Autosomal chromosome aberrations in ophthalmology

Journal of the neurological Sciences

Elsevier Publishing Company, Amsterdam - Printed in The Netherlands

511

Autosomal Chromosome Aberrations in Ophthalmology J. FRAN(~OIS Ophthalmological Clinic (Prof. J. Francois), University of Ghent, Ghent (Belgium)

(Received 23 October, 1965)

A genetically determined disorder may be due either to a pathological gene or to a chromosomal aberration. (1) In classical Mendelian heredity, disease is caused by one or several mutated genes (mono- or polygenic heredity). The genome or the total number of genes is not modified (haploid genome). The mutation of the gene is due to a chemical modification of the D N A and can only be confirmed by its effect on the phenotype. (2) A genetically determined disorder may also be due to an abnormal number of chromosomes (numerical aberration) or to an alteration in the morphological structure of the chromosomes (structural aberration). The genome with abnormal karyotype is thus quantitatively different from the haploid genome. The disease is no longer due to a pathological gene, but to an abnormal number of normal genes. The chromosome mutation depends upon a physical (and no longer a chemical) modification of the D N A , and it can be observed cytologically. In other words, if the number of genes is abnormal, and even if these genes are normal, the phenotype will be abnormal. This fact is well illustrated in the study ofuniovular twins reported by DE WOLFF et al. (1962). One of the twins was normal, and the other a mongol. Each had 46 chromosomes with the same number of identical genes, but the mongol had a supplementary chromosome No. 21, which nevertheless carried the same genes as one of the other two chromosomes No. 21. In the mongol there was no gene, nor any genetic information, which was not present in the normal twin. The important difference between the normal child and the mongol could be explained only by the different number of identical and normal genes. We know that there are 22 pairs of homologous chromosomes, called autosomes, which are identical in the male and female, and one pair of sex chromosomes (XX in the female, XY in the male): this is called haploidy. The chromosomes of a cell in metaphase (Fig. 1) are formed by two chromatides or four arms connected by a constricted zone, the centromere (or kinetochore). They are characterized by their dimensions (1.5-7.5/z), by the position of the centromere, and by the presence or absence of satellites (Fig. 2). J. neuroL Sci. (1967) 4:511-558

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Fig. 1. Chromosomes of a cell in metaphase.

Fig. 2. Chromosome with its two chromatides, its centromere and its two satellites.

Fig. 3. Ideogram with seven groups of chromosomes (A-G).

Seven groups of chromosomes (A-G) are distinguishable (Fig. 3): Group A: Chromosomes No. 1-3. They are the largest. Their centromere is median (large metacentric chromosomes). Group B: Chromosomes No. 4 and 5, which are quite large. Their centromere is submedian. Group C: Chromosomes No. 6-12 ( + X ) , the dimensions of which are medium. Their centromere is submedian. Group D: Chromosomes No. 13-15, with medium dimensions, but with the centromere almost terminal (large acrocentric chromosomes). J. neurol. Sci. (1967) 4:511-558

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Group E: Chromosomes No. 16-18, with smaller dimensions and with the centromere median or submedian. Group F: Chromosomes No. 19-20, with even smaller dimensions, and with the centromere median or submedian (small metacentric chromosomes). Group G: Chromosomes No. 21-22 ( + Y), which are the smallest. Their centromere is nearly terminal (small acrocentric chromosomes). Numerical chromosome-aberrations The abnormal number of chromosomes (aneuploidy), which often results in premature death of the embryo (abortion), is due to an absence of segregation during meiosis or mitosis (Fig. 4). During meiosis (gametogenesis) the 'non-disjunction' leads to a m o n o s o m y (hypodiploidy) or to a polysomy (hyperdiploidy), simple or double (trisomy, tetrasomy) (Fig. 5). During mitosis the 'non-disjunction' leads to mosaicism. In this case the chromoso-

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Fig. 4. a: normal gametogenesis; b: non-disjunction during the first division; c: non-disjunction during the second division.

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Fig. 5. Non-disjunction during the gametogenesis leads to monosomy or trisomy.

Fig. 6. Trisomy 21 (personal observation).

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mal aberration is not uniformly present in all the cells, but remains localized to certain tissues or certain organs. This is due to an abnormal mitosis during the first divisions of the zygote, or during the development of the embryo, or even postnatally. There are thus two populations of cells, each with a different chromosome constitution, which is transmitted to all the daughter-cells. Among these numerical aberrations, the trisomies are the best known. It was, in fact, the sensational discovery of trisomy 21 in mongolism by LEJEUNE et al. (1959) which gave a new impetus to cytogenetics (Fig. 6). It was at first believed that each trisomy was accompanied by symptoms that were characteristic, if not specific, but it must now be recognized that the anomalies observed are not only variable, but can also be found in other trisomies. Such anomalies include mental retardation, absence of development, cranial malformations, ocular anomalies, malformations of the ears and their low positioning, hypoplasia of the mandible, anomalies of the fingers, hands and feet, syndactyly, horizontal palmar creases, congenital cardiopathies and renal malformations. It is, therefore, difficult to make a clinical diagnosis of a given trisomy with certainty without the aid of cytogenetics. We do, in fact, know of cases that clinically resemble a trisomy E, but which are cytogenetically trisomies D (GOODMANet al. 1962b; TOWNESet al. 1962), or the contrary (VAN WIJCK et al. 1961). On the other hand, there are children who present with malformations identical with those found in children with trisomic symptoms, but who have normal karyotypes (BABEL 1964b ; MARSHALLet al. 1964). In such cases there is either a translocation with a partial and invisible trisomy, or else a phenocopy produced by pathological genes or exogenous agents. At the same time it should be remembered that the samephenotype may have different causes. Structural aberrations o f chromosomes Structural aberrations of chromosomes may be multiple, although they are invisible if they involve less than 1% of the haploid length. The most important are fragmentation, translocation, deletion, insertion, inversion, annular deformation (ring chromosome) and increased size of the satellites. (1) Fragmentation. Structural aberrations usually appear after fragmentation of the chromosome or of the chromatid, which is then followed by a normal or abnormal reunion of the fragments. Such fragmentation usually occurs in only one of a pair of homologous chromosomes, and is a heterozygous phenomenon. Following the breakage of a chromosome, the karyotype may show a supernumerary chromosome fragment. (2) Translocation. Following a breakage, a fragment of chromosome is transferred to another part of the same chromosome, or more often to another chromosome (Fig. 7) (reciprocal translocation between two non-homologous chromosomes). Translocation is most often observed between the acrocentric chromosomes of group D and group G. In 75~o of cases it is due to a spontaneous chromosome mutation, and in 25% of cases to a familial translocation, usually transmitted by the mother, more rarely by the father. J. neurol. Sci.

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Fig. 7. Translocation of a chromosome No. 15 on to a chromosome No. 2 (after MERCER AND DARAK.IIAN1962).

In the case of balanced translocation, that is to say when the translocation involves 2 normal chromosomes which remain within the cell, the karyogram contains only 45 chromosomes, but shows that a chromosome is made up of the greater part of two chromosomes. There is then genetic equilibrium, and the phenotype is normal. When the translocation is not balanced, 46 chromosomes are found, with 45 normal chromosomes and 1 abnormal chromosome, consisting of the principal fragments of 2 chromosomes, one of which is supernumerary. The result of this is a partial trisomy. (3) Deletion. Following the breakage of a chromosome, the detached piece may be lost, resulting in a 'microchromosome' in the karyogram. The loss of a chromosome segment is terminal if the extremity of a chromosome is eliminated. It is internal when there is a double breakage with elimination of the intermediary piece and reunion of the distal pieces. The loss of a chromosome-fragment gives rise to a partial monosomy. (4) Insertion. A supernumerary piece of a chromosome incorporates another chromosome. In effect a translocation occurs. (5) Inversion. Following a double breakage, the intermediary piece can pivot 180 ° and then reunite with the distal pieces. The inversion is paracentric when the double breakage occurs in the same arm of a chromosome. It is pericentric when two different arms are involved, so that the centromere is localized in the inverted part. I f the breakages occur at unequal distances from the centromere, the position of this will no longer be the same. (6) Annular deformation. After the double breakage of a chromosome, its two extremities may reunite to form a ring (ring chromosome). (7) Giant satellites. The acrocentric chromosomes of group D (13-15) and of group G (21-22) carry at the extremity of their short arms a tiny segment known as a satellite.

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These satellites are small heterochromatic bodies linked to the chromosome by a fine filament. It is not yet known whether satellites transmit genetic information, but it is probable that they are genetically inactive. Sometimes they are 'hypertrophied', and they are then called 'giants'. GROUP A ( 1 - 3 )

(I) Trisomy A Although the trisomies of group A, B and C are not usually compatible with life, a trisomy No. 1 has been described, forming the basis of oro-digito-facial dysostosis (Fig. 8) (KuSHNICK et al. 1963).

Fig. 8. Trisomy No. 1 in oro-digito-facialdysostosis(after KUSHNtO(et al. 1963). The oro-digito-facial syndrome is essentially characterized by: (1) Buccal anomalies, which are constant: bifid tongue, with hypertrophied frenulum and abnormal webs, pseudo-cleft of the upper lip with gingivo-labial fusion, high arched palate, submucous palatine cleft, absence of teeth, or malformed or malpositioned teeth with hypoplasia of the enamel. (2) Facial and cephalic anomalies (Fig. 9A), which are found in half the cases: microcephaly, porencephaly, hypoplasia of the inferior maxilla with retrognathia, hypertelorism, alopecia, dryness of the skin. (3) Digital anomalies (Fig. 9B), which are observed in a third of cases: brachydactyly, clinodactyly, incomplete syndactyly. (4) Psycho-motor retardation, with oligophrenia and neurological disorders, which may be accompanied by blindness, probably of cortical origin. According to some authors (PATAU et al. 1961 ; RUESSet al. 1962), this syndrome is J. neurol. Sci. (1967)4:511-558

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Fig. 9. Oro-digito-facial dysostosis. A. Facial anomalies in mother and daughters. B. Digital anomalies (brachydactyly, clinodactyly, partial syndactyly) (after Ru~s et al. 1962).

