pigmentosa, and mental deficiency, affecting four members of one family. In 1920 Bardet described a similar syndrome in a child with polydactylia. In 1922 Biedl reported a similar condition in a brother and a sister. In 1925 SolisCohen and Weiss suggested the name Laurence-Moon-Biedl syndrome for this condition. Since that time few ophthalmologic studies have appeared, although in the general literature there are 36 articles describing 80 cases. The following three cases are typical illustrations of the
* Candidate's thesis for membership accepted by the Committee on Theses.

Case 1.

Case 1.
Left eye. Photograph of fundus.

Case 2.

Case 2.

Right eye. Photograph of fundus.

CLAY: Laurence-Moon-Biedl Syndrome

275

syndrome, showing obesity, infantile genitalia, polydactylism, syndactylism, polyuria, and so-called retinitis pigmentosa.

CASE REPORTS CASE 1.-History.-A white boy, aged twelve years, was seen January 15, 1933. The patient complained of poor vision and obesity. He had been overweight since infancy. The parents first noticed, when he was about eighteen months of age, that his sight was poor, especially at night. His vision had gradually grown worse, until he was now virtually blind at night. He had steadily gained in weight and had had slight polyuria for years. The parents were in good health. They were second cousins. One sister, aged seventeen years, was free of any pathologic changes of the eye and obesity. One brother (Case 2) showed the same syndrome as this patient, and there was a cousin who presented a similar condition (Case 3). The patient was born at full term, with normal delivery, and weighed seven pounds. Dentition began at six months, speech at eight months, and walking at eighteen months. The child reached the third grade in school, but had to discontinue because of poor vision. The general health had been good except for an attack of scarlet fever.

Physical Examination. -The patient was markedly obese. The

skin was dry, fine, and slightly scaly in areas, and felt warm to the touch. -There were several areas where the veins were enlarged, especially over the back, above the breasts, and over the lower abdomen and thighs. The hairline was somewhat low on the brow and was irregular. There was a moderate growth of hair on the forearms and lower legs. The hair appeared to be of the usual texture and was dry. No pubic or axillary hair was present. There were well-defined deposits of fat, especially marked over the lower abdomen, breasts, hips, and thighs. There were no subclavicular pads, but there was a small pad over the last cervical vertebra. The penis was fairly short and seemed to be somewhat hooded beneath a well-developed mons. The testicles were of fair size. The polydactylism was of interest. On the right hand, at the base of the fifth finger, there was a small protrusion, the site of amputation of an extra finger. This protrusion was made by a small piece of bone which was clearly seen with the x-ray. The left hand showed no extra finger. At the base of the little toe, on

276

CLAY: Laurence-Moon-Biedl Syndrome

both sides, there were scars showing the site of amputation of extra toes. The second and third toes were not well separated. The fourth and fifth toes were distinctly separated. On the right foot the fifth toe was curled over the fourth. The hands were short and stumpy. The fingers were broad at the tips. There was a suggestion of clubbing at the base of the nails. There was a welldefined lordosis, which seemed to be the result of the effort of carrying about so large a panniculus. No abnormalities could be detected in the lungs. Except for a faint systolic murmur heard at the apex, the heart was normal. The liver and spleen were not palpable. Intelligence and Temperament.-The patient was definitely feebleminded. He manifested but slight interest in the examination and lay on the table in a semisomnolent state. He was extremely docile, was not very talkative, and exhibited no curiosity in the various procedures. He cried moderately during an injection, but made no resistance. The neurologic examination was negative. The blood examination was normal, and the blood Wassermann was negative. Following the administration of 80 gm. of dextrose in 200 c.c. of water a sugar tolerance test was made. The fasting level was 125 mg. The blood calcium was 10 mg. per 100 c.c. The urine was normal. The basal metabolism was minus 11. Roentgen-ray examination of the head gave normal findings. All the long bones were found to be thick; this abnormality was also observed in the fingers and toes. Opposite the head of the right and left fifth metatarsal was a fragment of bone, the remains of an accessory toe which had been amputated. A similar fragment was also present on the right hand. Roentgen-ray examination of the chest and heart gave normal findings. Eye Examination.-V.R.E.=6/36; L.E.=6/60. The pupils were normal. There was a slight horizontal nystagmus. The extra-ocular muscles were normal, as were also the tension and the external findings. Refraction; Each eye, -1.00 sph. _-4.00 cyl.
ax. 1800=6/36.

