7- ment. Defic. Res. (1975) 19, 225
225
A PROFOUNDLY MENTALLY HANDICAPPED WOMAN WITH A RING CHROMOSOME 22 R, M. VEALL Botleys Park Hospital, Chertsey, Surrey, KT16 OQA
A. T. RUNDLE St. Lawrence^s Hospital, Caterham, Surrey, CR3 5YA
R. G. GHITHAM St. Ebba^s Hospital, Epsom, Surrey and P. S A L D A N A - G A R G I A The Kennedy-Calton Centre, Harperbury Hospital, Radlett, Herts, WD7 9H(l
This is a description of a small, profoundly mentally handicapped woman of ihirty-eight who has been found to have one chromosome No. 22 replaced by a ring. CASE HISTORY The histories of her family and early development are meagre. There has been no contact with any relative since 1958 and their present whereabouts are unknown. She was born on 17/8/36. She did not walk until the age of three. She was reported as a mental defective by Victoria! Hospital for Children, Chelsea, on 12/4/40. Her father was a plumber in 1943 and a master-builder in 1958. Her mother in 1948 was receiving hospital treatment for gastritis. She had one sister born in 1945, probably of normal appearance and intelligence. She was admitted to Botleys Park Hospital on 22/3/41 and has remained there ever since. At the time of admission and on several subsequent occasions up to recently she was described as of typical mongolian appearance. She had much non-purpoaive activity, was restless, frequently screamed for long periods and had no speech. She showed no response to her environment. She had a small umbilical hernia. Her gait was unsteady due to inco-ordination but she showed no paralysis and her reflexes were brisk. She had a mild attack of rubella in 1947 and measles in 1948, She had several minor illnesses, mainly from bacterial infections. She menstruated irregularly from 1962 to 1965, but not again until November 1972. Sinee then she has menstruated about once a month. She had a sequence of four epileptic attacks in 1959 on one day, with only brief loss of consciousness, but movements of head and shoulders. On l^jWIll she was found unconscious and did not recover until the following day. She collapsed again the next day. The only definite abnormality on each occasion was lateral deviation of the right eye. For a short while the right plantar reflex was extensor and on another occasion the left knee jerk was brisker than the right. She recovered to her previous state within a day. On 1/12/72 phenytoin 50 mg. twice a day was commenced. On 2\j^jT?i she had one epileptic attack with twitching of her limbs and brief loss of consciousness, but none since. She has had several tranquilisers and sedatives during her stay in hospital. For the last eighteen months she has had thloridazine (Melleril) 50 mg. each evening and nitrazepam (Mogadon) 5 mg. at bedtime when required. PRESENT CONDITION Her appearance is shown in Figs. 1-4. Wlien her routine is disturbed she grimaces by opening her eyes wide and moving her lower jaw. She also moves her hands and fingers. Received 23rd January, 1975
226
RING CHROMOSOME
Fig, 1 (top left). Frontal view showing general habitus and mannerisms, also asymmentric breast development. Fig. 2 (top centre). Side view showing tnincal obesity and slight contractures of R. leg. Fig. 3 (top right). Full face showing grimacing, sloping eyebrows and slight epicanthus on left.
Fig. 4.
Profile showing prominent mandible.
These mannerisms can be seen in the photographs. When at rest her eyes are not abnormally widely open, her jaw is central and her hands are at rest. When sitting and she is disturbed she may move her legs rapidly, alternately and rhythmically in a drumming movement against her chair. For some years she has had ihe habit of putting her whole hand down her throat and her arms have had to be restrained with plastic elbow splints to prevent this. She oflcii protrudes her tongue which is rather large. She still has episodes of screaming. She does not appear to distinguish between people.
R. M. VEALL el al.
227
Her eyes follow moving objects, but it is difficult to attract her visual attention. She shows no response to sound and may be deaf. She will not hold any object in her hand. Her eyebrows slope upward and outward and her face is round, rhe.se two features give a superficial appearance of mongolism, but many other mongoloid features are absent and she cannot be said to be of typically mongoloid appearance. The most noticeable feature of her head is the prominent mandible and hypoplastic maxilla. The palpebral widtlis of her eyes are equally small. She has an inconspicuou.s epicanthus on the left and a very slight divergent strabismus. Her irises arc grey-brown. The helices of her auricles are hypoplastic. There is slight webbing of the neck (not usually so noticeable as the photograph would suggest), a moderate kyphosis, prominent abdomen with small umbilical hernia, slight contracture of the right knee and external rotation of the right foot, wilh mild genu valgum. Her thumbs are low-set. Her palms are only a little short and broad. Her hair is brown. She can walk unaided but unsteadily and with lapid very small steps. The right breast is smaller than the Irft. Axillary hair is scanty. Her tendon reflexes are brisk and equal. PSYCHOLOGICAL TESTINCi Her mental development has been assessed at less than I year, but she is inaccessible to formal testing. ANTHROPOMETRY Results are given in Table 1. It will be seen that she is of very small stature, but of near normal skeletal proportions. Her lower/upper segment ratio approaches that of mongols with their short legs but is only one standard deviation below the mean for the normal population. She is microcephalie and braehycephalic. The circumferences of her chest, abdomen and hips confirm her truncal obesity which is not shared by the rest of the body. KARYOTYPE When the diagnosis of mongolism was questioned in 1972 her chromosomes were studied. A blood culture showed a small ring chromosome replacing one member of the " G " group. The first culture on this girl was done with standard gienisa stain, which is better for visualising the whole of the ring than is the banding technique. In the first culture, 25 cells were analysed. Two had a count of 45 due to the random lo.ss of a chromosome but all cells possessed the ring. In the second culture, the trypsin giemsa banding technique was used, 30 cells were analysed, all had a count of 46 and all showed the ring (Fig. 5}. The ring was shown in various views but was always the same size. The diameter was approximately the length of the other " G " group chromosomes,no large rings or other forms were seen.The ring was often seen with its centromere in association with the satellites of other " D " and " G " group chromosomes. BIOCHEMISTRY The miscellaneous biochemical investigations shown in Table 2 show no significant abnormality except rather low levels of thyroxine and free T4 index. These probably indicate a low level of thyroid function secondary to low stimulation from the pituitary and/or hypothalamus as suggested by the low level of TSH and are not due to any disease of the thyroid gland. The levels of serum enzymes are shown in Table 3. The elevated values for LDH, MD, SPH, and GGTP could be due to liver damage, but other enzymes which would be expected to be raised, if this were the case, are normal. This patient was receiving phenytion (Epanutin) (5, 5'-diphenylhydaniton) 50 mg. twice a day. This has been shown to be a strong inducer of hepatic microsomal enzymes and the elevations of the circulating enzymes are typical of such a response (Rundle and Sudell, 1973b; Rundle, 1974). They probably have no significant
228
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Methods 1. Rundie and Sudell (1973a). 2. Rundle and .\tkin (1971), Rundle, Clothier and Sudell (1972) and Rundle and Sudell (I973h). 3. Atkin and Rundle (1974). 4. Rundle, Atkin and Sudell (1974b). Normal and mongol data 5. Rundle and Atkin (1973) and Atkin and Rundle (1974). 6. Rundie and Atkin (1971). 7. Rundle and Sudell (1973a). 8. Rundle and Sudell (1973b). 9. Rundle, Clothier and Sudell (1972) and Rundle, Atkin and Sudell (1974a). 10. Rundle, Atkin and Sudell (1974b). (In some instances the expected frequencies have been slightly modified in the light of experiences gained after the publications listed.)
