J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

Journal ofMedical Genetics, 1981, 18, 108-118

The aetiology of the cat eye reconsidered

GINEVRA GUANTI From the Institute of Genetics, University of Bari, Via Amendola 165/A, Bari, Italy

SUMMARY The cat eye syndrome (CES), usually ascribed to the presence of a deleted supernumerary 22 , is characterised by a typical clinical picture including anal atresia, ocular , preauricular tags or sinuses, congenital heart defects, urinary tracts anomalies, and mental and physical retardation. An analysis of published reports revealed that of the 57 reported cases, only 21 showed the complete form, and 11 had a normal karyotype. Several observations question the existence of a 22: (1) the absence of any report in living subjects of arising from an inherited Robertsonian translocation; (2) the recurrent abortions in carriers of Robertsonian translocations involving ; and (3) the existence of a syndrome, showing the same clinical features as trisomy 22, which is irrefutably dependent on a trisomy of the distal region of the 11 long arm. On the basis of a comparison of the clinical features in full trisomy 13, partial 13 , 13 rings, 13 deletions, and CES the small marker present in this syndrome is considered to be a chromo-copyright. some 13 with an interstitial . An attempt to map this chromosome has been made.

One century ago, Haab' described the clinical Case reports association of ocular coloboma and anal atresia. In http://jmg.bmj.com/ 1965 Schachenmann et al2 were the first to find a CASE 1 supernumerary acrocentric chromosome in three This was a newborn male infant, born after 40 weeks' subjects with these malformations. gestation, the first child of a 30-year-old mother The term 'cat eye', derived from the particular and 33-year-old father. The delivery was normal; appearance that the vertical iridochoroidal coloboma birthweight 3000 g, head circumference 33 cm, gives to these patients, was introduced by Gerald length 55 cm. The following anomalies were ob- served: sloping forehead, prominent occiput, large et al.3 on September 25, 2021 by guest. Protected The syndrome is usually ascribed to the presence fontanelles, widely patent cranial sutures, epicanthal of a small submetacentric or acrocentric chromo- folds, hypertelorism, antimongoloid slanting eyes, some, but there are several case reports in which no depressed nasal bridge, prominent nose, increased chromosomal abnormality is apparent.4-8 philtrum length, malformed ears, bilateral preauric- Although cytogenetic investigations have not ular skin tags and sinuses (fig 1A), high arched provided precise information, because of the palate, narrow chest, widely spaced nipples, and small size of the supernumerary element, a small scrotum with neither testicle palpable in the 22q - chromosome is believed to be involved. There- sac or in the inguinal canal. Anal atresia was noted fore, the syndrome would depend on a partial at 48 hours after birth and was surgically resolved 22 trisomy. on the third day. The baby showed failure to thrive A recent examination of three patients with cat and was admitted to hospital for salmonellosis and eye syndrome (CES) and an accurate analysis of the infection of the urinary tract. He died 50 days after previously reported cases2-49 (table 1 a, b, 2a, b) birth. Necropsy showed the following additional enabled us to make some observations about the abnormalities: micropolygyria of the frontal lobes, clinical and cytogenetic picture of this syndrome. intestinal malrotation (fig 1B), megacolon, megaur- Received for publication 26 May 1980 eter on right side, and abdominal testes. The death of 108 J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

The aetiology of the cat eye syndrome reconsidered 109

TABLE la Cat eye synidrome: patients with abnormal TABLE Ic Patients with partial trisomy 13 owing to karyotype translocation Case No Authors Sex Case No Authors Sex

I Ballesta et al9 Case 2 M I Crandall et a150 F 2 Case 3 F 2 Giraud et a!51 F 3 Bass et al10 F 3 Jacobsen et a152 53 M 4 Beyer et all1 M 4 Stoll et a!54 M 5 Bofinger and Soukupl2 F 5 Wilson and Melnyk55 F 6 *Buhler et al03 Case II1.I F Case 11.3 M 7 M 8 Cervenka et a115 F 9 Cory and Jamison16 F TABLE 1d Patients with 13 10 Curciol7 F 11 Darby and Hughes'8 F Case No Authors Sex 12 De Chieri et a!19 M 13 Fryns et a120 M I Ailderdice et a156 Case 2 M 14 tGerald et al3 Case 1 M 2 Biles et a!57 M 15 Case 2 M 3 Grace et a158 Case 2 F 16 Case 3 F 4 Kistenmacher and Punnett59 Case 2 F 17 Ginsberg et a124 F 5 Lejeune et a!60 Case 2 M 18 Giraud et a!25 F 6 Reisman et a161 M 19 Gustavson et a126 Case I F 7 Rethor6 et a162 F 20 Case 2 F 8 Sparkes et a163 M 21 Hirschhorn et a!27 F 9 Tolksdorf et a164 M 22 Iselius and Faxelius28 F 23 Ishmael and Laurence29 M 24 Johnson et a130 F 25 Krmpotik et al3l F 26 Kriger et a132 F the patient was attributed to diffuse infection of the 27 Kunze et al33 F 28 $Nishi et al34 F urinary tract and to salmonella septicaemia. 29 Noel and Quack,35 Noel et a136 M The family history was unremarkable, with the 30 Petit37 F copyright. 31 Pfeiffer et a138 F exception of a maternal cousin who died a few days 32 §Pierson et al39 M after birth of biliary atresia. Both the parents were 33 Punnett et a!4l M 34 Schachenmann et a12 Case 1 F in good health and the mother had bilateral pre- 35 Case 2 F auricular pits. 36 Case 3 F 37 Schmid42 Case 1 F 38 Taft et a!43 M Genetic stiudies

39 Taillemite et al44 F http://jmg.bmj.com/ 40 Toomey et al45 M Sex chromatin was negative. Cytogenetic studies on 41 Weber et a146 F peripheral blood showed a modal number of 47 42 Weleber et al47 F 43 Zackai et a148 Case 1 F with one extra chromosome smaller 44 Case 2 M than a G chromosome. It appeared to have satellites 45 Zellweger et al4 Case 1 F on one end and to participate in satellite association. 46 Our case 1 M The identification of this supernumerary chromo- *Same cases in Sebestyen and M6hesl4 some was even and C band- tSame cases in Freedom and Gerald,22 Petersen23 impossible using G, Q, case in Noel et a!36 serum were tSame ing (fig 2). Blood and groups normal. on September 25, 2021 by guest. Protected §Same case in Thomas et a140 The karyotype of both parents was normal. Same cases in Emanuel et al49