Fig. 10. Chromosomes No. 1 in a case of oro-digito-facial dysostosis (after RuEss et al. 1962). due to the insertion of a supernumerary fragment of a c h r o m o s o m e C in the medial part o f a c h r o m o s o m e No. 1, the a r m o f which is too long (Fig. 10). This partial trisomy has a lethal effect in males, which explains why all the affected patients are females. This s y n d r o m e is present in 8 - 1 6 % of cases of cleft lip. Other authors (KAPLAN et al. 1962; I)OEGE et aL 1964) have not found c h r o m o s o m e aberrations in oro-digito-facial dysostosis, which is transmitted by a u t o s o m a l J. neuroL Sci. (19673 4:511-558

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dominance according to GORLIN et al. (1961, 1964), and also RUESS et aL (1962) and DOEGE et al. (1964). (II) Translocation LEE et al. (1964) have described a translocation 2 ~ 3. The partial trisomy gave rise to the following anomalies: cebocephaly, ears malformed and low-set, bilateral complete cleft lip, micrognathia, interventricular defect, intestinal malformation, right hydronephrosis with double ureter, bilateral cryptorchidia and an anomaly of fingerflexion. MERCER AND DARAKJIAN (1963) noted a translocation of 2 ~ D in a boy of 12, who presented with mental retardation, large ears, narrow shoulders, rounded hips and a generalized hypotonia. YUNIS AND GORLIN (1963) found an asymmetrical chromosome No. I in a patient presenting with cysts of the jaw, a multiple naevoid carcinoma with basal cells, and bifid ribs. KOULISCHERAND ZANEN (1964) have reported the case of a mother and her son who presented with bilateral retraction with obliquity o f the palpebral fissure, epicanthus and ectropion of the lower lid. In these two subjects, all the karyotypes showed an asymmetry of chromosome pair No. 1, one of the two homologues having a definitely longer arm, which could be attributed to a translocation. Finally, WEISSet al. (1963) found a chromosome No. 2 that was too long in a boy of 4½, who presented with the following anomalies: mental retardation, peculiar facies, low-set ears, eccentric pupils, micrognathia, narrow teeth, muscular hypotonia, Meckel's diverticulum, absence of the right breast, left hydronephrosis, and bilateral cryptorchidia. (III) Inversion DE GROUCHYet al. (1963a) observed in a boy of 9 years old, 3 chromosomes of No. 1 dimensions and only 1 chromosome of No. 2 dimensions, probably as a result of a pericentric inversion at the level of a chromosome No. 2. They found the following anomalies: slight mental retardation, oxycephaly, hypertelorism, congenital cardiopathy, bilateral cubitus valgus, bilateral genu valgum, hyperlaxity of the articular ligaments, malformation of the fingers, and pes cavus. In conclusion, whether the aberration of group A chromosomes be numerical or structural, ocular signs are absent or mild in degree (hypertelorism, epicanthus, narrowing of the palpebral fissure, ectropion, eccentric pupils). GROUP B (4-5) (I) Partial trisomy B We do not know of any case of simple B trisomy, but there are cases of partial B trisomy, which involve either the short arm (GUSTAVSONet al. 1964) or the long arm (SHAw et al. 1965). (1) Trisomy for the short arm of chromosome B. GUSTAVSONet al. (1964) observed a balanced translocation (4-5) ~ (21-22) in a mother, whose multi-malformed son showed

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a partial trisomy, involving a fragment of the short arm of chromosome B. His symptoms recalled those of trisomies D, E and G. (a) Cranio-facial dysmorphosis: hydrocephaly, malformation of the pinna of the ear, the implantation of which was low, micrognathia, macroglossia, high-arched palate. (b) Ocular anomalies: blepharophimosis and bilateral colobomata of the iris. (c) Other anomalies: arachnodactyly, muscular hypotonia, premature synostosis of the sagittal suture, hydronephrosis, omphalocele, anal atresia, single umbilical artery, intestinal malformation. LF.JEtrNE et al. (1964) observed a balanced translocation of the short arm of a chromosome 5 on to a chromosome 13 in a subject who was phenotypically normal, and whose idiot daughter had a partial trisomy 5.

Fig. 11. Partial trisomy B (after SHAWet al. 1965). (2) Trisomy for the long arm of chromosome B by translocation 4 ~ 5. In a similar case SHAW et al. (1965) observed (Fig. 11): (a) Cranio-facial dysmorphosis: microcephaly, progeroid appearance of the face, malformation of the pinna of the ear with low implantation, narrowness of the superior maxilla, retrognathia. (b) Ocular anomalies: unilateral microphthalmiaSand heterolateral exophthalmos. (c) Skeletal anomalies: short neck, stiff knees and elbows, hands and wrists flexible and lax, fingers long, supple and tapering, with the index finger curved towards the thumb and the middle finger towards the fourth; partial syndactyly of the 2nd and 3rd fingers J. neuroL Sci. (1967) 4:511-558

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(webbed fingers) of both hands and of the 2nd and 3rd toes of both feet, rockerbottom feet with hyperflexion, and lack of abduction of the hip. (d) Other anomalies: cerebral malformations, single kidney, non-descended testicles.

(H) Deletion of chromosome 5 (cat's cry disease) Apart from the minimal deletions accompanying certain translocations, chromosome deletions generally seem to be lethal in man. There is, however, the syndrome known as the 'cat's cry', which is due to the partial deletion of the short arm of one of the chromosomes 5 (Fig. 12) (LEJEUNE et al. 1963; 1964; B66K et al. 1963; PANNETT et al. 1964; DUMARS et al. 1964; HIJMANS AND SHEARIN 1965).

Fig. 12. Partial deletion of the short arm of one of the chromosomes No. 5 in cat's cry disease (after LEJEUNEet al. 1963).

Fig. 13. Cat's cry disease(aRer LEJEUNEet aL 1963).

This syndrome is characterized by (Fig. 13): (1) A cranio-facial dysmorphosis, microcephaly, low-set ears, hypoplasia of the external auditory canal, hypertelorism with epicanthus, anti-mongoloid palpebral fissure, astigmatism, micro- and retrognathia. (2) Oligophrenia with significant psychomotor retardation. (3) Staturo-ponderal hypotrophy with muscular hypotonia. (4) Dermatoglyphic anomalies: axial triradius in position t', transverse palmar crease, and absence of the triradius of the 4th finger.

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(5) A characteristic cry, resembling in its sharp sound and plaintive tone the miaowing of a cat (caused by supra-glottal hypoplasia with laryngomalacia). HIRSCHHORN AND COOPER (1961) observed a chromosome aberration analogous to that of LEJEUNE'S syndrome, but the clinical manifestations were different: unilateral coloboma of the iris, central alopecia, absence of the septum pellucidum, cleft of the soft palate, hypospadias, dermatoglyphic abnormalities, convulsions. The chromosome concerned was probably no. 4. In conclusion, the ocular signs are more important and more frequent in the case of partial B trisomy (coloboma of the iris, microphthalmia) than in the deletion of chromosome 5. GROUP C

(6-12)

(I) Trisomy C RUFFI~ et al. (1964) observed a trisomy 6-12, associated with a haplosomy 21 in a case of laryngeal tuberculosis, presenting in addition a myeloblastosis of the blood and bone marrow. (H) Partial C trisomy BLUMEL et al. (1960, 1961) recorded the case of a brother and sister with cerebral paralysis and congenital nuclear cataracts with posterior capsular opacities. Their karyotype showed translocation of a chromosome fragment of unknown origin to a chromosome C. EDWARDS et aL (1962) noted in two siblings a monosomy for a short segment of the long arm of a chromosome B and a trisomy for the greater part of the short arm of a chromosome C by translocation 4 ~ 9. These children, a boy of 4 years old and a girl of 10 months, presented many anomalies: psycho-motor retardation, hypertelorism, constriction of the external auditory canal, wide fontanelle, adduction and flexion of the thumb, shortening of the medial phalanx of the 5th finger, 2nd and 3rd toes webbed, and transverse palmar crease. The boy showed, in addition, Brushfield's iris spots, a yellow pigmentation of the skin, an inguinal hernia, a flattening of the nose, and bilateral complete cleft lip. SALONIUS AND OPITZ (1964) have observed a partial trisomy C, characterized by numerous malformations, including microphthabnia. ROHDE AND CATZ (1964) found in a female patient a balanced translocation 9 ~ 6. Her daughter presented a trisomy for a large part of the long arm of chromosome No. 6, as well as a monosomy by deletion of a small piece of chromosome No. 9. She was found to have symptoms analogous to those of Langdon-Down's syndrome (pseudo-mongolism): cretinism with hypothyroidism, sexual infantilism, hypertension, abnormal determatoglyphics, anomalies of the eyes, the ears, mouth, hands and feet. In conclusion, the cases of numerical or structural aberrations of chromosomes 6-12 are still too few to allow assessment of the importance of ocular signs. GROUP D (13--15)

(I) Trisomy D1 Trisomy D (13-15) was first described by PATAU et al. (1960). An extra chromosome J. neurol. Sci. (1967) 4:511-558

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No. 13 is responsible for the syndrome (TuRPIN AND LEJEUNE 1965). For this reason it is called trisomy D1. This chromosome 13 is, in fact, distinguishable from the two other acrocentric chromosomes by prominent satellites on the short arm. Trisomy D1 is, with trisomy 18 and trisomy 21, one of the most frequent trisomies. It is found in one in 10,000 births, and even in one in 5000 according to SMITH (1964) or in one in 4000 according to PRADER (1962). At present there are about 50 references in the literature. The affected children usually die before the age of 2 or 3 months, and in every case before the age of 2 years. Trisomy D1 is characterized by multiple malformations - - ocular, cranio-facial, visceral and dermatoglyphic as well as of the extremities. The primary disturbance is located in the mesoderm, and all other changes, including those of the neuro-ectoderm, are secondary. We have had occasion to observe a case of trisomy D1, with Reese's retinal dysplasia and persistence of the primary vitreous. Observation*. Baby Br. C., a female (Fig. 14) was born at term oil December 15th 1963 and died on January 1 lth, 1964 at the age of 28 days. Her weight at birth was 71 lbs. The mother, aged 34, had a normal pregnancy. General examination. The infant had periods of apnoea with cyanosis and sibilant inspiration, probably following a laryngospasm. The heart was clinically normal. There was a pronounced bradycardia (less than 40 beats per minute). There was no dextrocardia. The abdomen was normal. On percussion, the liver was two fingers below the costal margin. The fontanelles were widely open. There was hair on the forehead. The pinna of the ear was malformed (Fig. 14). The palate was cleft posteriorly, but there was no cleft lip. There was a rightsided polydactyly (Fig. 15A), a transverse palmar crease, pseudarthrosis of the left wrist, hallux varus of the feet (Fig. 15B), hyperconvexity of the fingernails and retroflexion of the thumb. On the skin there were capillary haemangiomata (Fig. 14). Skull X-rays were normal. Examinations of the blood and the Border-Wassermann reaction were negative. Ocular examination. A conspicuous microphthalmia was noted (Fig. 16), more pronounced on the right than on the left, also an inferior coloboma of the uvea and a cornea plana. In addition there was microblepharia with a narrow palpebral fissure. Chromosome examination. This was made on cultures of leucocytes (Moorhead's technique, aceto-orcein staining, 30 cells counted). The karyotype was characterized by the presence of 47 chromosomes and a trisomy D 13-15 (Fig. 17). Autopsy Macroscopical examination. In addition to the anomalies already noted on clinical examination, the autopsy revealed, following coronartography, an anterior interventricular artery; this branch of the left coronary artery was not situated in the anterior interventricular groove, but in the anterior wall of the left ventricle. There was no interventricular defect. The heart was of normal size and weighted 20 g. ~he apex-base measurement was 5.5 * This case has been presented at the Belgian Society of Ophthalmology (1964). J. neurol. Sci. (1967) 4:511-558

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Fig. 14. Trisomy D1 (personal observation).