R. M. VEALL et al.
235
1966). The electrophoictit types aic divided into two main groups, Ppl with only one band of activity probably of bone and liver origin, and Pp2 showing an additional band probably of intestinal origin. Although the presence of this second band is under genetic control, its appearance and intensity is influenced by other factors such as age and diet (Schreffler, 1965; Langman, Leuthold, Robson, Harris, Lutfman and Harris, 1966; Fichtner, Cleve, Krupc and Wendt, 1967; and Walter, Baljatzadeh and Nemcskciri, 1970). It is this genetic and nongenetic variability which makes it difficult to give any "normal" frequencies of the various types, or to draw too many conclusions from ihe type of the proposita. Routine haematology yielded normal results, except that the reticulocyte count was slightly raised at five per cent. Blood groups are O R , r M + N + S + P i - f + + Lu a - K - e a - b - Fy a-|-. The only conclusions to be drawn from these are that the Rhesus, MNS, P and Dufiy loci have not been deleted. Urine: In November 1972 glucose was present to the extent of 1.2 gram./lOO ml., but repeated specimens since then have shown no glucose or other abnormality on routine examinations. RADIOLOGY Chest: The cardiac size is exaggerated by poor inspiration and moderate kyphosis. The lung fields are clear. Skeletal survey and bone age: The skull appears microcephalic. Bone age is above twenty-five years. No other abnormality apart from small stature. DERMATOGLYPHICS Figure 6 shows the palmar and plantar configurations. Table 8 gives the dermatoglyphic analysis. Pattern elements on palms and soles are classified using methods based on topological considerations as described by Penrose and Loesch (1969, 1970a). The fingerprint patterns—six ulnar loops, three whorls and one radial loop—show nothing striking, and the total finger ridge count (125) is close to the mean value of 127 ridges for English female controls (Holt, 1963). The palmar configurations show nothing peculiar but on the left palm are unusual due to the presence of a peripheral loop on areas I and IV. The pattern-type frequency in English female controls is for IV t' 4 on the right palm 20/450 but a pattern similar to I IV e t 4 was not found on the left palm in this sample of 450 normal females. On the soles, the pattern intensity (1.5) is lower than the average value (2.54) for normal females (Penrose and Loesch, 1970b). On the left sole the association of distal loop I and proximal loop II with a zygodactylous z triradius is uncommon in normals. The pattern-type resulting from this association (I II fz 4) was not found on the left sole in a sample of 150 English female controls. On the right sole the pattern-type I f 4 shows nothing of unusual interest and occurred with a frequency of 10.7 per cent on the right sole in this satnplc of 150 normal females (Penrose and Loesch, 1969). Schindeler and Warren (1973) have studied the dermatoglyphics of the G-deletion syndromes. Their allocation of patients to Gdl or Gdll is not always substantiated by identification of a ring chromosome 21 or 22 respectively by direct techniques. If their suggestion is adopted the proposita would fall into their Gdll group. She does not have an excess of whorls, nor does she have a hypothenar pattern, both of which are common in Gdll patients. .She does have a t' axial triradius in common wilh them. More dermatoglyphic analyses are needed of patients in whom a ring chromsome 22 has been positively identified. DISCUSSION
Lindenbaum, Bobrow and Barber (1973) reviewed the known cases of G-ring. They listed twenty-sixand referredtotwoniore (Noel) inakingtwenty-eightinall.They
236
RING CHROMOSOME
Fig. 6. Palmar and plantar configuration. grouped them into three phenotypes: mongoioid, anti-mongoloid and "other". They made the tentative suggestion that the "other" group would include all the ring 22s. In attempting to relate phenotype to chromosomal variation the eoncepts of anti-mongoloid and mongoloid have often been suggested as relating to abnormalities of chromosome No. 21. Other methods of identifying the chromosome at fault have been more direct. In fourteen of the cases referred to by Lindenbaum et al. (1973) the ring chromosome had been directly identified with varying degrees of reliability, five as No. 21 and nine as No. 22. Three of these, all No. 21, were based on length, whieh is a difficult and unreliable criterion. Three others, one No. 21 and two No. 22s, were based on autoradiography. Back, Dormer, Baumann and Olrich (1967) showed that this method is unsatisfactory for the G group. In short, there were only seven cases where a more reliable method, viz, banding techniques, had been used to identify a ring chromosome 22. The phenotypes of two of these (Noel, 1973) were
237
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not described, and there was only brief reference to a third (Nelson, 1973). Subsequent information has been used to modify and enlarge the above list as shown in Table 9. Magenis, Armendares, Hocht, Wclebcr and Overton (1972) identified the ring chromosome of the case of Weleber, Hecht and Giblett (1968) as No. 22 by fluorescent banding. Cases added to the "other" group are as follows: (1) The first child described by Warren and Rimoin (1970). (2) The child described by Chauvel, Schindeler and Warren (1972). The ring chromosome in these first two cases has been identified as a No. 22 by Warren, Rimoin and Summitt (1973) by fluorescent banding. (3) Case 4 of Pieeiano, Berlin, Davenport and Jacobson (1972). The ring chromosome is thought to be No. 22 on the basis of phenotype alone. (4) The patient of Stoll, Rohmer and Sauvage (1973). (5) The child described by Larget-Piet, Rouchy, Berthelot, Laiget-Piet and Collin (1974). In these last two cases the ehromosome was identified by the authors as No. 22 by banding techniques. Cases added to the anti-mongoloid groxip are as follows: (1) The second child described by Warren and Rimoin (1970). Warren et al. (1973) confirmed by fluoreseent banding that the ring chromosome was No. 21. (2) The ease of Armendares, Buentello and Cantu-Garza (1971). The ring ehromosome was identified by Magenis et al. (1972) as No. 21 by fluorescent banding. The child described by Broyer, Chevrie, Le Tan Vinh and Thieffry (1966) has not been included as the abnormal chromosome was only minute though "probablement en anneau". It probably replaced a ehromosome No. 21. The eoneept of a "contre-type" to mongolism or anti-mongolism associated with partial deletion of a No. 21 ehromosome has gained support since first suggested by Lejeune, Berger, Rethore, Archambault, Jerome, Thieffry, Aicardi, Broyer, Lafourcade, Cruveiller and Turpin (1964). The patient of Mcllree, Tulloeh and Newsam (1966) did not resemble this phenotype and was only abnormal in having azoospermia. They did not suggest that a different chromosome might be involved. The patient of Benson, Taylor and Gough (1967) had only four per eent of the leucocytes possessing a ring chromosome and this did not appear in the skin fibroblasts. The only abnormalities were hypoplasia of some lymphatics and cubitus valgus. The patient of Hocfnagcl, Schroeder and Bcnirschke (1967) was mentally and physically retarded. 1 he nasal bridge was broad and depressed. There was some asymmetry of the face. Epicanthi were present. She was hypertonic with brisk reflexes. These authors thought the chromosome involved was a No 22 but they did not suggest that the constellation of features described constituted another syndrome. Reisman, Darnell, Murphy, Hall and Kasahara (1967) described the following abnormalities in their patient: Large, low-set ears, hypertelorism, bilateral epicanthi, aortic stenosis, partial syndactyly of toes and hypotonicity, in addition to physical and mental retardation. They suggested that the ehromosome involved was No. 22 and thought that the loss of this chromosome caused only minor congenital abnormalities. Welcber et al. (1968) described a similar child but without aortic stenosis. Their ehild also had a bifid uvula. They were first to suggest that there is a syndrome corresponding to deletion of part of chromosome No. 22.
