A new oculocerebral syndrome with hypopigmentation

A new oculocerebral syndrome with hypopigmentation

398 March, I967 T h e Journal o[ P E D I A T R I C S A new oculocerebral syndrome with hypopigmen tat ion During the course o[ a survey/or neurologi...

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398

March, I967 T h e Journal o[ P E D I A T R I C S

A new oculocerebral syndrome with hypopigmen tat ion During the course o[ a survey/or neurologic disorders in a genetic isolate, three sibs with an unusual oculocerebral syndrome were [ound. The syndrome is mani[est at birth by cutaneous hypopigmentation and severe ocular anomalies. Spasticity, mental retardation, and athetoid movements become apparent at several months o[ age. Genetic evidence suggests autosomal recessive inheritance. Since no cases have been reported with a similar combination o[ findings, this [amily is believed to represent a "new" genetic disorder.

Harold E. Cross, M.D., ~ Victor A. McKusick, M.D., a n d W i l l i a m Breen, M.D. ~ BALTIMORE~

MD.

H ~ a :~ L V I N ~ a E e populations are likely to c o n t a i n a n increased n u m b e r of persons with rare recessive disorders. H a n h a r t 1 was one of the first investigators to emphasize the value of isolates for certain genetic studies. Subsequent reports 2, ~, ~ have corroborated this view. D u r i n g the course of a survey for genetic disorders in a population isolate, several rare a n d previously undescribed hereditary neurologic disorders were f o u n d 2 This report presents a family in which 3 sibs were affected with a syndrome of m e n t a l retardation, ocular anomalies, spastic diplegia, a n d cutaneous h y p o p i g m e n t a t i o n resembling albinism. This c o m b i n a t i o n has not been reported previously a n d is believed to represent a "new" genetic disorder. From the Division of Medical Genetics, Department of Medicine, Johns Hopkins University School of Medicine. Supported in part by Grant No. M.25.6374 [rom the National Institutes of Health. "~Address, The Moore Clinic, Johns Hopkins Hospital, Baltimore, Md. 21205. ~-Present address, Buffalo General Hospital, Buffalo, N. Y.

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CLINICAL DESCRIPTIONS Case 1. T. K. (J. H. H. 1t51654), a girl born July 1, 1953, was the product of an uncomplicated 9 month pregnancy. Labor was said to have been lon~ and delivery was aided by forceps. Birth weight was 8 pounds; there were no difficulties in the neonatal period. However, the lack of skin and hair pigmentation was apparent at birth, and the eyes were noted to be small and "cloudy." At 3 months of age the patient manifested writhing movements of the extremities, with constant sucking sounds interrupted by high-pitched, weak cries. She never developed physically or mentally and never achieved normal milestones such as head holding, sitting alone, walking, etc. At 2 years of age she weighed 9.5 kilograms. Her weight remained nearly constant until age 10 when, following initiation of a blenderized diet, she grew slowly to her present length of 102 cm. and weight of 16 kilograms, both measurements being far betow the third percentile. She has never manifested normal behavior, and all her reactions have remained infantile. The development of flexion contractures in the last several years has made custodial care more difficult. The mother indicates that the patient appears to recognize her

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Oculocerebral syndrome with hypopigmentation

