D13 Ring Chromosome Syndrome ANNE Mccandless and S

Arch Dis Child: first published as 10.1136/adc.51.6.449 on 1 June 1976. Downloaded from

Archives of Disease in Childhood, 1976, 51, 449.

D13 ring chromosome syndrome ANNE McCANDLESS and S. WALKER From the Department of Child Health, Alder Hey Hospital, Liverpool, and Cytogenetics Unit, University of Liverpool McCandless, A., and Walker, S. (1976). Archives of Disease in Childhood, 51,449. D13 ring chromosome syndrome. A case ofring D13 chromosome, confirmed by trypsin banding, is described. Reviewing 21 cases from published reports, the most common features of this syndrome are microcephaly and associated mental retardation, poor uterine growth, deformed auricles, hypertelorism, epicanthus, broad nasal bridge, and genital defects in males.

Many reports of D ring chromosomes have been assessment was done at 2 25 years, developmental made, of which 21 cases are confirmed as ring D13. quotient 14, equal to a child of less than 6 months. 16 of these were recognized by radioautography At the age of 3 years the circumference of the head only, the other 5 by chromosome banding tech- was 44 cm. The upper incisors protrude but there is no niques which allow accurate identification (see overcrowding of the teeth. There is no evidence of Table). We report a further case identified as Di3r by chromosome banding and summarize copyright. briefly the clinical findings in these cases. Case report A male was bom on 26 May 1972. Mother was 23 years and the father 25 years old. Delivery was normal at 34 weeks' gestation, birthweight 1550 g, length 40 6

cm, and head circumference 27-9 cmn. The facial .. W....~ http://adc.bmj.com/ appearance was abnormal, the frontal region of the skull was narrow; hypertelorism and almond shaped eyes were present (Fig. 1). A slight epicanthic fold was present on the right. The auricles were large and low set. A. broad nasal bridge, micrognathia, and a highly arched palate were apparent. In both hands the thumbs were low lying and there was a contracture of the right thumb. The feet were small and the second and fourth toes overlapped on each foot; bilateral clinodactyly was pre- on September 26, 2021 by guest. Protected sent in the outer three toes. Examination confirmed the presence of microphthalmos and microcomea, and large_ choroidal colobomata were present in both eyes. The .. parents already had 2 normal children. After diagnosis by chromosome studies, the infant's condition was discussed with the parents and a guarded prognosis was given regarding subsequent mental development. The parents however were anxious to...... take the child home. At a later date it was discovered that the infant was being kept closed up in a cupboard .... in the kitchen; feeds were given erratically. He was taken into the care of the Social Services Department. Since then he has gained weight but his height and weight lie below the 3rd centile. A full developmental Received 6 October 1975. FIG. 1 Patient at age of 1 week. 449 Arch Dis Child: first published as 10.1136/adc.51.6.449 on 1 June 1976. Downloaded from

450 McCandless and Walker TABLE Cases of ring

Case no. 1 2 3 I 4 5 6 7 8 9

c. _r 00~ ~ ~

0 X E %u

13r Identification (auto or G-bands) A A A |A A G A A

Sex M M M M F M F M

Age at investigation 20 m 21 m 15 yr 21 m 20 yr 9 yr 3 yr 1 w

Birthweight (g) 1875 3850 12750 2300 1950 2000 Gestation (w) 40 42 42 40

Dysmature +

Age of mother 21 20 27 21 26 25

Age of father 23 23 1l29 24 copyright. 33 Microcephaly and mental retardation + + + + + + + Arrhinencephaly + Microphthalmia L eye

Epicanthus + + + http://adc.bmj.com/ Hypertelorism + Broad prominent nasal bridge Auricles-large or deformed + + _ High-arched palate

Protruding upper incisors +

Micrognathia + + on September 26, 2021 by guest. Protected

Heart murmur Small penis

Small or bifid scrotum

+ Undescended testes Absent on L Hypospadias +

Imperforate anus +

Hand or foot anomalies + Renal defects + Arch Dis Child: first published as 10.1136/adc.51.6.449 on 1 June 1976. Downloaded from

D13 ring chromosome syndrome 451

,hromosome 13

11 10 12 13 14 15 16 17 18 19 20 22 21

u u ~~~~-' ,- (4 - ~~~-1-1

0 u~~0%Cuu - 0 0 0 4) . - ) ,0% 0

A A A A A A A A G G G G G F M F F M M F M M M M F M 10 yr 20 m 6 m 3 yr 25 yr 6 m 6 m 15 yr 14 m 14 m 14 yr 4 yr 1w 1650 1960 2200 2300 2016 2044 2100 1800 2050 2425 1900 1550 40 38 38 38 40 40 40 39 40 40 34

