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J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Journal of (1970). 7, 257.

Genetical Aspects of Severe in Childhood G. R. FRASER*

A quantitative assessment of the spectrum of amaurosis of Leber, corresponding to the retinal genetically determined diseases which cause severe aplasia of Sorsby and Williams (1960). There is impairment of vision in childhood is no easy matter. some evidence (Sorsby and Williams, 1960; First, apart from the exceptional cases where vision Franceschetti et al., 1963) that autosomal dominant is lost altogether, there are, of course, no universally forms may exist but, if so, they must be responsible acceptable criteria whereby 'severe impairment' may for only a small minority of cases. In addition, be defined. Secondly, this spectrum may be quite phenocopies may occur, and it is probable that significantly affected by the results oftreatment. At acquired causes acting both in the prenatal and the the qualitative level, however, the situation is less perinatal period can give rise to a clinical picture difficult and, in this presentation, clinical entities indistinguishable from that of the more common which often give rise to severe impairment of vision genetically determined variety. in childhood will be considered in turn together Characteristically, this condition is marked by with an attempt to assess the role of genetical factors visual failure from earliest infancy. At first no in their causation. retinal lesions may be visible ophthalmoscopically, This is followed by a section in which an attempt and, therefore, such visual failure has often been copyright. is made to give an over-all view, necessarily approxi- initially described as 'cerebral' or 'cortical' blind- mate in view of the difficulties mentioned above, of ness, while in other cases congenital optic the relative numerical contributions of these various or congenital has been diagnosed. The entities determined by simple Mendelian inheritance electroretinogram, however, is always grossly abnor- to the causation of severe visual impairment in mal in the earliest stages, and in later years ophthal- childhood, and in two final sections, the possible moscopically observable lesions often develop, and roles of polygenic inheritance and of gross chromo- may progress so that the final not picture is unlike http://jmg.bmj.com/ somal aberrations are discussed. that seen in pigmentosa. and are common late complications of the Choroido-retinal Degenerations condition. It is probable (Fraser and Friedmann, 1967) that This group of conditions, comprehensively de- Leber's congenital amaurosis, like autosomal re- scribed by Franceschetti et al. (1963), illustrates cessive deafness, may be determined by homozy- well very the phenomenon that, when visual im- gosity for an abnormal allele at any one of several impairment due to on September 27, 2021 by guest. Protected a heterogeneous genetically gene loci. Thus, the same phenomenon occurs as determined entity is considered, only some com- in the case of autosomal recessive deafness that per- ponents cause severe forms leading to significant childhood sons affected with Leber's congenital amaurosis handicap. As a general rule, though who marry may often have normal children (Waar- there are exceptions, it seems that autosomal re- cessive forms denburg and Schappert-Kimmijser, 1963). There give rise to more severe lesions of are some suggestions (Fraser and Friedmann, 1967) earlier onset than autosomal dominant forms and, of ophthalmoscopically definable variations in the therefore, the former are almost exclusively repre- appearances of the fundus which may correspond to sented among children with serious visual impair- different genetical forms of the condition. ment. Among these children, the overwhelming Some component entities of this group may be majority owe their disability to the condition known distin- guished by as as the associated clinical features such the tapeto-retinal degeneration or congenital syndrome of Leber's congenital amaurosis with * Address: Division of Medical Genetics, Department of Medi- renal abnormalities (Contreras and Espinoza, 1960; cine, University of Washington, Seattle, Washington 98105, U.S.A. Senior, Friedmann, and Braudo, 1961; L0ken et al., 5 257 J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