CASE 2 The patient was the first child of healthy unrelated TABLE lb Cat exe syndrome: patients with normal parents. At the birth the father was 28 years old and karyotype the mother 21 years old. Delivery was normal; birth Case No Authors Sex weight 3100 g, length 54 cm, head circumference 31-9 cm. During the first weeks the baby suffered I Franklin and Parslow5 Case I F from respiratory distress, cyanosis, constant feeding 2 Case 2 F 3 James et a!6 Case 2 problems, and failure to gain weight. Multiple con- 4 Case 5 genital malformations were noted including sloping 5 Case 8 6 Case 15 forehead, facial asymmetry, antimongoloid slanting 7 Neu et al7 F of eyes, bilateral coloboma of iris and choroid 8 Temtamy and McKusicks F (fig 1C), nose, 9 Zellweger et a!4 Case 2 F right palpebral ptosis, prominent 10 Our case 2 M macrostomia, micrognathia, low set ears, hyper- 11 Our case 3 M telorism, short neck with low posterior hairline, J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

110 Ginevra Guanti TABLE 2 Clinicalfindings (a) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Psychosomatic retardation + ++ ++ ++ +±++ + + ++ +++ ++ + + + + Genital malforniations + + + + Urinary tract anomalies + + + + + + Kidney malformations + + ++ + + + + Cardiovascular anomalies + ++ + + + + +±++ +±+ + + + + + + Foot malformations + Hand malformations + + + Other skeletal anomalies + + Limited hip abduction + + + Vertebral malformations Preauricular pits/tags/sinuses + +±+ + ++ ++ +±++ + + Low set malformed ears + + + + + +++ +++ + .+ Cleft lip or palate + + + + + Micrognathia + ++ Microcephaly + + + ++ + + + + + + Ptosis Downward slanting eyes + ±++ + + + + + + + ++ + ++ Epicanthus + + + + + + + Strabismus + + + + + Hypertelorism + + ++ + + + + + + + + + + ±+ + + Microphthalmia + Coloboma + + + + + ++±+ ++ + + + + + ++±+ Anal atresia or stenosis + + + + + ++ + ++ + + + ++ + + + ++ + copyright. http://jmg.bmj.com/ I

'vIIK on September 25, 2021 by guest. Protected

FIG 1 Case 1, ear malformations (A), intestinal malrotation (B); case 2, ocular coloboma (C), gemfital malformations (D). widely spaced nipples, umbilical hernia, right There was no familial history of congenital mal- cryptorchidism, incurved penis (fig ID), and hypo- formations. spadias. Anal stenosis was suspected because of persistent constipation and thread-like stools. Renal Genetic studies malformations were suspected because of the per- Buccal smears were negative for sex chromatin. sistent high azotaemia. Cytogenetic investigation on peripheral blood showed LIBRARY ,I MAY 0 5 1981 J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from The aetiology of the cat eye syndrome reconsidered IEDERLEEiELABORATORIESa BIV., . I (b) (c) (d) 33 34 35 36 37 38 39 40 41 42 43 44 45 46 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 1 _,2 3 4 5~~~~~---6 7 8 9 + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + ++ ++ + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + ++ + + ++ ++ ++ + ++++ + + + + + + + + + ++++ + + ± + + + + ++ + + + + + + + + + + + + + + + + + + + +±+ + + + + + + + + + + + + + + + + + + + + + + + + + + ±±++ + + + ++ + + + + + +++ + + + + + + + + + + ++++ + + + + ++±+ ++++ + + ++++ + ++ + ±+ ++++ ++ ++ ++ + ++++ + + +

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. 0 0- ...... '. Ai.=;;- Zt;IL-k I I S.o i c .. \%.,. 40f. \N- , Ilk 4e 0le http://jmg.bmj.com/ 6,4% 2 1 2 2 V - .:-,% M. omew %.. on September 25, 2021 by guest. Protected f. ) FIG 2 Giemsa stained metaphase. (A) The arrow indicates the supernumerary chromosome; (B) Group G, Y and marker chromosomes from two G banded mitoses.

a modal number of 46 chromosomes. G, C, and Q 34 cm, and length was 50 cm. He had the following banding techniques did not reveal any structural malformations: sloping forehead, hypertelorism, anomalies. Normal karyotypes were found in blood downward slanting eyes, epicanthal folds, bilateral cultures of both parents. iris coloboma, flattened nose, elongated philtrum, preauricular tags, radial dysplasia, vertebral mal- CASE 3 formations, ventricular septal defect, single umbilical This was a newborn male infant born after 42 weeks' artery, low set ears, narrow chest, small scrotum, gestation by caesarian section. He was the first child and bilateral cryptorchidism. Anorectal atresia was of a 26-year-old mother and 35-year-old father. noted 24 hours after birth and was immediately Birthweight was 3250 g, head circumference was resolved surgically. Two days after birth the patient J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

112 Ginevra Guanti developed respiratory distress and died on the third CYTOGENETICS OF CASES WITH ABNORMAL day. Unfortunately no pictures were taken. KARYOTYPE The family history was unremarkable. Of 57 subjects with clinical features of CES, 46 had a karyotype with an extra small marker chromo- Genetic studies some of variable morphology and of variable length, The sex chromatin was negative. Chromosome that is, similar to or shorter than a 22. analysis performed on peripheral blood cells of the As previously mentioned, the simplest explanation patient and his parents revealed normal karyotypes. for the origin of the abnormal chromosome is that of a partial deletion of chromosome 22, but the in- volvement of this chromosome has never been well Discussion documented.