Ophthalmoscopy.-Under a mydriatic, the pupils dilated evenly

and were round. Right Eye: The media were clear; the nerve head was decidedly oval, with the long axis at 900; the physiologic cup was shallow; the lamina cribrosa was not seen; the peripapillary rings were faint; the arteries and veins were extremely small-about one-

CLAY: Laurence-Moon-Biedl Syndrome

277

third the size of normal. The most striking change in the fundus was the marked chorioretinal atrophy, which was especially noted around the disc border, and in this area a large number of posterior vortex veins were seen. The choroidal vessels were very distinct throughout, and between these vessels brown pigment was present. No pigment was seen in the retina. In the macular region the retina appeared to be intact and the choroidal vessels were not visible. Otherwise the chorioretinal atrophy seemed to be uniform throughout the fundus. Left Eye: The fundus changes were similar to those described in the right eye, except that the vortex veins opposite 9, 12, and 3 o'clock were much larger than those seen in the right eye. Fields. -There was a contraction down to 100, with no color perception, using a 10-degree test object. The inhalation of amyl nitrite had no effect on the retinal blood vessels. CASE 2.-This patient, a white male, aged nine years, was a brother of Case 1. He complained of poor vision and was quite obese. Present Illness. -The patient had been overweight since infancy, and the obesity had gradually increased. At about eighteen months of age the parents noticed the poor vision, especially in the dark, and this had gradually increased. There had been moderate polyuria. Physical Examination.-The obesity was not so striking as in the older brother, although the patient was still overweight. The skin was fine, dry, slightly scaly, and warm. The plexus of veins was not so well developed as in the brother, but it was visible, especially over the back and thighs. The hair line was low on the brow. There was a normal amount of hair on the forearns and on the lower legs. The hair was dry and its texture was normal. The obesity was characterized by marked deposits of fat over the lower abdomen, thighs, and calves, with pads over the axillae and breasts. There were pads above the clavicles, and also a small pad was observed over the last cervical vertebra. The cheeks were quite full and loose. The genitalia were strikingly infantile, and the right testicle was atrophic. The penis was extremely small and the mons was well developed. He seemed to be well proportioned for his age. Polydactylism appeared only on the left foot, where an extra toe had been amputated on the inner surface of the fifth toe at the base. The fingers were short and broad at the tips. The

278

CLAY: Laurence-Moon-Biedl Syndrome

skin at the base of the nails was thickened, wrinkled, and slightly darkened; the nails suggested clubbing. There was definite lordosis of the lower spine, but no lateral curvatures. The thorax was large, and the costal angle was at 900. The muscular power was good, and there was no relaxation of the ligaments. The lungs were normal, and the heart was normal except for a faint systolic murmur heard at the apex. The abdomen was relaxed, and the liver and spleen were not palpable. Intelligence and Temperament. -The patient's intelligence was definitely impaired, but he was much more alert than this brother. He was somewhat talkative and showed some interest in the procedures. He was extremely docile and cooperative. Physical Examination.-The neurologic examination was negative. The blood and the urine examinations were normal, as were those of the blood sugar and calcium. Roentgen-ray examination of the head showed a slight convolution atrophy of the inner table, somewhat greater than is seen in a normal child. The sella turcica appeared to be normal. The long bones were similar to those described in the preceding case. Eye Examination. -The vision of each eye was 6/36. The pupils were normal. There was a slight horizontal nystagmus. Muscle excursion, tension, and external examinations were normal. The refraction for each eye was: -0.50 sph. -1.25 cyl. ax. 1800 =6/36.
-

Ophthalmoscopy.-The pupils dilated evenly and were round. The media were clear; the nerve heads were oval, with the axes at 900; they were slightly pale; the physiologic cups were deep; the laminae cribrosa were distinct; the arteries and veins were extremely small-about one-half the size of normal. The chorioretinal atrophy was marked throughout the entire fundi, especially around the disc margins. In the left eye there was a large posterior vortex vein opposite 9 o'clock and several smaller ones around the disc border; the choroidal vessels were slightly more distinct than those in the fundus of his brother (Case 1). No retinal pigment was seen anywhere. In the macular region there was a small area of retina that appeared to be intact. Fields.-There was a contraction to 150 with a 10-degree test object. There was no color perception. The inhalation of amyl nitrite had no effect on the retinal blood vessels. CASE 3.-A white male, aged four years, was first seen on July 13, 1932. He had had convulsions for three months and hemeral-

Case 3.