18 21 28 19 25 24 30 25 35 23 copyright. 20 24 32 21 28 24 31 24 39 25

+ + + + + +

+ http://adc.bmj.com/ + + +

+ + + + + + + + on September 26, 2021 by guest. Protected + +

+ Arch Dis Child: first published as 10.1136/adc.51.6.449 on 1 June 1976. Downloaded from

452 McCandless and Walker congenital malformation of the heart, and the pyelogram has shown severe mental retardation. There are was normal. The testicles are very small but the penis also a number of other features which occur in is normal in size. The child is happy and smiles almost more than 60% of the cases and which can be re- continuously during the waking hours. garded as characteristic of the syndrome. These are poor uterine growth resulting in dysmaturity Cytogenetic studies. From peripheral bloc d cul- at birth, large low-set or malrotated auricles, tures in 1972 chromosome counts were made on 60 cells. hypertelorism, epicanthus, broad prominent nasal Of these, 57 contained 46 chromosomes and 3 contained bridge, and genital defects in males. The most 45 only. Those with 46 chromosomes showed the frequent genital defects were small or bifid scrotum presence of a ring chromosome apparently replacing a and undescended testes. Less common were a member of the D group. The ring chromosome was small penis and hypospadias. missing from cells with 2n=45. Culture of blood features from both parents indicated they had normal karyotypes. The next most common group of ap- Reinvestigation in 1975 permitted G-banding of the pearing in more than 30% of the cases are microg- chromosomes from the patient using a modification of nathia, high arched palate, protruding upper the trypsin method of Seabright (1971). This showed a incisors, foot or hand anomalies, and heart murmur. D13 ring chromosome in all cells with a count of 2n =46 In the 8 cases in which cardiac murmurs were (Fig. 2). found there were no consistent abnormalities. Case 9 (Biles, Liiers, and Sperling, 1970) had an atrial septal defect confirmed at necropsy and Case 13 (Hollowell et al., 1971) Fallot's tetralogy. Foot and hand anomalies were various. Over- lapping of the toes seen in the present case was evident also in Case 2 (Gerald et al., 1967), Case 4 (Lejune et al., 1968), Case 5 (Allerdice et al., 1969), and Case 21 (Fried et al., 1975). Other defects were absent thumbs and fifth toes in Case 18 (Niebuhr and Ottosen, 1973), absent or fused copyright. metacarpals with extra digits in Case 9 (Biles et al., 1970), plano valgus in Case 2 (Gerald et al., 1967), and arthrogryposis with multiple skeletal defects in Case 16 (Grace et al., 1971). The low lying thumbs and contracture seen in the present case FIG. 2.-Group D chromosomes of patient. Upper row have not been described previously. stained in lactic-acetic orecin; lower row after trypsin Several authors described the eyes of their cases http://adc.bmj.com/ banding and Leishman's stain. as oriental or 'almond-shaped'; this is well shown in our case (Fig. 1). Other than microphthalmia, defects of the eyes were rare, including squint or Serology. Blood groups ABO, CDE, MN, S, K, and Fy were investigated in the patient and his parents. colobomata of the irides. Only 3 infants had Only in the case of the MNS groups did the patient renal defects; Case 5 (Allerdice et al., 1969) and show heterozygosity, indicating that the MNS loci could Case 9 (Biles et al., 1970) had ptosis of the right

not be carried on the deleted sections of D,3. The level kidney; Case 9 also had a hypoplastic left kidney; on September 26, 2021 by guest. Protected of haptoglobin in the patient was normal. Immuno- and Case 19 (Hoo, Obermann, and Cramer, 1974) globulins IgA, IgM, and IgG were investigated in the had agenesis of the right kidney. Anal atresia was child (age 6 months) and his parents. All were con- reported in 5 cases. sidered normal. As may be expected in an effective chromosome deletion syndrome there is wide variation in the Discussion phenotypic expression of the recorded ring D13 The most frequent anomalies associated with the cases, probably related to the amount of chromatin published ring D13 cases are recorded in the Table, lost. However, there are sufficient common fea- together with those found in the present case. tures as illustrated above to lead to a possible There is no association with maternal or paternal diagnosis. age. With one exception, maternal age, when given, was below 30 years. The only consistent We thank Dr. J. Bradley, Mr. W. T. A. Donohoe, and feature in all cases is microcephaly. Associated Mr. J. Ireland for the serology, and Miss G. A. Rowlands with this the intellectual assessment, when done, for technical assistance. Arch Dis Child: first published as 10.1136/adc.51.6.449 on 1 June 1976. Downloaded from