CLINICAL SPECTRUM The clinical spectrum of this anomaly is fairly wide OBSERVATIONS WHICH QUESTION THE as shown by several cases in which the extra chromo- EXISTENCE OF TRISOMY 22 IN LIVING some was transmitted directly from a phenotypically SUBJECTS normal parent to a son with the cat eye syn- The following observations question the existence of drome.2 317 18 31 The typical malformations include trisomy 22. anal atresia, usually associated with a rectoperineal (1) Living subjects with 22 trisomy arising from an or rectovaginal fistula, ocular coloboma, downward inherited Robertsonian translocation have never slanting eyes, microphthalmia, hypertelorism, strab- been reported. ismus, epicanthus, preauricular tags, sinuses or (2) The carriers of a Robertsonian translocation in- fistulas, congenital heart defects, particularly septal volving a chromosome 22, which is an extremely defects, urinary tract abnormalities, skeletal anomal- rare event, 6672 frequently have recurrent abor- ies, and, frequently, mental and physical retardation. tions. (3) A syndrome dependent on trisomy of the distalcopyright. DIAGNOSTIC CRITERIA region of the long arm of chromosome 1173 82 iS Initially, the combination of coloboma and anal characterised by the same features as trisomy atresia was the essential requisite for the diagnosis 22, namely craniofacial dysmorphia, broad nose, of CES. Subsequently the criteria became less re- long philtrum, micrognathia, malformed low set strictive, and thereafter several cases of the incom- ears with preauricular pits or tags, cleft palate,

plete syndrome were reported. cardiac malformations, etc. http://jmg.bmj.com/ According to Hsu and Hirschhorn85 the diagnosis ofcat eye syndrome (CES) should be made according to the following minimal clinical criteria: OBSERVATIONS WHICH QUESTION THE EXISTENCE OF PARTIAL TRISOMY 22 (1) a combination ofthe two major features, namely Doubts about the existence of partial trisomy 22 are coloboma and anal atresia, with or without other underlined by the following considerations. associated abnormalities; (1) If the extra chromosome gives rise to partial

(2) a combination of one major feature, coloboma on September 25, 2021 by guest. Protected or anal atresia, plus at least one of the most trisomy for a chromosome 22, the affected per- frequent associated specific anomalies, for sons would be expected to have some clinical example, preauricular skin tags or sinuses or features similar to the recognised full trisomy renal anomalies; syndrome carriers, who obviously should present more marked consequences of the genome (3) a combination of one major feature plus two alterations. Instead one finds a more severe less frequent features, such as antimongoloid phenotypic picture in the cat eye syndrome than slanting eyes, skeletal anomalies, congenital in the trisomy 22 syndrome. heart disease, and other eye defects; (2) If the CES is the phenotypic expression of partial (4) a combination of five or more minor specific 22 trisomy, the affected patients should have a features. shorter chromosome 22 than normal. Instead In the light of criteria 2 and 3 we have included there are subjects with an extra chromosome of in tables 1 and 2 several cases of full trisomy 22 the same length as a 22 who exhibit the cat eye described as trisomy 22 syndrome.10 15 27 28 44 48 syndrome10 15 26-29 32 45 and subjects with a However, based on criterion 4, all the cases of supernumerary deleted chromosome who have trisomy 22 syndrome could be included. the trisomy 22 syndrome.83 84 J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

The aetiology of the cat eye syndrome reconsidered 113 TABLE 3 Compar-isoni ofsome features in full 13 trisomy*, in par-tial 13 tr-isomiest, and in cat eye syndrome Conmplete Distal Proximal CES with CES without 13 trisomy trisomy trisomy marker marker

Menital retardation 26/26 100 30/30 100 7/9 78 29/36 80 6/11 55 Microcephaly 16/25 64 13/30 43 3/7 43 18/39 46 4/11 36 Low set malformed ears 20/25 80 22/28 79 3/7 43 43/46 93 9/11 82 Cleft lip or palate 30/40 75 7/30 23 2/9 22 12/46 26 3/11 27 Hypertelorism 24/26 92 7/30 23 3/6 50 23/45 51 4/11 36 Epicanthus 14/25 56 8/30 27 2/6 33 12/45 27 4/11 36 Coloboma 17/37 46 3/30 10 1/9 11 26/46 57 11/11 100 Microphthalmia 19/25 76 6/30 20 1/9 11 8/45 20 3/11 27 Cardiovascular anomalies 19/26 73 5/27 19 2/8 25 25/46 54 6/11 55 Genital malformations 21/32 66 8/27 30 2/9 22 7/44 16 3/11 27 Kidney malformations 13/32 41 9/27 33 0/6 0 9/46 20 2/11 18 Inguinal/umbilical hernia 10/25 40 9/27 33 1/9 11 2/46 4 1/11 9 Haemangioma 15/21 71 18/30 60 1/8 12 0/46 0 0/11 0 Polydactyly 19/25 76 19/30 63 0/9 0 0/46 0 0/11 0 Simian crease 16/25 64 11/19 58 2/9 22 4/21 19 3/7 43 Distal t triradius 14/20 70 4/12 33 4/8 50 5/21 24 0/7 0 Anal atresia or stenosis 0/37 0 1/30 3 0/9 0 33/46 72 6/11 55 Sex (F: M) 35: 29 18 : 12 4: 4 31: 15 5: 2 Maternal age 31.6 26.2 26-5 30-3 27.0 Paternal age 31.9 30.3 29.6 32-9 31-5 Gestational age 39-0 39-7 39.8 40.0 41.0 Birthweight (g) 2610 3263 2926 2917 2691 *Data from Warkany et al15 and Taylor.86 tData from Niebuhr.87

