- Email: [email protected]
Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia
29 2
Brief clinical and laboratory observations
The ]ournal of Pediatrics February 1972
of the m o u t h and pharynx without the need for the hands of attendants to be placed under the fluoroscope. It is possible to clamp the t u N n g so that feeding can be stopped. SUMMARY
A rapidly assembled device is described for use in feeding infants during fluoroscopy. It permits controlled feeding of the infant without the need for anyone to put their hands under a fluoroscope. REFERENCES
Fig. 2. The assembled device ready for use.
Infancy-onset cliabetes mellitus and multiple
epiphyseal dyyplasia Carol D e t t m a n W o l c o t t , M.D., and M a r v i n L. Rallison, M.D.,* Salt Lake City, Utah
From the Department of Pediatrics, University of Utah Medical Center. Supported in part by a grant from The Kror Foundation. *Reprint address: Department o~ Pediatrics University o] Utah Medical Center, 50 N. Medical Dr., Salt Lake City, Utah 84112.
1. Forster, A.: Die Spezialflasche und ihre Anundung bei der Rontgendurchleuchtung, Ann. Radiol. 11: 442, 1968. 2. Giedion, A.: Pacifier nipple (dummy) in pediatric radiology. A. Remote control pacifier. B. Radiological identification .of pacifiers as a cause of intestinal obstruction, Ann. Radiol. 11: 437, 1968. 3. Pozanski, A.: A simple device for administering barium to infants, Radiology 93: 1106, 1969. 4. Sittup Baby Bottle Insert: Noair Manufacturing Co., Inc., Farrningdale, N. Y. 5. Flexitron Anesthesia Extension Set R 33A: Travenol Laboratories, Inc., Morton Grove, Ill. 6. Venotube 30": Abbott Laboratories, North Chicago, Ill.
W E I~ A v ~. recently studied a family with three children who had onset of diabetes mellitus in early infancy; multiple epiphyseal dysplasia and abnormalties of the teeth and skin were also observed. T h e association of multiple epiphyseal dysplasia with infancyonset diabetes mellitus has never been reported to our knowledge and suggested to us that we might be dealing with a new familial syndrome. CASE REPORTS
Case 1. Patient J. S. S., a boy, was hospitalized at 8 weeks of age with the history of frequent urination of 2 weeks' duration. The infant's urine showed 4+ glucosuria. The blood sugar concentration was 500 rag. per 100 ml. The diabetes was stabilized with 10 units of Lente insulin daily. Later hospitalizations were required for treatment of hypoglycemia, diabetic
Volume 80 Number 2
Fig. 1A. Radiograph of Case 1, demonstrating multiple epiphyseal dysplasia, bone demineralization, and tubulation defects of metacarpals and phalanges. ketoacidosis, and three fractures of the femurs, which occurred over a 6 month period (two on the right and one on the left). Radiographs taken at the time of the child's first fracture showed diffuse demineralization of the bones. The child was admitted to the University of Utah Medical Center at 3 years of age because of the multiple fractures. An odd, stiff-kneed gait was noted, along with muscular atrophy and weakness of both legs, thought to be secondary to disuse and prolonged immobilization for treatment of the fractures. There was full range of motion in both hips, but limitation of knee flexion and elbow extension bilaterally. In addition, a brown mottling of the teeth near the gums and a cardiac murmur, thought to be functional, were noted. He was receiving 11 units of NPH insulin daily with supplements of regular insulin. Laboratory tests revealed glucosuria, acetonuria, and hyperglycemia (490 mg. per 100 ml.). Blood urea nitrogen ranged from 20 to 49 mg. per 100 ml.; serum creatinine and creatinine
Brief clinical and laboratory observations
29 3
clearance were normal. Intravenous urogram and voiding cystourethrogram were also normal. Values for blood electrolytes, serum proteins, alkaline phosphatase, SGOT, calcium, and phosphorus were normal. Radiographs of the pelvis and extremities showed diffuse demineralization. The epiphyses were small, irregular, and poorly calcified. There was prominent beaking of the metaphyses of the distal femora and proximal radii. There was also a tubulation defect of the metacarpals and phalanges. Radiographs of the skull and chest were normal (Fig. I). Biopsy of the iliac crest showed the cartilage ceils at the epiphyseal line to have a narrow zone of vacuolation. The zone of provisional calcification was practically nonexistent. Bone trabeculae of irregular width and orientation abutted directly onto the hypoplastic epiphyseal line. The bone trabeculae in the metaphysis contained small foci of incomplete ossification (Fig. 2). The biopsy and radiologic findings were consistent with the diagnosis of multiple epiphyseal dysplasia. Re-examination at 4~2 years of age showed relatively little change. Muscular atrophy of the lower extremities was again noted. There was limited abduction of both hips. Bilateral genu valgus was present. The gait was lordotic and waddling. The liver was enlarged, and, although SGOT was elevated to 104 m/z per milliliter, no other evidence of liver disease was found. Urinary excretion of mucopolysaccharides was normal (total uronic acid was 8 rag. per gram of creatinine). Urinary IT-ketosteroids were 1.7 rag. per day, and 17-hydroxycorticosteroids were 1.6 mg. per day. Radiographs revealed irregularity of most of the epiphyses of the long bones with some fragmentation and coarse trabeculation. There was bilateral coxa magna and coxa valga. The acetabular roofs were somewhat irregular. Case 2. Patient J. S., a girl, was hospitalized at 8 weeks of age with a brief history of irritability, fever, and vomiting. Physical examination at the time of admission revealed an emaciated, dehydrated irritable infant. A blood sugar concentration of 1,000+ mg. per 100 ml., glucosuria, and acetonuria led to recognition of diabetes mellitus. The child was treated with regular insulin and fluids. Grand mal seizures, which occurred the morning following admission, responded poorly to intravenous administration of glucose, although the blood sugar concentration prior to
294
Brief clinical and laboratory observations
The Journal of Pediatrics February 1972
Fig. lB. Radiograph of Case 1 demonstrating normal healing of femoral fractures.