R. M. VEALL et al.
239
Table 9 Cases of G-rings described to date
Phenotype Mongoloid
Mosaicism {when present)
Blank and Lorber (1969) Grosse e( a/. (1971) case I Grossee(a/. (1971) case 2
46,Gr/45,G-
Basisfor allocatton to Nos. 21 or 22 olher than phenotype
21 (length) 21 (length)
Antimongoloid
German and Beam (1962) Lejcune et al. (1964) Reisman et al. (1966) Challacombe and Taylor (1969) Sa-yetal. (1970) Warren and Rimoin (1970) case 2 Armcndares el al, (1971) Ncvm etal, (1971) Crandall etal. (1972) case 1 "Other" Mclhcc etal. (1966) Benson ei a/. (1967) Hoefnagel ei fl/. (1967) Reisman W a/. (1967) Wcleher etal, (1968) Tal'vik and Mikel'saar (1969) Zdansky et al. (1969) Podugol'nikova and Blumina (1970) Warren and Rimoin (1970) case 1 Dubowitz et al, (1971) case 1 Dubowitz et al. (1971) case 2 Richards e/a/. (1971) Crandall et al. (1972) case 2 Crandall el al. (1972) case 3 Chauveleia/. (1972) Picciano el al. (1972) case 4 Nelson (1973) Noel (1973) Noel (1973) Lindenbaum e( a/. (1973) case 1 Lindenbaum et al. (1973) case 2 Stoll el al. (1973) Larget-Piet ei a/. (1974) Present case CB = chromosome banding. AR = autoradiography.
21 AR 46,Gr/45,G21 (length) 46,Gi746,Gq-/45,G^ 46,Gr/45,G45,G-/46,Gr
21 CB 21 CB 21 CB
46 normal/46,Gr (4%) 22 AR 22 CB 22 AR 46,Gr/45,G-(I4%) 22 CB
46, Gr/45,G-
22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB
Since then the authors listed in Table 9 have differed in their views as to whether the abnormalities described in cases of ring 22 constitute a syndrome. Authors in favotir of this have stressed the similarities in reported cases and have paid little attention to their variability. Other authors have stressed the lack of physical
240
RING CHROMOSOME
abnormalities. Some of the former group of authors have picked out features which are said to be constant. For example, Largct-Piet et al. (1974) list hypotonia, aplasia of the nasal bridge, epicanthus and syndactyly as constant signs distinctive of this syndrome, but none of these except epicanthus has been present in all cases. Even this sign was not noted in the patients of Mcllree et al. (1966) and Benson et al. (1967) though it may have gone unnoticed. The present case includes only a slight epicanthus among the "constant" signs. The mental and physical retardation of the present case have been noted in varying degrees in all previous cases except those of McIlrec et al. (1966) and Benson et al. (1967). The facial grimacing, prominent mandible, asymmetry of the breasts and ears and small palpebral fissures have not been noted before, though in case 4 of Picciano et al. (1972) "one observer described small eyes". Other features, including the anthropometry, have not been sufficiently documented in previous cases to make adequate comparisons possible. Most authors have equated a ring chromosome with a deletion of part of that chromosome. This is not necessarily true in every case, as stated by Dubowitz, Cooke, Colvcr and Harris (1971). Crandall, Weber, Muller and Burwell (1972) give other reasons which may explain the phenotypic variations observed in patients with a ring chromosome. CONCLUSIONS In the light of present knowledge it is not possible to describe a syndrome for ring chromosome 22. In fact, there are very few, if any, features which are consistently present or absent. The two most consistently present are mental retardation and epicanthus, though muscular hypotonia and growth retardation are usual. It may be that, as in mongolism, the hypotonia of childhood is lost in the adult. This would account for its absence in the present case. There is still a need for detailed descriptions of more patients with a ring chromosome 22 identified by banding techniques, replacing wherever possible terms such as hypertelorism, large ears, short legs, etc., with anthropometric data and giving adequate photographs, results of formal pyschological tests and descriptions of the mental state. SUMMARY A small thirty-eight-year-old profoundly retarded woman is described who has a ring chromosome identified by banding techniques. Details are given of her behaviour, anthropometry, dermatoglyphics, karyotype and biochemistry with extensive investigations of her blood proteins and enzymes. Other described cases of ring 21 and 22 are reviewed. There is so much variability among the ring 22 chromosomes that it is not considered justifiable to speak of a ring 22 syndrome.