258 G. R. Fraser

1961; Fraser and Friedmann, 1967); concomitant with defects of leucocyte function usually leading to neurological abnormalities, possibly including deaf- early death through infection, and to the syndrome ness, may distinguish other variants (Franceschetti of Hermansky and Pudlik (1959) in which albinism et al., 1963; Dekaban and Carr, 1966; Fraser and is associated with a bleeding diathesis of an inde- Friedmann, 1967). terminate nature. Apart from the group of conditions of the type of Sex-linked choroido-retinal degenerations may Leber's congenital amaurosis, blindness of later also cause severe visual impairment in males. They onset in childhood may be caused by autosomal re- include , choroideraemia, and a cessive choroido-retinal degenerations due to homo- group of retinal dystrophies clinically allied to zygosity at other gene loci. These dystrophies involve . In such cases, diagnosis is primarily the macula, but the periphery of the greatly assisted by minor ophthalmoscopic changes may participate in the degenerative process. Thus, commonly found in heterozygotes. This pheno- the group includes such entities as Stargardt's macu- menon provides one of the main lines of evidence lar dystrophy and 'central' retinitis pigmentosa; as bearing on the existence and the nature of X in the case of Leber's tapeto-retinal degeneration, chromosomal inactivation (Lyon, 1961) in man. homozygosity at one of several gene loci may be in- volved. Some entities within this group may be distinguished by associated clinical features such as the various forms of amaurotic idiocy, or cerebro- One of the most common autosomal dominant , and other less clearly defined causes of blindness in childhood is bilateral retino- associations of choroido-retinal degenerations with blastoma. Discovery of the genetical determina- neurological disorders. In addition, there are pro- tion of retinoblastoma became possible only when bably several distinct forms of autosomal dominant surgical treatment ensured the survival of a substan- choroido-retinal degenerations involving the macula, tial proportion of affected subjects to reproductive but, in general, these do not cause severe visual im- age. It was then soon noted that the condition pairment in It childhood. is probable that pheno- could be handed on from parent to offspring incopyright. copies ofthis group ofchoroido-retinal degenerations a Mendelian dominant manner. However, the with onset in infancy and childhood may occasionally studies of Vogel (1957) first clearly showed that this arise due to viral infections. In such cases, a typical explanation could not apply to all cases, in that the history may be elicited of sudden onset of visual proportion of affected children of affected subjects symptoms during or shortly after an episode of high was very much less than the 5000 expected under fever commonly associated with an exanthematous the hypothesis of dominant inheritance. Vogel eruption. (1957) suggested that the majority (perhaps as much It should be noted that in the usual forms of as 80°,') of cases of unilateral sporadic retinoblas- http://jmg.bmj.com/ retinitis pigmentosa, both autosomal dominant and toma represented phenocopies, possibly due to soma- autosomal recessive, the lesions are primarily peri- tic , and, therefore, in such cases the disease pheral. Thus, the macula is relatively spared and is not transmissible to offspring of affected persons, central vision may be preserved till an advanced age. whereas bilateral retinoblastoma usually, if not These conditions, therefore, which include Usher's invariably, represents the results of a germinal and, syndrome (autosomal recessive deafness with reti- therefore, transmissible mutation. This hypothesis nitis pigmentosa), only very rarely cause severe was confirmed in the case of bilateral retinoblastoma on September 27, 2021 by guest. Protected visual impairment in childhood. by the work of Hemmes, Nijland, and Schappert- Another autosomal recessive condition that may Kimmijser (1964) who studied 7 persons with cause serious visual handicap ininfancyand childhood sporadic bilateral retinoblastoma who survived to is albinism. This, too, is a genetically heterogeneous procreate; they had 22 children of whom 12 were condition, and, as the families described by Trevor- themselves affected, in good accord with the 5000 Roper (1952) and Witkop et al. (1970) show, the expected under the hypothesis that all cases of marriage of albinos may lead to normal offspring. bilateral tumour represent germinal and transmis- Two gene defects at different loci may correspond sible . to the clinical distinction between complete (or In a condition such as bilateral retinoblastoma, universal) and incomplete albinism, and there is which until relatively recently was almost invariably evidence that this difference may be distinguishable fatal in early life, it is to be expected that a large at the biochemical level also (Witkop et al., 1970). proportion of sporadic genetically In determined cases addition, homozygosity at further gene loci gives will be caused by freshly arisen mutations. Not all rise to the Chediak-Higashi syndrome of albinism such cases, however, are due to this mechanism, J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Genetical Aspects of Severe Visual Impairment in Childhood 259 since there is considerable evidence ofreduced pene- lated, the end stage in such cases being phthisis trance of the gene concerned, so that sometimes bulbi. such sporadic cases will arise because of trans- An extensive description of pseudoglioma (or mission of the abnormal gene from a parent in whom Norrie's disease) has been published by Warburg it has not caused disease. Perhaps a realistic (1966), with a report of many Scandinavian families estimate of the clinical penetrance of the gene would with this condition. Mental subnormality and be 8Oo/, and thus, occasionally, an unaffected perceptive deafness, with onset in middle childhood carrier may have more than one affected child; in and later, are relatively frequent accompaniments this way autosomal recessive inheritance may be of the condition. simulated. A particularly fascinating phenomenon is spon- Optic Atrophy taneous regression of retinoblastoma which has Genetically determined optic atrophy giving rise been documented relatively frequently in members to serious visual disability in childhood often forms of families who have been under close observation part of complex neurological syndromes such as because of the presence of the disease in relatives, spastic paraplegias, hereditary ataxias, Behr's com- but who have not undergone treatment (Steward, plicated optic atrophy, cerebral lipidoses, or leuco- Smith, and Arnold, 1956; Watillon et al., 1964; dystrophies. 'Simple' types without an associated Fraser and Friedmann, 1967). It is clear that in- widespread involvement of the central nervous sys- tensive study of the mechanism of spontaneous re- tem may also occur. Complex types are sometimes gression of retinoblastoma, and of malignant associated with retinal involvement and are often tumours in general, could lead to the development inherited in an autosomal recessive manner, though of revolutionary therapeutic techniques in the field dominant forms may occasionally be seen. One of cancer, based on attempts to simulate these particularly interesting form of autosomal recessive natural cures. complex optic atrophy is that associated with juv- enile diabetes mellitus (Rose et al., 1966). While

Pseudoglioma the neurological disturbance in this condition is copyright. Pseudoglioma, as its name implies, is any con- often restricted to optic atrophy, other cases may dition of the eye which simulates retinoblastoma. show features such as retinal degeneration, mild per- It may be unilateral or bilateral and it is the latter ceptive deafness, ataxia, and myelopathy; in addi- variety that is of primary concern here. It may be tion, abnormalities of the electroencephalogram, air due to acquired causes such as retrolental fibro- encephalogram, and cerebrospinal fluid protein level plasia, congenital toxoplasmosis, Coats' disease, or may occur, suggesting the existence of a more diffuse metastatic . If such causes can be involvement of the central nervous system. An- confidently excluded, a large proportion of residual other frequent concomitant feature of this syndrome http://jmg.bmj.com/ cases is genetically determined, most commonly in a or group of syndromes is . sex-linked recessive manner. Occasionally, how- Autosomal recessive inheritance is very rare in ever, autosomal recessive types of pseudoglioma 'simple' optic atrophy (Kjer, 1959), and some cases may occur. Detachment of the retina forms part described under this heading may in fact represent of the pathological picture of pseudoglioma; it is in examples of Leber's congenital amaurosis or reti- most cases congenital, but it may occur in early nal aplasia. Autosomal dominant inheritance of postnatal life. As a result of such differences in 'simple' forms is undoubtedly far more common. on September 27, 2021 by guest. Protected the timing and extent of the primary lesion, the Anomalous inheritance patterns are found in condition in question (sometimes known as Norrie's Leber's optic atrophy; in view of the demonstration disease) can masquerade under a variety of diag- by Bruyn and Went (1964) of widespread neuro- noses including persistent hyperplastic primary logical disturbances in some such cases, it is not vitreous, congenital retinal fold, congenital falciform clear whether this condition should be regarded as a , congenital (or infantile) cystic 'simple' or 'complex' type of optic atrophy. It retinal detachment, congenital vascular veils in the only rarely causes severe visual handicap in child- vitreous, and juvenile . This multitude hood and then exclusively in males. More typi- of clinical diagnoses may indicate heterogeneity at cally, the onset of significant symptoms is deferred the clinical level also. The retinal detachment is till adolescence or adult life, and the disease is far followed by disorganization of the eye of varying less severe in females. Provisionally the condition degree, and, when the extent of this process is may be best regarded as inherited in a sex-linked particularly obvious and its progress particularly manner with very variable manifestations in female rapid, microphthalmos with cataracts may be simu- heterozygotes. There are two major difficulties J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