Fig. 15. Trisomy D1. A. Polydactyly (personal observation). B. Halux varus of the feet. Flexion of the big toe onto the 2nd toe (personal observation).

cm. The width at the horizontal groove was 4 cm. The thickness of the ventricular wall was 2 m m o n the right a n d 6 m m o n the left. The circumference of the valves was 25 m m for the aortic, 27 m m for the p u l m o n a r y , 39 m m for the tricuspid a n d 35 m m for J. neuroL SoL (1967)4:511-558

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Fig. 16. Trisomy D1. Microphthalmia (personal observation).

Fig. 17. Trisomy D1 (personal observation). the mitral. The ductus arteriosus had a diameter of 2.5 mm. The foramen ovale was patent. There was a slight protrusion o f the ethmoid into the cranium, by dint of an enlargement o f one of its cells. There were no abnormalities o f the skull, the meninges or the brain. N o exterior agenesis of the olfactory lobe was observed. The ears were not low-set. There were no macro- or microscopical changes in the lungs. Injection of the pulm o n a r y artery showed a normal vascular picture. The a b d o m e n was normal. There J. neurol. Sci.

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was no hydronephrosis nor supernumerary spleen; no enlargement of the gallbladder; no dextrorotation of the colon; no umbilical hernia; no uterus bifido-bicornis. Macroscopical examination of the eyes. The two eyes were microphthalmic (Fig. 18A). The right eye was smaller than the left. The corneal diameter was 4.5 m m right and 6 m m left; the transverse diameter of the eyeball was 10 m m right and 12 m m left, the antero-posterior diameter 11 m m right and 13 m m left.

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Fig. 18. Trisomy D1. A. Microphthalmic eyes (personal observation). B. Whitish membrane behind the lens (persistence of primary vitreous) (personal observation).

In addition there was a corneaplana and an inferior coloboma of the uvea. "[he right eye did not appear to have a lens. On each side, behind the iris in the fight and the lens in the left eye, there was a whitish membrane (Fig. 18B). In the right eye this membrane was connected to the periphery of the eyeball inferiorly by a single wide implantation. In the left eye it was connected to the equator of the eyeball by seven bands, of which four were wide and the rest filiform. On each side there was a whitish mass in front of the disc. The optic nerve of the right eye (the smaller) was larger and more prominent than that of the left eye. Microscopical examination of eyeballs. The cornea was flat (cornea plana). The epithelium had in some parts 2 and in other parts 3 cell layers. Bowman's membrane was relatively thick (Fig. 19). The stroma was sparse and contained vessels. Descemet's membrane was barely developed and even absent in some areas. The endothelium was detached at the periphery and continued on to the anterior surface of the lens. "[he chamber angle was almost non-existent. The canal of Schlemm was present. The trabecular meshwork was still obstructed by conjunctival tissue, rich in immature cells. There was an inferior coloboma (typical) of the uvea, and here only the muscular part of the ciliary body was present, inserted anteriorly, almost on the trabeculum. In the right eye there was apparently no lens (Fig. 20). However, the capsule, emptied of its contents, partially filled the anterior chamber. In the left eye the lens was relatively large; it was completely cataractous and occupied almost all the chamber space (Fig. 21). ' Behind the lens or what remained of it, there was a very vascularized membrane of

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Fig. 19.

Fig. 20.

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conjunctival tissue, which arose from below and continued with the uvea back towards the central part of the eyeball. This conjunctival membrane supported a retinal mass, containing pseudo-rosettes, round and oval, suggesting a retinoblastoma (Fig. 22). These rosettes, formed solely by the outer granular layer, sometimes surrounded a vessel and sometimes, at least in the right eye, lenticular remnants. Between the retinal tissue and the fibrous membrane there was everywhere a pigmented layer. In the left eye, this was doubled even anteriorly (Fig. 23), so that it continued not only on to the posterior surface of the iris but on to the posterior surface of the fibrous membrane, where it reappeared at the point of insertion of the retinal tissue. In the right eye, the retinal mass with rosettes and the fibrous membrane which supported it, separated everywhere by the pigmented layer, continued on to the infero-posterior part of the eyeball, where they surrounded a kind of cavity before rejoining the retina, which here assumed a more normal structure Wig. 24). In the left eye, in front of the equator, the retina (the recognisable structure of which was essentially fibrillary), the uvea and the lens formed the boundaries of a space filled with tissue debris. Farther back there was in each eye a manifestly thinned choroid, and a fairly normal retina. "[here did not seem to be any vitreous except in the immediate neighbourhood of the retina. The intrabulbar optic nerve was well develop ed, but more so in the right eye (the smaller), where the fibres emanating from the superimposed retina appeared to be added to those of the retina itself, giving the repression of a double optic disc. In th hyaloid vessels was found. The front of this embryonic mesodermal tissue intrabulbar optic nerve showed cavernous deger eration. In contrast, the extrabulbar optic nerve was nc •real, and the lamina cribrosa and the sclera were also normal. The two eyeballs th Js showed multiple malformations, identical with those observed in Reese's retinal d ysplasia, with persistence and hyperplasia of the primary vitreous. Ocular signs in trisomy D1 It is exceptional for the eyes to be found norm. fl as in the cases of LuBs et al. (1961) and GOODMANAND KAUFMAN (1962). On the cor trary, ocular malformations are very important and more or less constant (Table 1). In addition to slight anomalies, such as epica~ 1thus and blepharophimosis, serious abnormalities are generally present, such as ano 9hthalmos observed in 11% of cases (PATAU et al. 1960; FERGUSON-SMITH 1961) an microphthalmia noted in 36% of cases. ~Ihe typical or atypical coioboma of the iris or coloboma of the uvea is frequent

Fig. 19. Trisomy D1. Cornea epithelium with 2- and 3-cell layers. Thick Bowman's membrane. Sparse stroma (personal observation). Fig. 20. Trisomy D 1. Anterior segment of the right eye. I : ciliary body; 2: lens capsule; 3 : vascularized connective tissue; 4: retinal mass with pseudo-rosettes (personal observation). Fig. 21. Trisomy D 1. Anterior segment of the left eye. I : lens; 2: iris; 3: ciliary body; 4: vascularized connective tissue; 5: retina (personal observation). J. neuroL ScL (1967) 4:511-558

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Fig. 22.

Fig. 23.

Fig. 24. J. neurol. Sci. (1967) 4:511-558

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TABLE 1 FREQUENCY OF OCULAR ANOMALIES IN TRISOMY

Ocular anomalies Microphthalmia Hypoplasia of the optic nerve Coloboma of the iris and of the uvea Cataract Anophthalmos Retrolental membrane

Dl 95 ~o 36 ~o 33 30 25 Y/o 11 10~o

(30% of cases), and also hypoplasia or aplasia of the optic nerve (33~o of cases). Cataract is not rare (25% of cases), and may be reduced to posterior subcapsular opacities. The following anomalies have also been noted in some cases: a retrolental membrane (10% of cases), probably representing a persistence of the primary vitreous; remains of the vascular tunic of the lens or of the pupillary membrane (CAGIANUT et al. 1965); a coloboma of the optic disc (ROSENFIELDet al. 1962; YANOFFet al. 1963) ; or corneal opacities. In almost a quarter of the cases the ocular anomalies, or at least some of them, are unilateral. We know that KRAUSE(1946) and REESE AND BLODI (1950) have described a retit:al dysplasia (encephalo-ophthalmo splanchnic dysplasia or encephalo-ophthalmic dysplasia). This congenital malformation essentially consists, on the one hand, of a bilateral dysplasia of the retina, associated with persistence of the primary vitreous; and, on the other hand, of multiple visceral malformations (cerebral, cardiac, pulmonary, intestinal, skeletal and genito-urinary). From the ccular point of view, the following symptoms have been noted: (1) the ocular condition is always bilateral; (2) the eyes are microphthalmic, of variable degree; (3) the anterior chamber is shallow; (4) remnants of the pupillary membrat e often persist; (5) there may be a coloboma of the iris; (6)posterior synechiae are not rare; (7) the lens is transparent at first, but opacities soon form; (8) immediately behind the lens, a mass of opaque connective tissue is found; (9) in some cases the ciliary processes are stretched; (10) in the rare cases in which the fundus can be seen, retinal folds are found, or else a large retinal detachment; (11) an electro-retinographic response is absent; and (12) histo-pathological examination shows the same lesions as in persistence of the primary vitreous, and also malformation and complete disorganization of the retina, with pseudo-rosettes, due to folding of the membrane. It can be seen at once how this description resembles that of the ocular malforma-

Fig. 22. Trisomy DI. Retinal mass with pseudo-rosettes (personal observation). Fig. 23. Trisomy D1. a: tissular debris; b: pigmented layer (duplicated); c: retina (personal observation). Fig. 24. Trisomy D1. Posterior segment of the right eye. a: connective membrane and retinal mass; b: retina; c: optic nerve (personal observation). J. neuroL Sci. (1967) 4:511-558

