Two different chromosome abnormalities resulting from a translocation carrier father

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Brief clinical and laboratory observations

caring that this X-linked form of G S D I X is not a generalized disorder. It is noteworthy that some residual phosphorylase kinase activity was detected in each biopsy specimen. This fractional remnant is probably responsible for the glycogenolytic response to glucagon seen in our patients, and at least in part for the benign clinical course noted in the older patient. Exactly how a single enzyme deficiency can be inherited in more than one way is not immediately clear. An earlier suggestion that affected girls were manifesting heterozygous carriers of the X-linked disorder G is not supported by clinical, genetic, and biochemical evidence?, 2 All other interpretations of the dual inheritance patterns of GSD I X will be merely speculative until more is known about the molecular structure of phosphorylase kinase.

T vo different chromosome abnormalities resulting from a translocation catrier )Cather Harold N. Bass, M.S., M.D., ~ Panorama City, Calif.,

Barbara F. Crandall, M.D., Los Angeles, Calif., and S. Michael Marcy, M.D., Panorama City, Calif. Supported in part by: California State Department of Mental Hygiene; Mental Retardation Program, N.P.I., U.C.L.A.; MCH-927, Interdisciplinary Training in Mental Retardation; HD-04612, Mental Retardation Research Center, U.C.L.A.; HD-00345, Research Training in Mental Retardation; HD-05615, Developmental Biology in Mental Retardation. Presented in part to the Society ]or Pediatric Research, San Francisco, California, May 17-19, 1973. ~Reprint address: Department of Pediatrics, Kaiser Permanente Medical Center, Panorama City, Calil. 91402.

The Journal of Pediatrics December 1973

REFERENCES 1. Hug, G., Schubert, W. K., and Chuck, G.: Phosphorylase kinase of the liver: Deficiency in a girl with increased hepatic glycogen, Science 153: 1534, 1966. 2. Hug, G., Schubert, W. K., and Chuck, G.: Deficient activity of dephosphophosphorylase kinase and accumulation of glycogen in the liver, J. Clin. Invest. 48: 704, 1969. 3. Huijing, F., and Fernandes, J.: X-chromosomal inheritance of liver glycogenosis with phosphorylase kinase deficiency, Am. J. Hum. Genet. 21: 275, 1969. 4. Cori, G. T., Ilingworth, B., and Keller, P. J.: Muscle phosphorylase, in Colowick, S. P., and Kaplan, N. O., editors: Methods in enzymology, vol. 1, New York, 1955, Academic Press, Inc., pp. 200-205. 5. Hug, G.: Nonbilirubin genetic disorders of the liver, in Gall, E. A. editor: The liver, Baltimore, 1972, The Williams & Wilkins Company, pp. 21-71. 6. Huijing, F., and Fernandes, J.: Letter to the Editor, Am. J. Hum. Genet. 22: 484, 1970.

T H E

ADVE N T

of

the

differential

chro-

stains has resulted in the recognition of chromosome abnormalities both pre- and postnatally in patients considered to have normal karyotypes with routine analyses. In addition, these techniques may lead to the delineation of phenotypes associated with the duplication or deficiency of specific chromosomes. We have studied a family in which a balanced translocation in a phenotypically normal father resulted in one child with a partial trisomy and a fetus with a partial monosomy. None of these chromosome changes could be detected with routine chromosome stains. Because of our strong suspicion of a chromosome imbalance in the propositus, differential staining with trypsinGiemsa banding was performed. T h e importance of differential banding for the detection of these chromosome changes, the occurrence of three different chromosome abnormalities in one family, and the high incidence of chromosomally unbalanced offspring from a father who was a balanced carrier are the reasons for this report. mosome

