HASHIMOTO'S DISEASE IN TURNER'S SYNDROME WITH ISOCHROMOSOME X

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molecules, which lack the expression of both of the individual’stwo Gm genes. Gm(a-b-) sera are exceedingly rare, butGm(a-b-) 7S y-myeloma-globulins 4 6 and anti-Rh anti-bodies 9 are common. Further, the two specificities Gm(a)and Gm(b) are determined by allelic genes but Gm(a) appearsto be carried by a considerably larger proportion of the 7S y-globulin molecules than Gm(b).4 6 ’ 1 An analogous situationexists for allelic genes governing haemoglobin synthesis.2The relevance of these findings for theories of antibody

formation is obvious. They have also contributed to ourgeneral understanding of the relationship between genepairs and their products.

LARS MÅRTENSSON.University of California,

San Francisco Medical Center,San Francisco, California.

HASHIMOTO’S DISEASE IN TURNER’SSYNDROME WITH ISOCHROMOSOME X

SiR,-We have recently investigated 2 unrelated patientswith sex-chromatin-positive Turner’s syndrome andisochromosome X, who have histological evidence ofHashimoto’s thyroiditis.The patients are 23 and 24 years old, are short in stature

(4 ft. 7 in. and 4 ft. 8 in.), and have primary amenorrhrea and ashort neck without definite webbing. The first patient hadhad a palpable nodule in the thyroid gland, and a regionallymph-node biopsy revealed anaplastic carcinoma for which athyroidectomy was done. In addition to the primary anaplasticcarcinoma, microscopic examination of the thyroid showedHashimoto’s thyroiditis with focal aggregates of lymphocytesand lymph follicles with germinal centres distributed through-out the gland. The second patient also had a large nodulargoitre. Histological examination of this gland, removed atsurgery, disclosed Hashimoto’s thyroiditis, with part of thenormal lobular structure replaced by marked interfollicularfibrosis and infiltration of lymphocytes and plasma cells, inaddition to well-developed lymphatic follicles with largegerminal centres.Karyotypes of peripheral leucocytes in both patients were

interpreted as showing a complement of 46 chromosomes withone apparently normal X chromosome and one additionallarge chromosome closely resembling chromosome 3. Theclinical picture and the finding of larger than normal

" drum-sticks suggested that the abnormal chromosome was anabnormal X chromosome formed of two long arms of theX chromosome.Measurements of the drumstick-nuclear ratio by planimetry

from photographs of polymorphonuclear leucocytes 10 con-firmed the impression of enlarged drumsticks in both patients,in comparison with the normal as shown by the followingmean values for this ratio : normal, 1-97%; first patient,310%, second patient, 3-07% (P< 0-001 for both patientscompared with normal).Other data have shown that the number of sex-chromatin

bodies in a cell is one less than the total number of X chromo-somes in that cell. The sex-chromatin body has been shownto be derived from either the maternal or the paternal Xchromosome." Since one of the X chromosomes in thesepatients is normal, one could expect to find two classes ofdrumstick size: large and normal. In fact, the measurementsin both patients were unimodally distributed, consistent withthe presence of only large sex-chromatin bodies.The mean values of the drumstick size in the patients were

significantly larger than the mean for the normal control,indicating that the sex-chromatin body may always be formedof the same abnormal chromosome-the isochromosome X.But cells with sex-chromatin bodies formed of the normalX chromosome may have been present early in development,and because they lacked a normal active X chromosome,were unable to reproduce, leaving only the cells with sexchromatin formed of the isochromosome X.

9. Martensson, L. Unpublished observations.10. Maclean, N. Lancet, 1962, i, 1154.11. Ohno, S., Hauschka, T. S. Cancer Res. 1960, 20, 541.

The thought-provoking finding in these two patients is theassociation of the isochromosome X with histologically provenHashimoto’s thyroiditis. The relative infrequency of bothconditions makes a chance event unlikely.