R. M. VEALL et al.
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between human serum phosphatases and blood groups. Ada Genet. 13, 366. ARMENDARF.S, S., BUENTELLO, L . and CANTU-GARZA, J.-M. (1971) Partial monosomy of a G
group chromosome (45,XY,G —/46,XY,Gr): report of a new case. Ann. Genet. 14, 7, ATKIN, J . and RUNDLE, A. T. (1974) Scrum Pj-glycoprotein 1 phenotype frequencies in an English population, Humangenetik 21, 81. BACK, F . , DORMER, P., BAUMANN, F . and OLRICH, E . (1967) Trisomy 21 or 22 in Down's
syndrome. Lancet 1, 1228. BAYER, L . M . and BAYI.F.Y, N . (1959) Growth diagnosis. University of Ghicago Press. BECKMAN, L . (1966} Isozyme variation in man. Momg. in Human Genetics^ Vol. L Basel: Karger. BF.CKM.AN, L . and WEITERBERG, L . (1967) Genetic and drug induced variations of serum naphthylamidasc isoenzymes. Acta Genet. Stat. Med. 17, 314. BE.NSON, P . F . , TAYLOR, A. L and GOUGH, M . H . (1967) Chromosome anomalies in primary
lymphoedema. Lancet 1, 461. BERRY, R . A. and PORTEOUS, S. D . (1920) Intelligence and Social Valuation. Publication No. 20. Vineland Training School, New Jersey. BLANK. C . E . and LORBKR, J. (1969) A patient with 45,XX,G-/46,XX.Gr mosaicism. J. med. Genet. 6, 220. BROVER. M . , CHEVRIE, J , - J . , AICARDI,J., VINH, LE T . and THIEFFRV, S. (1966) Malformations
multiples chez un enfant porteur d'une monosomie partielle pour un chromosome 21-22. Pressemed. 74, 791. CHALLACOMBE, D . N . and T.\YLOR, A. (1969) Monosomy for a G autosome. Arch. Dis. Child. 44, 113. CHAUVEL, P . J . , SCHINDELER, J. D. and WARREN, R . J . (1972) G-deletion syndrome II. Hum.
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CHOUKE, K . S. (1929) The epicanthus or Mongolian fold in Caucasian children. Amer. J. phys. Anthrop. 13, 255. CRANDALL, B . F., WEBER, F . , MULLER, H . M . and BURWELL, J. K. (1972) Identification of
2lr and 22r chromosomes by quinacrine fluorescence. Clin. Genet. 3, 264. DiiBOwrrz, V., COOKE, P., GOLVER, D . and HARRIS, F . (1971) Mental retardation, unusual facies, and abnormal nails associated with aGroup-G ring chromsome.J. med. Genet. 8, 195. FicHTNER, K., CLEVE, H . , KRUPE, M . and WENDT, G . G . (1967) Die blutgruppenaasoziation
in Electrophoresetypen der alkalischen Serum-Phosphate und bei Patienten mit gastrointestinalcn Erkranktmgen. Hnmangenetik 4, 47. GERMAN, J . L. and BEARN, A. G. (1962) Cited in Penrose, L. S. (1966) Antimongolism. Lancet 1, 497; and PENROSE, L . S. and SMITH, G . F . (1966) Dowti's anomaly. London: J. & A. Churchill. GROSSE, K . - B . , BOWING, B., HOPFENOARTNF.R, F . , REINHARDT, G . and SITZMAN, C . F . (1971)
Ring G-Ghromosom. Humangenetik 12, 142, HOEFNAGEL, D . , SCHROEDER, T . M . and BENIRSCHKE, K . (1967) A child with a Group-G
Ring Chromosome. Humangenetik 4, 52. HOLT, S . B . (1963) Current advances in our knowledge of the inheritance of variations in finger prints. Proc. 11 Int. Cong. hum. Genet., Rome 3, 1450. Kir.siNG, E, (1966) Cranial .Morphology in Down's Syndrome. Copenhagen: Munksgaard. KrrCHEN, F. D. and BEARN, A. G. (1964) Distribution of serum group-specific component (Gc) in Afghanistan, Korean, Nigerian and Israeli populations, feature 202, 827. LAESTADIUS, N . D . , AASE, J . M . and SMrrn, D. W. (1969) Normal inner cantlial and outer orbital dimensions. J. Paediat. 74, 465.
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LANGMAN, M . J . S., LEUTHOLD, E . , ROBSON, E . B., HARRIS, J., LUFFMA.N,J. E . and HARRIS, H .
(1966) Influence of diet on the intestinal component of serum alkaline phosphatase in people of different ABO blood groups and secrelor status. Nature 212, 41. LARGET-PIET, L., ROUCHY, R . , BERTHELOT, J., LARGET-PIET, A. and COI.LIN, G . (1974)
Chromosome 22 en anneau (22r). Rev.fran^. Gynec. 69, 3, 195. LEJEUNE, J . , BERGER, R . , RETHORE, M . - O . , ARCH^VMBAULT, L . , JEROME, H . , THIEFFRV, S., AiCARDi, J., BROVER, M . , LAFOURCADE, J . , CRUVEILLER, J . and TURPIN, R . (1964)
Monosomie partielle pour un petit acrocentrique. C. R. Acad. Sc. (Paris) 259, 4187. LINDENBAUM, R . N . , BOBROW, M . and BARBER, L . (1973) Monozygotic twins with ring
chromosome 22. J. med. Genet. 10, 85. Luc.\s, W. P. and PRVOR, H . B . (1935) Range and standard deviations of certain physical measurements in healthy children. J. Paediat. 6, 533. MCILREE, M . E . , TULLOCH, W . S. and NEWSAM, J. E. (1966) Studies on human mciotic
chromosomes from testicuJar tissue. Lancet 1, 679. MAGENIS, R . E . , ARMENDARES, S., HECHT, F . , WELEBER, R . G . and OVERTON, K . (1972)
Identification by fluorescence of two G rings: (46,XY,2lr) G deletion syndrome I and (46,XX,22r) G delelion syndrome II. Ann. Genet. (Paris) 15, 265. MANCINT, G . , CARBONARA, A. O. and HEREMANS. J. F. (1965) Imnumochemicai qiiantitalion
of antigens by single radial immunodiffusion. Inl. J. Immunochemistry 2, 235. MosiER, H. D., CROSSMAN, H . J. and DINGMAN, H . F . (1965) Physical growth in mental defectives. A study in an institutionalized population. Pediatrics 36, No. 3, Part II (Supp.) 465. NANDI, M . , LEWIS, G . P., HERSHEL, J., SLONE, D . , SHAPIRO, S. and SISKIND, V. (1970) Evalua-
tions of haptoH:lol)in phenotype O-O in cirrhotic and non-cirrhotic hospital populations. J. clin. Path. 23, 695. NELSON, W . E . (1969) Textbook of Pediatrics, 9th Ed. Philadelphia: W. B. Saunders. NELSON, R . (1973) Cited in Lindenbaum, Bobrow and Barber (1973). NEVIN, N . C , MACLAVERTV, B . and CAMPBELL, W . A. B . (1971) A child with a ring G chromo-
some (46,XX,Gr). J. med. Genet. 8, 231. NOEL, B. (1973) Cited in Lindenbaum, Bobrow and Barber (1973). I'EARSON, K . and TIPPETT, L . H . C . (1924) On stability of the cephalic index within the race. Biomelrika 16, 118.