Volume 83 Number 6

CASE

Brief clinical and laboratory observations

1 03 5

HISTORY

Patient C. H. 08 11 71 (Fig. 1) is an 18month-old girl born to a healthy 27-year-old mother and 31-year-old father after an uneventful 40 week gestation, labor, and delivery. The infant weighed 1,928 Gm. (below third percentile) and measured 51 cm. (fiftieth percentile). Head and chest circumference were 31 crn. and 28 cm. respectively. Growth and development have been markedly delayed. By 2 months of age, the patient was noted to have bilateral cataracts, frontal bossing, low-set ears, micrognathia, a heart murmur (thought to represent mild pulmonic stenosis), dysplastic left hip, and scoliosis with hemivertibrae of Tll and T12. When examined at age 18 months, the propositus was unable to sit, roll over, or to transfer objects from hand to hand. She appeared to hear but had no intelligible speech. Weight and height were 4.4 Kg. and 60.9 cm., respectively (both below the third percentile), whereas the head circumference was 45 cm. (fiftieth percentile). At age ~ to 3 months, the following studies were performed and the results were normal: serum titers for rubella, cytomegalovirus, and toxoplasmosis; intravenous pyelography; urinary amino acid chromatogram; T 4 by Murphy-Pattee; complete blood count; urinalysis including ferric chloride and measurement of total reducing substances; and blood glucose, calcium, and phosphorus. Examination of dermatoglyphics in the propositus revealed palmar axial triradii in the t position and eight ulnar loops and two whorls. Both the father and the mother had palmar axial triradii in the t position bilaterally with eight ulnar loops and two radial loops in the former and seven ulnar loops, one whorl, and two arches in the latter. Eleven months after the birth of Patient C. H., her mother had a spontaneous abortion at 6 weeks of gestation. Four months later she had another spontaneous abortion at 6 to 8 weeks of gestation; chromosome studies were performed on the fetus. RESULTS

C h r o m o s o m e analyses of the propositus were p e r f o r m e d on p e r i p h e r a l blood lymphocytes a n d skin fibroblasts. Both quinacrine fluorescent mioroscopy 1 a n d trypsin-Giemsa b a n d i n g 2 revealed an additional b a n d on the 10ng arms of a No. 21 chromosome in all

Fig. 1. The propositus (Patient C. H.) at age 18 months. Note frontal bossing and low-set rotated ears. cells e x a m i n e d (Fig. 2). T h e rest of the karyotype was normal. This a b n o r m a l i t y was not evident with routine chromosome analysis. Peripheral blood lymphocytes in the m o t h e r revealed a n o r m a l chromosome complement, b u t trypsin-Giemsa studies in the father d e m o n s t r a t e d the translocation of the terminal b a n d on the long a r m of the No. 7 chromosome to the end of the long arm of the No. 21 chromosome (Fig. 3). This translocation a p p e a r e d to be balanced. T h e first abortion h a d occurred prior to our examination of this family; the chromosome complem e n t of the abortus is unknown. T h e m o t h e r aborted again at 6 to 8 weeks; chromosome analysis with trypsin-Giemsa b a n d i n g of skin from the fetus demonstrated t h a t the d a r k b a n d from the end of the long a r m of the No. 7 chromosome h a d been deleted, but the No. 21 chromosomes were n o r m a l (Fig. 4). This fetus was, therefore, p a r t i a l l y monosomic for the long a r m of the No. 7 chromosome. T h e p a t e r n a l g r a n d p a r e n t s a n d their only other child, the p a t e r n a l aunt, h a d n o r m a l karyotypes with the same differential chromosome stain. R e d cell antigens, red cell enzymes, serum proteins, white cell typing, and G m a n d I n v

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Brie[ clinical and laboratory observations

The ]ournal o[ Pediatrics December 1973

Fig. 2. Full karyotype of the propositus (Patient C. H.) (trypsin-Giemsa technique). The arrow indicates the No. 21 chromosome with an additional band on the long arm. The rest of the karyotype is normal. This patient is, therefore, partially trisomic for the No. 7 chromosome.