530

J. FRAN9OIS

tions we have noted in our case of trisomy D1, to the degree that we think that Reese's retinal dysplasia is in fact a trisomy D1, and where the latter occurs we ought always to look for a retinal dysplasia, not only by way of ophthalmological examination, but also by electro-retinographic study, which will not show any response to light stimulus. In addition it should be noted that Reese's retinal dysplasia has already been described at least ten times in trisomy D I : (1) MILLERetal. (1963b): Histopathological examination showed an irido-corneal angle of foetal type, a hypoplasia and metaplasia of the iris and ciliary body, persistence of the pupillary membrane, proliferation of the lens epithelium, retinal dysplasia and the presence of fibrous retrolental tissue. (2) YANOFFet al. (1963) also found histologically all the signs of Reese's retinal dysplasia with persistence of the primary vitreous. (3) WARBURG AND NIKKELSEN(1963): The results of a histological study of a similar case was given by R. Anderson at the third meeting of the European Society of Ophthalmic Pathology (Vienna, 1964); (4) SERGOVICHet al. (1963) found on histo-pathological examination an irido-corneal angle of foetal type; hypoplasia of the iris and ciliary body; absence of the dilator muscle of the iris; cataract; retinal dysplasia; the presence of fibrous retrolental tissue; and hypoplasia of the optic nerve. (5) MARIN-PADILLA(1964) also found on histological examination an aplasia with retroflexion of the iris, unilateral cataract and a retinal dysplasia. (6) SARAUXet al. (1964): Behind the lens there was discovered a proliferous mass of retinal tissue. It abounded in structures characteristic of pseudorosettes, resulting from the grouping around a central area of the most external layers of the retina. This dysplasic, detached, retinal mass seemed to correspond with the proliferation in the form of multiple folds of the internal layer of the optic cup, which had remained adherent to the persistent primary vitreous. In contact with the posterior surface of the lens, and separating it from the dysplasic retina, there was a very vascularized mesodermal tissue, which represented the persistent primary vitreous. The byaloid artery participated in the vascularization of this primary vitreous. 1he vascular tunic was easily seen around the lens, and prevented the development of the iris. The abnormal persistence of intraocular primary mesoderm also explained the coloboma of the iris and choroid, the congenital cataract, and other malformations involving all parts of the eye. (7) CAGIANUTet al. (1965) were able to make 4 histopathological examinations of eyes in trisomy D 1. In their first case there was bilateral microphthalmia; colobomata of the iris and persistence of the pupillary membrane were found. Microscopical examination showed in addition an irido-corneal angle of foetal type, a pronounced hypoplasia of the iris and ciliary body, and in places disorganization of the retina, with pseudo-rosettes due to folds in the membrane. In their second case, bilateral microphthalmia was noted, and there were also colobomata of the iris. Histo-pathological examination showed in the right eye a dysplasia and slight peripheral proliferation of the retina, with no other malformed lesions. In the left eye the changes were much more pronounced: irido-corneal angle of foetal type, severe hypoplasia of the iris and ciliary body, dysplasia and profuse proliferation of the retina with the formation of folds leaving the optic nerve and adhering in places to the posterior surface of the lens. ~neuroL ScL (1967) 4:511-558

AUTOSOMAL CHROMOSOME ABERRATIONS IN OPHTHALMOLOGY

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The third case showed bilateral microphthalmia. Microscopically an obvious dysplasia of the retina was noted in the region of the posterior pole, a partial aplasia of the iris and ciliary body, absence of the lens, unilateral absence of the irido-corneal angle and anomalies of the cornea. The fourth case in their series showed a bilateral microphthalmia, and there were also colobomata of the iris, a whitish, opaque mass behind the lens on the nasal side, and optic atrophy. Histo-pathological examination showed a narrow irido-corneal angle of foetal type, hypoplasia of the ciliary body and iris, a dysplasia of the retina involving mainly the ora serrata, where proliferation and disorganization of the retinal layers were found, as well as the formation of a very vascularized connective tissue partially covering the posterior surface of the lens. In addition to these ocular histological examinations, there are 4 others relating to trisomy D1 : (1) ATKINSAND ROSENTHAL(1961). These authors found an irido-corneal angle of foetal type; a cataract; total detachment of the retina with calcification, and absence of myelin fibres in the optic nerve. (2) GtJSTAVSONet al. (1962b). (3) NORTHCUTT (1962) did not find any significant anomalies apart from cataract. I(4) MILLERet al. 0963a) found a cataract and a hypoplasia of the optic nerve. In addition to ocular malformations, cranio-facial, visceral and dermatoglyphic deformities which might include the extremities are constant in trisomy D1. (1) Cranio-facial anomalies. Chief among these are microcephaly (small spherical skull sometimes with bony lacunae), malformations of the ears (anomalies of the pinna in two-thirds of cases, low implantation in a third of cases), and cleft-lip, generally bilateral, with a complete palatal cleft, seen in 58% of cases (Fig. 25). In addition the following anomalies have been found: abnormal calcification of the cranial bones, retracted temples, alopecic plaques, hypertrichosis of the forehead, cutaneous ulcers, total aplasia of the nasal prominence, a flattening of the root of the nose, macrostomia and a high-arched palate. It is not rare to find capillary haemangiomata on the face and particularly on the forehead (in a third of cases), deafness and micrognathia (in 13% of cases). (2) Anomalies of the extremities. These are frequent, and include polydactyly, syndactyly, hyperflexion of the hand and fingers, retroflexion of the thumb, clinodactyly of the little finger, flexion of the little finger on to the fourth, exaggerated convexity and narrowness of the nails, convexity of the sole of the foot with abnormal projection of the heel and rocker-bottom foot, hallux varus and exaggerated dimensions of the big toe. (3) Visceral anomalies. These are often found at autopsy. They may involve any organ. Cardiac malformations: The following have been observed: an interventricular defect, interauricular defect, pulmonary stenosis, patent ductus arteriosus, patent foramen ovale, dextrocardia, aplasia of the left heart, and malposition of the coronary artery. Intestinal malformations: these may be variable and may principally involve the colon: Meckel's diverticulum, malposition of the colon, omphalocele, stenosis of the cardia. Renal malformations: Hydronephrosis, renal hypoplasia and polycystic kidneys are not rare. Accessory spleens have also been found. Genital malformations:

J. neurol. Sci. (1967) 4:511-558

532

J. FRANCOIS

Fig. 25. Cranio-facial malformations in trisomy DI. Malformations of the ears, cleft lip (after ZELLWEGERet at. 1963).

These include an ambiguous appearance of the external genital organs, atrophic bursae, shrinkage of the corpora cavernosa, and cryptorchidism. Cerebral malformations: Internal hydrocephalus, hypoplasia or absence of the olfactory lobes t arhinencephaly in a third of cases), agenesis of the corpus callosum, encephalo- or meningocele. Other malformations: Spina bifida and other vertebral malformations have been found, and also dislocation of the hip and umbilical or inguinal hernia. (4) Mental debility. Mental retardation may be accompanied by other neurological symptoms, such as convulsions, muscular hypertonia or hypotonia, loss of reflexes. (5) Dermatoglyphic anomalies. These anomalies are constant, but are not pathognomonic. The transverse palmar crease should be mentioned, and also the mediopalmar position of the axial triradius (position t"). BE~AK et aL (1963) have described two cases of trisomy D that were cytogenetically positive, but clinically very atypical, since the symptoms only consisted of a congenital analgesia and slight mental retardation. (II) Double trisomy These cases are remarkable. B~CK~R et al. (1963) have noted a trisomy D1 and a trisomy No. 21 in the same subject. There was, however, no ocular anomaly apart from J. neuroL Sei. (196"7)4:511-558

AUTOSOMAL CHROMOSOME ABERRATIONS IN OPHTHALMOLOGY

533

strabismus. In an analogous case GtJSTAVSON et aL (1962b) found, however, a microphthalmia with aniridia. It should also be noted that HECHT et al. (1964) found a child with a trisomy D1, while the uncle had a trisomy No. 21.

(II1) Partial trisomy D1 In addition to the true trisomies D1, there are partial trisomies D I through familial translocation (WALKER AND HARRIS 1962) or sporadic translocation (JoNGBLOETet al. 1964). The findings are: (1) Either a small supernumerary acrocentric chromosome, difficult to distinguish from chromosomes G (21-22). A trisomy 21 can be excluded by the absence of mongoloid stigmata. Identification of the small supernumerary chromosome can sometimes be made by a karyotype study of the other members of the family (JAcoBSEN et al. 1963). (2) Or a large chromosome No. 13-15. In this case there are only 46 chromosomes. The fragment inserted on the abnormal chromosome of group 13-15 may come from another group. LEJEUNE et al. (1964) found in a sibship one case of the 'cat's cry' syndrome with deletion of the short arm of chromosome No. 5, and two cases of trisomy with translocation of the short arm of chromosome No. 5, on to chromosome No. 13. In one of these two cases there was pronounced mental retardation without any general malformations of note, and in the other there were no anomalies. The anomalies seen in partial D1 trisomy are almost identical with those found in true D1 trisomy, but they are usually less severe, and those affected also live longer. DELHANTY ANt) SHAPIRO (1962) noted microphthalmia in a child, whose karyotype showed an abnormally long chromosome No. 13 by translocation between two chromosomes No. 13 or by duplication of the long arm of a chromosome No. 13. GUSTAVSON et al. (1962a) reported two cases. In a girl of 5½ years old there was a translocation D ~ E. A strabismus was noted. In a girl of 7½ years old with 47 chromosomes there was strabismt,s with unilateral ptosis. VISLIE et al. (1962) also reported two cases. In a boy of 8 years old there was a translocation D ~ E ; microphthalmia was noted. In a girl of 4 years old with 47 chromosomes there was microphthalmia with strabismus. ZELLWEGERet al. (1962) reported 2 cases. In a girl of 6½ years old with 47 chromosomes there was myopia with optic atrophy. In a girl of 3½ years old with 46 chromosomes (translocation D ,-~D) there was bilateral coloboma of the uvea. THERMANN et al. (I 963) have reported the case of a boy of 9 years old, who showed a translocation D ,~ D. There was microphthalmia with a coloboma of the iris. JACOBSON et al. (1963) found an epicanthus, a coloboma of the iris and a cataract in a boy of 9 years old, who had a supernumerary fragment of chromosome No. 13 (translocation D ~ D). FERGUSON AND PITT (1963) observed a girl of 2 years old, with a translocation D ~ G with 47 chromosomes. There were no ocular anomalies. STALDER et aL (1964) reported two cases. In a girl of 1 year old, who showed a translocation D ~ C, there was microphthalmia with strabismus. In a girl of 6 years old, with the same chromosome aberration, there was also microphthalmia with strabismus. J. neurol. Sci. (1967) 4:511-558