voice but otherwise shows no comprehension of her environment. Total blindness has been present since birth. She has had no seizures. The patient had measles and ehickenpox without serious sequelae. She had one bout of pneumonia and two eye infections of an unknown nature. She has frequent gingival infections and has bed sores much of the time. On admission to the Johns Hopkins Hospital on April 2, 1965, the patient (Fig. 1A) was a pale, underdeveloped, and undernourished female who was severely retarded and incapable of any cooperation. Her skirt was pale and yellowish white, but several darkly pigmented nevi were apparent over the back, buttocks, and thighs. Her hair was also white, with a faint yellow tinge. The skull appeared dolichocephalic, normal in size, and proportional to body size. Head circumference was 52 cm. The palate was highly arched. The thoracic spine was slightly scoliotic and mild hallux valgus was present. Cardiovascular and abdominal examinations uncovered no abnormalities. Secondary sexual characteristics were undeveloped. OphthalmoIogic examination. Both lower lids showed a spastic ectropion with marked injection of the exposed palpebral conjunctivae (Fig. 2A). The globes were small and the corneal borders could not .be located because of extensive opacification and vascularization of both corneas (Fig. 2B). A direct beam of light produced no perceptible reaction. Both eyes manifested coarse, jerky movements which could not be further characterized because of poor cooperation. The fundi could not be visualized due to extensive corneal opacification. Neurologie examination. The patient was severely retarded and reacted only by smiles or shrieks. When she was undisturbed, her head was hyperextended and she would make sucking noises and flail her arms and legs about aimlessly. Severe spasticity and flexion contractures were present in both knees, elbows, and shoulders, and the right thigh was maintained in an abducted position (Fig. 1A). Her hands, fingers, and toes manifested almost constant, slow, writhing movements. Skeletal musculature was poorly developed and no fasciculations or dystonic movements were apparent. All deep tendon reflexes were symmetrically exaggerated, and plantar responses were extensor bilaterally. No clonus could be elicited. Bilateral grasp and sucking reflexes were present. The gag reflex was intact, and the patient was able to swallow

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Fig. 1. Photographs of affected individuals demonstrating hypopigmentation and retardation. Dark areas on the extremities represent self-inflicted bruises. A, Patient 1, showing flexion contractures and severe growth retardation. B, Patient 2, demonstrating exaggerated Moro reflex. Note the extended toes. C, Patient 3, the boy who shows less retardation and hyperexcitability than his two older siblings. without difficulty. Sensory examination was inadequate, but there was prompt withdrawal to painfuI stimuli. Laboratory findings. Routine blood and urine analyses were normal. The sleep electroencephalogram showed some transient asymmetries but was interpreted as essentially normal. Paper chromatography of urine revealed a normal pattern. Fasting serum phenylalanine level was less than 0.1 mg. per cent, and fasting serum tyrosine level was 2.6 mg. per cent, both values being within the normal range. Case 2. P. K. (J. H. H. 1151325) is a boy who was born at home July 13, 1962. Pregnancy had been complicated only by a trace of bleeding in the first trimester. Delivery was apparently

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Fig. 2. A, Photograph of the eye in Patient 1 showing the microphthalmos and spastic ectro.pion. B, Ocular anomalies in Patient 1. The bulb is turned slightly upward and the area containing the questionable cornea is the darkened area just below the upper lid. C, Ocular anomalies in Patient 2. The globe is turned medially and the darkened area containing the poorly delineated cornea is partially visible. uncomplicated and birth weight was 8 89 pounds. "Cloudy" eyes and hypopigmentation, similar to the findings in Patient 1, were evident at birth. At several months of age, the patient was noted to be abnormally slow in development and shortly thereafter developed "spasms" and in-

The Journal of Pediatrics March 1967

voluntary writhing movements in the extremities. However no frank seizures have been noted. The patient has remained blind and has never walked, talked, or sat alone. The patient had measles, mumps, and chickenpox without sequelae, and one mild episode of pneumonia. He has received no immunizations. On admission to the Johns Hopkins Hospital on April 2, 1965, the patient was a severely retarded, hypopigmented boy, with slight growth retardation (Fig. 1B). His length (88 cm.) was in the third percentile, but his weight (10.5 kilograms) was below the third percentile. His head was normally shaped with a circumference of 51 cm. The skin was a pale yellow color without pigmented nevi; a small capillary hemangioma was present at the base of the skull. Hair pigmentation was extremely light, although there were rare, darkly pigmented strands. Ears and mouth were normal except for small, widelyspaced teeth and a highly arched palate. Examination of the chest and abdomen revealed no abnormalities. The extremities were normal. A normal, infantile penis was present but no testes could be palpated either in the scrotum or in the inguinal canal. Ophthalmologic examination. Both eyes showed an ectropion of the lower lids with marked injection of the palpebrat conjunctivae, narrow lid fissures, and small, recessed globes (Fig. 2C). Occasional gross, rhythmical eye movements were noted. There was no detectable response to bright light. A small oval area identifiable as cornea was noted, although it was opaque and its borders were poorly delineated. No fundal view could be obtained and no iris was visible. Neurologic examination. The patient appeared retarded; he responded to handling with smiles. In response to the slightest stimulus, he exhibited an extremely brisk startle (Moro) reflex (Fig. 1B), with extension of the arms, flexion of the lower extremities, and extension of the great toes. There was minimal wasting of the skeletaI musculature. Spontaneous, slow, writhing movements were apparent in the fingers and toes. The extremities were severely spastic, and deep tendon reflexes were markedly exaggerated. No clonus could be elicited. Plantar stimulation produced extension of the great toes. Sensory examintaion was limited, but an adequate withdrawal response followed painful stimuli. Laboratory findings. Routine blood and urine analyses were normal. Cerebrospinal fluid glu-