Fig. 3. Full karyotype from the father (II-2). The upper arrow denotes a No. 7 chromosome from which the distal band has been translocated to the long arm of the No. 21 chromosome (lower arrow). The translocation appears to be balanced. allotypes were studied by s t a n d a r d methods a n d showed n o r m a l inheritance patterns. Galactokinase, g a l a c t o s e - l - p h o s p h a t e uridyl transferase, a n d q u a n t i t a t i v e serum i m m u n o globulin levels were normal. DISCUSSION This r e p o r t of a child with a p a r t i a l trisomy and a fetus with p a r t i a l m o n o s o m y from a f a t h e r with a balanced translocation is presented because of the rarity of finding antithetical chromosome abnormalities in the

products of two pregnancies. T h e points to be discussed include the indications for the differential chromosome stains, the import a n c e of this diagnosis in the p r e n a t a l detection of other chromosome abnormalities in this family, a n d the high incidence of unb a l a n c e d chromosome abnormalities resulting from this translocation. T h e differential chromosome stains have m a d e it possible to identify every chromosome a n d also certain subtle chromosome changes n o t a p p a r e n t w i t h the s t a n d a r d tech-

Volume 83

Number 6

Brief c l i n i c a l a n d laboratory observations

1 03 7

Fig. 4. Full karyotype of the fetus (III-8). The arrow indicates the No. 7 chomosome from which the terminal band has been deleted. The rest of the karyotype is normal. This fetus is, therefore, partially monosomic for the No. 7 chromosome. nique. At present, we do not use trypsinGiemsa banding routinely, but only when we have a strong suspicion of a chromosome abnormality, as in the present case. Although 'the succeeding pregnancy ended in a spontaneous abortion, it was equally possible for another child with the same findings as Patient C. H. The apparently balanced translocation of the father could result in equal numbers of chromosomally balanced and unbalanced zygotes. The likelihood that the latter m a y implant and survive to term may vary with the translocation. I t is of interest that this couple has had no normal children. The chromosomally balanced offspring have equal chances of a normal or balanced translocation complement. Amniocentesis in future pregnancies together with trypsin-Giemsa chromosome banding is strongly indicated. We examined many mitotic spreads stained with trypsin-Giemsa to determine whether the translocation was insertional (with the dark band on the No. 7 being inserted into the long arm of the No. 21) or reciprocal. The position of the band on both affected chromosomes makes either interpretation possible in this situation. A reciprocal translocation involves one break in each chromosome and the i.nsertional type, two in the No. 7, and one in the No. 21. Only.insertional translocations represent simple monosomies or

trisomies. Reciprocal translocations result in both duplications and deficiencies of the two chromosomes involved. Although there are a number of reports of partial C group trisomy in the literature, only one has been shown by differential stains to involve the long arms of the No. 7 chromosome.S, 4 In these reports the propositus appeared to be trisomic for a larger part of the chromosome No. 7 than was our patient. Although this child resembled our patient in certain aspects, she had, in addition, a cleft palate and died shortly after birth. Gene marker studies were undertaken to determine whether the presence of a third allele could be demonstrated, and thus the gene located on the long arm of the No. 7 chromosome. Quantitative studies including serum immunoglobulins, galactokinase, and galactose-l-phosphate uridyl transferase were all normal in Patient C. H. Qualitative studies might also indicate the presence of a third allele in the red cell acid phosphatase, rhesus, and H L - A systems. None was found. SUMMARY

The importance of differential chromosome stains despite an apparently normal routine chromosome analysis is emphasized by the studies presented here. TrypsinGiemsa banding revealed a partial trisomy 7 in an 18-month-old girl with failure to

10 3 8

Brie[ clinical and laboratory observations

thrive, slow development, a n d multiple physical anomalies. T h e father was f o u n d to be a balanced translocation carrier. Before amniocentesis could be carried o u t in a succeeding pregnancy, the m o t h e r a b o r t e d and the fetus was found to be p a r t i a l l y monosomic for the No. 7 chromosome. The authors wish to thank Drs. Helga Muller and Eleanor Bates for technical assistance, Dr. Phillip Sturgeon for red cell typing, Dr. Paul Terasaki for white cell typing, Dr. E. Beutler for galactose enzyme assays, and Mrs. Thelma Dietrich, R.N., for clinical assistance.