CLAY: Laurence-Moon-Biedl Syndrome

279

opia for two years. He weighed 12 pounds at birth and his weight had gradually increased until now he weighed 62 pounds. The parents (who were second cousins) were normal in stature and were in good health. He had one brother and three sisters who were in good health. Physical Examination.-The child was well developed. The obesity was of the pituitary type, with marked deposits of fat over the abdomen and thighs and over the axillae and breasts. The genitalia were small and undeveloped. The fingers and toes were pudgy, and were about the same size and length. The second and third toes of each foot were webbed. Other physical findings were normal. According to the Binet-Simon test, he was about normal, but had a tendency to perseveration, which was interpreted as possibly indicative of cortical nervous deficiency. The blood examination was normal, including sugar, calcium, and Wassermann. The spinal fluid and urine examinations were normal. An encephalogram showed that the ventricles were normal in shape, but slightly larger than usual. The fluid pathways over the brain were normal. The patient remained in the hospital for one week, during which time he had about 10 convulsions, most frequently confined to the left side of the body, each attack lasting about two minutes. Under treatment with luminal these convulsions were gradually controlled. On January 15, 1933, the patient returned. The convulsions had ceased, and he had lost 10 pounds in weight. Eye Examination.-Vision, each eye, = 6/24. The pupils reacted normally; the muscle excursions and tension were normal. There was an extremely slight nystagmus. Ophthalmoscopy.-Each eye: The media were clear; the nerve head was oval, with the axis at 900; peripapillary rings were present; a physiologic cup was present; the nerve head was of normal color. Arteries and veins were about half the normal caliber. The choroidal vessels were distinctly seen throughout the fundus, except in the macular region; they were especially distinct around the nerve head, where several posterior vortex veins were visible. Distributed between the choroidal interspaces was a moderate amount of fine brownish pigment. The retina was atrophic and no retinal pigment could be seen. The whole macula was extremely granular. The fields were markedly constricted.

280

CLAY: Laurence-Moon-Biedl Syndrome

The injection of acecoline and the inhalation of amyl nitrite had no effect on the retinal blood vessels.

Clinical Summary.-The diagnosis of the Laurence-MoonBiedl syndrome was very evident, since the three cases reported presented adiposity, sexual dystrophy, polyuria, mental deficiency, polydactylism, and so-called atypical retinitis pigmentosa. The night blindness and the fundus findings are typical of the majority of the cases reported. In these cases the optic nerve showed no atrophy. Consanguinity of parents, mentioned in these cases, is also reported in three other families who presented LaurenceMoon-Biedl syndrome. The roentgenograms, with reference to the sella, and the laboratory examinations were normal.
THEORIES SUGGESTED The early writers suggested that the pituitary gland was responsible for this disease. Biedl, in 1922, reporting three cases, found the sella turcica to be normal and considered that the disease was due to a lesion in the diencephalon. Raab, in 1924, reviewing 38 cases, stated that the hypophysis played a material r6le in the genesis of this condition. He suggested a mechanical factor, namely, that a high or massive dorsum sellae caused pressure on the infundibular stalk and disturbed the passage of secretion from the posterior hypophysis to the floor of the third ventricle, where metabolic centers are located. It was his opinion, however, that the syndrome may develop independently of the hypophysis, as the result of a direct lesion of the trophic centers in the floor of the third ventricle, or as a result of encephalitis, tumors, tubercles, gummas, and trauma in the region of the hypophysis. Congenital malformation may also produce it. Ornsteen, in 1932, explained the frequent association of obesity, genital dystrophy, and retinitis pigmentosa on the basis of a developmental defect of the ectopic zone of the