COMPARISON BETWEEN THE CAT EYE chromosome could derive from a translocation be- copyright. SYNDROME AND THE FYNDROMES ASSOCIATED tween the long arm of a 13 and the short arm of WITH TRISOMY OF another D or G chromosome, for example the 22, On the basis of the clinical features, several the presence of only some characteristics (fluorescent authors25 2B29-32 have already suggested that the satellites, centromere, etc) of chromosome 22 cannot extra chromosome present in the CES may be a constitute sufficient criteria for the correct identifica- deleted 13; in fact, many clinical and pathological tion of the marker (fig 3c-e). features usually associated with trisomy 13 are pre- http://jmg.bmj.com/ sent in the cat eye syndrome (table 3). MAP OF CHROMOSOME 13 Besides this, in some cases of CES25 the extra The clinical findings characteristic of partial tri- chromosome shows a bright centromere, a cyto- somy of proximal and distal regions of chromosome genetic feature typical of chromosome 13. 13 (table 3) have been delineated by Niebuhr.87 We analysed all the malformation Recently attempts to map chromosome 13 on the depending on numerical and structural aberrations basis of clinical features have been carried out.5' 88 89 of chromosome 13 and, according to criteria 2 and Obviously a perfect phenotype-karyotype correla- 3 of Hsu and Hirschhorn,65 we found striking simi- tion cannot be achieved, since the genetic material on September 25, 2021 by guest. Protected larities between the cat eye syndrome and the contained in a chromosomal band corresponds clinical pictures associated with some 13 ring to several hundred genes. Furthermore the attempt chromosomes 56-64 and some partial 13 trisomies50-55 to map a chromosome meets with several difficulties occurring in unbalanced translocations (table ic, as stressed by Schutten et al.89 Nevertheless, we d, 2c, d). should attempt to localise the regions responsible Obviously the 13 rings and the partial 13 trisomies for the cardinal signs of the CES and, at the same show the same clinical picture as the cat eye syn- time, compare some of the clinical features of the drome whenever they give rise to a duplication of the partial trisomies with the clinical picture of the CES same regions present on the supernumerary chromo- (fig 4). some in this syndrome. In deriving such a small For this comparison we must keep in mind that extra chromosome from a 13, different portions of the proposed model (fig 3a, b) of chromosomal 13 may be involved in the constitution of the marker. rearrangement which most frequently gives rise to This may account for the variability of the syndrome the is an interstitial deletion and make the identification of the marker impossible involving the central region of the 13 long arm by banding (fig 3). Furthermore, since the marker (bands q2.--q33). J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

114 Ginevra Guanti Ub

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13 FIG 3 Schematic representation ofpossible 13 rearrangements ofchromosome 13. (a, b) Interstitial deletion which in b gives rise to copyright. a chromosome showing the same banding pattern as a 22. (c, d) 13/22 translocation a.A giving rise to a marker chromosome with characteristics (centromere and/or satellites) ofa 22. (e) Partial karyotype illustrating 13 how a rearranged 13 chromosome resembles

a 22 (G banding). http://jmg.bmj.com/

COMPARISON BETWEEN CES AND TRISOMIES the q13 region, excluding the coloboma locus; and on September 25, 2021 by guest. Protected OF PROXIMAL REGION OF LONG ARM (3) the locus is included in the trisomic region, but OF CHROMOSOME 13 is silent. The latter could be accepted, if we consider Psychosomatic retardation, microcephaly, low set that the coloboma is present in only about 50% of ears, micrognathia, clinodactyly, microstomia, epi- cases of complete trisomy 13. canthus, cleft palate, abnormal dermatoglyphs, The trisomy of the region slightly distal (ql4) increased t triradius, which are frequently described would determine cardiac, renal, and genital mal- in trisomies of the proximal q region, are present in formations, anomalies rare in trisomies of the the CES too. The ocular coloboma frequent in the proximal q region and more frequent in the CES. CES has been found once in trisomies of the proxi- mal q region.52 COMPARISON BETWEEN CES AND TRISOMIES The lack ofcoloboma in the other eight cases88 9096 OF DISTAL REGION OF LONG ARM OF may be for the following reasons: (1) the trisomic CHROMOSOME 13 region does not include the coloboma locus which, A comparison between partial trisomy of the distal q according to our map (fig 4), may be in the q13 region50 51 54 55 90 93 94-112 and CES is more difficult, region; (2) the trisomic region partially comprises since most of the cases of the former include the J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

The aetiology of the cat eye syndrome reconsidered 115 fled as chromosome 13,87 of 1 3q interstitial or terminal deletions. As stressed by McClintock,117 terminal deletions are very rare events, since their formation, requiring the loss of the telomere, determines an unstable condition which can bring about elimination or further chromosomal change resulting from the fusion of chromatid ends.118 Therefore the idea that the anal atresia depends on a simple deficiency of the q terminal ends can be excluded. The presence of the same anomaly in monosomic ( (rings and deletions) and trisomic (CES) conditions 0. could be explained by postulating the presence of a ° 2 (regulatory?) site on the distal region q33 or q34 >- which whenever involved in breakage may produce - .E such a dominant . E Eo o0 CES WITH NORMAL KARYOTYPE D A normal karyotype was found in 1 4-8 of 57 sub- O jects with the CES (table lb, 2b). These cases sug- gest that there may be a non-chromosomal basis for I the syndrome, even in so called familial cases5 where the various features may be transmitted in an auto- somal fashion. If we admit the existence of a non-chromosomal basis, we can consider the association of CES with copyright. the extra chromosome to be fortuitous whenever an affected patient inherits the abnormal chromosome from a normal carrier parent.2 31718 31 This hypothesis is not very convincing because, if in the latter cases the normal phenotype depends on a -I4

condition of mosaicism, the mosaicism also found http://jmg.bmj.com/ FIG 4 Schematic drawing ofchromwsome 13 map. in patients with CES remains unexplained.3 24 45 Another possible explanation for the apparently normal karyotype may be the existence of a chromo- central region of the long arm (q2-+q33) which is somal aberration beyond the limits of our present never present in the small marker in the CES. techniques. This may account for the fact that polydactyly, However, the possibility which must also be con- syndactyly, and other hand and foot deformities, sidered is that we are dealing with two different hernia, haemangioma, long incurved eyelashes, and disorders resembling each other clinically. on September 25, 2021 by guest. Protected bushyeyebrows, which are frequentlyobserved inthese partial trisomies, are almost alwaysabsent in the CES. CES AND VATER ASSOCIATION Ocular coloboma is mentioned by Crandall et a150 A similar combination of defects occurring in CES (trisomy ql2-*qter), Wilson and Melnyk,55 and, is present in VATER association (a non-random unexpectedly, (trisomy q21-*qter) by Stoll et al.54 combination of congenital malformations consisting Its absence in other cases51 88 96 97 may be attributed of vertebral defects, anal atresia, cardiac mal- to the reasons mentioned above. formations, tracheo-oesophageal fistula, oesophageal atresia, radial and renal dysplasiall9 120) in such a way ANAL ATRESIA IN CES AND IN 13 RINGS that some overlapping of the two forms exists (our AND DELETIONS case 3).4-6 8 The anal atresia frequently present in CES, but never Most of the reported cases with the VATER assoc- described in complete or partial trisomies ofchromo- iation are sporadic. However, gene could some 13, except the case reported by Giraud et al,51 conceivably cause all these associated malformations. has been observed in seven56-58 61 63 64113 of 50 cases Several examples of dominant inheritance of some of 13 rings and in three114-11 of 21 cases, 70% identi- VATER traits are reported.121-123 It is of interest to J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

