The 17-18 trisomy and 21 trisomy syndromes in siblings Brian T u r n e r , M.B., B.S., * Gesina M. den Dulk, Dra. Med. (Leiden), B.Sc., a n d Gillian Watkins, "x'x" M.B., Ch.B., M.R.C.P.E., D.C.H. NORTH
toxemia in the later months. Labor was induced at 36 weeks, delivery was normal, and the child cried spontaneously. Birth weight was 5 pounds, 4 ounces. The number of umbilical arteries was not recorded. The child was taken home at 10 days, where feeding was said to be slow and difficult. On the twelfth day the child became limp, cold, and slightly blue and remained unresponsive for 12 hoUrs. The mother spent 5 hours giving an ounce of glucose and water by spoon after which the child began gradually to respond and to cry. The baby was admitted to hospital when 2 weeks old. The clinical findings are: (1) apparent mental retardation, (2) failure to thrive, (3) low-set malformed ears, (4) small mandible, (5) left facial paralysis, (6) flexion deformity of the fingers, (7) ulnar deviation of the hands, (8) low dermal arch pattern on all fingers and thumbs, ( 9 ) b i l a t e r a l simian creases, (10) absence of crease between the middle and distal phalanges, (11) rocker-bottom feet, and (12) systolic murmur (? patent ductus arteriosus). The characteristic face and hands are shown in Figs. 1 and 2, respectively. In the hospital the infant has gained weight slowly and no further episodes similar to the previous one have occurred. Investigations. On admission the following estimations were performed: Hemoglobin was 16.2 Gm. per 100 ml.; white blood cell count, 18,600
T H E possibility of a predisposition to nondisjunction has been suggested by the finding of families in which abnormalities of chromosomal n u m b e r are present in siblings or near relatives, z, 2 These abnormalities may involve the same chromosome or different chromosomes. A case of 17-18 trisomy whose sibling showed trisomy 21 is considered sufficiently u n u s u a l to w a r r a n t reporting. CLINICAL RECORD Case 1. A female infant, first seen when a week 61d, showed the typical clinical features of trisomy 17-18. The mother was 38 years old and the father 41 at the time of conception. Pregnancy was complicated by the development of
From the Oliver Latham Laboratory, The Psychiatric Centre, North Ryde; and Institute o[ Child Health, Royal Alexandra Hospital [or Children, Camperdown, Sydney, Australia. eThe Psychiatric Centre, Neuropathology Laboratory, Cox's Road North Ryde, N.S.W., Australia. ~'~Present address, 66 Academy Medical Building, Calga~3J, Alb., Canada.
Articles submitted [or this section should not exceed 1,000 words and many contain 1 o,r,,2 illustrations or tables. Bibliography should not exceed 7 re[erences.
Brief clinical and laboratory observations
per cubic millimeter with normal differential; routine urine examination showed no abnormality; serum protein 5.3 Gm. per 100 ml. with a gamma globulin of 8.5 per cent on paper electrophoresis; normal values for electrolytes, urea, calcium and glucose were obtained. A 24 hour urine volume of 250 ml. was recorded and contained 29 mg. total amino nitrogen and gave normal chromatographic patterns for amino acids, keto acids, and indoles. Electrocardiography showed a left axis deviation and electroencephalography a basic 4 or 5 c.p.s, rhythm with random sharp wave potentials. Case 2. A 2-year-old male sibling of Case 1, showed the typical clinical features of mongolism and has been in an institution from birth. Remainder of family. The parents showed no abnormalities and gave no history of irradiation. The eldest child, who was not available for examination, was said to be a normal female of 11 years. There have been two miscarriages, one at one month and the other at 5 months gestation. No history of abnormalities in near relatives could be obtained. Chromosomal analysis. Chromosome preparations were made on 4 day cultures of peripheral blood leukocytes. Case 1. Consistent counts of 47 chromosomes were obtained on several cultures. Analysis of the karyotypes showed the extra chromosome to be of the 17-18 group (Fig. 3). Case 2. Consistent counts of 47 chromosomes were obtained. Karyotypes showed an additional small acrocentric chromosome of group 21-22 (Fig. 4). Chromosome analysis of the parents showed no abnormality. The normal sibling was not made available for examination.