CLAY: Laurence-Moon-Biedl Syndrome

281

prosencephalon, since the hypothalamus, infundibulum, optic chiasm, and retinal fibers take their origin from the ventral segment, and the end brain takes its origin from the cephalic segment of the ectopic zone of Schulte. The other developmental abnormalities, namely, polydactylism, skull deformities, atresia ani, and others, are the result of the coupling of defective somatic genotypic characters. Ornsteen believes that the optic atrophy is produced by the chiasmal defect, and that the retinitis pigmentosa is due to a disturbance of the efferent fibers of the optic nerve, which probably govern certain chemical changes in the retina and also the movement of pigment in the retina.
THE HYPOTHALAMUS The mass of clinical and experimental proof definitely localizes the hypothalamus as the controlling station for certain vegetative functions, namely, metabolism (fat, carbohydrate, water), sex development, temperature regulation, vasomotor control, centers for gland control, and others, and in much of this function the hypophysis and these autonomic centers act as a unit. The autonomic functions of the hypothalamus involve such known centers as the tuber cinereum, corpus subthalamicum, nucleus mammillo, infundibularis, and nucleus paramedianus. The tuber cinereum includes: (a) the substantia grisea centralis; (b) the nucleus supra-opticus, and (c) the nucleus paraventricularis. It has been demonstrated by animal experimentation (Camus and Roussy in 1920, Bailey and Bremer in 1921) that lesions restricted to the tuber cinereum produce polyuria, adiposity and sexual dystrophy, and fat metabolism; and that the paraventricular nuclei contain a center for the regulation of water metabolism, polyuria, and transient glycosuria (Roussy in 1925). The only function which is attributed to the hypophysis is the regulation of the growth of the skeleton, which could not be influenced by- artificial

282

CLAY: Laurence-Moon-Biedl Syndrome

lesions of the tuber region (Roussy). Cases of encephalitis and of brain tumors located in the region of the third ventricle (Cushing) present marked adiposity, glycosuria, polyuria, and sexual dystrophy, further substantiating the belief that these centers control such phenomena. Urechia and Elekes, in 1925, examined a case of adiposo-genital dystrophy and polyuria microscopically, and found the hypophysis normal and a marked inflammatory lesion in the tuber cinereum. The mechanism and control of vasomotor function have not been determined definitely. There appear to be centers in the hypothalamus, however, which control vasodilator and vasoconstrictor action. Pilocarpin and pituitrin have been injected into the human ventricles (Cushing), and electrical stimulation has been applied to an area in the floor of the fourth ventricle (Billingsley), and both experiments caused vasodilatation. It was Cushing's belief that the vasodilatation was due to stimulation of the hypothalamus, and that the neurohypophysis bears the same relation to the parasympathetics that the adrenal medulla does to the sympathetic division of the vegetative nervous system. The efferent nerve fibers to the retina control the movement of pigment in the retina and certain chemical changes (Arey, Tilney, and Riley). Arey, in 1916, states that he has shown in fish: "Experimental physiologic proof for the existence of two distinct components of a mechanism, through the balanced action of which the movements of the visual cells and retinal pigment are alone possible. One component involves the efferent nerve fibers of the optic nerve, the second component (possibly autonomic nerves) is closely associated with the eye muscles. This latter set of nerve fibers exerts a constant inhibition upon the movements of the retinal elements, while the impulses in the efferent optic nerve fibers, on the other hand, serve only as a block to this tonic inhibition, thus allowing photomechanical re-