260 G. R. Fraser

which indicate that such a simple explanation is not condition; and various investigators have suggested entirely adequate. One is that the disease has never that deficiency of glucose-6-phosphate-dehydro- been transmitted by an affected male-that is from genase, another sex-linked recessive error of meta- grandfather to grandson through a heterozygous bolism, may be associated with cataracts in early female-and the second is that the proportion of life, but the evidence is not convincing [see Fraser daughters of heterozygotes who are themselves and Friedmann (1967) for references]. carriers is far greater than the 50% expected. Further autosomal recessive types of Apart from the specific conditions mentioned may be distinguished by their association with other above, optic atrophy as a cause of severe visual clinical features as part of various syndromes. handicap in childhood is often found in association These include the Marionesco-Sjogren syndrome, with evidence of brain damage such as epilepsy, the Rothmund-Thomson syndrome, the Werner cerebral palsy, neurological defect, mental sub- syndrome, the association of cataracts with con- normality, and deafness. Such cases frequently genital (Jancke, 1950; Pinkerton, 1958), occur in premature children and are in all prob- with renal tubular necrosis, dwarfism, mental re- ability not genetically determined; they are usually tardation, and epilepsy (Crome, Duckett, and associated with evidence of traumatic episodes in Franklin, 1963), and with various other less clearly the perinatal period. The whole complex has, defined constellations of neurological abnormalities therefore, been tentatively designated as the 'peri- such as progressive cerebral diplegia or congenital natal damage syndrome' by Fraser and Friedmann choreoathetosis. It should be emphasized that the (1967); males are more often affected than females. time of onset of cataract in many of these syndromes Occasionally difficulty may arise in distinguishing is very variable. Thus, it may often cause visual between conditions in this category and genetically impairment only in adolescence or adult life. Such determined complex neurological syndromes such later development of cataract is also a common as Behr's complicated optic atrophy. complication of several autosomal recessive choroido-retinal degenerations, including both

Cataracts those of the type of Leber's congenital amaurosiscopyright. Apart from bilateral retinoblastoma, cataracts and of the type of retinitis pigmentosa. constitute the other common autosomal dominant As in the case ofoptic atrophy, there is a good deal lesion causing severe visual handicap in childhood. of evidence (Fraser and Friedmann, 1967) that un- Since retinoblastoma is potentially lethal as well as favourable events of an unidentified nature in usually giving rise to total blindness, it reduces fit- pre- or perinatal life, occurring predominantly in ness far more than cataracts which are not only premature children, give rise to cataracts in associa- fully compatible with a normal life expectancy but tion with other symptoms characteristic of brain also often lead to visual handicap of only moderate damage; the possibility has been raised by several http://jmg.bmj.com/ severity. Thus, a far smaller proportion of cases of investigators that this syndrome may be associated cataracts than of retinoblastoma represents freshly with idiopathic neonatal or infantile hypoglycaemia arisen mutations, and a family history characteristic (O'Connor and Crawford, 1967; Fraser and Fried- of dominant inheritance is much more common. mann, 1967; Hull, 1969; Gabilan and Chaussain, Nevertheless, there always remains a possibility 1969). As in the case of the 'perinatal damage that a sporadic case may be due to a freshly arisen syndrome' involving optic trophy (mentioned above) mutation. Autosomal recessive congenital and males are affected more frequently than females. on September 27, 2021 by guest. Protected infantile cataracts do occur but are much more rare There is, in addition, a well-known connexion be- than the autosomal dominant variety; occasional tween cataracts and maternal rubella infection. pedigrees have been reported which are suggestive Cataracts due to such primarily acquired causes may of sex-linked intermediate inheritance (Walsh and be confused with genetically determined varieties. Wegman, 1937; Fraccaro et al., 1967; Fraser and Schemes of classification ofgenetically determined Friedmann, 1967). cataracts based on morphological patterns of In several of the recessive forms a metabolic ab- involvement have been proposed, for example by normality has been identified, and these include Francois (1959). The correspondence between galactosaemia, galactokinase deficiency (Gitzelmann, forms defined by such criteria and distinct genetical 1967), and a form of glycogen storage disorder (De entities is limited, and such schemes are not par- Loore and Van Gelderen, 1967). Cataracts may be ticularly relevant to the congenital and infantile associated with hyperaminoaciduria in the oculo- severe types under discussion since these cataracts cerebro-renal syndrome of Lowe, Terrey, and are very often total. Involvement of affected rela- MacLachlan (1952), which is a sex-linked recessive tives of dominant cases is very variable, however, J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Genetical Aspects of Severe Visual Impairment in Childhood 261 and many have only mild visual impairment. Other cause of keratitis in infancy and childhood, and factors apart from the cataract are involved in the other prenatally acquired causes may be of signifi- prognosis for vision, notably the degree of micro- cance (Speakman and Crawford, 1966). Infection phthalmos. Thus, when the eye is very small, may also leave keratitis as a sequel. vision is reduced to a greater extent and the results of surgery are less successful. -Microphthalmos- Anophthalmos Microphthalmos, per se, may be a feature of a Uncomplicated high myopia may occasionally be great number of different entities both genetical, of sufficient severity to cause serious visual handicap such as dominant cataract and sex-linked pseudo- in childhood. Dominant forms are known but glioma, described in other sections, and acquired, these usually cause blindness through associated such as toxoplasmosis and retrolental fibroplasia. retinal detachment. A very well-defined entity is Other genetically determined forms may be associ- that of sex-linked recessive congenital myopia with ated with myopia and corectopia (Usher, 1921) and nystagmus and night blindness (Nettleship, 1912). with retinitis pigmentosa (Hermann, 1958) in Autosomal recessive forms of high myopia have autosomal dominant syndromes, and with macro- been described but the evidence is not entirely con- phakia, hypermetropia, retinal degeneration, and vincing. Sufficiently severe myopia to cause dental anomalies in an autosomal recessive syndrome serious childhood handicap may sometimes repre- (Franceschetti and Gernet, 1965). sent the extreme of the normal 'physiological' re- In addition, an association seems to exist be- fraction curve, and presumably in such cases it is tween colobomatous defects of the eye and micro- under the control of polygenic inheritance. Lastly, phthalmos which in its extreme form ranges into prematurity predisposes to an acquired form of high anophthalmos. Irregular dominant inheritance myopia; some such cases may represent abortive is characteristic of this group of defects. Thus, forms of retrolental fibroplasia. only a proportion of persons of the appropriate