Fig. 2. Biopsy from iliac crest in Case 1 showing dysplastic bone growth. The area of cartilage vacuolation is narrow and the zone of provisional calcification is essentially nonexistent.
administration was 40 mg. per 100 ml. Blood electrolyte values were normal. Blood urea nitrogen was 23 mg. per 100 ml., calcium 9.6 rag. per 100 ml., and phosphorus 7.2 mg. per 100 ml. The cerebrospinal fluid was normal. The child improved thereafter and was discharged 13 days after admission, well regulated on 6 units of Lente ittsulin daily, and with no apparent residuaI neurologic damage. However, the child continued to have seizures and was treated with anticonvulsant medication. Three subsequent hospitalizations were necessary for insulin-induced hypoglycemia. The fifth and final admission at 2~e years of age was marked by refractory hypoglycemia and urinary tract
infection with hemolytic E. coil Decreasing urine output and rising blood urea nitrogen led to a diagnosis of renal failure. The child died 4 days following admission; permission for autopsy was denied. At no time during any of the hospitalizations were abnormalities of the extremities noted by the examiners, and no history of fractures was obtained. However, genu vaIgus (a common clinical manifestation of multiple epiphyseal dysplasia) was evident on family photographs; no radiologic studies were made. She was noted to have tooth discoloration as welI as scaliness and "erratic" pigmentation bands of the skin, which were diagnosed as ectodermal dysplasia.
Volume 80 Number 2
Brie[ clinical and laboratory observations
295
Fig. 3. A and B, Radiographs of Case 3 demonstrating smaIl, dysplastic epiphyses.
Case 3. Patient C. S. was hospitalized at 6 weeks of age with the history of frequent urination since birth. Physical examination was normal. Laboratory tests revealed a mild anemia (volume packed red ceils 27 per cent, hemoglobin 10.5 Gm. per cent). Urinalysis showed glucosuria with no acetonuria. Fasting blood sugar values ranged from 102 to 155 rag. per I00 ml. Treatment with NPI-t insulin resulted in good control of hyperglycemia and glucosuria. I-Ie was seen at the University of Utah Medical Center at 14 months of age, The liver was
palpable 4 cm. below the right costal margin and the skin over the fingers, hams, toes, and dorsum of the feet was dry, smooth, and shiny. Hemogram was normal. Urinalysis showed no glucosuria or acetonnria, although the fasting blood sugar concentration was 300 rag. per 100 ml. Values for serum electrolytes, calcium, phosphorus, blood urea nitrogen, creatirfine, and blood proteins were normal. SGOT was 75 mu. per milliliter. Urinary excretion of mucopoly* saccharides was normal (total uronic acid was 17.7 rag. per gram of creatinine).