CLAY: Laurence-Moon-Biedl Syndrome

283

sponses to occur." Thus on section of the optic nerve these movements fail to occur, because they are inhibited by oculomotor nerve impulses; however, stimulation of the peripheral and of the severed optic nerve will overcome the inhibition and movements of these elements will then occur. Karplus and Kreidl, in 1909, located a center in the hypothalamus for the reflex dilatation of the pupil and the control of the small musculature of the eye.
EYE FINDINGS The ocular report by Laurence and Moon is the most complete of all recorded, and their fundus description could apply to the three cases here reported. These observers stated that the title of their paper should have been "Four Cases of Arrest of Development and Atrophy of the Eye," and that the arrest of development was by no means confined to the eye, but affected several other organs of the body. The ocular findings of the cases presented in the literature vary. The majority were described as atypical retinitis pigmentosa; about 15 per cent. were cases of true retinitis pigmentosa, and in a few of these the findings were those of retinitis punctata albescens. In Lisser's case, reported in 1929, the retinal vessels were extremely small and in the periphery pigment was noted along the course of these vessels; in addition, the chorioretina was atrophied; nevertheless he called the case one of retinitis punctata albescens! De Schweinitz, in his Bowman lecture, makes brief mention of three cases associated with pituitary disease. Velhagen, in 1932, reported three cases of atypical retinitis pigmentosa; in two of these there was maculocerebral degeneration, and one case he classified as Laurence-MoonBiedl syndrome. He states that the eye findings of these two conditions are identical and that the two diseases can be differentiated only by their neurologic findings. This is

284

CLAY: Laurence-Moon-Biedl Syndrome

the only reference that I have found indicating a similarity of these conditions. Reilly and Lisser, in 1932, reported four cases, three of which apparently were atypical retinitis pigmentosa; the fourth case showed unusual findings for this syndrome, namely, vitreous hemorrhages with detachment of the retina and white exudates with splotches of pigmentary infiltration. The discs were pale. No opinion was given for this unusual fundus picture. In Ornsteen's report the eyes showed a so-called atypical retinitis pigmentosa. Quoting his description: "The optic discs were grayish; the vessels reduced in size; the retina showed a pigmentary degeneration of atypical character with an uncovering of the choroidal circulation." The disturbance of sight, especially night blindness, is generally the first symptom to attract attention to some disease process which has usually dated from infancy. Six cases apparently began later; for instance, in a report by McCrae and Weiss the patient was normal until he was four years of age, when, following an acute illness with high fever for four months, he developed atypical retinitis pigmentosa. Optic atrophy is frequently mentioned, but the type is not clearly defined; apparently in all cases atrophy is a final complication. The development of the atypical retinitis pigmentosa in this syndrome is believed to be due to heredity, consanguinity, or an heredodegeneration, to which amaurotic family idiocy belongs (Serejski). Ornsteen was the first investigator definitely to give some pathologic basis for the production of the retinal atrophy. He was of the opinion that the efferent nerve fibers in the optic nerve which govern certain chemical changes and pigment movement in the retina are involved in the hypothalamic lesion, which results in atypical retinitis pigmentosa.

CLAY: Laurence-Moon-Biedl Syndrome

285

Nystagmus has been reported in all cases, and although no mention has been made concerning the type,-whether ocular or central, -one might consider it of central origin since nystagmus has been observed prior to definite visual disturbance. The frequent occurrence of myopia in this group is an observation that deserves further study and may lead to the explanation of the marked atrophy of the pigment layer and certain choroidal changes so frequently seen in high myopia. The eye findings in this syndrome are similar to the cerebromacular degeneration of the Tay-Sachs, the Spielmeyer, and the Vogt types, to retinitis pigmentosa, to retinitis punctata albescens, and to certain reports of acromegaly and cretins with retinitis pigmentosa. There is also a certain similarity to some of the reported cases of choroideremia and atypical retinitis pigmentosa due to syphilis, so it seems possible that this entire group may be classified as one and the same disease, having the same etiologic basis but differing in type.

DISCUSSION The Laurence-Moon-Biedl syndrome is most often a familial disease. The reports of cases following encephalitis and occurring later in life would show that it is not necessarily a hereditary disease. Consanguinity does not play an important part in this group, as it is mentioned in only three instances and could not be an etiologic factor of much importance. Experimental studies and the clinical reports of a large number of cases showing adiposity, sexual dystrophy, atypical retinitis pigmentosa, and mental deterioration would indicate that the pathologic lesion explaining these phenomena lies in the hypothalamus. It has been asserted by Arey that efferent retinal nerve fibers control the movements of the retinal pigment. A lesion, therefore, in the nuclei controlling these nerves might