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Oculocerebral syndrome with hypopigmentation

cose content was 58 mg. per cent, and the protein content was 17 rag. per cent. Two mononuclear cells per cubic millimeter were found in the cerebrospinal fluid. The electroencephalogram was normal. An x-ray of the skull showed a steep basilar angle consistent with compensated hydrocephalus. Paper chromatography of the urine showed a normal pattern. The karyotype was normal. Case 3. J. K. (J. H. H. 1151326), a brother of the two children described as Patients 1 and 2, was born at home-on Aug. 8, 1963, following a 9 month gestation period which had been unremarkable except for a minimal amount of bleeding in the first trimester. Delivery was uneventful, and birth weight was 8~2 pounds. The light pigmentation and abnormal eyes were noted at birth to resemble those of his similarly affected sibs. At 4 to 5 months of age, the patient developed writhing movements in the extremities with "spasms" similar to those of his affected sibs. He has been hyperirritable, but no seizure activity has been noted. He has been blind from birth. None of the normal developmental milestones have been attained. The patient had none of the usual childhood illnesses and has had no immunizations. There have been no previous hospitalizations and he has apparently been in good health except for the neurologic and ocular difficulties. On admission to the Johns Hopkins Hospital on April 2, 1965, the patient appeared to be a well-nourished, slightly underdeveloped, hypopigmented youngster in no distress (Fig. 1C). He weighed 9.4 kilograms and measured 78 cm. in length, both measurements being below the third percentile. Skin and hair pigmentation was identical to that of his sibs, and he also had rare black strands of hair. The head was normally shaped with a circumference of 47 cm. The teeth were small and widely spaced. The palate was highly arched. Chest, heart, and abdominal examination revealed no abnormalities. A normal male phallus was present, but no testes could be palpated in either the scrotum or the inguinal canals. Ophthalmologic examination. The lid fissures were narrow with apparent recession of the globes. Constant wandering movements of the eyes were present, interrupted only by spasms of skeletal muscle concomitant with an upward movement of both globes. No response to strong light could be detected in either eye. That area identifiable as cornea was diffusely cloudy with

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vascuIarization extending to within 3 ram. of its oval center. This small oval area, measuring 2 by 2 mm. in the central portion of the globe, was also partially opacified, but a faint red reflex could be obtained. Funduscopic examination was, however, not possible. In the upper portion of the cornea in the left eye, slit-lamp examination showed an abortive ring-type configuration to which uveal pigment was adherent, suggesting peripheral iris adhesions. No normal iris could be identified in either eye. NeuroIogic examination. When undisturbed the patient lay quietly, but when stimulated he exhibited slow, writhing movements of the hands, fingers, and toes. Sudden sensory or auditory stimuli produced a prompt, exaggerated Moro reflex with slow relaxation. There was pronounced spasticity in all extremities and deep tendon reflexes were brisk, though not so marked as in the patient's brother, Patient 2. Plantar stimulation produced flexion of the great toe on the right and extension on the left. No clonus, fasciculations, or flexion contractures were noted: There was a normal withdrawal response to painful stimuli. Laboratory findings. Routine blood and urine analyses were normal. The x-rays of the chest and skull were interpreted as normal. The cerebrospinal fluid contained 65 mg. per cent glucose and 10 mg. per cent protein. No cells were seen. Lactic dehydrogenase level in the cerebrospinal fluid was 58 units, the normal value being 15 to 71 units. The electroencephalogram was interpreted as a normal record. Paper chromatography of the urine revealed no abnormalities, and the karyotype was normal. FAMILY DATA T h e m o t h e r has had 10 pregnancies, 8 resulting in live births (Fig. 3). All 5 u n affected living sibs have n o r m a l pigmentation a n d have no ocular or neurologic defects. T h e m o t h e r gave birth to stillborn twin males on M a r c h 3i, 1966, following severe gastrointestinal h e m o r r h a g e secondary to a duodenal ulcer. O n e twin weighed 6 pounds, 7 ounces, and. had no congenital anomalies or hypopigmentation. T h e other twin weighed 7 pounds a n d was affected with ocular anomalies and h y p o p i g m e n t a t i o n similar to the 3 sibs reported above. Both parents are normal. T h e r e is n o family history of ocular defects, a l b i n i s m , or