116 Ginevra Guanti note that in the history of several carriers of CES a family with trisomy 22 syndrome. Ophthalmologica (our case 1)4 21 29 31 47 there is familial occurrence of 1973;166:360-71. 15 Cervenka J, Hansen CA, Franciosi RA, Gorlin RJ. typical malformations. Trisomy 22 with "cat eye" anomaly. J Med Genet 1977; From these observations two questions arise. Is 14:288-90. there a correlation between CES and the familial 16 Cory CC, Jamison DL. The cat eye syndrome. Arc/h occurrence of any particular malformations? Does Ophthalmnol 1974;92 :259-62. a relation between CES and VATER 17 Curcio 0. Malformazione del retto e della vagina there exist associata ad anomalia cromosomica (47,XX,?G+). Cliii association ? Ostet Ginecol 1967 ;72:533-9. In conclusion, from the cytogenetic point of view, 18 Darby CW, Hughes DT. Dermatoglyphics and chromo- we would like to postulate that the extra chromo- somes in cat-eye syndrome. Br MedJ 1971 ;iii:47-8. some present in CES is essentially constituted of 9 De Chieri PR, Malfatti C, Stanchi F, Albores JM. Cat- eye syndrome: evaluation of the extra chromosome with genetic material belonging to chromosome 13. banding technique. J Genet Hum 1974;22:101-7. Since banding techniques proved to be inefficient 20 Fryns JP, Eggermont E, Verresen H, van den Berghe H. in identifying the abnormal chromosome, another A newborn with the cat eye syndrome. Huinangenietik useful investigation would be to search for a gene 1972 ;15 :242-8. 21 Gerald PS, Davis C, Say BM, Wilkins JL. Syndromal dosage effect or an abnormal inheritance pattern in association of : the cat eye syndrome. some gene markers for the genes mapped on these Birth Defects 1972;8, No 2:79-84. chromosomes. From the clinical point of view it is 22 Freedom RM, Gerald PS. Congenital cardiac disease and necessary to explain whether the incomplete forms cat eye syndrome. Am J Dis Child 1973;126:16-8. 23 Petersen RA. Schmid Fraccaro syndrome (cat's eye reflect a reduced expressivity or the existence of one syndrome). Partial trisomy of G chromosome. Arch or more different entities. Ophthalmol 1973;90:287-91. 24 Ginsberg J, Dignan P, Soukup S. Ocular abnormality References associated with extra small . Am] J Ophthallnol 1 Haab 0. Beitrage zu den angeborenen Fehlern des auges. 1968 ;65 :740-6. Albrecht von Graefes. Arch Ophthalmol 1878;24:257-81. 25 Giraud F, Mattei JF, Hartung M, Mattei MG. Petit 2 Schachenmann G, Schmid W, Fraccaro M, et al. chromosome submetacentrique surnumeraire et syndrome Chromosomes in coloboma and anal atresia. Lancet de yeux de chat. Ann Pediatr 1975;22:449-52. copyright. 1965 ;ii:290. 26 Gustavson KH, Hitrec V, Santesson B. Three non- 3 Gerald PS, Davis C, Say BM, Wilkins JL. A novel mongoloid patients of similar phenotype with an extra chromosomal basis for imperforate anus (the cat's eye G-like chromosome. Clin Genet 1972;3:135-46. syndrome) Pediatr Res 1968 ;2 :297. 27 Hirschhorn K, Lucas M, Wallace 1. Precise identification " Zellweger H, Mikamo C, Abbo G. Two cases of multiple of various chromosomal abnormalities. Ann Humn Genet malformations with an autosomal chromosomal aber- 1973 ;36:375-9. ration-partial trisomy D? Helv Paediatr Acta 1962;17: 28 Iselius L, Faxelius G. Trisomy 22 in a newborn girl with