296
Brie[ clinical and laboratory observations
Skeletal survey revealed symmetrically small epiphyses. At the distal femur and proximal tibia, they were noted to be irregular in outline and poorly calcified (Fig. 3), consistent with the diagnosis of multiple epiphyseal dysplasia. FAMILY
HISTORY
Both parents were Caucasian with no history of consanguinity. Both were of above average height with no bony deformities. The mother had 7 pregnancies. T h e first, of 34 weeks' gestation, resulted in an infant who died at 2 months of age from a cerebral hemorrhage. The second and third pregnancies yielded normal female infants who are living and well. The fourth pregnancy resulted in Case 2. The fifth child was born prematurely and died shortly after birth. The mother's sixth and seventh pregnancies resulted in Cases 1 and 3. T w o maternal aunts and the maternal great-grandmother, now deceased, had diabetes mellitus. T h e paternal grandfather was said to have had "sugar in the urine." Oral glucose tolerance tests and skeletal surveys performed on both parents were normal. Skeletal surveys of the two living nondiabetic siblings were also normal. DISCUSSION
Diabetes mellitus is rarely found under the age of one year? Imerslund 2 found only 13 patients among the 3,847 juvenile diabetic patients followed by the Joslin Clinic from 1922 to 1956. True diabetes mellitus (as seen in our three patients) is insulin dependent, permanent, and has a predisposition for ketosis. Imerslund 2 found a positive family history in 51 per cent of the children diagnosed before one year of age. By contrast, in 20 cases of transient neonatal diabetes reviewed by Kloss 3 in 1967, in only one was there a family history of diabetes mellitus. We were not able to determine the etiology of the bone demineralization in Case 1. It was present at the time of his initial fracture and has persisted. Blood calcium and phosphorus values were normal, and there was no evidence, either by physical examination or laboratory determinations, to suggest a diag-
The Journal of Pediatrics February 1972
nosis of Cushing's syndrome, which might account for both diabetes and bone deroineralization. Multiple epiphyseal dysplasia is not characterized by osteoporosis or fractures. We found no evidence of osteoporosis in the surviving diabetic sibling, the nondiabetic siblings, or the parents. Two of the siblings had tooth discoloration and two had skin abnormalities, suggesting a possible link to ectodermal dysplasla. Multiple epiphyseal dysplasia may occur sporadically or may be inherited as an autosomal dominant trait. I n either case, it is characterized by symmetrical involvement of the epiphyses of the long bones and of the primary ossification centers of the tarsal and carpal bones. The epiphyses have irregular outlines, are often fragmented or stippled, and ossification centers are small. There may be some metaphyseal irregularity. The spine and skull are usually normal. T h e parents and the two nondiabetic siblings did not have radiologic or clinical evidence of this disorder, but we were able to demonstrate it in two of the diabetic siblings. No radiographs were obtained of Case 2 before her death, but she did have genu valgus. One case of multiple epiphyseal dysplasia and hyperglycemia associated with mental retardation has been reported by Norman. * The patient was a 15-year-old child with spatulate fingers, sparse coarse hair, large joints, and dwarfing. T h e glucose tolerance test was abnormal, and there were elevated levels of glycine, ornithine, and asparagine in the urine. The association of the diabetes and multiple epiphyseal dysplasia was thought to be coincidental. From the information which we have gathered, we can offer no unifying biochemical or physiologic mechanism to explain the simultaneous occurrence of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia~ and elements of ectodermal dysplasla in this family, but suggest that this may be a new syndrome. SUMMARY
Three siblings with onset of diabetes mellitus in infancy are reported. Two (and pos-
Volume 80 Number 2
sibly all three) of the c h i l d r e n also h a d m u l t i p l e epiphyseal dysplasia. Demineralization o f bone with m u l t i p l e fractures, t o o t h discoloration, a n d skin abnormalities were also observed. A unifying biochemical or physiologic m e c h a n i s m for the simultaneous a p p e a r a n c e of diabetes, epiphyseal dysplasia, a n d possible e c t o d e r m a l dysplasia has not suggested itself, b u t this m a y represent a new syndrome.
Brief clinical and laboratory observations
29 7
REFERENCES 1. Guest, G. M.: Diabetes mellitus in early infancy, treated without dietary restrictions, Acta Paediatr. 38: 196, 1949. 2. Imerslund, O.: The prognosis in diabetics with onset before age two, Acta Paediatr. 49: 243, 1960. 3. Kloss, J. L.: Transient diabetes in the newborn, Clin. Pediatr. 6: 303, 1967. 4. Norman, A. P.: Chondrodysplasia epiphysalis multiplex with diabetes mellitus and mental retardation, Proc. Roy. Soc. Med. 54: 333, 1961.
We are indebted to Dr. William McMain of Salt Lake City for referral of the cases for our study.
Pitfalls in prenatal diagnosis resulting from chromosomal mosaicism N a t a l i n e B. K a r d o n , M . D . , * P a t r i c e R. C h e r n a y , M.D.,* Lillian Y. Hsu, M.D.,
Joan L. M a r t i n , B.S., a n d K u r t Hirschhorn, M.D.,** N e w York, N. Y.