genotype will be severely affected in both eyes copyright. Retinal Detachment while minor abnormalities, often unilateral, will occur in others. Sometimes inheritance be Retinal detachment in childhood is usually a will complication of apparently recessive but this may be an artefact due high myopia, and the combination to lack of of the is often inherited in an autosomal dominant manner. penetrance gene in previous In addition, there are instances of autosomal domi- generations. Possibly, truly recessive types of nant, autosomal recessive, and sex-linked anophthalmos may occur, but such families may recessive reflect homozygosis for genes which in heterozygous types of retinal detachment in http://jmg.bmj.com/ early life, which are form cause milder forms of not associated with high myopia; such a lesion this group of lesions may (Sorsby, 1934; van Canneyt and Vandemeule- readily be classified as a pseudoglioma. Indeed, broecke, the diagnostic label applied may reflect only dif- 1936). ferences in a spectrum of continuous variation in- volving the timing and extent of the retinal detach- Like microphthalmos, aniridia can also be ment, though it remains quite possible that, to take associated with the sex-linked group as an example, lesions of the colobomatous lesions either in the same individual or in other members of the family. on September 27, 2021 by guest. Protected pseudoglioma group and those defined as juvenile It retinal detachment or retinoschisis represent distinct usually follows a regular pattern of dominant genetical entities. inheritance, but variable expressivity does occur and apparent examples of 'recessive' inheritance Corneal Lesions may be explicable on the basis of minor manifesta- tions in one of the parents. A rare truly recessive Both autosomal dominant and autosomal reces- form in association with cerebellar ataxia and mental sive types of corneal dystrophies are known and, as retardation exist in may, however, (Gillespie, 1965). the case of cataract, may tentatively be classified Sporadic cases are probably mostly attributable to according to morphological patterns of involvement freshly arisen mutations. of the . They are relatively common but rarely cause severe impairment of vision in child- hood. Great care must be taken to exclude ac- Buphthalmos or infantile is sometimes quired causation in an individual case. Thus, a secondary manifestation of other ocular abnor- was formerly an important malities such as, for example, aniridia. Primary J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

262 G. R. Fraser buphthalmos, on the other hand, presents a con- eye involvement is of very variable type, and severe siderable problem of nosological delineation. visual impairment in childhood is rare (osteogenesis Autosomal recessive types undoubtedly occur, as imperfecta, Ehlers-Danlos syndrome, pseudo- shown by the involvement of multiple sibs and by xanthoma elasticum), while in others the eye an increase of parental consanguinity. In a few manifestations are constant and lead more fre- cases, dominant inheritance seems likely and, in quently to serious and early visual impairment. addition, buphthalmos may occasionally be identi- Thus, (often associated with high fied as a component of Lowe's oculo-cerebro-renal myopia) and its secondary complications frequently syndrome which is inherited in a sex-linked reces- occur in Marfan's syndrome, homocystinuria, and sive manner. In this context, Franceschetti (1961) the Weill-Marchesani syndrome, while severe found evidence of hyperaminoaciduria in 22 of 44 corneal dystrophies are common in mucopoly- males and 6 of 19 females with buphthalmos, and saccharidoses I (Hurler's syndrome), V (Scheie's suggested the existence of oculo-renal disturbances syndrome) and VI (Maroteaux-Lamy syndrome). of a wide range of severity, possibly related to In addition, choroido-retinal degenerations may Lowe's syndrome. occur in almost all forms of , Fraser and Friedmann (1967), however, came to but severe visual impairment in childhood is always the conclusion that these single gene patterns of due to the corneal changes. inheritance could account only for a minority of In addition, generalized genetically determined cases, since most are non-familial and there is a skeletal disorders exist, in association with which large excess of males in all reported series which severe visual impairment may occur in childhood, cannot be explained solely in terms of the small such as autosomal recessive chondrodystrophia proportion due to sex-linked inheritance. They calcificans congenita with cataracts (Conradi's postulated, therefore, that more complicated poly- syndrome), and myopia and retinal detachment with genic mechanisms of inheritance were operative in dysplasia spondyloepiphysaria congenita and, pos- the majority of cases. Under this hypothesis, such sibly, with other related conditions (Fraser et al., multiple genetical factors, perhaps interacting with 1969), inherited in an autosomal dominant manner.copyright. others determined environmentally, might be Retinal lesions of the type of retinal aplasia or thought of as resulting in deviations from normal retinitis pigmentosa occur in association with poly- embryogenesis of the eye structures giving rise to dactyly and the other features of the Laurence- malformations which, in common with many lesions Moon-Bardet-Biedl syndrome, with microcephaly with this type of causation, show a strong association (McKusick et al., 1966; Schmidt, Jaeger, and with sex, boys being affected much more frequently Neubauer, 1967), and with dwarfism and other than girls in this case. anomalies in Cockayne's syndrome, all three con- ditions being inherited in an autosomal recessive http://jmg.bmj.com/ manner. Abnormalities of the of the type of Severe Visual Impairment in Childhood Rieger's (1934) as One of autosomal dominant mesodermal Component Complex Syndromes dysgenesis of the anterior segment may coexist Determined by Single Gene Inheritance with skeletal and visceral abnormalities. In the main, the effects of the pathological condi- Microphthalmos, often in association with cata- tions discussed above have been confined to the visual ract, may occur in several complex syndromes. apparatus though sometimes other portions of the Thus, oculo-dento-digital dysplasia is probably an on September 27, 2021 by guest. Protected central nervous system have been involved. Many autosomal dominant condition, consisting of micro- additional syndromes exist which are inherited in a phthalmos in association with small nose, hypotri- simple Mendelian manner and in which the eye is chosis, dental anomalies, camptodactyly of the fifth involved in conjunction with other organ systems. fingers, syndactyly, and missing toe phalanges. In Thus, severe visual impairment in childhood may addition, Lenz (1955) described a sex-linked be a feature of many of the generalized disorders of recessive form of microphthalmos in association connective tissue comprehensively discussed by with digital, genital, and other malformations. McKusick (1966). These include autosomal Congenital cataracts with microphthalmos may dominant conditions such as Marfan's syndrome, also be responsible for severe visual impairment in Ehlers-Danlos syndrome, and osteogenesis imper- childhood in the Francois-Hallermann-Streiff syn- fecta, and autosomal recessive conditions such as drome, involving proportionate dwarfism, lack of pseudoxanthoma elasticum, homocystinuria, Weill- head hair, dental maldevelopment, and osseous Marchesani syndrome, and some forms of muco- anomalies of the skull which give rise to a charac- polysaccharidosis. In some of these conditions, teristic facial appearance. Autosomal dominant J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Genetical Aspects of Severe Visual Impairment in Childhood 263 inheritance seems likely in this condition, but hypoplasia is common and when extreme, as is often evidence of direct transmission from parent to the case, is incompatible with postnatal survival. child and of familial incidence in general is some- The gene concerned, therefore, is sublethal and the what equivocal. This may be because of reduced homozygous survivors may be regarded as 'Durch- fitness of affected persons, on account of blindness brenner' in the sense of Hadorn (1955), meaning and an unprepossessing appearance, and its conse- that they have escaped the lethal effects of the gene quence that virtually all cases may represent freshly by passing a critical threshold in the range of vari- arisen mutations.* Bueno Saunchez (1966) described ation of renal development found in this syndrome. a family in which this condition was apparently in- A rough and ready rule governing the clinical herited in an autosomal recessive manner, but an manifestations of genetically determined conditions examination of his report reveals that it was based on seems to be that malformative syndromes are in- a misdiagnosis, and the affected sibs certainly did not herited in a dominant manner whereas recessive have the Francois-Hallermann-Streiff syndrome. conditions are often such as to be explicable in Another syndrome involving cataracts with dental terms of deficient action of a single usually maldevelopment and webbed toes was responsible in postnatal life. The syndrome for visual handicap in 3 of the 776 children studied and several other complex malformation syndromes by Fraser and Friedmann (1967): all 3 were girls. form exceptions to this rule, and, in the case of the The exact genetical and nosological status of this cryptophthalmos syndrome, Fraser and Friedmann syndrome is unclear but, like the Francois-Haller- (1967) have adduced evidence that this condition mann-Streiff syndrome, it may be determined by may be due to homozygosis for a gene which in the autosomal dominant inheritance, the 3 cases in heterozygous state may be responsible for minor question representing freshly arisen mutations. ocular abnormalities such as moderate degrees of Other malformative syndromes where single microphthalmos and .t gene dominant inheritance may be operative and Lastly, severe visual impairment in childhood may which many include severe visual impairment in occur not as a component of a complex syndrome