534

J. FRAN(~OIS

WALLACE AND ANDERSON(1964) observed a woman of 35 years old, who presented with multiple malformations, including an anophthalmos, mental retardation, complete bilateral cleft lip, adherence of the upper lip to the nose, low implantation and anomalies of the ears. The karyotype showed 45 chromosomes, a translocation D ,~ 4/5 with loss of the short arms and the satellites of this chromosome D. We have been able to observe a patient with partial D1 trisomy, who presented with bilateral colobomata of the iris and lens opacities. Observation* F. N., a male, was born on July llth, 1963. His weight was 6½ lbs. The family antecedents are of no interest. The mother, a primipara aged 24, had a normal pregnancy. The father, aged 23 years, was not related to her. The child was examined at the age of 6 weeks. Numerous anomalies or malformations were noted: (1) Head: Bilateral complete cleft lip; low-set ears; microcephaly (cranial circumference 35.5 cm); capillary haemangioma of the forehead. ~2) Limbs: Rudimentary hexadactyly on the left; hands and fingers in irreducible flexion, except for the little finger, which was in extension and abnormally long; nails narrow and very convex; bilateral dislocation of the hip; projecting heels. (3) Genital organs: Scrotal skin extending as far as the tip of the penis, testicles not palpable. Clinical examination of thorax and abdomen did not reveal any anomalies. The EEG was normal. The autopsy, however, revealed a small accessory spleen, an enlarged gallbladder, slight bilateral hydronephrosis, and arhinencephaly. (4) Eyes: Typical bilateral colobomata of the iris; opacities in the nasal part of the lenses. The fundi were normal. Cytological examination. A study of the chromosomes was made from the leucocytes. The majority of these cells showed 46 chromosomes (31/35). Ten cells were analysed: all contained only 5 acrocentric chromosomes in group 13-15, but there was one large metacentric extrachromosome resembling a chromosome No. 3; it can be considered as a translocation D/D (central fusion of 2 acrocentric chromosomes). (IV) Translocation D,,~ D Most frequently translocations D ,-~D do not produce malformations, because they are balanced. But in the children of such individuals, who present this chromosome aberration, a partial D1 trisomy can be found, which will give rise to anomalies, as we have just seen. The first translocation in group D was described in 1960 by LEJEUNEet al. (1960) in a patient presenting with Klinefelter's syndrome. Beside the two chromosomes X ( + Y), it was noted that 2 chromosomes of group D were replaced by an enormous mesocentric chromosome. (V) Deletion D The deletion of part of a chromosome No. 13-15 (partial disomy) can give rise to a syndrome resembling trisomy D1. BMN AND GAULD (1963) noted a stillborn girl who had many malformations, including a bilateral microphthalmia. The karyotype * Already published by JONGBLOETet al. (1964). J. neurol. Sci. (1967) 4:511-558

AUTOSOMAL CHROMOSOME ABERRATIONS IN OPHTHALMOLOGY

535

showed only 46 chromosomes, but a chromosome of group 13-15 was very much altered, smaller, and here and there annular. In a foetus of 42 weeks BAIN AND GAULD (1963) found only 5 chromosomes in group D, but in addition there was a small chromosome that they thought to be a ring chromosome. They noted the following anomalies: thumb absent on one side, rudimentary on the other; equinovarus foot; short big toe; fusion of the 4th and 5th toes; simian creases of hands and feet; renal hypoplasia; bifid uterus, absence of the anterior part of the falx cerebri, with fusion of the hemispheres. Ophthalmologically, there was bilateral microphthalmia. WANG et al. (1962) also noted the absence of a chromosome D and the presence of a ring chromosome in a child, in whom the anomalies, however, differed notably from those of the preceding case. It should be noted that in one case of retinoblastoma out of 6, LELE et al. (1963) found a deletion of the long arm of a chromosome No. 13-15. ( VI) Mosaicism In 4 mosaic subjects, who presented two populations of cells, the first trisomics D l, the other normal, there were no ocular anomalies: B66K AND SANTESSON (1960), WARKANY et al. (1962), BE~AK e t al. (1963), FERRIER et al. (1964). In conclusion, ocular malformations, from the simple iris coloboma to Reese's retinal dysplasia and anophthalmos, are a major manifestation of trisomy D1 and even of partial trisomy D 1. GROUP E (16-18) (I) Trisomy E (16-18) Trisomy E, also called trisomy 18 or Edwards' syndrome, is relatively frequent. About a hundred cases have been reported. It may be seen in 1 in 500 births, according to HECHT et al. (1963b), and in 1 in 4000 according to PRADER (1962). It occurs two or three times more often in girls than in boys. Most of such children do not live more than 6 months; only 10~/o reach 1 year, and only 1% survive to the age of 10 years (WEBER et al. 1964). The malformations are multiple, and may involve any organ and system. (1) Ocular signs. Ocular anomalies are as rare in trisomy E as they are constant in trisomy D. This is perhaps the major difference between the two syndromes. In trisomy E, hypertelorism has nevertheless been noted (GAGNON et al. 1963; GENEST et al. 1963), epicanthus (GENESTet al. 1963), malformation of the eyelids; ptosis (seen in 15% of cases); ocular paralyses (ROSENFIELD et al. 1962); coloboma of the iris or choroid; corneal opacities (SMITH 1962; TOWNES et al. 1962) or lens opacities (SMITH et aL 1960), and a congenital glaucoma with optic atrophy (TOWNES et aL 1962). We have had occasion to observe 4 cases of trisomy E. In each case there was a ptosis or a blepharophimosis. In 2 cases there was bilateral coloboma o f the optic disc, in 1 case a coloboma of the uvea, in 2 cases hypertelorism, and in 2 cases epicanthus. (2) Cranio-facial signs: The most important and constant signs are microcephaly J. neuroL Sci. (1967)4:511-558

536

J. FRAN~OIS

with prominence of the occiput, low-set ears with malformed pinnae, micro- and retrognathia. Other anomalies are more rare: scaphocephaly with frontal bossing, hypertrichosis of the forehead, imperforation of the external auditory canal, hypoplasia of the middle ear, deafness, small triangular mouth, cleft lip with or without cleft palate, high-arched palate. (3) Musculo-skeletal signs: Anomalies of the hands and feet are more or less constant. Particularly characteristic is the flexion of the index on to the middle finger, or the little finger on to the fourth, or of the second toe on to the third. The following anomalies have also been noted: lateral deviation of the wrist or of the axis of the hand; fixation of the fingers in flexion; clinodactyly of the little finger; syndactyly ; polydactyly; absence or malformation of the thumb; absence of the first metacarpal; narrow and convex nails; shortening or retroflexion of the big toe; increase in the distance between the first and second toes; projection of the heel; rocker-bottom foot; clubfoot. Many other musculo-skeletal anomalies have been noted: short neck; short thorax; short sternum; scapulae widely separated; nipples depressed and rudimentary; scoliosis; epiphyseal dysplasia; dislocation of the hip; limitation of abduction of the thighs; multiple arthrogryposis in flexion; muscular hypertonus. (4) Cardiovascular signs: The cardiopathies are almost constant (an interventricular defect, interauricular defect, patent ductus arteriosus, patent foramen ovale, coarctation of the aorta, dextrocardia, etc.). ROSENFIELD et al. (1962) noted an infantile arteriosclerosis (degeneration of the internal elastic membrane with calcification of the media and proliferation of the intima). (5) Pulmonary, abdominal and intestinal signs: Many anomalies have been noted, but none is characteristic: bilobal lung; pulmonary microcysts; tracheo-oesophageal atresia with or without fistula; Meckel's diverticulum; malposition of the colon; heterotopic pancreatic tissue; anomalies of the biliary tract; umbilical, diaphragmatic or inguinal hernia; and anal imperforation. (6) Genito-urinary signs: Horseshoe kidney; double ureter; polycystic kidney; solitary kidney; hydronephrosis; paravesicular cyst; hypoplasia of the pelvis; hypertrophied clitoris; recto-urethral fistula; hypospadias; scrotal cleft. (7) Mental and psychomotor retardation, retardation of growth. (8) Dermatoglyphics: Transverse palmar crease; finger prints in which the arch type predominates (instead of forming a whorl or a loop, the ridges are arranged one on the other, regularly, like geological strata on an anticlinal). In Table 2 we have summarized the observations on the 4 cases of trisomy 18 we have seen*.

(H) Double trisomy HECHT et al. (1964) have seen 3 siblings, in whom there was at the same time a trisomy 18 and a trisomy 21. * Observations I, I I and I I 1 are by courtesy o f Professor Hooft (Paediatric Clinic of the University of Ghent), and Observation IV by courtesy o f Doctor Cieters. d. neurol. Sci. (1967) 4:511-558

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(III) Partial trisomy E The manifestations of partial trisomy E are identical with those of true trisomy E (CRAWFORD 1961; GUSTAVSON et al. 1962; BRODIE AND DALLAIRE 1962; GAGNON et al. 1963; BRAY AND JOSEPHINE 1964; BRAY AND SISTER 1964). (IV) Deletion E The deletion involves the short arm of a chromosome E, as in the case of DE GROUCHY et al. (1963b), and in that of THIEFFRY et al. (1963). A boy of 6 years old showed the following anomalies: divergent strabismus, hypertelori~m, blepharophimosis,

Fig. 26. Trisomy D1. E. Double cleft lip (personal observation 2).