D13 ring chromosome syndrome 453 REFRENCES Lejeune, J., Lafourcade, J., Berger, R., Cruveiller, J., Rethor6, Allerdice, P. W., Davis, J. G., Miller, 0. J., Klinger, H. P., War- M. O., Dutrillaux, B., Abonyi, D., and Jrt6me, H. (1968). burton, D., Miller, D. A., Allen, F. H., Jr., Abrams, C. A. L., Le phenotype (Dr). ttude de trois cas de chromosomes D en and McGilvray, E. (1969). The 13q- deletion syndrome anneau. Annales GOnetiques, 11, 79. American journal of Human Genetics, 21, 499. Mikkelsen, M., and Niebuhr, E. (1969). A ring chromosome Biles, A. R., Luers, T., and Sperling, K. (1970). D1 ring chromo- (46, XY, 13r) occurring in a family with a D-D translocation, some in newborn with peculiar face, polydactyly, imperforate 13-, 14-, t(13q, 14q). Annales Ginetiques, 12, 51. anus, arrhinencephaly and other malformations. Journal of Neimann, N., Ducas, J., Gilgenkrantz, S., and Peters, A. (1967). Medical Genetics, 7, 399. Un cas de chromosome eu annau du groupe 13-15. Archives Coffin, G. S., and Wilson, M. G. (1970). Ring chromosome D13. Fran;aises de Pediatrie, 24, 584. American Journal of Diseases of Children, 119, 370. Niebuhr, E., and Ottosen, J. (1973). Ring chromosome D13 Fried, K., Rosenblatt, M., Mundel, G., and Krikler, R. (1975). associated with multiple congenital malformations. Annales Ring chromosome 13 syndrome. Clinical Genetics, 7, 203. Gbnstiques, 16, 157. Fryns, J. P., Deroover, J., Van Den Berghe, H., Cassiman, J. J., Orbeli, D. J., Lurie, I. W., and Goroshenko, L., Jr. (1971). The Goffaux, P., and Lebas, E. (1974). Malformative syndrome syndrome associated with partial D-monosomy. Humangenetik, with ring chromosome 13. Humangenetik, 24, 235. 13, 296. Gerald, P. S., Warner, S., Singer, J. D., Corcoran, P. A., and Reisman, L. E., Darnell, A., and Murphy, J. W. (1965). Abnor- Umansky, I. (1967). A ring D chromosome and anomalous malities with ring chromosome. Lancet, 2, 445. inheritance of haptoglobin type. Journal of Pediatrics, 70, 172. Salamanca, F., Buentello, L., and Armendares, S. (1972). Ring Grace, E., Drennan, J., Clover, D., and Gordon, R. R. (1971). D1 chromosome with remarkable morphological variation in a The 13q-deletion syndrome. Journal of Medical Genetics, boy with mental retardation. Annales Gdnetiques, 15, 183. 8, 351. Seabright, M. (1971). Rapid banding techniques for human Hollowell, J. G., Littlefield, L. G., Dharmkrong-at, A., Folger, chromosomes. Lancet, 2, 971. G. M., Heath, C. W., and Bloom, G. E. (1971). Ring 13 Tolksdorf, M., Goll, U., Wiedemann, H. R., and Pfeiffer, R. A. chromosome with normal haptoglobin inheritance. Journal (1970). Die symptomatik von ringchromosomen der D-gruppe. of Medical Genetics, 8, 222. Archiv fur Kinderheilkunde, 181, 282. Hoo, J. J., Obermann, U., and Cramer, H. (1974). The behaviour of ring chromosome 13. Humangenetik, 24, 161. Kistemnacher, M. L., and Punnett, H. H. (1970). Comparative behaviour of ring chromosomes. American Journal of Human Correspondence to Dr. A. McCandless, Department Genetics, 22, 304. Lehrke, R., Thelen, T., and Lehrke, R. (1971). Syndrome asso- of Child Health, Alder Hey Children's Hospital, Eaton ciated with group D chromosome deletions. Lancet, 2, 98. Road, Liverpool L12 2AP. copyright. http://adc.bmj.com/ on September 26, 2021 by guest. Protected