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Cross, McKusick, and Breen

JH:

IMM. 1736

[ ~

The Journal o/ Pediatrics March 1967

MISS L.

I[

l

I

Z Z VTF IZ

Z

1 9

9

2 3

AFFECTED

9 ABORTION ~ ] * d R E P U T E D TO BE IsT COUSFNS

Fig. 3. Pedigree of the K family. Consanguineous marriages are indicated by double lines. The numbers adjacent to the affected individuals refer to the numbers of the cases presented in this report. There is a common ancestral couple in both generations II and VI.

mental deficiency except for a maternal halfuncle with mongolism. This family derives from the Old Order Amish of Ohio. One of the many characteristics which make the Amish favorable for genetic studies 6 is their relatively high coefficient of inbreeding as a result of the small number of founding individuals and subsequent strict endogamy. In such a group, a number of recessively inherited disorders including perhaps some previously undescribed are likely to occur. Examples of new recessive disorders already found in the Amish are cartilage-hair hypoplasia, 7 a form of pyruvate kinase deficient hemolytic anemia, s a disorder of bile salt metabolism, ~ and several degenerative neurologic disordersP, 10 The cases reported here are believed to represent another new recessive disorder. The pedigree in Fig. 3 presents the pertinent

genealogic information and suggests autosomal recessive inheritance. There is considerable consanguinity among the ancestors of these subjects. For example, the paternal grandmother and the maternal grandfather are first cousins. It is also reputed that a maternal grandfather and grandmother were first cousins. In addition, both parents of these children can be traced back to a common ancestral couple. In fact, not only are J. H. and his wife ancestors of both parents, but there is another common ancestral couple in the sixth generation. Since only one of the twins was affected, it is unlikely that nongenetic factors alone are responsible for the manifestations of the syndrome. Sex-linkage is excluded by the fact that, among the offspring of normal parents, both sexes are involved. Heterozygotes, e.g., the parents, show no apparent abnormality which might represent heterozygous manifestation. SPECIAL

LABORATORY

INVESTIGATIONS No biochemical defect was found. Urine chromatography showed only normal amino acid excretory patterns; no chromosomal abnormalities were present, and cerebrospinal fluid cell numbers and protein and glucose concentrations were normal. The electroencephalograms were all within normal limits. Karyotypes of the 2 youngest children revealed modal counts of 46 with normal chromosome morphology. Skull x-rays were unrevealing except in Patient 2 where the possibility of a compensated hydrocephalus was raised because of the steep basilar angle. This is probably an incidental finding since neither of his sibs had similar changes and, furthermore, the normal head circumference and proportions minimize the possibility that hydrocephalus contributed significantly to the symptomatology. The method described by Kugelman and Van Scott xl was employed as a test of in vitro tyrosine incorporation by hair bulbs of these patients. H a i r bulbs were mechanically epilated and the root portions immediately immersed in the following solutions: (a)