childhood include the Pierre Robin syndrome but as a result, often because of malformations of copyright. (Smith, Cavanaugh, and Stowe, 1960), and condi- the skull leading to raised intracranial pressure and tions involving maldevelopment of the eyes and optic atrophy. Among conditions of this type ears together with osseous anomalies of the facial determined in a simple Mendelian manner, the fol- skeleton and vertebrae of the type of the oculo- lowing may be mentioned: Crouzon's craniofacial vertebral syndrome of Weyers and Thier (1958). dysostosis, Apert's acrocephalosyndactyly, and other may sometimes give rise less well-defined forms of craniostenosis and of to severe visual impairment usually due to lesions oxycephaly, all probably inherited in an autosomal of the type of pseudoglioma. The mode of inheri- dominant manner, autosomal recessive osteopetro- http://jmg.bmj.com/ tance of this condition has not been elucidated but sis, and occasional sex-linked recessive cases of it may best provisionally be regarded as due to a hydrocephalus (Fanconi, 1934; Edwards, 1960). gene on the X chromosome which gives rise to the disease in heterozygous females (X-linked dominant Quantitative Aspects of Conditions inheritance) and is usually lethal in early foetal life Determined by Simple Mendelian in males. Inheritance in Causation of Severe Visual

Most of the malformative syndromes discussed Impairment in Childhood on September 27, 2021 by guest. Protected thus far are inherited in an autosomal dominant manner, but the autosomal recessive cryptophthal- Apart from the difficulties mentioned in the mos syndrome forms an exception to this rule which introduction that no universally acceptable criteria is of particular interest. This comprises an exceed- exist for the definition of severe visual impairment ingly complex constellation of malformations invol- in childhood and that the spectrum of causation is ving both the viscera and the skeletal system (Fraser, modified by treatment, especially in the case of such 1962).The feature which gives the condition its name conditions as cataract, corneal lesions, and buphthal- and which leads to blindness is failure offormation of mos, there are other problems involved in attempt- a division between the , combined with rudi- ing to define the numerical roles of the various t The possibility cannot of course be excluded that the 'gene' in mentary development of the ocular . Renal question represents a small chromosomal rearrangement which is not * Circumstantial evidence of the presence of fresh mutation may detectable by currently available microscopical methods; such a be afforded by an increase in parental, especially paternal, age at the defect could readily give rise to Mendelian patterns of inheritance, birth of affected children. While this information is often not re- and perhaps accords better with phenotypes involving this and other corded, in a recent case report (Ide and Webb, 1969) the paternal multiple malformation syndromes than does a mutation of a single age at birth was 61 years and the maternal 33 years. gene. J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