PENROSF,. L . S. and LOESCH, D . (1969) Dermatoglyphic sole patterns, a new attempt at classification. Hum. Blol. 41, 427. PENROSE, L . S. and LOESCH, D . (1970a) Topological classification of palmar dermatoglyphics. J. ment. Defic. Res. 14, 111.
PENROSE, L . S. and LOESCH, D . (1970b) Comparative study of sole patterns in chromosomal abnormalities. J. ment. Defic, Res. 14, 129. PICCIANO, D . J., BFRI.IN, C . M . , DAVENPORT, S. L . H . and JACOBSON, C . B . (1972) Human
ring chromosomes: a report of five cases. Ann. Genet. 15, 241. PODUGOL'NIKOVA, O . A. and BLUMINA, M . G . (1970) The ring chromosome of G-group of a
child with congenital mental deficiency. Genetika 6, 156. pRYOR, H. B. (1966) Charts of normal body measurements and revised width-weight tables in graphic form. J, Paediat. 68, 615. QuAADE, F. (1955) Obese children. Anthropology and Environment. C o p e n h a g e n : Danish Science
Press. REISMAN, L . E . , KASAIIARA, S., CHUNG, C.-Y., DARNELL, A. and HALL, B . (1966) Anti-
mongolism. Studies of an infant with a partial monosomy of the 21 chromosome. Lancet 1, 394. REISMAN, L . E . , DARNELL, A., MURPHY, J. W., HALL, B . and KASAIIARA, S . (1967) A child
with partial deletion of a G-group autosome. Amer. J. Dis. Child. 114, 336. RICHARDS, B. W . , RUNDLE, A. T., HATTON, W . M . and STEWART, A. (1971) G-group ring
chromosome in a mentally subnormal girl. J. ment. Defic. Res. 15, 6L ROCHE, A. F., SEWARD, F . S. and SUNDERLAND, S. (1961) Growth changes in the mongoloid
head. Acta Paediat. 50, 133.
R. M. VEALL et al.
243
RUNDLE, A. T. (1970) Anthropometry: a ten-year survey of growth and sexual maturation. In: Mental Subnormality: Modern Trends in Research (Ed. RICHARDS, B . W . ) . London: Pitman Medical & Scientific Publishing Co. Ltd. RuNDi.E, A. T. (1974a) Problems in the diagnosis of liver function in the mentally subnormal. Proc. 3rd Int. Cong. Study of Ment. Subnorm. 249. RUNDLE, A. T. (1974b) Unpublished. RUNDLE, A. T. and ATKIN, J . (1971) Serum alkaline phosphalase isoenzymes in Down's syndrome. Amer. J. ment. Dcftc. 75, 613. RUNDLE, A. T. and ATKIN, J . (1973) Pj-glycoprotein-1 polymorphism and Down's syndrome. IRCS International Res. Communications System. July 1973. RUNDLE, A. T., ATKIN, J . and CLOTHIER, B. (1973) Serum proteins in Down's syndrome. Develop. Med. & Child Neurol. 15, 736. RUNDLE, A. T., ATKIN,J. and SUDKI.L, B . (1974a) The effects of parental age on some phenolypc fiequenccs in Down's syndrome. Hum. Genet. 23, 137. RUNDLE, A. T., ATKIN, J. and SUDELL, B. (1974b) Serum polymorphisms in Down's syndrome. Hum. Genetik. 24, 105. RUNDLE, A. T., CLOTHIER, B. and SUDELL, B. (1972) Haptoglobin phenotype frequencies in
mentally retarded persons. Clin. Chem. 18, 1368. RUNDLE, A. T. and SUDELL, B . (1973a) Red cell polymorphisms in Down's syndi'ome. Gene fi'equencies and phenotype associations. Glin. Genet. 4, 536. RuNDi-E, A. T. and SUDELL, B . (1973b) Leucine aminopeptidase isoenzyme changes after treatment with anticonvulsant drugs. Clin. Clum. Acta 44, 377. RUNDLE, A. T. and SYLVESTER, P. E. (1965) Growth and development of young females. Amer. J. ment. Defic. 69, 635. SAY, B., TUNCBILEK, E., YAMAK, B . and BALCI, S. (1970) An unusual chromosomal aberration
in a case of Chediak-Higashi syndrome. J. med. Genet. 7, 417. ScHLiNDELER, J . D. and WARREN, R . J . (1973) Dermatoglyphics in the G-deletion syndromes. J. ment. Defic. Res. 17, 149. SCHREFFLER, D . C . (1965) Genetic studies of blood group associated variations in a human alkaline phosphatase. Amer. J. hum. Genet. 17, 71. ScHULTZE, H. E. and HEREMANS, J . F. (1966) Molecular Biology of Human Proteins, Vol. I. London: Elsevier Publ. Co. SCOTT, J. A. {1961) Report on the heights and weights [and other measurements) of school pupils in the County of London. London: London County Council No. 4086. STOLL, C , ROIIMER, A . and SAUVAGE, P. (1973) Chromosome 22 en anneau r(22): identification par denaturation thermique m6nag^e. Ann. Genet. 16, 193. STORIKO, K . (1968) Normal values for 23 difierent human plasma proteins determined by single radial diffusion. Blut 16, 200. TAL'VIK, T . A . and MIKEL'SA.\R, A . - B . H . (1969) a new case of ring chromosome of the group 21-22 (G,?). Genetika5, 129. TANNER. J. M. (1962) Growth at Adole.fcene, 2nd Ed. Oxford: Blackwell Scientific Publications. WALTER, H . , BAKJATAZADEII, M . and NEMESKERRI, J. (1970) Sex and age relations of alkaline
phosphatase phenotypes. Hum. Hered. 20, 427. WARREN, R . J . and RIMOIN, D . J. (1970) The G deletion syndromes. J. Pediat. 77, 658, 663. WARREN, R . J., RIMOIN, D . L . and SuMMnT, R. L. (1973) Identification by fluorescent microscopy of the abnormal chromosomes associated with the G-deietion syndromes. Amer.J. hum. Genet. 25, 77. W/VTSON, H. and LOWREV, G . H . (1962) Growth and Development of Children, 4th Ed. Chicago: Year Book Publishers, Inc. WELEBER, R . G., HECIIT, F . and GIBLETT, E . R . (1968) Ring-G chromosome, a new G-deletion
syndrome. Amer. J. Dis. Child. 115, 489. ZDA.NSKY, R . , BUHLER, E . M . , VEST. M . , BUHLER, U . K . and STALDER, G . (1969) Familiares
mosaic mit G-ring. Hum. Genet. 7, 275.