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1-tyrosine, 50 mg. per cent in 0.1M phosphate buffer at p H 6.8; and (b) 0.1M phosphate buffer at p H 6.8 as the control. Incubation was carried out at 37 ~ C. for 24 hours. T h e hairs were then washed in distilled water and m o u n t e d unfixed on slides. Tyrosinase activity was estimated under a light microscope by the a m o u n t of increased darkening of cells in the lower bulb matrix. A b n o r m a l hair shaft fragility was noted during epilation and less than 10 per cent of the extracted shafts contained bulbs. T h e majority of shafts were abnormally thin when viewed u n d e r the light microscope. Prior to incubation, all hair bulbs satisfactory for analysis contained some pigment, although this was of low degree both with respect to intensity and n u m b e r of pigment cells present. U p o n incubation in the tyrosine solution, there was some increase in intensity of pigmentation, but this never reached the level seen in hair bulbs from normal individuals. DISCUSSION T h e salient features of the 3 cases are summarized in Table I. T h e syndrome is

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congenital, being manifest at birth by pigm e n t a r y and ocular abnormalities, and early in infancy by neurologic deficits. T h e neurologic abnormalities alone are progressive and account for most of the h a n d i c a p in the oldest child. T h e tabulation demonstrates the remarkable similarity of the cases and illustrates the four main components of the syndrome: ocular abnormalities, severe mental deficiency, spastic diplegia, and cutaneous hypopigmentation resembling albinism. Hypogonadism m a y be a feature of this syndrome. At age 12 the oldest child, Patient 1, a girl, has normal female external genitals but has deveIoped no secondary sexual characteristics. T h e 2 affected males have no detectable gonads, although cryptorchidism rather than absence of the gonads m a y be responsible. T h e ocular anomalies are an unusual combination of microphthalmos, enophthalmos, microeornea, corneal opacity, and spastic ectropion with nystagmus and total blindness. Possible aniridia is also a feature. I n at least one instance (Patient 1) the ectropion has led to. repeated ocular infections. It was never possible to elicit any reaction to

Table I. Features of Amish oculocerebral syndrome ~ Case 1

Age Sex Hypopigmentation Mental retardation Spasticity Eyes Microphthalmos Small, opaque cornea Coarse nystagmus Growth retardation Cryptorchidism (?) Serum phenylalanine Serum tyrosine Electroencephalogram Karyotype Skull x-rays Cerebrospinal fluid Glucose (mg.%) Protein (mg.%)

I

Case 2

Case 3

12 F ++++ ++++ ++++

3 M ++++ ++ ++

2 M ++++ + +

++ ++++ ++ ++++ -1.0 mg.% 2.6 mg.% Normal ---

++ ++++ ++ ++ ++++ --Normal Normal Steep basilar angle

++ ? ++ + ++++ --Normal Normal Normal

58 17

65 10

---

* T h e n u m b e r of pins (+) signs is approximately correlated with the degree os severity of the characteristic. F ~ M ---~ male. A dash ( - - ) indicates lack of information.

female.

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intense light beams, even in the third child (Patient 3), in whom a red reflex could be obtained. The nature and degree of fundaI and optic nerve involvement are not known. Without pathologic material it is not possible to determine the extent of involvement of the central nervous system. Hyperreflexia, spasticity, Babinski reflexes, hyperirritability, athetoid movements, and apparent mental retardation are the outstanding neurologic signs. Involvement of the pyramidal system, basal ganglia, and cerebral cortex is indicated by these symptoms, and the process may be even more extensive. Surprisingly, the electroencephalograms showed no evidence of decreased or anomalous brain activity. Cerebellar signs are conspicuous by their absence in all three children. Muscle wasting, evident in the living children and progressively more marked in the two older ones, is probably at least partly disuse atrophy. These patients thus manifest an oculocerebral syndrome with cutaneous hypopigmentation as an additional feature. A number of oculocerebral syndromes, most of them also rare recessive disorders, have been reported. The Marinesco-SjSgren syndrome 12 characterized by mental retardation, cerebellar signs, and cataracts, and Lowe's oculocerebrorenal syndrome la with hyporeflexia, cataracts or punctate opacities, and aminoaciduria are obviously quite unlike the syndrome in the K family because the affected members of this family lack cerebellar signs, discernible cataracts, or aminoaciduria. For similar reasons, one may consider the oculocerebral syndrome reported by McCance and coworkers, a* to be different from the cases reported here. In 1935, SjSgren 15 reported 4 patients with congenital cataracts, oligophrenia, and spastic diplegia and suggested that this combination of symptoms constitutes a distinct entity. Later, in a population survey, SjSgren and Larsson ~Gfound 5 unrelated persons who had microphthalmos and spastic diplegia. In 3 female sibs ranging in age from 1 to 3 years, Pinsky and associates ~7 described microphthalmos, corneal opacities, mental retardation, and spastic cerebral