286

CLAY: Laurence-Moon-Biedl Syndrome

explain the marked atrophy of the retinal pigment layer and the migration of pigment into the retina. The most striking pathologic fundus changes observed in these cases are the atrophy of the pigment layer of the retina and the contracted caliber of the retinal and choroidal vessels. The vessels appear to contract gradually or to become atrophic, ultimately becoming thread-like. The question, therefore, arises whether this vascular change is the result of tissue atrophy or of a primary disease of the vasomotor mechanism. In the cases that I have reported the inhalation of amyl nitrite and the injection of acecoline had no effect on the retinal circulation that could be observed by the ophthalmoscope and by measurements of the retinal blood vessels from repeated photographs of the fundus. From these experiments one might infer that there was a disturbance of the vasomotor mechanism. Such a disturbance of the vascular supply could bring about a disturbance of metabolism, with its accompanying degeneration of the retina and choroid. The fact that the macula is first disturbed in some cases and in others is left intact might be explained on the basis that this area has an independent autonomic vasomotor control. The chorioretinal atrophy is responsible for the secondary optic atrophy which in most cases ultimately develops. The rapid development of an optic atrophy, as has been described in some cases, would indicate a degeneration of the primary visual ganglia. The final solution awaits a complete pathologic study of both eye and hypothalamic changes in persons showing Laurence-Moon-Biedl syndrome.

CONCLUSIONS 1. The Laurence-Moon-Biedl syndrome can now be regarded as a disease entity characterized mainly by adiposity, sexual dystrophy, and atypical retinitis pigmentosa.

CLAY: Laurente-Moon-Biedl Syndrome

287

2. The ocular findings in this group are similar to those of retinitis pigmentosa, maculocerebral degeneration, and certain reported cases of atypical retinitis pigmentosa associated with acromegaly, cretinism, and syphilis. 3. The atrophy of the pigment layer of the retina, with its accompanying pigment deposits in the retina, is probably associated with a lesion involving the nuclei of the efferent nerve fibers of the retina. 4. The vascular changes are probably associated with nuclear lesions controlling the vasomotor autonomic mechanism of the intra-ocular vessels. 5. In most cases an optic atrophy is secondary to the chorioretinal atrophy. 6. The term chorioretinal atrophy with or without retinal pigment best describes the fundus lesion as it occurs in this syndrome. I wish to thank Dr. William H. Kiser for referring Cases 1 and 2 to me, and for the complete physical study of all three patients; Dr. William A. Smith for referring Case 3 and for the complete neurologic study of all patients; and Dr. Mason Baird for making the photographs of the fundi.
REFERENCES
Laurence and Moon: Brit. Ophth. Rev., 1866, ii, p. 32. Jacobshon: Klin. Monatsbl. f. Augenh., 1888, xxvi, p. 202. Cutler: Arch. f. Augenh., 1894, xxx, p. 117. Fuchs, E.: Arch. f. Augenh., 1896, xxxii, p. 11. Bednarski: Arch. f. Augenh., 1899, xl, p. 420. Hutchinson: Arch. Surg., 1900, xi, p. 118. Grossman: Wien. med. Wchnschr., 1908, lix, p. 742. Kruckman and Meyer: Deutsche med. Wchnschr., 1908, xxxiv, p. 574. Nettleship: Roy. Lond. Ophth. Hosp. Rep., xvii. Nettleship: Tr. Ophth. Soc. U. Kingdom, 1909, xxxix, p. 57. von Jaksch: Med. Klin., 1912, viii, p. 1931. Malone: Anat. Record, 1912, vi, p. 281. Rozabetl-Farnes: Rev. clin. de Madrid, 1913, ix, p. 401. Bertolotti: Gior. d. r. Accad. di med. di Torino, 1914, xxx, p. 6. Komoto: Klin. Monatsbl. f. Augenh., 1914, lii, p. 416. Arey: J. Comp. Neurol., 1916, xxvi, p. 213. Schweitzer: Soc. Argentina de Pediatria, September 22, 1917. Madigan and Moore: J.A.M.A., 1918, lxx, p. 669. Hansen: Hospitalstid., 1920, lxiii, p. 417. Bardet: These de Paris, 1920, cvii, p. 470.