Other reports of patients with isochromosome X do notmention Hashimoto’s disease, which is currently regarded as anautoimmune disease with thyroid antibodies in the serum.12Many more females than males are affected by Hashimoto’s

disease (14 females, 1 male).13 When thyroid antibodies weresearched for in the families of patients with Hashimoto’sdisease, there was a less pronounced-though still significant-female preponderance among those with thyroid antibodies(47/73 females and 11/30 males: ;(2=5.57; 0.05> p > 0.01). 14 15More recent studies by Hall et al.16 on 35 parents of 19 patientswith Hashimoto’s disease confirm the greater frequency ofthyroid antibodies in female relations. The evidence from suchstudies for a genetic predisposition to form autoantibodiesis very strong, although the genetic mechanism for thisphenomenon is completely unknown.The association of Hashimoto’s disease with isochromo-

some X in our 2 patients may provide a lead to the under-standing of the genetic basis of autoimmunity. Two

reports 1’ 18 on thyroid function in another X-chromosomeabnormality, Klinefelter’s syndrome, indicate a highincidence of thyroid dysfunction. Neither the thyroidhistology nor thyroid antibodies was investigated. Furtherclinical, serological, and family investigations for auto-immune thyroiditis in patients with and without iso-chromosome X, as well as in other X-chromosome

abnormalities, may throw light on this obscure relationship.

ROBERT S. SPARKESARNO G. MOTULSKY.

Division of Medical Genetics,Department of Medicine,University of Washington,Seattle, Washington, U.S.A.

DOWN’S SYNDROME (MONGOLISM) WITHNORMAL CHROMOSOMES

SiR,&lstrok;I should like to answer as far as I can the questionsraised by Dr. Hamerton and Professor Polani 19 concerningmy paper.20 I certainly agree that every effort should bemade to clarify all aspects of the case. It seems to me thatthe crucial issue lies in their statement : " In all cases

diagnosed confidently as having Down’s syndrome wehave found an excess of material of chromosome no. 21,either as an additional chromosome in the regular trisomictype or as a translocation." That raises the question ofhow to establish a " confident " diagnosis of mongolism.

Historically the syndrome of mongolism has been definedand diagnosed on clinical grounds. Two prominent workers(Penrose and 0ster) have defined mongolism as follows (thesigns present in the patient under discussion are italicised):

Penrose 21 "The seven characters chosen here are fairlyeasy to observe: other characters would have served the same

purpose. (A) Intelligence quotient between 15 and 29 inclusive,*i.e., the most likely range of intelligence for mongols. (B) Cephalicindex 0-83 or higher. (c) Epicanthic fold on either eye. (D)Fissured tongue. (E) Conjunctivitis at time of examination.(F) Transverse palmar line on either hand. (G) One crease onlyon minimal digit of either hand. It will be observed that someof the features are much more diagnostic than others, A and B12. Roitt, I. M., Doniach, D. Brit. med. Bull. 1960, 16, 152.13. Woolner, L. B., McConahey, W. M., Beahrs, O. H. J. clin. Endocrin.

1959, 19, 53.14. Hall, R., Owen, S. G., Smart, G. A. Lancet, 1960, ii, 187.15. Doniach, D., Roitt, I. M., Forbes, I. J., Senhauser, D. A. Coloquio

Europea de Endocrinologia, 1961, p. 20.16. Hall, R., Saxena, K. M., Owen, S. G. Lancet, 1962, ii, 1291.17. Barr, M. L., Shaver, E. L., Carr, O. H., Plunkett, E. R. J. ment. Defic.

Res. 1960, 4, 89.18. Davis, T. E., Canfield, C. J., Herman, R. H., Goler, D. New Engl. J.

Med. 1963, 268, 178.19. Lancet, 1962, ii, 1229.20. ibid. p. 1026.21. Penrose, L. S. Mental Defect. London, 1933.* Our patient’s i.Q. has not been determined accurately, but the

child is quite retarded mentally.