225
A PROFOUNDLY MENTALLY HANDICAPPED WOMAN WITH A RING CHROMOSOME 22 R, M. VEALL Botleys Park Hospital, Chertsey, Surrey, KT16 OQA
A. T. RUNDLE St. Lawrence^s Hospital, Caterham, Surrey, CR3 5YA
R. G. GHITHAM St. Ebba^s Hospital, Epsom, Surrey and P. S A L D A N A - G A R G I A The Kennedy-Calton Centre, Harperbury Hospital, Radlett, Herts, WD7 9H(l
This is a description of a small, profoundly mentally handicapped woman of ihirty-eight who has been found to have one chromosome No. 22 replaced by a ring. CASE HISTORY The histories of her family and early development are meagre. There has been no contact with any relative since 1958 and their present whereabouts are unknown. She was born on 17/8/36. She did not walk until the age of three. She was reported as a mental defective by Victoria! Hospital for Children, Chelsea, on 12/4/40. Her father was a plumber in 1943 and a master-builder in 1958. Her mother in 1948 was receiving hospital treatment for gastritis. She had one sister born in 1945, probably of normal appearance and intelligence. She was admitted to Botleys Park Hospital on 22/3/41 and has remained there ever since. At the time of admission and on several subsequent occasions up to recently she was described as of typical mongolian appearance. She had much non-purpoaive activity, was restless, frequently screamed for long periods and had no speech. She showed no response to her environment. She had a small umbilical hernia. Her gait was unsteady due to inco-ordination but she showed no paralysis and her reflexes were brisk. She had a mild attack of rubella in 1947 and measles in 1948, She had several minor illnesses, mainly from bacterial infections. She menstruated irregularly from 1962 to 1965, but not again until November 1972. Sinee then she has menstruated about once a month. She had a sequence of four epileptic attacks in 1959 on one day, with only brief loss of consciousness, but movements of head and shoulders. On l^jWIll she was found unconscious and did not recover until the following day. She collapsed again the next day. The only definite abnormality on each occasion was lateral deviation of the right eye. For a short while the right plantar reflex was extensor and on another occasion the left knee jerk was brisker than the right. She recovered to her previous state within a day. On 1/12/72 phenytoin 50 mg. twice a day was commenced. On 2\j^jT?i she had one epileptic attack with twitching of her limbs and brief loss of consciousness, but none since. She has had several tranquilisers and sedatives during her stay in hospital. For the last eighteen months she has had thloridazine (Melleril) 50 mg. each evening and nitrazepam (Mogadon) 5 mg. at bedtime when required. PRESENT CONDITION Her appearance is shown in Figs. 1-4. Wlien her routine is disturbed she grimaces by opening her eyes wide and moving her lower jaw. She also moves her hands and fingers. Received 23rd January, 1975
226
RING CHROMOSOME
Fig, 1 (top left). Frontal view showing general habitus and mannerisms, also asymmentric breast development. Fig. 2 (top centre). Side view showing tnincal obesity and slight contractures of R. leg. Fig. 3 (top right). Full face showing grimacing, sloping eyebrows and slight epicanthus on left.
Fig. 4.
Profile showing prominent mandible.
These mannerisms can be seen in the photographs. When at rest her eyes are not abnormally widely open, her jaw is central and her hands are at rest. When sitting and she is disturbed she may move her legs rapidly, alternately and rhythmically in a drumming movement against her chair. For some years she has had ihe habit of putting her whole hand down her throat and her arms have had to be restrained with plastic elbow splints to prevent this. She oflcii protrudes her tongue which is rather large. She still has episodes of screaming. She does not appear to distinguish between people.
R. M. VEALL el al.
227
Her eyes follow moving objects, but it is difficult to attract her visual attention. She shows no response to sound and may be deaf. She will not hold any object in her hand. Her eyebrows slope upward and outward and her face is round, rhe.se two features give a superficial appearance of mongolism, but many other mongoloid features are absent and she cannot be said to be of typically mongoloid appearance. The most noticeable feature of her head is the prominent mandible and hypoplastic maxilla. The palpebral widtlis of her eyes are equally small. She has an inconspicuou.s epicanthus on the left and a very slight divergent strabismus. Her irises arc grey-brown. The helices of her auricles are hypoplastic. There is slight webbing of the neck (not usually so noticeable as the photograph would suggest), a moderate kyphosis, prominent abdomen with small umbilical hernia, slight contracture of the right knee and external rotation of the right foot, wilh mild genu valgum. Her thumbs are low-set. Her palms are only a little short and broad. Her hair is brown. She can walk unaided but unsteadily and with lapid very small steps. The right breast is smaller than the Irft. Axillary hair is scanty. Her tendon reflexes are brisk and equal. PSYCHOLOGICAL TESTINCi Her mental development has been assessed at less than I year, but she is inaccessible to formal testing. ANTHROPOMETRY Results are given in Table 1. It will be seen that she is of very small stature, but of near normal skeletal proportions. Her lower/upper segment ratio approaches that of mongols with their short legs but is only one standard deviation below the mean for the normal population. She is microcephalie and braehycephalic. The circumferences of her chest, abdomen and hips confirm her truncal obesity which is not shared by the rest of the body. KARYOTYPE When the diagnosis of mongolism was questioned in 1972 her chromosomes were studied. A blood culture showed a small ring chromosome replacing one member of the " G " group. The first culture on this girl was done with standard gienisa stain, which is better for visualising the whole of the ring than is the banding technique. In the first culture, 25 cells were analysed. Two had a count of 45 due to the random lo.ss of a chromosome but all cells possessed the ring. In the second culture, the trypsin giemsa banding technique was used, 30 cells were analysed, all had a count of 46 and all showed the ring (Fig. 5}. The ring was shown in various views but was always the same size. The diameter was approximately the length of the other " G " group chromosomes,no large rings or other forms were seen.The ring was often seen with its centromere in association with the satellites of other " D " and " G " group chromosomes. BIOCHEMISTRY The miscellaneous biochemical investigations shown in Table 2 show no significant abnormality except rather low levels of thyroxine and free T4 index. These probably indicate a low level of thyroid function secondary to low stimulation from the pituitary and/or hypothalamus as suggested by the low level of TSH and are not due to any disease of the thyroid gland. The levels of serum enzymes are shown in Table 3. The elevated values for LDH, MD, SPH, and GGTP could be due to liver damage, but other enzymes which would be expected to be raised, if this were the case, are normal. This patient was receiving phenytion (Epanutin) (5, 5'-diphenylhydaniton) 50 mg. twice a day. This has been shown to be a strong inducer of hepatic microsomal enzymes and the elevations of the circulating enzymes are typical of such a response (Rundle and Sudell, 1973b; Rundle, 1974). They probably have no significant
228
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Methods 1. Rundie and Sudell (1973a). 2. Rundle and .\tkin (1971), Rundle, Clothier and Sudell (1972) and Rundle and Sudell (I973h). 3. Atkin and Rundle (1974). 4. Rundle, Atkin and Sudell (1974b). Normal and mongol data 5. Rundle and Atkin (1973) and Atkin and Rundle (1974). 6. Rundie and Atkin (1971). 7. Rundle and Sudell (1973a). 8. Rundle and Sudell (1973b). 9. Rundle, Clothier and Sudell (1972) and Rundle, Atkin and Sudell (1974a). 10. Rundle, Atkin and Sudell (1974b). (In some instances the expected frequencies have been slightly modified in the light of experiences gained after the publications listed.)