288

CLAY: Laurence-Moon-Biedl Syndrome

Camus and Roussy: Endocrinology, 1920, iv, p. 507. Variot and Bouquier: Gaz. d. h6p., 1920, xciii, p. 613. Chaillous: Ann. d'ocul., 1921, clvii, p. 100. Bailey and Bremer: Endocrinology, 1921, v, p. 761. Meissner: Klin. Wchnschr., 1922, i, p. 497. Biedl: Deutsche med. Wchnschr., 1922, xlviii, p. 1630. Rosenstein: Klin. Monatsbl. f. Augenh., 1922, lxviii, p. 204. Baily: Ergebn. d. Physiol., 1922, xx, p. 163. Bremer: Bull. Soc. Roy. d. M6d., Bruxelles, 1923, viii, p. 129. de Schweinitz: Tr. Ophth. Soc. U. Kingdom, 1923, xliii, p. 12. Raab: Wien. Arch. f. inn. Med., 1924, vii, p. 443. Borschardt: Inkretologie, 1927, Bayer u. van den Belden, Leipzig; Elin. Konstitutionlehre, Berlin u. Wien, 1924. Frigerio: Zentralbl. f. d. ges. Ophth., 1925, xiv, p. 634. Sols-Cohen and Weiss: Am. J. M. Sc., clxix, p. 489. McAlpine: Brain, 1925, xlviii, p. 140. Denzler: Ztschr. f. Kinderh., 1925, xxxix, p. 104, Deusch: Deutsche Ztschr. f. Nervenh., 1925, lxxxvii, p. 117. Timme: Assn. Res. Nerv. & Ment. Dis., 0. B. Hoeber, Inc., New York, 1925, p. 6. Urechia and Elekes: Rev. neurol., 1925, xxxii, p. 330. Roussy: Ann. de m6d., 1925, xviii, p. 407. Collin: Ibid., 1925, xviii, p. 428. Zondek: Die Krankheiten der endokrinen Drusen, Berlin, 1926. Beck: Endocrinology, 1926, xiii, p. 375. Lange: Allg. Ztschr. f. Psychiat., 1927, lxxxvi, p. 398. Ratner: Monatschr. f. Psychiat. u. Neurol., 1927, lxiv, p. 283. Bauer: Innere Sekretion, 1927. Ransom: Anatomy of the Nervous System, W. B. Saunders Co., Philadelphia, 1927, Ed. 3, p. 225. Ricaldoni and Isola: Bull. et m6m. Soc. m6d. d. hop. de Paris, 1928, lii, p. 131. Boenheim: Endokrinologie, 1928, iv, p. 263. Bernhardt: Ztschr. f. kli. Med., 1928, cvii, p. 488. De Cyon: Bull. Acad. de m6d., Paris, 1928, xl, p. 444. Rieger and Trauner: Ztschr. f. Augenh., 1929, lxviii, p. 235. Bech: Endocrinology, 1929, xiii, p. 375. Lisser: Ibid., 1929, xiii, p. 533. Serejski: Med. Klin., 1929, xxv, p. 1620. Cushing: Lancet, July 19 and 26, 1930. Jennings: The Biological Basis of Human Nature, Norton, New York, 1930. Bailliart and Schiff-Wertheimer: Bull. Soc. d'opht. de Paris, 1931, xliii, p. 350. Griffiths: J. Neurol. & Psychopath., 1931, xii, p. 53. McKinney: J. Nerv. & Ment. Dis., 1931, lxxiv, p. 50. Orgaz: Rev. Med. Latino-Am., 1931, xvi, p. 966. Turner: J. Oklahoma M. A., 1931, xxiv, p. 148. McCrae and Weiss: M. Clin. N. Amer., 1931, xiv, p. 825. Bing: Norsk. Mag. f. Laegevidensk., 1931, xcii, p. 933; Abst. J.A.M.A., 1932 xcviii, p. 440. Velhagen: Klin. Monatsbl. f. Augenh., 1932, Lxxxviii, p. 825. Cushing: Pituitary Body and Hypothalamus, C. C. Thomas, 1932. Weiss: Am. J. M. Sc., 1932, clxxxiii, p. 268. McGuire: Arch. Ophth., 1932, viii, p. 372. Lyle: Am. J. Ophth., 1932, xv, p. 1165. Ornsteen: Am. J. M. Sc., 1932, clxxxiii, p. 256. Weiss: Endocrinology (to be published).