264 G. R. Fraser

entities discussed thus far in the causation of severe be responsible for almost a half of all cases of severe visual impairment in childhood. Diagnosis is visual impairment in childhood, though the pro- often difficult and the condition originally re- portion may be somewhat less among ineducable sponsible for visual loss can frequently not be identi- children in whom acquired causes probably play a fied unequivocally. Again, even if diagnosis is larger role. It is notable that, whereas in other possible at the pathological level, the mode of common forms of childhood handicap due to segre- inheritance may not be identifiable in each indi- gation of single genes, such as deafness, mental vidual case. Nevertheless, children with severe retardation, or cerebral palsy, autosomal recessive visual handicap are in many countries segregated inheritance plays by far the major role, in the case in schools or institutions for the ineducable, and of visual impairment autosomal dominant in- surveys such as those of Fraser and Friedmann heritance is as important if not more so. This may (1967) or Fontaine et al. (1969) may be used to obtain be due, in part at least, to the fact that dominant an approximate idea of the quantitative distribution conditions do not cause such severe restrictions of of these entities determined in a simple Mendelian fertility in the case of visual impairment as in the manner in these populations. Needless to say, this case of these other forms of childhood handicap. spectrum is likely to vary considerably in different Thus, dominant cataracts often lead only to mod- parts of the world, and conclusions drawn from such erate visual loss, and retinoblastoma, previously populations in Western Europe, where most such almost invariably fatal in infancy, is now frequently surveys have been performed, cannot be regarded compatible with reproduction. Whatever the cause as universally applicable. of this frequent occurrence of autosomal dominant Of all the main subgroups discussed above, inheritance in the case of severe visual impairment choroido-retinal degenerations represent the most in childhood, it is of considerable importance from common single cause of severe visual impairment in the point of genetical counselling, since, as a conse- childhood. The vast majority are inherited in an quence, such impairment may relatively often be autosomal recessive manner, and homozygosity at transmitted from parent to offspring. one of a number of different gene loci is likely to be copyright. involved. Congenital lesions of the type of Leber's Severe Visual Impairment in Childhood amaurosis, or retinal aplasia, are the most frequent due to Polygenic Inheritance and to but a substantial proportion of cases owe their Interactions Between Multiple Genetical handicap to choroido-retinal degenerations of later and Environmental Factors onset involving primarily the macula (Stargardt's Severe visual impairment in childhood may be macular dystrophy, 'central' retinitis pigmentosa). due in as much as 50% of cases to primarily ac- In a further number, the visual impairment is quired causes, though this proportion is decreasing associated with one of the forms of albinism. A rapidly as children with retrolental fibroplasia reach http://jmg.bmj.com/ few cases of sex-linked recessive choroido-retinal adult life. The qualification 'primarily' is used degenerations may be seen, and very occasionally advisedly since, of course, in virtually all cases, autosomal dominant inheritance is involved. In genetical factors, probably of a complex nature, all, choroido-retinal degeneration may be re- interact with environmental factors to produce the sponsible for a third or so of all cases of severe visual damage. Thus, cataracts due to maternal visual impairment in childhood due to Mendelian rubella in pregnancy are the most common cause of segregation of single genes. prenatally acquired severe visual impairment in on September 27, 2021 by guest. Protected Almost another third is shared approximately childhood; clearly, however, the genotype both of equally between cataracts and bilateral retinoblas- the mother and of the foetus interact with exposure toma. The vast majority of cataracts are inherited to the virus in determining the extent of foetal in an autosomal dominant manner, but occasionally involvement. recessive forms, both sex-linked and autosomal, are Again, severe visual impairment in childhood is seen and, in such cases, metabolic abnormalities can very often due to primarily acquired causes acting sometimes be detected. in the perinatal period which may give rise to The other entities discussed above collectively retrolental fibroplasia, cataracts, optic atrophy, and make up the remaining third or so of causes of probably, in occasional cases, myopia, buphthal- severe visual impairment in childhood. None is mos, and choroido-retinal degenerations. Not individually very common, but quite a substantial only is the genotype of the child, in general, im- proportion involves the complex syndromes dis- portant in determining his susceptibility to the cussed in the previous section. effect of noxious environmental influences in this In all, Mendelian segregation of single genes may critical perinatal period, but also such disastrous J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Genetical Aspects of Severe Visual Impairment in Childhood 265 results occur predominantly in premature children the sex chromosomes (Francois, 1967; Francois, and, ipso facto, in twins; in this way, the complex Matton-van Leuven, and Gombault 1970). Thus, genetical bases of prematurity and of twinning are in conditions due to trisomy of the D and E involved. chromosomes gross morphological maldevelop- Lastly, causes acting in infancy and childhood ment of the eyes is frequently seen, but such involve mainly infectious and autoimmune diseases, children rarely survive more than a few days and, and cerebral tumours. In each case, complex therefore, do not make a significant contribution to genetical factors play a role in aetiology, by deter- severe visual handicap in childhood. The as- mining susceptibility to infectious disease, the sociation of Down's syndrome or G group trisomy onset and extent of autoimmune damage, and the with cataracts is well known. predisposition to malignant neoplasia. In addition to conditions that are associated with Apart from these primarily acquired causes, it is aberrations involving entire chromosomes, specific probable that, in a substantial number of cases (per- associations of eye defects with less severe chromo- haps as much as 5-10%), severe visual impairment somal anomalies have been described. Thus, for in childhood is due primarily to polygenic inheri- example, Schachenmann et al. (1965) described a tance, that is to say to the synergistic action of a large syndrome consisting of coloboma of the iris, anal number of genes, each with a small individual effect stenosis, and renal malformation in association with but collectively giving rise to an extreme distur- a small additional acrocentric chromosomal frag- bance of eye structure causing severe visual im- ment, this anomaly being inherited as an autosomal pairment. This type of inheritance is familiar in dominant condition. It is interesting to note that the case of intelligence or height; it is a no less anal stenosis may be seen in association with Rieger's probable mechanism in the determination of the mesodermal dysgenesis of the anterior segment parameters of shape and size of the eye, extreme (Brailey, 1890; Crawford, 1967), so that anomalies 'physiological' variation in these parameters giving ofthe iris coexist with anal stenosis in two autosomal rise to high degrees of myopia. A refinement of the dominant syndromes, one associated with a visible theory ofpolygenic inheritance involves a 'threshold' chromosomal anomaly and the other not. effect which implies that when the deviation from Allderdice et al. (1969)have suggested that deletion copyright. average population values determined by multiple of part of the long arm of a D chromosome, pro- genes, each with a small effect, reaches a certain bably 13, gives rise to a characteristic clinical level, some process essential to normal development syndrome, with facial dystrophy, psychomotor re- can no longer take place. Such a mechanism may tardation, and absent or hypoplastic thumbs, which control the relation between skull width and palatal often also involves the eyes in that retinoblastoma, closure and, by the same token, disturbances of the microphthalmos, and coloboma of the iris may occur. normal anatomical relationships of the eye leading Fraser et al. (1970) have reported karyotype http://jmg.bmj.com/ to such lesions as coloboma and buphthalmos. studies in families of 23 of the 776 children with Apart from such 'simple' forms of high myopia, severe visual handicap studied by Fraser and Fried- coloboma, and buphthalmos tentatively ascribed to mann (1967). These children were selected for these mechanisms, they may also be operative in the karyotype study because of unusual constellations causation of various complex conditions such as the of congenital defects in association with their Sturge-Weber syndrome and various other ill- visual handicap, or because of anomalous hereditary defined associations of eye defects with involvement patterns ofthe primary ocular lesion. No abnormal of other organ systems, especially the skeleton. In karyotypes were found. It should be emphasized, on September 27, 2021 by guest. Protected addition, severe visual impairment may be due to however, that all of the children studied by Fraser optic atrophy as a secondary result ofmalformations, and Friedmann (1967) attended schools or training presumably determined in this way, which are centres and none was so mentally subnormal as to associated with increases of intracranial pressure be regarded as entirely ineducable. Thus, in view such as hydrocephalus, meningocele, and encephalo- of the virtually constant association of gross mental cele. subnormality with major chromosomal aberra- tions, the absence of Severe Visual Impairment in Association abnormal findings in this group with Gross is not unexpected. The situation may well be Anomalies of Karyotype different among children selected both through Serious ocular involvement is extremely com- visual handicap and mental subnormality. mon in known syndromes due to chromosomal Support from Public Health Service Grant GM15253 aberrations involving the autosomes, though much during the preparation ofthis paper is gratefully acknow- less frequent in persons with abnormalities of ledged. J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