290-300. multiple malformations. Hereditas 1978 ;89 :269-70. http://jmg.bmj.com/ 5 Franklin RC, Parslow ML. The cat-eye syndrome, review 29 Ishmael J, Laurence KM. A probable case of incomplete and two further cases occurring in female siblings with trisomy of a chromosome of the 13-15 group. J Med normal chromosomes. Acta Paediatr Scand 1972 ;61: Genet 1965;2:136-41. 581-6. 30 Johnson LD, Harris RC, Henderson AS. Ribosomal 6 James PML, Karseras AG, Wybar KC. Systemic DNA in a metacentric chromosome fragment. Humnan- association of uveal coloboma. Br J Ophthalmol 1974 ;58: genetik 1974;21 :21-9. 917-21. 31 Krmpotik E, Rosnick MR, Zollar LM. Genetic counsel- 7 Neu RL, Assemany SR, Gardner LI. Cat eye syndrome ing. Secondary non disjunction in partial trisomy 13. with normal chromosomes. Lancet 1970;i:949. Obstet Gynecol 1971 ;37:381-90. 8 Temtamy SA, McKusick V. Absence deformities as part 32 Kruger E, Witkowski R, Piede U. Partielle trisomie on September 25, 2021 by guest. Protected of syndromes. Birth Defects 1978;14, No 3:135-46. D1 -eine seltene chromosomen-anomalie. Humantgenetik 9 Ballesta Martinez F, Repiso J, Altirriba 0, Villaz L. 1968 ;6:181-8. Three new cases of a small extra chromosome. Sym- 33 Kunze J, Tolksdorf M, Wiedemann HR. Cat-eye posium on "Karyotype phenotype", Pavia, 10-1I syndrome. Humangenetik 1975;26:271-89. September 1973. Bull Eur Soc Hum Genet 1973: 67-9. 34 Nishi Y, Tanabe K, Takeda M. A case of the cat eye 1 Bass HN, Crandall BF, Sparkes RS. Probable trisomy 22 syndrome. Analysis of 20 cases including our case identified by fluorescent and trypsin-Giemsa banding. (Japanese). Ann Paediatr Jpn 1975 ;21 :18-24. Ann Genet (Paris) 1973;16:189-92. 35 Noel B, Quack B. Petit metacentrique surnumeraire chez Beyer P, Ruch JV, Rumpler Y, Girard J. Observation un polymalforme. J Genet Hum 1970;18:45-56. d'un enfant debile mental et polymalforme dont le 36 Noel B, Mottet J, Nantois Y, Quack B. Contribution a caryotype montre la presence d'un petite extra chromo- l'identification du petit chromosome submetacentrique some mediocentrique. Pediatrie 1968 ;23 :439-42. surnumeraire dans la syndrome des yeux de chat. J Genet 12 Bofinger MK, Soukup SW. Cat eye syndrome: partial Hum 1973;21:23-32. trisomy 22 due to translocation in the mother. Am J Dis 37 Petit P. Identifying the extra chromosome in cat eye Child 1977;131:893-7. syndrome with Q, G and C technique. Symposium on 13 Buhler EM, Mehes H, Muller H, Stalder GR. Cat-eye "karyotype-phenotype", Pavia, 10-11 September 1973. syndrome, a partial trisomy 22. Humangenetik 1972;15: Bull Eur Soc Hum Genet 1973:70-3. 150-62. 38 Pfeiffer RA, Heimann K, Heiming E. Extra Sebestyen J, Mehes K. Ocular movement disturbances in in "cat-eye" syndrome. Lancet 1970;ii:97. J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

The aetiology of the cat eye syndrome reconsidered 117 39 Pierson M, Gilgenkrantz S, Saborio M. Syndrome dit de clinique de phenotype correspondant A un chromosome l'oeil de chat avec nanisme hypophysaire et developement D en anneau. Press Med 1970;78:995-9. mental normal. Arch Fr Pediatr 1975;32:832-48. 63 Sparkes RS, Carrel RE, Wright SW. Absent thumbs with 40 Thomas C, Cordier J, Gilgenkrantz S, Reny A, Raspiller a ring D2 chromosome, a new deletion syndrome. Am J A. Une syndrome rare: atteinte colobomatose du globe Hum Genet 1967;19:644-9. oculaire, atresie anale, anomalies congenitales, multiples 64 Tolksdorf M, Goll U, Wiedemann HR, Pfeiffer RA. Die et presence d'un chromosome surnumeraire. Ann Oculist Symptomatic von Ringchromosomen der D-Gruppe (Paris) 1969;202:1021-31. (Zwei neue Bobachtungen des typs 13r). Arch Kinder- 41 Punnett HH, Kistenmacher MI, Toro-Sola MA, Kohn heilkd 1970;181:282-95. G. Quinacrine fluorescence and Giemsa banding in 65 Hsu LYF, Hirschhorn K. The trisomy 22 syndrome and trisomy 22. Theor Appl Genet 1973;43:134-8. the cat eye syndrome. In: Yunis JJ, ed. New chromosomal 42 Schmid W. Pericentric inversion. J Genet Humn 1967;16: syndromes. New York, San Francisco, London: Academic 89-90. Press, 1977:339-68. 43 Taft PD, Dodge PR, Atkins L. Mental retardation and 66 Schwinger E. Translocation 22/22?Lancet 1973;ii:854-5. multiple congenital anomalies. Am J Dis Child 1965;109: 67 Fried K, Bukowsky J, Rosenblatt M, Mundel G. Familial 554-7. 15/22 translocation. A possible cause for abortions in 44 Taillemite JL, Baheux-Morlier G, van den Akker J, et al. female carriers. J Med Genet 1974;11:280-2. Trisomie 22 partielle. Ann Genet (Paris) 1977;20:291-3. 68 Farah LMS, de S Nazareth HR, Dolnikoff M, Delascio 45 Toomey KE, Mohandas T, Leisti J, Szalay G, Kabak D. Balanced homologous translocation t(22q22q) in a MM. Further delineation of the supernumerary chromo- phenotypically normal woman with repeated spontaneous some in the cat-eye syndrome. Clin Genet 1977 ;12:275-84. abortions. Hum Genet 1975;28:357-60. 46 Weber FM, Dooley RR, Sparkes RS. Anal atresia, eye 69 Maeda T, Ohno M, Shimada N, Nishida N, Jobo T. anomalies, and an additional small abnormal acrocentric A 22/22 translocation carrier with recurrent abortions chromosome (47,XX,mar+). Report of a case. J Pediatr demonstrated by a Giemsa banding technique. Hum 1970;76:594-7. Genet 1976;31:243-5. 47 Weleber RG, Walknowska J, Peakman D. Cytogenetic 70 Lewis BV, Ridler MAC. Recurrent abortion associated investigation of cat eye syndrome. Am J Ophthalmol with a balanced 22;22 translocation, or isochromosome 1977 ;84 :477-86. 22q in a monozygous twin. Hum Genet 1977;33:81-5. 48 Zackai E, Aronson M, Kohn G, Moorhead P, Mellman 71 Mameli M, Cardia S, Milia A, Seabright M. A further W. Familial trisomy 22. .4m J Hum Genet 1973;25:89A. case of a 22;22 Robertsonian translocation associated 49 Emanuel BS, Zackai EH, Aronson MM, Mellman WJ, with recurrent abortions. Hum Genet 1978;41:359-61. copyright. Moorhead PS. Abnormal chromosome 22 and recurrence 72 Friedrich U, Nielsen J. Chromosome studies in 5049 of trisomy 22 syndrome. J Med Genet 1976;13:501-6. consecutive newborn children. Clin Genet 1973 ;4:333-43. 59 Crandall BF, Carrel RE, Howard J, Schroeder WA, 73 Laurent C, Biemont MCL, Bethenod M, Cret L, David Muller H. Trisomy 13 with a 13-X translocation. Am J M. Deux observations de trisomie I1q(q231 - qter) avec Hum Genet 1974 ;26:385-92. la meme anomalie des organes genitaux externes. Ann 51 Giraud F, Mattei JF, Mattei MG. Trisome 13 partielle Genet (Paris) 1975;18:179-84. par translocation (2;13) maternelle. Ann Genet (Paris) 74 Wright YM, Clarke WE, Breg WR. Craniorachischisis 1977 ;20 :203-8. in a partially trisomic 11 fetus in a family with reproduc- 52 Jacobsen P, Dupont A, Mikkelsen M. The translocation tive failure and a reciprocal translocation t(6p + 11 q-). http://jmg.bmj.com/ in the 13-15 group as cause of partial trisomy and J Med Genet 1974;11 :69-75. spontaneous abortion in the same family. Lancet 1963;ii: 75 Tusques J, Grislain JR, Andre MJ, et al. Trisomie 584-5. partielle 1 lq identifie grace A l'etude en denaturation 53 Jacobsen P, Mikkelsen M, Froland A, Dupont A. menagee par la chaleur, de la translocation equilibr6e Familial transmission of a translocation between two paternelle. Ann Genet (Paris) 1972 ;15 :167-72. non homologous large acrocentric chromosomes. Clinical, 76 Rott HD, Schwanitz G, Grosse KP, Alexandrow G. cytogenetic and autoradiographic studies. Ann Cl1/D113 translocation in four generations. Human- Hum Genet 1966;29:391-9. genetik 1972;14:300-5.