R. M. VEALL et al.
235
1966). The electrophoictit types aic divided into two main groups, Ppl with only one band of activity probably of bone and liver origin, and Pp2 showing an additional band probably of intestinal origin. Although the presence of this second band is under genetic control, its appearance and intensity is influenced by other factors such as age and diet (Schreffler, 1965; Langman, Leuthold, Robson, Harris, Lutfman and Harris, 1966; Fichtner, Cleve, Krupc and Wendt, 1967; and Walter, Baljatzadeh and Nemcskciri, 1970). It is this genetic and nongenetic variability which makes it difficult to give any "normal" frequencies of the various types, or to draw too many conclusions from ihe type of the proposita. Routine haematology yielded normal results, except that the reticulocyte count was slightly raised at five per cent. Blood groups are O R , r M + N + S + P i - f + + Lu a - K - e a - b - Fy a-|-. The only conclusions to be drawn from these are that the Rhesus, MNS, P and Dufiy loci have not been deleted. Urine: In November 1972 glucose was present to the extent of 1.2 gram./lOO ml., but repeated specimens since then have shown no glucose or other abnormality on routine examinations. RADIOLOGY Chest: The cardiac size is exaggerated by poor inspiration and moderate kyphosis. The lung fields are clear. Skeletal survey and bone age: The skull appears microcephalic. Bone age is above twenty-five years. No other abnormality apart from small stature. DERMATOGLYPHICS Figure 6 shows the palmar and plantar configurations. Table 8 gives the dermatoglyphic analysis. Pattern elements on palms and soles are classified using methods based on topological considerations as described by Penrose and Loesch (1969, 1970a). The fingerprint patterns—six ulnar loops, three whorls and one radial loop—show nothing striking, and the total finger ridge count (125) is close to the mean value of 127 ridges for English female controls (Holt, 1963). The palmar configurations show nothing peculiar but on the left palm are unusual due to the presence of a peripheral loop on areas I and IV. The pattern-type frequency in English female controls is for IV t' 4 on the right palm 20/450 but a pattern similar to I IV e t 4 was not found on the left palm in this sample of 450 normal females. On the soles, the pattern intensity (1.5) is lower than the average value (2.54) for normal females (Penrose and Loesch, 1970b). On the left sole the association of distal loop I and proximal loop II with a zygodactylous z triradius is uncommon in normals. The pattern-type resulting from this association (I II fz 4) was not found on the left sole in a sample of 150 English female controls. On the right sole the pattern-type I f 4 shows nothing of unusual interest and occurred with a frequency of 10.7 per cent on the right sole in this satnplc of 150 normal females (Penrose and Loesch, 1969). Schindeler and Warren (1973) have studied the dermatoglyphics of the G-deletion syndromes. Their allocation of patients to Gdl or Gdll is not always substantiated by identification of a ring chromosome 21 or 22 respectively by direct techniques. If their suggestion is adopted the proposita would fall into their Gdll group. She does not have an excess of whorls, nor does she have a hypothenar pattern, both of which are common in Gdll patients. .She does have a t' axial triradius in common wilh them. More dermatoglyphic analyses are needed of patients in whom a ring chromsome 22 has been positively identified. DISCUSSION
Lindenbaum, Bobrow and Barber (1973) reviewed the known cases of G-ring. They listed twenty-sixand referredtotwoniore (Noel) inakingtwenty-eightinall.They
236
RING CHROMOSOME
Fig. 6. Palmar and plantar configuration. grouped them into three phenotypes: mongoioid, anti-mongoloid and "other". They made the tentative suggestion that the "other" group would include all the ring 22s. In attempting to relate phenotype to chromosomal variation the eoncepts of anti-mongoloid and mongoloid have often been suggested as relating to abnormalities of chromosome No. 21. Other methods of identifying the chromosome at fault have been more direct. In fourteen of the cases referred to by Lindenbaum et al. (1973) the ring chromosome had been directly identified with varying degrees of reliability, five as No. 21 and nine as No. 22. Three of these, all No. 21, were based on length, whieh is a difficult and unreliable criterion. Three others, one No. 21 and two No. 22s, were based on autoradiography. Back, Dormer, Baumann and Olrich (1967) showed that this method is unsatisfactory for the G group. In short, there were only seven cases where a more reliable method, viz, banding techniques, had been used to identify a ring chromosome 22. The phenotypes of two of these (Noel, 1973) were
237
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not described, and there was only brief reference to a third (Nelson, 1973). Subsequent information has been used to modify and enlarge the above list as shown in Table 9. Magenis, Armendares, Hocht, Wclebcr and Overton (1972) identified the ring chromosome of the case of Weleber, Hecht and Giblett (1968) as No. 22 by fluorescent banding. Cases added to the "other" group are as follows: (1) The first child described by Warren and Rimoin (1970). (2) The child described by Chauvel, Schindeler and Warren (1972). The ring chromosome in these first two cases has been identified as a No. 22 by Warren, Rimoin and Summitt (1973) by fluorescent banding. (3) Case 4 of Pieeiano, Berlin, Davenport and Jacobson (1972). The ring chromosome is thought to be No. 22 on the basis of phenotype alone. (4) The patient of Stoll, Rohmer and Sauvage (1973). (5) The child described by Larget-Piet, Rouchy, Berthelot, Laiget-Piet and Collin (1974). In these last two cases the ehromosome was identified by the authors as No. 22 by banding techniques. Cases added to the anti-mongoloid groxip are as follows: (1) The second child described by Warren and Rimoin (1970). Warren et al. (1973) confirmed by fluoreseent banding that the ring chromosome was No. 21. (2) The ease of Armendares, Buentello and Cantu-Garza (1971). The ring ehromosome was identified by Magenis et al. (1972) as No. 21 by fluorescent banding. The child described by Broyer, Chevrie, Le Tan Vinh and Thieffry (1966) has not been included as the abnormal chromosome was only minute though "probablement en anneau". It probably replaced a ehromosome No. 21. The eoneept of a "contre-type" to mongolism or anti-mongolism associated with partial deletion of a No. 21 ehromosome has gained support since first suggested by Lejeune, Berger, Rethore, Archambault, Jerome, Thieffry, Aicardi, Broyer, Lafourcade, Cruveiller and Turpin (1964). The patient of Mcllree, Tulloeh and Newsam (1966) did not resemble this phenotype and was only abnormal in having azoospermia. They did not suggest that a different chromosome might be involved. The patient of Benson, Taylor and Gough (1967) had only four per eent of the leucocytes possessing a ring chromosome and this did not appear in the skin fibroblasts. The only abnormalities were hypoplasia of some lymphatics and cubitus valgus. The patient of Hocfnagcl, Schroeder and Bcnirschke (1967) was mentally and physically retarded. 