Fig. 27. Trisomy E. Microcephaly (personal observation 2).

low-set ears, crowded teeth, large hands, clinodactyly of the little finger, high implantation of the thumb, syndactyly of the 3rd and 4th toes, mental retardation. FAINT AND LEWIS(1964) observed a female cyclops, born to normal parents and with no other anomalies except arhinencephaly. In the orbit there was a single eye without an optic nerve. The karyotype showed a deletion of the short arm of chromosome 18. Certain authors (Bi3nLER et al. 1964) have considered that there could be a connection between a deletion of the short arm of one chromosome E and a disorder in the synthesis of thyroxin. The deletion may also involve the long arm of a chromosome 18, as in the case of DE GROUCHY et al. (1964). A little girl of 1 year showed the following anomalies: significant psycho-motor retardation, microcephaly, high-arched palate, atresia of the middle ear, probable tapeto-retinal degeneration, transversal palmar crease, digital patterns of the arch type, horseshoe kidney and generalized hypotrophy. Other structural aberrations of chromosomes 16-18 have been noted. DE GROUCHY et al. (1964b) noted a ring-shaped chromosome 18 in a girl of 5 years old, who presented with hypertelorism, epicanthus, low hairline, pterygium colli, horizontal ribs, palmar triradius in position t", and hypotonia. GENESTet al. (1963) observed a ring chromosome associated with the absence of J. neuroL Sci. (1967) 4:511-558

538

J. F R A N ( ~ O I S

TABLE 2 SOMMARY OF PERSONAL OBSERVATIONS OF TRISOMY

Anomalies

Familial existence of congenital anomalies Consanguinity of forbears Course of pregnancy

Obs. 1

Obs. H (Fig. 26)

--

hydramniossmall placenta

Duration of pregnancy Age of mother Age of father Abortions or premature births

normal 25 years 29 years 2 abortions

Number of siblings

2 sisters

Delivery Weight at birth Sex Hypertonus Mental retardation EEG

normal 4½ lbs F. ± + normal

18 (Fig. 33)

Obs. I11

Obs. I V (Fig. 30)

+

no increase in size of uterus after 7 months normal 41 years 39 years 4 abortions, 1 premature birth (at 6½ months) 2 brothers normal 5½ Ibs F. ± + normal

normal

enteritis at 10th week

normal 35 years 40 years premature birth at 7 months (normal boy) 2 brothers and 2 sisters normal 4 t lbs F. (hypotony)

3 weeks too long 38 years 41 years

9

6 brothers and sisters normal 5 lbs F. + + ?

Crania-facial malformations Microcephaly

+

+ (Fig. 27)

+

Prominent occiput

±

+

÷

+ (Figs. 30, 31 A, m +

÷

+ +

Ocular attomalies Ptosis, blepharophimosis Epicanthus Hypertelorism Fundus anomalies

÷ +

Anomalies of mouth Small triangular mouth Cleft lip High-arched palate Micro-and retrognathia

--÷ ÷

Anomalies of ears Low-set Malformation of pinna Deafness Neck short Thorax

Thorax short Widely separated scapulae

+ + + coloboma of optic disc (2 eyes, Fig. 28)

coloboma of optic disc (2 eyes)

coloboma of the uvea

÷

÷ --

+ -÷ ÷

÷

÷

+ ÷ ?

÷ + ±

! ÷

+ ÷ ?

+

+

+

+

+ +

+ +

~÷

+ +

J. neural Sci. (1967) 4:511-558

539

AUTO$OMAL CHROMOSOMEABERRATIONSIN OPHTHALMOLOGY TABLE 2 (continued)

Anomalies

Obs. I

Obs. H (Fig. 26)

Obs. III

Obs. IV (Fig. 30)

Abdomen Umbilical hemia

--

+

--

+

Genital organs Hypertrophic clitores

+

+ (the mother received hormones)

--

4-

Cardiopathy

+

4-

+

-~-

Hands Deviation of axis of hand Fingers fixed in flexion Index finger curved medially Nails narrow and convex Clinodactyly of little finger Simian crease

+ + + + + +

+ (Fig. 29A) + + + + +

+ + + + + +

+ (Fig. 32A) + + + + 4-

--

+ (Fig. 29B)

--

4- (Fig. 32B)

Feet Syndactyly of 2nd-3rd toe 1st phalanx of big toe too short Exaggerated distance between 1st and 2nd toe Projecting heel club foot

+

+

+

+

+ + --

-+ --

-+ on the right

4+ --

Urinary tract Horseshoe kidney

+

Mega-ureter or double ureter

+

--

Intestinal tract Meckel's diverticulum Malformation of biliary tracts

+ +

,~ ~

double kidney on left

Other abnormalities

+

+ ?

+ ?

(cytomegalic inclusion bodies)

c h r o m o s o m e E. T h e short a r m o f a c h r o m o s o m e D was, on the other hand, a little t o o long, in c o n s e q u e n c e no d o u b t o f the t r a n s l o c a t i o n o f an E fragment. Th e patient presented with an epicanthus and hypertelorism, i m p e r f o r a t i o n o f the external a u d i t o r y canal, hypoplasia o f the m i d d l e ear, r o c k e r - b o t t o m feet, short big toe, flexion o f the 2nd toe on to the 3rd, a n d slight m e n t a l retardation.

( V) Mosaicism E I n E m o s a i c i s m the s y m p t o m s are identical with those o f t r i so m y 18 (WEIss et al. 1962; KOULISCHER et al. 1963; WARKANY et al. 1964; WOLF et al. 1965). In conclusion, ocular manifestations seem to be rather rare in t r i s o m y 18. When present, J. neurol. Sci. (1967) 4:511-558

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J. FRANCOIS

Fig. 28. Trisomy E. Coloboma of the optic disc (personal observation 2).

Fig. 29. Trisomy E. A. Deviation of the axis of the hands (personal observation 2). B. Syndactyly of the 2nd and 3rd toe (personal observation 2). they are identical with those o f trisomy 13 15. It is interesting to note the c o l o b o m a o f the optic disc and the c o l o b o m a o f the uvea, which we observed in three o u t o f four cases. GROUP F (19--20) C h r o m o s o m e a b e r r a t i o n s in g r o u p F are again very few. Only three cases o f trisomy 19-20 are known. Trisomy F (19-20) CIVANTOS (1961) f o u n d a t r i s o m y F in a case o f COCKAYNE'S s y n d r o m e (1936) (Fig. 34). WINDMILLER et al. (1963), on the other hand, f o u n d a n o r m a l k a r y o t y p e . J. neurol. Sci. (1967) 4:511-558

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Fig. 30. A and B: Trisomy E (personal observation 4). We know that Cockayne's syndrome is characterized by an atypical pigmentary retinopathy of the salt and pepper type, with optic atrophy and cataract; by a progressive infantile deafness; a disproportionate dwarfism with skeletal anomalies; a progeroid appearance with microcephaly; a cutaneous photosensitivity, mental deficiency and a spasticity of the lower limbs with difficulty in walking. COCKAYNE'S syndrome is, in fact, transmitted as an autosomal recessive character, as shown by its appearance in several children of the same sibship (COCKAYNE 1936, 1946; NEILL AND DINGWALL 1950; MACDONALD et al. 1960), and the occasional consanguinity of the parents (/,.JESUGI 1960).

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Fig. 31. Trisomy E. A. Microcephaly, anomalies of the pinna (personal observation 4). B. Micro cephaly, short neck (personal observation 4).

!D

Fig. 32. Trisomy E. A. Flexion of the index onto the thumb and of the little finger onto the ring-finger (personal observation 4). B. Flexion of the big toe onto the 2nd toe (personal observation 4).

It should be noted that B66K et al. (1960) have observed two cases o f congenital c a r d i o p a t h y who presented a trisomy F. GROUP G (21-22) It is u n d o u b t e d l y c h r o m o s o m e No. 21 t h a t m o s t often presents numerical and structural aberrations. T r i s o m y 21 was first recognised by LEJEUNE et al. (1959) It is J. neurol. Sci. (1967) 4:511-558

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Fig. 33. Trisomy E. (No. 18) (personal observation 4).

Fig. 34. Trisomy F in a case of COCKAYNE'Ssyndrome (after CIVANTOS1961). responsible for Langdon-Down's syndrome (mongolism) (Fig. 6). As this syndrome is well known and is not usually accompanied by major ocular malformations, we will not study it in detail. Trisomy 21

Mongolian idiocy, the most frequent of all autosomal trisomies, is found in one in J. neuroL Sci. (1967) 4:511-558

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600 births. In nearly 5°,/0 of cases one finds the translocation of a supernumerary chromosome 21 on to a chromosome No. 13, 22, or even 21 (partial trisomy). The principal signs of Down's syndrome are: (1) Retardation of both physical and mental development; major psychic disorders. (2) Brachycephaly; thick and glossy hair; face fiat, round and mongoloid; saddlenose; maxillary hypoplasia; anomalies of the pinna of the ear; lower lip thick and fissured; tongue voluminous and scrotal; dental malformations with microdentism; sinuses poorly developed; raucous voice. (3) Small stature; limbs short and thickset; fingers and toes short with clino- or syndactyly; skin loose and seborrhoeic; obesity; muscular hypotonus; articular hyperlaxity. (4) Diverse anomalies (genital abnormalities, cardiopathy, intestinal stenosis and atresia, etc.). From the ocular point o f view, hypertelorism is found, and also narrowing of the palpebral fissures which are oblique downwards and inwards. There is frequently an epicanthus. The free edge of the upper lid is very arched. Ectropion is not rare. The iris stroma is often thin and hypoplastic, particularly in girls. Its periphery shows Brushfield's yellow spots, which are more frequent when the iris is light grey or blue. There is often convergent strabismus, a keratoconus which is sometimes acute, or high myopia, which is found in a third of cases. In more than half the cases of mongolism, lens opacities are found. These are of 4 types: (1) Arched opacities, astride the equator of the foetal nucleus. These opacities, often thin and narrow, are at times quite large, when they cover a wide sector; sometimes they form a true zonular cataract. (2) Opacities of the embryonic sutures. (3) Diverse congenital cataracts (posterior polar cataract for example). (4) Acquired opacities, similar to those of a cerulean cataract. No ocular or general sign is pathognomonic for mongolism; none is present in every case. Each of these signs may, on the other hand, be found in other diseases, and even in normal individuals. In certain children presenting with mongoloid stigmata (mental retardation, epicanthus, Brushfield's spots, macroglossia, cleft palate) the karyotype showed a small supernumerary chromosome fragment: [LBERGet al. (1961); DENT et al. (1963); ZELLWEGER(1965). Cases of mosaicism have been described in: (1) Patients presenting with signs of mongolism, the mental development being normal (CLARKE et al. 1961) and (2) patients with evident mental retardation, but with a normal physical appearance (FITZGERALD AND LYCETT 1961). Trisomy 22