266 G. R. Fraser Gillespie, F. D. (1965). Aniridia, cerebellar ataxia and oligophrenia REFERENCES in siblings. Archives of , 73, 338-341. Gitzelmann, R. (1967). Hereditary galactokinase a Allderdice, P. W., Davis, J. G., Miller, 0. J., Klinger, H. P., War- deficiency, newly D., D. A., Allen, F. H., Jr., Abrams, C. A. L., and recognized cause ofjuvenile cataracts. Pediatric Research, 1, 14-23. burton, Miller, Hadorn, E. (1955). McGilvray, E. (1969). The 13q - deletion syndrome. American Letalfaktoren in ihrer Bedeutung fur Erbpatho- J'ournal of Human Genetics, 21, 499-512. logie und Genphysiologie der Entwicklung. Thieme, Stuttgart. Brailey, W. A. (1890). Double microphthalmos with defective Hemmes, G. D., Nijland, R., and Schappert-Kimmijser, J. (1964). development of iris, teeth and anus. Glaucoma at an early age. De kans op ontwikkeling van retinoblastoma bij kinderen uit gezin- Transactions of the Ophthalmological Society of the United King- nen waarin deze ziekte is voorgekomen. Nederlandsch Tijdschrift dom, 10, 139-140. voor Geneeskunde, 108, 1906-1908. Bruyn, G. W., and Went, L. N. (1964). A sex-linked heredo- Hermann, P. (1958). Le syndrome microphtalmie-retinite pig- degenerative neurological disorder, associated with Leber's optic mentaire-glaucome. Archives d'Ophtalmologie et Revue Generale d'Ophtalmologie, 18, 17-24. atrophy. I. Clinical studies. Journal of the Neurological Sciences, 1, 59-80. Hermansky, F., and Pudlak, P. (1959). Albinism associated with Bueno Sanchez, M. (1966). Sindrome de Hallerman-Streiff- hemorrhagic diathesis and unusual pigmented reticular cells in the Francois. A prop6sito de una presentaci6n familiar. Boletin de marrow; report of two cases with histochemical studies. la Sociedad Vasco-Navarra de Pediatria, 1, 21-35. Blood, 14, 162-169. Contreras, B. C., and Espinoza, S. J. (1960). Discusi6n clinica y Hull, D. (1969). Cataracts associated with metabolic disorders in anatomopatologica de enfermos que presentaron un problema infancy. Proceedings of the Royal Society ofMedicine, 62, 694-696. diagnostico. Pediatria (Santiago), 3, 271. Ide, C. H., and Webb, R. W. (1969), Hallermann-Streiff syndrome. Crawford, R. A. D. (1967). Iris dysgenesis with other anomalies. American Journal of Ophthalmology, 67, 151-153. British Journal of Ophthalmology, 51, 438-440. Jancke, G. (1950). Cataracta syndermatotica und Ichthyosis con- Crome, L., Duckett, S., and Franklin, A. W. (1963). Congenital genita. Klinische Monatsbldtter fur Augenheilkunde, 117, 286-290. cataracts, renal tubular necrosis and encephalopathy in two Kjer, P. (1959). Infantile optic atrophy with dominant mode of sisters. Archives of Disease in Childhood, 38, 505-515. inheritance. A clinical and genetic study of 19 Danish families. De Loore, I., and Van Gelderen, H. H. (1967). Liver glycogenosis Acta Ophthalmologica, Suppl. 54,1-147. and cataracts in a mentally deficient child. Archives of Disease in Lenz, W. (1955). Recessiv-geschlechtsgebundene Mikrophthalmie Childhood, 42, 435-440. mit multiplen Missbildungen. Zeitschrift fur Kinderheilkunde, 77, Dekaban, A., and Carr, R. (1966). Congenital amaurosis of retinal 384-390. origin. Frequent association with neurological disorders. L0ken, A. C., Hanssen, O., Halvorsen, S., and J0lster, N. J. (1961). Archives of Neurology, 14,294-301. Hereditary renal dysplasia and blindness. Acta Paediatrica, 50, Edwards, J. H. (1960). The syndrome of sex-linked hydrocephalus. 177-184. Archives of Disease in Childhood, 36, 486-493. Lowe, C. U., Terrey, M., and MacLachlan, E. A. (1952). Organic- Fanconi, G. (1934). Zur Diagnose und Therapie hydrocepha- aciduria, decreased renal ammonia production, hydrophthalmus lischer und verwandter Zustande. Schweizerische medizinische and mental retardation. American_Journal of Diseases of Children, Wochenschrift, 64, 214-223. 83, 164-184. Fontaine, M., Aron, J.-J., Perdriel, G., and Rousselie, F. (1969). Lyon, M. F. (1961). Gene action in the X-chromosome of the copyright. Les Cicitis de l'Enfance. Masson, Paris. mouse (Mus Musculus L.). Nature (London), 190, 372-373. Fraccaro, M., Morone, G., Manfredini, U., and Sanger, R. (1967). McKusick, V. A. (1966). Heritable Disorders of Connective Tissue, X-linked cataract. Annals of Human Genetics, 31, 45-50. 3rd ed. Mosby, St. Louis. Franceschetti, A. (1961). Aminoacidurie dans la cataracte et le -, Stauffer, M., Knox, D. L., and Clark, D. B. (1966). Chorio- glaucome d'origine congenitale. Analogies avec le syndrome with hereditary microcephaly. Archives of Ophthal- oculo-cerebro-renal de Lowe-Terrey-MacLachlan. Bulletin der mology, 75, 597-600. Schweizerischen Akademie der medizinischen Wissenschaften, 17, Nettleship, E. (1912). A pedigree of congenital night-blindness 414-422. with myopia. Transactions of the Ophthalmological Society of the -, Francois, J., Babel, J., de Rouck, A., Dieterle, P., Forni, S., United Kingdom, 32, 21-45. Klein, D., Ricci, A., and Verriest, G. Les Hirido- (1963). O'Connor, C. F., and Crawford, J. D. (1967). Hypoglycemia in http://jmg.bmj.com/ Dlginirescences Chorio-Ritiniennes (Digenirescences Tapito- infancy. Appraisal of the problem, methods of investigation, Ritiniennes), 2 vols. Masson, Paris. possible association of cataracts. Clinical Pediatrics, 6, 94-105. -, and Gernet, H. (1965). Diagnostic ultrasonique d'une Pinkerton, 0. D. (1958). Cataract associated with congenital microphtalmie sans microcornee, avec macrophakie, haute hyper- ichthyosis. Archives of Ophthalmology, 60, 393-396. metropie associee a une degenerescence tapeto-retinienne, une Rieger, H. (1934). Beitrage zur Kenntnis seltene Missbildungen der disposition glaucomateuse et des anomalies dentaires (nouveau Iris. II. OYber Hypoplasie des Irisvorderblattes mit Veragerung syndrome familial). Archives d'Ophtalmologie et Revue Ginerale und Entrundung der Pupille. Albrecht v. Graefes Archiv fiur d'Ophtalmologie, 25, 105-116. Ophthalmologie, 133, 602-635. Francois, J. (1959). Les Cataractes Congenitales. Masson, Paris. Rose, F. C., Fraser, G. R., Friedmann, A. I., and Kohner, E. M. (1967). Autosomal chromosome aberrations in ophthalmology. (1966). The association of juvenile diabetes mellitus and optic J7ournal of the Neurological Sciences, 4, 511-558. atrophy: clinical and genetical aspects. Quarterly Journal of on September 27, 2021 by guest. Protected Matton-van Leuven, M. Th., and Gombault, Ph. (1970). Medicine, 35, 385-405. Uveal coloboma and true Klinefelter syndrome. J'ournal of Schachenmann, G., Schmid, W., Fraccaro, M., Mannini, A., Medical Genetics, 7, 213-223. Tiepolo, L., Perona, G. P., and Sartori, E. (1965). Chromosomes Fraser, G. R. (1962). Our genetical 'load'. A review of some in coloboma and anal atresia. Lancet, 2, 290. aspects of genetical variation. Annals of Human Genetics, 25, 387- Schmidt, B., Jaeger, W., and Neubauer, H. (1967). Ein Mikroze- 415. phalie-Syndrom mit atypischer tapetoretinaler Degeneration bei 3 , and Friedmann, A. I. (1967). The Causes of Blindness in Child- Geschwistern. Klinische Monatsbldtter fur Augenheilkunde, 150, hood. A Study of 776 Children with Severe Visual Handicaps. 188-196. Johns Hopkins, Baltimore. Senior, B., Friedmann, A. I., and Braudo, J. L. (1961). Juvenile -, , Delhanty, J. D. A., Edwards, J. H., Glen-Bott, A. M., familial nephropathy with tapetoretinal degeneration. A new Insley, J., Lele, K. P., Mittwoch, U., and Mutton, D. (1970). oculorenal dystrophy. American Journal of Ophthalmology, 52, Karyotype studies among children with severe visual handicap. 625-633. British Journal of Ophthalmology, 54, 79-89. Smith, J. L., Cavanaugh, J. J. A., and Stowe, F. C. (1960). Ocular -, -, Maroteaux, P., Glen-Bott, A. M., and Mittwoch, U. manifestations of the Pierre Robin syndrome. Archives of (1969). Dysplasia spondyloepiphysaria congenita and related Ophthalmology, 63, 984-992. generalized skeletal dysplasias among children with severe visual Sorsby, A. (1934). Anophthalmos: an unpublished manuscript by handicaps. Archives of Disease in Childhood, 44, 490-498. James Briggs giving the first account of the familial occurrence Gabilan, J.-C., and Chaussain, J.-L. (1969). L'association hypo- of the condition. BritishJournal of Ophthalmology, 18, 469-472. glycemie idiopathique et cataracte chez l'enfant. Archives -, and Williams, C. E. (1960). Retinal aplasia as a clinical entity. Franfaises de Pidiatrie, 26, 633-640. British MedicalJournal, 1, 293-297. J Med Genet: first published as 10.1136/jmg.7.3.257 on 1 September 1970. Downloaded from