The Journal o[ Pediatrics March 1967

palsy. These sibs also had a history of clonic seizures and the electroencephalogram was abnormal in aII cases. Gillespie 1~ reported sibs with aniridia, cerebellar ataxia, and mental retardation and pointed out the similarity of these cases to the MarinescoSjSgren syndrome, except for the presence of aniridia instead of congenital cataracts. In none of these reports is there any indication of pigmentary abnormalities. Although the combination of hypopigmentation and neurologic abnormalities is frequently seen in phenylketonuria, the severe ocular anomalies and normal phenylalanine plasma level are against this diagnosis. T h e cutaneous hypopigmentation has many characteristics of true albinism, although the skin and hair color does not have the typical pasty-white hue that is sometimes seen. Without visualization of iris and retina, it is of course impossible to determine whether the hypopigmentation is complete or incomplete. However, many Caucasian subjects with oculocutaneous (complete) albinism have cream-colored or yellow hair, and their skin may contain similar pigmented nevi. 1~ Recent evidence suggests that albinism results from a metabolic defect in melanocytes with consequent failure in the production of normal amounts of melanin. 1~ Melanin is, however, never completely absent in human albinos, and there is good evidence that melanocytes are present in the tissues of albinos. 1~ It seems likely, therefore, that decreased metanogenesis in the human albino subject is due either to unavailability of the substrate tyrosine or to deficient or abnormal tyrosinase. Serum tyrosine levels are usually normal, 2~ however, and, in most patients, there is some tyrosinase activity in epilated hair bulbs. 11, 20 In the present cases also, the defect in melanin formation is apparently accompanied by normal blood tyrosine levels and inadequate hair bulb pigmentation in tyrosine solution. There is evidence of heterogeneity in albinism 2~ and related hypopigmentary states, and these cases thus may represent another variant. One may ask what ocular or neurologic findings have been associated with albinism.

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OculocerebraI syndrome with hypopigmentation

The ocular findings in this family have not been noted in reported cases of albinism. The albino eye is usually normal histologically except for the decrease or absence of pigment in the retinal epithelium and choroid and occasionally hypoplasia or aplasia of the macular area. 21 In fact, eye anomalies such as correctopia, atrophy of the disc, persistent pupillary membrane, partial aniridia, hypoplasia or coloboma of the iris, and aplasia of the sphincter muscles in association with the albinism, are rare. 22, 23 Neurologic disorders associated with albinism are also rare. Mental deficiency and spastic diplegia are unknown, although Waardenburg 22 mentions a personal case and cites Saunders 24 as reporting another case in which epilepsy was associated with albinism. There are several reports of deaf-mutism occurring in cases of albinism. 25' 26 One can conclude that the complex of symptoms found in the K family has not been a feature of reported cases of albinism. None of the several ocular anomalies seen in the K family are regularly found in combination with the extraocular features of this syndrome. True microcornea is not associated with other ocular abnormalities 21 and is apparently not a consistent feature of oculocerebral syndromes. While corneal opacities have been reported in certain 'oculocerebral syndromes,l~, 17 they are not a feature of any known forms of albinism. There is no evidence that any pigmentary changes are associated with microphthalmia in man, although microphthalmia and albinism may be transmitted together in the rat. 27 The combination of microphthalmos, mental retardation, and corneal opacity in the absence of other ocular anomalies must be extremely rare. Waardenburg 22 indicates that only one example of this combination exists in the literature, although Pinsky and his group 17 have since added another family with similar findings. I n addition, while corneal opacities are sometimes associated with microphthalmos, ~1 this combination is rarely associated with extraocular abnormalities. 17 The hypopigmentation in this syndrome is