Several cases of trisomy 22 have been reported (ZELLWEGER1965). But the symptomatology varies so much from one case to another that one wonders whether this trisomy really exists, or whether it does not involve another group of chromosomes. The fact remains that ocular anomalies are very rare. J. neurol. Sci. (1967)4:511-558

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TURNER AND JENNINGS (1961) noted bilateral high myopia ( R . E . - 12 D., L . E . - 14 D.) in a boy of 8 years old, who presented withlschizophrenia, micro- and retrognathia, enlarged nostrils, a flattening of the occiput and hyperextension of the elbows. BOOK et al. (1961) have described a retinal degeneration in a girl with mental deficiency, dislocation of the hip and some mongoloid signs. The karyotype of 46 chromosomes was interpreted as a trisomy G and a m o n o s o m y 16. ZELLWEGER et al. (1962) found bilateral congenital cataract in a girl who presented with pronounced mental retardation, convulsions and deafness. CAGIANUT et al. (1965) have observed two cases of trisomy 22, in which there were iris colobomata, associated with anal atresia. In half these cases of trisomy 22 there was an epicanthus, and in a third of cases a mongoloid palpebral fissure (DuNN et al. 1961). In a case of Sturge-Weber angiomatosis, HAYWARD AND BOWER (1961) found a trisomy 22 (small supernumerary acrocentric chromosome) (Fig. 35), PATAU et al. (1961) a partial trisomy (translocation of a fragment of chromosome 22 on to a chromosome D, Fig. 36). Other authors, on the other hand, have not found this chromosome aberration (LEHMANNet al. 1960, GUSTAVSONet aL 1961 ; HALL 1961 ; HAYWARD et al. 1961).

~/~i~i~i~!i~ii~i~i~i~i~i~i~i~i~ii~i~i~ii~ii~i~i~i~i~i¸!i~i~i~i~i~ii~i~i!~ii!~!~!~i~!!! ~i~~ii~iiiiiiiii?iiiiiiii~iiii¸~i

A

Fig. 35. Trisomy No. 22 in a case of Sturge-Weber angiomatosis (after HAYWARDANDBOWER1961).

~ ~~!i!~ii!!i~iiil ?~ ~ ii i¸i Fig. 36. Partial trisomy No. 22 in a case of Sturge-Weber angiomatosis (after PArAU et al. 1961).

In this connection we note the observation of BLEAKe t al. (1963) concerning a boy of 2½ years old who presented with giant haemangiomata and secondary thrombocytopenia. The karyotype showed a supernumerary chromosome in group G.

Deletion G In chronic granulocytic myeloid leukaemia the bone marrow or the blood may contain cells with a partial deletion of a chromosome G, known as the 'Philadelphia' chromosome. The somatic cells other than those of the blood and the haematopoietic organs have a normal karyotype. The anomaly is probably present for a long time before the clinical symptoms appear (KEMP et al. 1964). J. neurol. Sci. (1967)4:511-558

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In acute myeloblastic leukaemia the disappearance of a mesocentric chromosome has been noted (total deletion). In conclusion, ocular anomalies are frequent in trisomy 21 or 22, but are generally minor in character. Severe ocular malformations appear to be exceptional. Indeterminate polysomy In many cases of Waldenstr6m's macroglobulinaemia one finds, in addition to cells with a normal karyotype, cells with 47 chromosomes. The supernumerary chromosome is large and cannot be paired with any other chromosome (BATE1OEE1964). One wonders whether the chromosome aberration is the cause of the macroglobulinaemia, or whether it is the consequence, following an increase in the viscosity of the cellular environment.

Polyploidy Instead of 46 chromosomes (diploidy) the somatic cells contain a multiple of the haploid number (23). Triploidy (69 chromosomes) is lethal and is found only in aborted embryos. One does, however, know of some cases in which triploidy was present in mosaicism with diploidy (B66K AND SANTESSON 1960; ELLIS et al. 1963; FERRIER et al. 1964). These children showed many anomalies: mental retardation, body asymmetry, hemiatrophy, malformation of the fingers, cryptorchidism. Structural chromosome aberrations These are still little known. We shall only discuss here the importance of the occurrence of giant satellites, in which ocular signs may be observed. Giant satellites In two familial cases of Marfan's syndrome, which is essentially characterized by bilateral subluxation of the lens, an elongation of the long bones, muscular hypoplasia, absence of subcutaneous tissue and cardiac lesions, TJIO et al. (1960) noted giant satellites in a single chromosome of a pair of acrocentric homologous chromosomes (Fig. 37). HANDMAKER (1963) found the same anomaly in 5 cases out of 8, but recognized that the apparently abnormal satellite was not larger than that in certain relatives or even normal individuals. This anomaly, incidentally, has also been observed by other authors in individuals who had no sign of Marfan's syndrome (McKusIcK 1960; ELLISAND PENROSE 1961 ; COOPERAND HIRSCHHORN 1962). It has not, moreover, been found in all cases of Marfan's syndrome (FORD 1960; McKuSICK 1960, 1961). In these conditions it is not possible to establish a correlation between enlarged satellites and arachnodactyly. In 4 cases with this disease, K.~LLENAND LEVAN (1962) found that chromosomes 21 and 22 were shorter than normal. But the chromosome anomalies of group G have been found in syndromes so completely different that one wonders how far they are responsible for the malformations. Thus FRI~DI~RICet al. (1964) found in two sisters hypertelorism and narrowing of the palpebral fissures; a short nose and small upper lip; malformations of the sternum, ~neuroL Sci. (1967) 4:511-558

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Fig. 37. Giant satellites of chromosome No. 13 in a case of Marfan's syndrome (after TJiOet al. 1960). and hypertrophy of the clitoris. In one of the two sisters there was, in addition, a syndactyly with polydactyly and vertebral anomalies. In the two sisters there were only 46 chromosomes, but chromosomes 22 showed a difference in the length of the short arms. It is of interest, too, that the parents were consanguineous to the 6th degree. DE LA CHAPELLE et al. (1963) found an analogous chromosome anomaly in 5 subjects of the same family (grandmother, father, and 3 children out of 9): 4 of these subjects were normal, but one girl had well-marked neurological signs. A brother showed the same neurological symptoms, but did not have the chromosome anomaly, which is apparently compatible with normal development. In conclusion, we may say that the importance of giant satellites has not yet been established. Action o f chromosome aberrations It is still difficult to explain the action of chromosome aberrations which produce equally and at the same time anomalies of gastrulation, disturbances of embryogenesis (e.g. arhinencephaly) and an arrest of organogenesis (e.g. microphthalmia). The fact that similar malformations can be observed in different trisomic syndromes shows moreover that the chromosome aberration has a generalized and non-specific effect on foetal development. Since chromosome aberrations necessarily involve groups of genes, it is evident that they can give rise to multiple malformations and to complex syndromes. J. neuroL Sci. (1967) 4:511-558

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But how can normal genes produce anomalies solely by the fact that their number is triple instead of being double? We must no doubt invoke the theory of 'one gene, one enzyme', and recognize that the presence of too great a quantity of enzyme, 3 units instead of 2, can produce malformations. In any case, it is a fact that alkaline phosphatase, present in the polymorphonuclear leucocytes, is more abundant in mongoloid children than in normal children (3: 2) and that it is diminished in cases of leukaemia with a 'Philadelphia' chromosome. SUMMARY AND CONCLUSIONS (1) The eye is very often malformed in cases of chromosome aberration. The following anomalies may be found: chorioretinal degeneration, high myopia, congenital cataract, anophthalmos, microphthalmia, coloboma of the uvea, persistence of the primary vitreous with Reese's retinal dysplasia, palpebral anomalies, etc. When one of these manifestations is present, a cytogenetic examination should therefore be considered, particularly if there are associated general malformations. (2) When a chromosome aberration is found in a malformed subject, cytogenetic examination of the parents and siblings should be carried out. Balanced translocations will often be found. (3) The different chromosome aberrations give rise to multiple anomalies and malformations, which may be found, isolated or associated, whatever chromosome group is involved, showing that they have no really specific action. (4) When interpreting a karyotype, it should be remembered that the tissue culture in vitro can produce artificial mutations, which do not correspond to a mutation in vivo. An example has been given by TRUfILLO et al. (1961). Their patient presented with multiple bone fractures, blue sclera and other signs of Van der Hoeve's syndrome. An initial culture of blood showed a reciprocal translocation A ~ C. In contrast, the cells obtained from a second blood culture showed normal karyotypes. Tissue cultures should therefore be repeated. (5) The possibility of mosaicism should always be borne in mind, and several tissues should therefore be examined (Mood, skin, muscle, fascia lata). (6) It should not be immediately concluded that there is a cause-and-effect relation between a chromosome aberration and a phenotypic manifestation. The cytogenetic anomaly may, in fact, be the consequence of the disease, as in WaldenstrSm's macroglobulinaemia or in disorders of thyroid metabolism. (7) It is probable that still more chromosome aberrations will be found, particularly when we can make better studies of the intimate structure of chromosomes and the chemical composition of enzymes. It seems, however, that the number of 'chromosome disorders' will remain relatively limited for the simple reason that the majority of deletions and other chromosome aberrations are lethal. The list of disorders in which a karyotype anomaly has been sought in vain is already much longer than that in which a chromosome aberration has been demonstrated. Moreover, as long as it is not possible to recognize with certainty to which group a given chromosome belongs, to identify the chromosome itself or a fragment of chromosome, we must be cautious in the interpretation of a karyotype in a clinical case, and avoid creating new syndromes without sufficient proof. J. neuroL Sci. (1967) 4:511-558