d u r i n g the meiotic divisions of one of the parents with a higher frequency than might be expected. T h e most frequently r e c o r d e d instance of abnormalities of chromosome n u m b e r occurring a m o n g siblings is tee presence of two 21 trisomic mongols in a sibship? I n this laboratory 4 such cases have been studied. I n all the families w h e r e the p a r e n t a l chromosomes have been examined, n o a b n o r m a l i t y has been detected. A p a r t from trisomy 21, no abnormalities of chromosome n u m b e r involving the same chromosome h a v e been r e p o r t e d in siblings. Several families have been described in which abnormalities of c h r o m o s o m e n u m b e r involving different chromosomes have been f o u n d in more than one m e m b e r of a sibship. Zellweger a n d M i k a m o 3 described, in two families, cases of T u r n e r syndrome and m o n golism in siblings. T h e parents in each case were cytologically normal. Benirschke and co-workers ~ described a 21/21 translocation mongol and a Klinefelter syndrome, offspring of a c y t o l o g i c a l ! y n o r m a l mother. T h e children were f a t h e r e d by different males; the
A clinical diagnosis of 17-18 trisomy was m a d e on the index patient. T h e mongol sibling satisfied the clinical criteria for the diagnosis of mongolism and showed no unusual features. Abnormalities of chromosomal n u m b e r , i.e., trisomy and monosomy, a r e generally agreed to arise, for the most part, by nondisjunction during meiosis. T h e relative infrequency of aneuploid individuals suggests, that, when they occur m o r e t h a n once in a sibship, nondisjunction m a y be occurring
Fig. 1. The characteristic facial appearance in Case 1.
Fig. 2. T h e clenched fist of Patient 1.
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Fig. 3. Karyotype of Case 1 showing trisomy 17-18. father of the translocation mongol was cytologically normal. Therman and associates 2 described a patient with 13-15 trisomy, whose sibling showed an X O Turner syndrome. The parental chromosomes were not examined. Hauschka and co-workers 5 described a phenotoypically normal male with an XYY sex chromosome pattern whose offspring ineluded a regular mongol, a "blue baby," and a presumptive X O / X Y mosaic female. Two miscarriages were also recorded. Two families in which cases of Klinefelter syndrome, mongolism, and twinning occurred in a sibship have been described by Wright and others2 With the occurrence of similar or dissimi-
Brie[ clinical and laboratory observations
lar abnormalities of chromosome number in a sibship, several possible modes of origin may be considered: 1. Chance association. The possibility of aneuploidy occurring in siblings would be increased with advancing maternal age, but would, nevertheless, constitute the occurrence of two unlikely events. H a m e r t o n and his coworkers 1 have shown that the increased risk of a second mongol child to the cytologically normal young mother is greater than could be expected by chance association and suggest that some factor other than chance is operating. While no comparable data can yet be assembled for the association of 17-18 trisomy and 21 trisomy or of 13-15 trisomy and X O Turner syndrome, we can only agree with Therman and her associates 2 that "the co-concurrence of two such rare entities in a sibship is no mere co-incidence." 2. Chromosomal anomaly in the parent. The possibility has been suggested 1 that an unrecognized mosaicism may exist in the phenotypically normal parent of two regular 21 trisomic mongols. This, however, is unlikely where the aneuploid offspring have differing chromosome anomalies. The XYY male, described by Hauschka and his associates, 5 produced children, 50 per cent of Whom were abnormal, and would suggest an association between the paternal chromosomal abnormality and the chromosomal abnormalities in the offspring. It is of interest that there was a high proportion of discordant chromosome counts in the skin c u l tures from this XYY male which suggests that aberrant cell divisions were also increased in somatic tissues.