1 he nasal bridge was broad and depressed. There was some asymmetry of the face. Epicanthi were present. She was hypertonic with brisk reflexes. These authors thought the chromosome involved was a No 22 but they did not suggest that the constellation of features described constituted another syndrome. Reisman, Darnell, Murphy, Hall and Kasahara (1967) described the following abnormalities in their patient: Large, low-set ears, hypertelorism, bilateral epicanthi, aortic stenosis, partial syndactyly of toes and hypotonicity, in addition to physical and mental retardation. They suggested that the ehromosome involved was No. 22 and thought that the loss of this chromosome caused only minor congenital abnormalities. Welcber et al. (1968) described a similar child but without aortic stenosis. Their ehild also had a bifid uvula. They were first to suggest that there is a syndrome corresponding to deletion of part of chromosome No. 22.
R. M. VEALL et al.
239
Table 9 Cases of G-rings described to date
Phenotype Mongoloid
Mosaicism {when present)
Blank and Lorber (1969) Grosse e( a/. (1971) case I Grossee(a/. (1971) case 2
46,Gr/45,G-
Basisfor allocatton to Nos. 21 or 22 olher than phenotype
21 (length) 21 (length)
Antimongoloid
German and Beam (1962) Lejcune et al. (1964) Reisman et al. (1966) Challacombe and Taylor (1969) Sa-yetal. (1970) Warren and Rimoin (1970) case 2 Armcndares el al, (1971) Ncvm etal, (1971) Crandall etal. (1972) case 1 "Other" Mclhcc etal. (1966) Benson ei a/. (1967) Hoefnagel ei fl/. (1967) Reisman W a/. (1967) Wcleher etal, (1968) Tal'vik and Mikel'saar (1969) Zdansky et al. (1969) Podugol'nikova and Blumina (1970) Warren and Rimoin (1970) case 1 Dubowitz et al, (1971) case 1 Dubowitz et al. (1971) case 2 Richards e/a/. (1971) Crandall et al. (1972) case 2 Crandall el al. (1972) case 3 Chauveleia/. (1972) Picciano el al. (1972) case 4 Nelson (1973) Noel (1973) Noel (1973) Lindenbaum e( a/. (1973) case 1 Lindenbaum et al. (1973) case 2 Stoll el al. (1973) Larget-Piet ei a/. (1974) Present case CB = chromosome banding. AR = autoradiography.
21 AR 46,Gr/45,G21 (length) 46,Gi746,Gq-/45,G^ 46,Gr/45,G45,G-/46,Gr
21 CB 21 CB 21 CB
46 normal/46,Gr (4%) 22 AR 22 CB 22 AR 46,Gr/45,G-(I4%) 22 CB
46, Gr/45,G-
22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB 22 CB
Since then the authors listed in Table 9 have differed in their views as to whether the abnormalities described in cases of ring 22 constitute a syndrome. Authors in favotir of this have stressed the similarities in reported cases and have paid little attention to their variability. Other authors have stressed the lack of physical
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abnormalities. Some of the former group of authors have picked out features which are said to be constant. For example, Largct-Piet et al. (1974) list hypotonia, aplasia of the nasal bridge, epicanthus and syndactyly as constant signs distinctive of this syndrome, but none of these except epicanthus has been present in all cases. Even this sign was not noted in the patients of Mcllree et al. (1966) and Benson et al. (1967) though it may have gone unnoticed. The present case includes only a slight epicanthus among the "constant" signs. The mental and physical retardation of the present case have been noted in varying degrees in all previous cases except those of McIlrec et al. (1966) and Benson et al. (1967). The facial grimacing, prominent mandible, asymmetry of the breasts and ears and small palpebral fissures have not been noted before, though in case 4 of Picciano et al. (1972) "one observer described small eyes". Other features, including the anthropometry, have not been sufficiently documented in previous cases to make adequate comparisons possible. Most authors have equated a ring chromosome with a deletion of part of that chromosome. This is not necessarily true in every case, as stated by Dubowitz, Cooke, Colvcr and Harris (1971). Crandall, Weber, Muller and Burwell (1972) give other reasons which may explain the phenotypic variations observed in patients with a ring chromosome. CONCLUSIONS In the light of present knowledge it is not possible to describe a syndrome for ring chromosome 22. In fact, there are very few, if any, features which are consistently present or absent. The two most consistently present are mental retardation and epicanthus, though muscular hypotonia and growth retardation are usual. It may be that, as in mongolism, the hypotonia of childhood is lost in the adult. This would account for its absence in the present case. There is still a need for detailed descriptions of more patients with a ring chromosome 22 identified by banding techniques, replacing wherever possible terms such as hypertelorism, large ears, short legs, etc., with anthropometric data and giving adequate photographs, results of formal pyschological tests and descriptions of the mental state. SUMMARY A small thirty-eight-year-old profoundly retarded woman is described who has a ring chromosome identified by banding techniques. Details are given of her behaviour, anthropometry, dermatoglyphics, karyotype and biochemistry with extensive investigations of her blood proteins and enzymes. Other described cases of ring 21 and 22 are reviewed. There is so much variability among the ring 22 chromosomes that it is not considered justifiable to speak of a ring 22 syndrome.
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