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REFERENCES AmTEaS-BAWR, V. L. AND R. J. KLEINHENG(1963) Chromosomes in 15 cases of congenital anomalies, Hum. chromos. Newsl., 10: 5. ANOELMA~rN, H. (1961), Syndrome of coloboma with multiple congenital abnormalities in infancy, Brit. med. J., i: 1212-1214. ASTLEY, R. (1962) Chromosomal abnormalities in childhood, with particular reference to Turner's syndrome and mongolism, Brit. J. Radiol., 36: 2-10. ArraYS, L. AND M. K. ROSENraAL (1961) Multiple congenital abnormalities associated with chromosomal trisomy, New EngL J. Med., 265: 314-319. BABEL,J. (1964a) Communication personnelle ~tSaraux H. et coiL, Arch. Ophtal. (Paris), 24: 582-601. BABEL, J. (1964b) Les malformations pseudotumorales du globe oculaire, Acta Soc. Europ. Ophth., Vienna, Ophthalmologica (1966) 151:405--425. BABINI, B., G. PIAZZI AND P. SCORZA(1962) Su di un caso di malformazioni congenite multiple con trisomia del gruppo cromosomico 16-18, Clin. Pediat. (Bologna), 44: 684-699. BAIN, A. D. AND I. K. GAULD (1963) Multiple congenital abnormalities associated with ring chromosome, Lancet, ii: 304-305. BATERJEE, A. R. (1964) Chromosome abnormalities in Waldenstr/Sm's macroglobulinaemia, Hum. chromos. Newsl., 14: 2. BEtTAKet al. (1963) Extra acrocentric chromosome in a case of giant cavernous haemangioma with secondary thrombocytopenia, Lancet, i: 468. BE(TAK,W., M. L. BEt~AKAND J. D. ANDRADE(1964) A genetical investigation of congenital analgesia, Part 1 (Cytogenetic studies), Acta genet. (Basel), 14: 133-142. BEC~AK,W., M. L. BE(~AKAND B. J. SCHMIDT(1963) Chromosome trisomy of group 13-15 in two cases of generalised congenital analgesia, Lancet, i: 664-665. BECKER, K. L., E. C. BURKE AND A. ALBERT (1963) Double autosomal trisomy (D-Trisomy and mongolism), Proc. Mayo Clin., 38: 242-248. BELMONTE,C. R. (1964) Trisomy 17-18 syndrome. A brief review with a clinical case report, Manila HIth. Dep. Bull., 13: 362-368. BERNARD,R. AND F. GIRAUD (1964) Les mosaiques chromosomiques, Marseille-mdd., 101 : 601-622. BISHUN, N. P., M. N. RASHAD,W. R. M. MORTON, P. L. MANNION, M. R. NELLY AND G. BURKE (1964) Chromosomal mosaicism in a case of repeated abortion, Lancet, i: 936-937. BLANCK, C., B. JALLING, J. LINDSTENAND P. ZETYERQVIST(1964) Trisomy 13-15. Report of a case with clinical, cytogenetic and pathologic findings, Acta path. microbiol, scand., 60: 36--46. BLUMEL,J., E. BURKEAND G. W. N. EGGERS(1960) A combination of congenital cataract and cerebral palsy in a brother and a sister, Arch. Ophthal. (Chic.), 63 : 246-253. BLUMEL, J., Y. OHNUKI AND A. AWA (1961) Chromosome anomaly in two cases of cerebral palsy, a brother and a sister, Nature (Lond.), 189: 154-155. B66K, J. A., L. ATKINSAND B. SANTESSON(1963) Some new data on autosomal aberrations in man, Path. et Biol., 11 : 1159-1162. B66K, J. A. AND B. SANTESSON(1960) Malformation syndrome in man associated with triploidy (69 chr.), Lancet, i: 858. B66K, J. A., B. SANTESSONANDP. ZETTERQVIST(1960) Association between congenital heart malformation and chromosomal variations, Acta paediat. (Uppsala), 50: 217-227. BOWEN, P. (1964) Chromosomal abnormalities in clinical orthopaedics and related research. In: R. A. DE MILCH AND V. A. McKuSNICK (Eds.), Genetics of Congenital Deformity, No. 33, Sect. 1, Lippincott, Philadelphia, pp. 40-58. BRANDT, N. S., A. FROLAND, M. MIKKELSEN,A. NIELSENAND N. TOLSTRUP(1963) Galactosaemia locus and the Down's syndrome chromosome, Lancet, ii: 700-703. BRAY, P. F. AND ST. A. JOSI~PHINE(1963) A probable autosomal trisomy-translocation in an infant with multiple congenital anomalies, J. Pediat., 63: 712-715. BRAY, P. F. AND ST. A. J'OS~PHINE(1964) Partial autosomal trisomy and translocation. Report of an infant with multiple congenital anomalies, J. amer. reed. Ass., 187: 566-569. BRAY, P. F. AND B. B. MtnCHERJEE(1963) A chromosome anomaly in an infant with a degenerative disease of the central nervous system, J. Pediat., 62: 230-234. BRAY, P. F. AND A. J. SISTER(1964) Partial autosomal trisomy and translocation, J. amer. reed. Ass., 187: 566-569. BREIBART, S., W. J. MELLMANAND W. R. EBERLEIN (1963) A 1315/18 Chromosome translocation, J. Pediat., 63 : 712-715.

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BRODIE, H. R. AND L. DALLAIRE (1962) The E syndrome (trisomy 17-18) resulting from a maternal chromosomal translocation, Canad. reed. Ass. J., 87: 559-561. BfJHLER, E. M. VON, I. BODIS, R. ROSSIER AND G. STALDER (1962) Trisomie 13-15 mit Cebocephalie, Ann. Paediat. (Basel), 199: 198-205. BUHLER, E. M. VON, R. ROSSIER, I. BODIS, V. VULLIET, U. K. BOHLER AND G. STALDER (1963) Chromosomal translocation in a mentally deficient child with cryptorchidism, Acta paediat. (Uppsala), 52: 177-182. Bi3HLER, I. M. et al. (1964) Partial monosomy 18 and anomaly of thyroxine synthesis, Lancet, i: 170. BuRgs, J. L. AND S. SINKFORD (1964) Clinical trisomy E syndrome (16-18). A cytogenetic enigma, Clin. Pediat., 3 : 233-235. BUTLER, L. J., N. E. FRANCE, A. RUSSELL AND L. SINCLAIR (1962) A chromosomal aberration associated with multiple congenital anomalies, Lancet, i: 1216-1218. CAGIANUT, B., E. HAUSCHTECK, K. THEILER AND D. W. SMITH (1965) Manifestations oculaires de la trisomie D1, Bull. Soc. franc. Opht., 78: 452-459. CARLI, L. DE, F. N u z z o , B. CHIRARELLIAND E. POLI (1960) Trisomic condition of a large chromosome in a woman with mongoloid traits, Lancet, ii: 130-131. CARR, D. H. (1963a) Chromosome studies in abortuses and stilborn infants, Lancet, ii: 603-606. CARR, D. H. (1963b) Chromosomal abnormalities and their relation to disease, Canad. med. Ass. J., 88 : 456-461. CHANDRA, H. S. AND D. A. HUNGERFORD (1963) An aberrant autosome 13-15 in human female and her father both apparently normal, Cytogenetics, 2: 34-41. CHAPELLE, A. DE LA, P. ADLA AND E. KIVALO (1963) Enlarged short arm or satellite region. A heritable trait probably unassociated with developmental disorder, Cytogenetics, 2: 129-139. ClVANTOS, F. (1961) H u m a n chromosomal abnormalities, Bull. Tulane reed. Fac., 20: 241-253. CLARKE, C. M., J. H. EDWARDS AND V. SMALLPEIGE(1961) Trisomy/normal mosaicism, Lancet, i: 1028. CLARKE, G., A. C. STEVENSON,P. DAVIES, C. E. WILLIAMSAND S. B. HOLT (1964) A family apparently showing transmission of a translocation between chromosome 3 and one of the 'X-6-12' or Cgroup, J. reed. Genet., l : 27-34. COCKAYNE, E. A. 0936) Dwarfism with retinal atrophy and deafness, Arch. Dis. Childh., 11: 1-8. COCKAYNE,E. A. (1946) Case reports: Dwarfism with retinal atrophy, Arch. Dis. Childh., 25 : 52-54. CONEN, P. E., K. G. PtaILIPS AND L. S. MAUNTNER (1962) Multiple developmental anomalies in a trisomy of a 13-15 group chromosome (D-syndrome), Canad. reed. Ass. J., 87: 709-712. COOPER, H. L. AND R. HERNITS (1963) A familial chromosome variant in a subject with anomalous sex differentiation, Amer. J. hum. Genet., 15: 465-475. COOPER, H. L. AND K. HIRSCHHORN 0962) Enlarged satellites as a familial chromosome marker, Amer. J. hum. Genet., 14: 107-124. CRAWFURD,M. D'A. (1961) Multiple congenital anomalies associated with an extra autosome, Lancet, ii : 22-24. DELHANTY, J. D. A. AND A. SHAPIRO (1962) An unusual acrocentric found in a case of idiocy with microphthalmia, J. ment. Defic. Res., 6: 38-40. DE MEYER, W. (1964) A 46 chromosome cebocephaly with remarks on the relation of 13-15 trisomy to holoprosencephaly (arhinencephaly), Ann. Paediat. (Basel), 203: 169-177. DENT, T., J. H. EDWARDS AND J. D. A. DELHANTY (1963) A partial mongol, Lancet, ii: 484-487. DOEGE, T. C., H. C. THULINE, J. H. TRIEST, D. E. NORBY AND J. S. BRYANT (1964) Studies of a family with the oral-facial-digital syndrome, New Engl. J. Med., 271 : 1073-1080. DUMARS, K. W. JR., C. GASKILL A~D N. KITZMILLER (1964) Le cri du chat (crying cat) syndrome, Amer. J. Dis. Child., 108: 533-537. DYKE, H. F. VAN, A. VALDMANIS AND J. D. MANN (1964) Probable deletion of the short arm of chromosome 18, Amer. J. hum. Genet., 16: 364-374. EDWARDS, J. H., T. DENT AND E. GULI (1963) Sporadic mongols with translocations, Lancet, ii: 902. EDWARDS, J. H., M. FRACCARO, P. DAVIES AND R. B. YOUNG (1962) Structural heterozygosis in man: analysis of two families, Ann. hum. Genet., 26: 163-178. EDWARDS, J. H., D. G. HARNDEN, A. H. CAMERON,V. M. CROSSE AND O. H. WOLff (1960) A new trisomic syndrome, Lancet, i: 787-791. EDWARDS, J. H., R. B. YOUNG AND H. V. L. FINLEY (1961) Coloboma with multiple congenital anomalies, Brit. Med. J., ii: 586-587. EL-ALFI, O. S., J. J. BIESELEAND P. M. SMITH (1964) Trisomy 18 in a hydrocephalic fetus, J. Pediat., 65: 67-70. ELLIS, J. R. et al. (1963) A girl with triploid cells, Nature (Lurid.), 198:411.

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