3. Genetic predisposition to nondisjunction. A genetic control of chromosome dis-
Fig. 4. Karyotype of Case 2 showing trisomy 21.
junction during meiotic divison has been demonstrated in Drosophila, maize, and c o r n / T h e claret gene in Drosophila simulans causes aberrant spindle formation during meiosis with resultant disorder of chromosome disjunction. Hamerton and his associates 1 have suggested that a similar mutant in man could be the basis of the increased risk to the young mother of a regular mongol; similar considerations would apply to
Brie[ clinical and laboratory observations
the occurrence of dissimilar abnormalities of chromosome n u m b e r in the sibship. T h e a c c u m u l a t i o n of f u r t h e r d a t a concerning the incidence of chromosomal abnormalities a n d their associations with each other will, no doubt, elucidate this p r o b l e m in the future. The permission of the Director General oI Public Health and State Psychiatric Services to publish this report is acknowledged. Thanks are due Drs. Charles Lee, M. Stening, B. C. Pirie, and A. N. Jennings for their co-operation in this study. REFERENCES 1. Hamerton, J. L., Briggs, S. M., Gianelli, F., and Carter, C. O.: Chromosome studies in detection of parents with high risk of second child with Down's syndrome, Lancet 2: 788, 1961.
2. Therman, E., Patau, K., Smith, D. W., and de Mars, R. I.: The D trisomy syndrome and XO gonadal dysgenesis in two sisters, Am. J. Human Gen. 13: t93, 1961. 3. Zellweger, H., and Mikamo, K.: Autosomal Cytogenetics, Helvet. paediat, acta 16: 385, 1961. 4 . Benirschke, K., Br0Wnhill, L., Hoefnagel, D., and Alien, F. H.: Langd0n Down anomaly (mongolism) 21/21 translocation and Klinefelter's syndrome in the same sibship, Cytogenetics 1: 75:, 1962. 5. Hauschka, T. S., Has3on, j. E., Goldstein, M. N., Koepf, G. F2, and Sandberg, A. A.: An XYY man with p r o g e n y indicating familial tendency to non-disjunction, Am. J. Human Gen. 14: 22, 1962.. 6. Wright, S. W., Day, R. W., Mosier, H. D., Koons, A., and Mueller', H.: KIinefelter's syndrome, Down's syndrome (mongolism), and twinning in the same sibship, Pediatrics, 62: 217, 1963. 7. Swanson, C. P.: Cytology and cytogenetics, London, 1958, The MacMiIlan Company.
Occurrence of beterotopic gastric mucosa in the tongue R o b e r t J. Gorlin, D.D.S., M.S., ~" Viktors Kalnins, Sc.D., M . D . , D . D . S . , a n d R o b e r t J. Izant, Jr., M . D . MINNEAPOLIS~ MINN.
H E T E R O T O e I C islands of gastric mucosa have been found in the esophagus, small intestines, thoracic cysts, vitelline duct, p a n creas, gallbladder, and Meckel's diverticulum.a, 4, r However, there are few descriptions of gastric mucosa in the tongue. From the Division of Oral Pathology, School o[ Dentistry, University o/Minnesota, Minn.; Department of Oral Pathology, School o[ Dentistry, Western Reserve University, Cleveland; and Division o/Pediatric Surgery, Medical School, Western Reserve University, Cleveland. This study has been made possible by a Program Grant in Oral Pathology [rom the United States Public Health Service. eAddress, Pro[essor o] Oral Pathology School o[ Dentistry, University oJ Minnesota, Minneapolis 14, Minn.
T o y a m a ~ a p p e a r s to be the first to record such an occurrence. His patient, a 31-yearold male, h a d a bean-sized, firm, smooth a n d polyplike lesion on the base of the tongue which h a d been noted since early childhood a n d h a d never caused pain. T h e mass, which h a d been enlarging for 3 m o n t h s p r i o r to its removal, was associated with increased salivation a n d with difficulties in deglutition. K r a u s p e 2 described a congenital, small, pea-sized mass on the tip of the tongue of an 8-year-old boy. E a t i n g a n d speech were impaired. Schultz 5 r e p o r t e d a m u l t i l o c u l a t e d sublingual mass a b o u t the size of a hen's egg t h a t h a d been present from birth in a 2-