54 Stoll C, Messer G, Weitzenblum S, Warkel S. An unusual 77 Franke U. Quinacrine mustard fluorescence of human on September 25, 2021 by guest. Protected partial trisomy 13. Clin Genet 1976;9:1-4. chromosomes: characterization ofunusual translocations. 55 Wilson MG, Melnyk J. Translocation/normal mosaicism Am J Hum Genet 1972;24:189-213. in D1 78 Aurias A, Turc C, Michiels Y, Sinet PM, Graveleau D, syndrome. Pediatrics 1967;40:842-6. Lejeune J. Deux cas de trisomie llq(q231 qter) par 56 Allderdice PW, Davis JG, Miller OJ, et al. The 13q- translocation t(11 ;22)(q231 ;ql 11) dans deux familles deletion syndrome. Am J Hum Genet 1969;21:449-512. differents. Ann Genet (Paris) 1975 ;18 :185-8. 5 Biles AR, Luers T, Sperling K. D1 ring chromosome in 79 Giraud F, Mattei JF, Mattei MG, Bernard R. Trisomie newborn with peculiar face, polydactyly, imperforate partielle 11 q et translocation familiale 11-22. Human- anus, arrhinencephaly, and other malformations. J Med genetik 1975 ;28 :343-7. Genet 1970;7:399-401. 80 Noel B, Levy M, Rethore MO. Trisomie partielle du 58 Grace E, Drennam J, Colver D, Gordon RR. The 13q- bras long du par malsegregation d'une deletion syndrome. J Med Genet 1971 ;8:351-7. translocation maternelle t(11;22)(q231;qlll). Ann Genet 59 Kistenmacher ML, Punnet HH. Comparative behaviour (Paris) 1976;19:137-9. of ring chromosomes. Am J Hum Genet 1970;22:304-18. 81 Ayraud N, Galiana A, Lloyd M, Deswarte M. Trisomie 60 Lejeune J, Lafourcade J, Berger R, et al. Le phenotype 11 q(q231 qter) par translocation maternelle t( 11 ;22) (Dr). Etude de trois cas de chromosomes D en anneau. (q231 ;ql 11). Une nouvelle observation. Ann Genet Ann Genet (Paris) 1968;11:79-87. (Paris) 1976;19:65-8. 61 Reisman LE, Darnell A, Murphy JW. Abnormalities 82 Kessel E, Pfeiffer RA. 47,XY,+der(11 ;22)(q23;ql2) with ring chromosome. Lancet 1965;ii:445. following balanced translocation t(11 ;22)(q23 ;q12) mat. 62 Rethore MO, Praud E, Le Loch J, et al. Diagnostic Hum Genet 1977;37:111-6. J Med Genet: first published as 10.1136/jmg.18.2.108 on 1 April 1981. Downloaded from