Hemoglobins S and J coexisting in tbe same

A n d r e w M. Gellady, M.D., a n d Allen D. Schwartz, M.D., * Chicago, Ill. T I-I E increasing interest in s c r e e n programs for the detection of sickle cell hemoglobin states, occasional persons with rare hemoglobinopathies will be identified. Some of these variants result in disease or have i m p o r t a n t genetic implications, whereas other variants lead to no clinical a b n o r m a l i ties. T w o siblings, who are the subjects of this report, were discovered to have complete absence of hemoglobin A (Hgb. A ) , b u t h a d no evidence of hematologic disease. W i T H

ing

CASE REPORT

A 7-year-old black girl was admitted to the Children's Memorial Hospital because of an asthmatic attack which was unresponsive to treatment From the Department o[ Pediatrics, Northwestern University Medical School and The Children's Memorial Hospital. Supported in part by United States Public Health Grant RR-05475 and the Otho S. A. Sprague Memorial Institute. ~Reprint address: The Children's Memorial Hospital 2300 Children's Plaza Chicago, Ill. 60614.

The ]ournal of Pediatrics December 1973

REFERENCES

1. Caspersson, T., Zech, L., Johansson, C., and Modest, E. J.: Identification of human chromosomes by DNA-binding fluorescent agents, Chromosoma 30: 215, 1970. 2. Seabrlght, M.: Rapid banding technique for human chromosomes, Lancet 2: 971, 1971. 3. Carpenter, S., Rethor~, M-D, and Lejeune, J.: Trisomie partieIle 7q par translocation familiale t(7:12) (q22:q24), Ann. de Genet. 15: 283, t972. 4. Lejeune, J., Rethorg, M. O., Berger, R., Abonyi, D., Dutrillaux, B., and See, G.: Trisomie C partielle par translocation familiale t(Cq-;Cq+), Ann. de Genet. 11: 171, 1968.

with epinephrine. The child had a history of previous asthmatic episodes. There was no past history of anemia or symptoms suggestive of painful sickle crises, Physical examination revealed a child in moderate respiratory distress with diffuse expiratory wheezes. There was no hepatosplenomegaly or scleral icterus. The patient was treated with intravenous fluids and aminophylline, and was markedly improved within 24 hours. The hematologic laboratory values were unremarkable: hemoglobin, 13.5 Gm. per 100 ml.; hematocrit, 42 per cent; reticulocyte count, 1 per cent. Red cell morphology was normal on microscopic examination of the blood smear. Because a sodium metabisulfite preparation revealed the presence of sickled red cells, a hemoglobin electrophoresis was performed. HEMOGLOBIN

IDENTIFICATION

Cellulose acetate electrophoresis of the patient's hemolysate at a p H of 9.3 demonstrated two distinct bands (Fig, 1). H e m o globin S comprised 41 p e r cent of the hemolysate a n d a fast-moving c o m p o n e n t comprised 59 p e r cent. Starch block electrophoresis at a p H of 8.6 revealed similar resuits. A g a r gel electrophoresis at a p H of 6.2 d e m o n s t r a t e d a p a t t e r n identical to t h a t of sickle cell trait (Hgb. AS) with the fast c o m p o n e n t m i g r a t i n g in a fashion similar to Hgb. A. T h e unidentified r a p i d c o m p o n e n t was fingerprinted and found to be identical with a v a r i a n t previously designated Hgb. J ( B a l t i m o r e ) . This hemoglobin has a substi-