Genetical Aspects of Severe Visual Impairment in Childhood 267

Speakman, J. S., and Crawford, J. S. (1966). Congenital opacities of Waardenburg, P. J., and Schappert-Kimmijser, J. (1963). On the cornea. British Journal of Ophthalmology, 50, 68-78. various recessive biotypes of Leber's congenital amaurosis. Acta Ophthalmologica, 41, 317-320. Steward, J. K., Smith, J. L. S., and Amold, E. L. (1956). Spon- Walsh, F. B., and Wegman, M. E. (1937). A pedigree of hereditary taneous regression of retinoblastoma. British Journal of Ophthal- cataract, illustrating sex-limited type. Bulletin of the Johns mology, 40, 449-461. Hopkins Hospital, 61, 125-135. Trevor-Roper, P. D. (1952). Marriage of two complete albinos with Warburg, M. (1966). Norrie's disease. A congenital progressive normally pigmented offspring. British Journal of Ophthalmology, oculo-acoustico-cerebral degeneration. Acta Ophthalmologica, 36, 107-108. Suppl. 89, 1-147. Watillon, M., Weekers, R., Marriaux, E., and Joachim, M. (1964). Usher, C. H. (1921). A pedigree of with myopia Retinoblastome hereditaire. Archives d'Ophtalmologie et Revue and corectopia. British Journal of Ophthalmology, 5, 289-299. Generale d'Ophtalmologie, 24, 279-283. Weyers, H., and Thier, C. J. (1958). Malformations mandibulo- van Canneyt, and Vandemeulebroecke (1936). A propos d'un cas faciales et delimitation d'un syndrome oculo-vertebral. J7ournal de d'anophtalmie bilaterale. Bulletin de la Societl Belge d'Ophtal- Genetique Humaine, 7, 143-173. mologie, 73, 17-20. Witkop, C. J., Jr., Nance, W. E., Rawls, R. S., and White, J. G. Vogel, F. (1957). Neue Untersuchungen zur Genetik des Retino- (1970). Autosomal recessive oculocutaneous albinism in Man; blastoms (Glioma Retinae). Zeitschrift fur menschliche Vererbungs- evidence for genetic heterogeneity. American Journal of Human und Konstitutionslehre, 34, 205-236. Genetics, 22, 55-74. copyright. http://jmg.bmj.com/ on September 27, 2021 by guest. Protected