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the only form of "albinism" found in the Amish. In contrast to another inbred group, the San Blas Indians of Panama, in whom albinism is as frequent as 5 per 1,000, 2~ there is less albinism among the Amish than is found among the general population. This is likely a reflection of the fact that none of the founding fathers of the present day Amish demes carried the gene for albinism and subsequent lack of "contamination" by non-Amish genotypes has effectively excluded this particular genetic disorder from the group. The syndrome manifested by the K family thus has several unusual features. It is the first reported instance in which cutaneous hypopigmentation has been associated with severe ocular and neurologic abnormalities. It represents one of the rare instances in which microphthalmos, corneal opacity, and mental retardation have been found in combination. The remarkable clinical similarity of these cases and the absence of any of the features of the syndrome in other members of the family make it unlikely that this rare combination of symptoms was coincidental. Instead, it is believed that this symptom complex represents a new genetic disorder of metabolism inherited as an autosomal recessive. SUMMARY

A family has been described in which 3 living sibs are affected with mental retardation, spastic diplegia, cutaneous hypopigmentation resembling albinism, and multiple ocular anomalies. These symptoms appear to comprise a unique syndrome transmitted as an autosomal recessive. This oculocerebral syndrome with associated pigmentary abnormalities has not been previously described. The basic defect is thought to be an inborn error of metabolism but no biochemical abnormality has thus far been found. We are indebted to Dr. John W. McFadden of Hartville, Ohio, for calling our attention to this family. We wish to thank Dr. David Paton of the Wilmer Institute, Johns Hopkins Hospital, Baltimore, Maryland, for the ophthalmologic examinations.

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1. Hanhart, E.: Ueber die Bedeutung der Erforschung von Insuchtsgebieten an Hand von Ergebnissen bei mit heredit~irer Ataxia, heredodegenerativem Zwergwuchs und sporadische Taubstammheit, Schweiz. reed. Wchnschr. 5: 1143, 1924. 2. S~6gren, T.: Klinisehe und vererbungsmedizinische Untersuchungen fiber Oligophrenie in einer Nordschwedischer Bauernpopulation, Acta psychiat, et neurol, scandinav. 7: 1, 1932. Suppl. 2. 3. Klein, D., and Ammann, F.: Geographical distribution of some isolates with neurogenetic affectations in Switzerland, J. genet. humaine 13: 122, 1964. 4. Hirano, A., Kurland, L. T., Krooth, R. S., and Lessell, S.: Parkinsonism-dementia complex, an endemic disease on the island of Guam. I. Clinical features, Brain 84: 642, 1961. 5. Cross, H. E.: Neurologic disorders in the Amish, Trans. Am. Neurol. Soc. 90: 236, 1965. 6. McKusick, V. A., Hostetler, J. A., and Egeland, J. A.: Genetic studies of the Amish; background and potentialities, Bull. Johns Hopkins Hosp. 115: 203, 1964. 7. McKusick, V. A., Eldridge, R., Hostetler, J. S., Ruanguit, V., and Egeland, J. A.: Dwarfism in the Amish: II. Cartilage-hair hypoplasia, Bull. Johns Hopkins Hosp. 116: 285, 1965. 8. Bowman, H. S., McKusick, V. A., and Dronamraju, R. R.: Pyruvate kinase deficient hemolytic anemia in an Amish isolate, Am. J. Human Genet. 17: 1, 1965. 9. Clayton, R., Iber, F. L., Ruebner, B. H., and McKusick, V. A.: Byler's disease. Fatal familiar intrahepatic eholestasis in an Amish kindred, J. P~I)IAT. 67: 1025, 1965. Abst. 10. Cross, H. E.: Unpublished observations. 11. Kugelman, T. P., and Van Scott, E. J.: Tyrosinase activity in melanocytes of human albinos, J. Invest. Dermat. 37: 73, 1961. 12. Garland, H., and Moorhouse, D.: Extremely rare recessive hereditary syndrome including cerebellar ataxia, oligophrenia, cataract, and other features, J. Neurol. Neurosurg. & Psychiat. 16: 110, 1953. 13. Lowe, C. V., Terrey, M., and MacLaehlan, E. A.: Organic-acidemia, decreased renal ammonia production, hydrophthalmos and mentat retardation, Am. J. Dis. Child, 83: 164, 1952. 14. McCance, R. A., Matheson, W. J., Gresham, G. A., and Elkinton, J. R.: The cerebro-

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