1181Ginevra Guanti 83 Garlinger P, McGeary SA, Magenis RE. Partial trisomy of a child with Patau's syndrome. Ann Hum Genet 1975; 22: a recognizable syndrome. Clin Genet 1977;12:9-16. 38:305-7. 84 Zellweger H, Ionasescu V, Simpson J. Trisomy 22. J 105 Mutchinick 0, Ruz L, Jimenez R. Partial trisomies 13 Genet Hum 1975 ;23 :65-75. and 22 due to nondisjunction of a maternal reciprocal 85 Warkany J, Passarge E, Smith LB. Congenital mal- translocation t(l3 ;22)(q22 ;ql 1). Hum Genet 1978 ;45: formations in autosomal trisomy syndromes. Am J Dis 89-95. Child 1966;112:502-17. 108 Rosenkrantz W, Kaloud H. Nicht Balanzierte D/E 88 Taylor Al. Autosomal trisomy syndromes: a detailed Translokation. Paediatr Paedol 1972;7:377-9. study of 27 cases of Edwards's syndrome and 27 cases of 107 Schinzel A, Hayashi K, Schmid W. Further delineation Patau's syndrome. J Med Genet 1968;5:227-52. of the clinical picture of trisomy for the distal segment of 87 Niebuhr E. Partial trisomies and deletions of chromo- chromosome 13. Report of three cases. Hum Genet 1976; some 13. In: Yunis JJ, ed. New chromosomal syndromes. 32:1-12. New York: Academic Press, 1978:273-99. 108 Schwanitz G, Schmid P, Berthold HG, Grosse KP. 88 Noel B, Quack B, Rethor6 MO. Partial deletions and tri- Partial trisomy 13 with clinical signs of , somies of chromosome 13; mapping of bands associated resulting from a complex paternal rearrangement of with particular malformations. Clin Genet 1976;9: chromosome 6, 10 and 13. Ann Genet (Paris) 1978;21: 593-602. 100-3. 89 Schutten HJ, Schutten BT, Mikkelsen M. Partial trisomy 109 Stalder GR, Buhler EM, Gadola G, Widmer R, Freuler F. of chromosome 13. Case report and review of literature. A family with balanced D'-C8 translocation carriers Ann Genet (Paris) 1978;21:95-9. and unbalanced offspring. HIumangenetik 1964;1 :197- 90 Bloom GE, Gerald PS. Localization of genes on chromo- 200. some 13: analysis of two kindreds. Am J Hum Genet 110 Talvik T, Mikelsaar AV, Mekelsaar R, Kaosaar M, Tuur S. 1968 ;20:495-51 1. Inherited translocations in two families (t(14q+ ;lOq-) 91 Escobar JI, Sanchez 0, Yunis JJ. Trisomy for the distal and t(13q- ;21q+). Hum Genet 1973;19:215-26. segment of chromosome 13. Am J Dis Child 1974;128: Taysi K, Bobrow M, Balci S, Madan K, Atasu M, Say B. 217-20. Duplication deficiency product of a pericentric inversion 92 Maclntyre MN, Stapless WL, Lapolla JJ. Partial D, in man: a cause of D1 trisomy syndrome. J Pediatr 1973; trisomy in a child whose mother and maternal grand- 82:263-8. mother demonstrate a D/F translocation. Am Soc Hum 112 Yanagisawa S, Yokoyama H, Agena N. Partial distal Genet 1964:21. trisomy 13q resulting from familial reciprocal 5/13 93 Schinzel A, Schmid W, Murset G. Different forms of translocation. Hum Genet 1978;45:345-50.

incomplete trisomy 13. Mosaicism and partial trisomy 113 Kurokyi Y, Nagano Y. On the ring 13 chromosome incopyright. a for the proximal and distal long arm. Humangenetik malformed infant with special regard to the break point. 1974;22:287-98. Proc Jpn Acad 1974;50:645-7. 94 Schwanitz G, Grosse KP, Semmelmayer V, Mangold H. 114 Thompson H, Lyons RB. Retinoblastoma and multiple Partielle freie trisomie 13 in einer familie mit balancierter congenital anomalies associated with complex mosaicism translokation (13q-;16q+). Monatsschr Kinderheilkd with deletion of a D chromosome and probable D/C 1974;122:337-42. translocation. Hum Chrom Newsletter 1965;15:1. 95 Yunis JJ, Hook EB. DNA replication and mapping of the 115 Laurent C, Cotton JB, Nivelon A, Freycon MT. Deletion group D D, chromosome. Am J Dis Child 1966;111 :83-9. partielle du bras long d'un chromosome du http://jmg.bmj.com/ 96 Wilroy RS, Summitt RL, Martens P, Manford Gooch W. (13-15) :Dq -. Ann Genet (Paris) 1967;10:25-31. Partial and partial trisomy for different 116 Leisti J. Structural variations in human mitotic chromo- segments of chromosome 13 in several individuals of the somes. Ann Acad Sci Fenn (Biol) 1971 ;4:1-69. same family. Ann Genet (Paris) 1977;20:237-42. 117 McClintock B. The stability of broken ends of chromo- 97 Coco R, Del Rey G. Partial trisomy 13q inherited from somes in Zea Mais. Genetics 1941;26:234-82. balanced translocation (5;13)(pl4;ql3). J Genet Hum 118 McClintock B. The fusion of broken ends of chromo- 1978 ;26:303-10. somes following nuclear fusion. Proc Natl Acad Sci USA 98 Escobar JI, Yunis JJ. Trisomy for the proximal segment 1942;28:458-63. of the long arm of chromosome 13. Am J Dis Child 119 Quan L, Smith DW. The Vater association: vertebral

1974;128:221-2. defects, anal atresia, tracheoesophageal fistula with on September 25, 2021 by guest. Protected 99 Fryns JA, Eggermont E, Verresen H, van der Berghe H. esophageal atresia, radial dysplasia. Birth Defects 1972; Partial 13 trisomy: karyotype 46,-6,+t(l3q,6q). 8, No 2:75-8. Humangenetik 1974;21 :47-54. 120 Quan L, Smith DW. The Vater association: vertebral 100 de Grouchy J, Turleau C, Danis F, Kohout G, Briard ML. defects, anal atresia T-E fistula with esophageal atresia, Trisomy 13qter by tandem duplication. 46,XX,dir radial and renal dysplasia: a spectrum of associated dup 13(q21 -qter),9qh+. Ann Genet (Paris) 1978 ;21: defects. J Pediatr 1973;82:104-7. 247-51. 121 Fuhrmann W, Rieger A, Vogel F. Zwei beobachtungen 101 Hauksdottir H, Halldorsson S, Jensson 0, Mikkelsen M, zum genetik der atresia ani. Arch Kinderheilkd 1958 ;158: McDermott A. Pericentric inversion of chromosome No 264-9. 13 in a large family leading to duplication deficiency 122 Say B, Balci S, Pirnar T, Hicsonmez A. Imperforate anus causing congenital malformations in three individuals. (polydactyly) vertebral anomalies syndrome. a heredity J Med Genet 1972;9:413-21. trait? J Pediatr 1971 ;79:1033-4. 102 Hoehn H, Wolf U, Schumaker H, Wehinger H. A 223 Townes PL, Brocks ER. Hereditary syndrome of im- chromosome 13q + in a patient with characteristics of the perforate anus with hand, foot and ear anomalies. J trisomy 13 syndrome. Humangenetik 1971;13:34-42. Pediatr 1972;81:321-3. 103 Jotterand M, Juillard E. A new case of trisomy for the distal part of 13 due to maternal translocation t(9;13) Requests for reprints to Dr G Guanti, Institute of (p21 ;q21). Hum Genet 1976;33:213-22. 104 McDermott A, Parrington JM. Elucidation of a peri- Genetics, University of Bari, Via Amendola 165/A, centric inversion of a D group chromosome in the mother Bari, Italy