THE UTILIZATION of the technique of amniocentesis for purposes of p r e n a t a l diagnosis has achieved w i d e s p r e a d a c c l a i m ? W e r e p o r t here a n instance of p r e n a t a l cytogenetic studies in which a diagnosis of 45,X From the Division of Medical Genetics, Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York. Supported by United States Public Health Service Grant HD-02552. Reprint address: Lilllan Y. Hsu, M.D., Division o] Medical Genetics, Department ot Pediatrics, Mount Sinai School o[ Medicine of the City University oI New York, lOOth St. and Fi#h Ave., New York, N. Y. 10029. ~Unlted States Public Health Service Postdoctoral Trainee in Human Genet~os (HD-O0210). **Career Scientist o[ the Health Research Council o[ the City o[ New York (1-513).
was m a d e on the first amniofic fluid specimen obtained by amnlocentesls, a n d subsequent culture of the amniotic fluid o b t a i n e d at t h e time of abortion revealed 46,XY.
CASE REPORT Patient E. E., a 36-year-old Caucasian woman with no previous miscarriages or stillbirths and two living children, was referred to our laboratory when she was 15 weeks' pregnant. Amniocentesis had been performed because the patient had a 2~-year-old daughter with Tay-Sachs disease. Subsequent assay for hexosaminidase-A performed on both uncultured and cultured amniotic fluid cells revealed that the fetus was not affected. Because of the advanced maternal age, the cultured cells of multiple flasks from the initial amniocentesis were harvested for chromosome analysis (See Results). Pertinent family history was that Mr. E., 41 years of age, had been exposed to heavy doses of radiation for the treatment of acne at the age of 14. In addition both he and the patient were of Eastern European ancestry. The couple elected to have a therapeutic abortion on the basis of the cytogenetic studies obtained from the first specimen. A "salting-out" procedure using hypertonic saline was performed at 22 weeks' gestation. A male fetus was expelled and amniotic fluid, as well as specimens from the fetus, were obtained for tissue culture. Postmortem examination of the fetus revealed a normal male, and hlstologlc sections of the- testes were reported as normal testicular tissue.
Brief clinical and laboratory observations
The ]ournal of Pediatrics February 1972
of the m o u t h and pharynx without the need for the hands of attendants to be placed under the fluoroscope. It is possible to clamp the t u N n g so that feeding can be stopped. SUMMARY
A rapidly assembled device is described for use in feeding infants during fluoroscopy. It permits controlled feeding of the infant without the need for anyone to put their hands under a fluoroscope. REFERENCES
Fig. 2. The assembled device ready for use.
Infancy-onset cliabetes mellitus and multiple
epiphyseal dyyplasia Carol D e t t m a n W o l c o t t , M.D., and M a r v i n L. Rallison, M.D.,* Salt Lake City, Utah
From the Department of Pediatrics, University of Utah Medical Center. Supported in part by a grant from The Kror Foundation. *Reprint address: Department o~ Pediatrics University o] Utah Medical Center, 50 N. Medical Dr., Salt Lake City, Utah 84112.
1. Forster, A.: Die Spezialflasche und ihre Anundung bei der Rontgendurchleuchtung, Ann. Radiol. 11: 442, 1968. 2. Giedion, A.: Pacifier nipple (dummy) in pediatric radiology. A. Remote control pacifier. B. Radiological identification .of pacifiers as a cause of intestinal obstruction, Ann. Radiol. 11: 437, 1968. 3. Pozanski, A.: A simple device for administering barium to infants, Radiology 93: 1106, 1969. 4. Sittup Baby Bottle Insert: Noair Manufacturing Co., Inc., Farrningdale, N. Y. 5. Flexitron Anesthesia Extension Set R 33A: Travenol Laboratories, Inc., Morton Grove, Ill. 6. Venotube 30": Abbott Laboratories, North Chicago, Ill.
W E I~ A v ~. recently studied a family with three children who had onset of diabetes mellitus in early infancy; multiple epiphyseal dysplasia and abnormalties of the teeth and skin were also observed. T h e association of multiple epiphyseal dysplasia with infancyonset diabetes mellitus has never been reported to our knowledge and suggested to us that we might be dealing with a new familial syndrome. CASE REPORTS
Case 1. Patient J. S. S., a boy, was hospitalized at 8 weeks of age with the history of frequent urination of 2 weeks' duration. The infant's urine showed 4+ glucosuria. The blood sugar concentration was 500 rag. per 100 ml. The diabetes was stabilized with 10 units of Lente insulin daily. Later hospitalizations were required for treatment of hypoglycemia, diabetic
Volume 80 Number 2
Fig. 1A. Radiograph of Case 1, demonstrating multiple epiphyseal dysplasia, bone demineralization, and tubulation defects of metacarpals and phalanges. ketoacidosis, and three fractures of the femurs, which occurred over a 6 month period (two on the right and one on the left). Radiographs taken at the time of the child's first fracture showed diffuse demineralization of the bones. The child was admitted to the University of Utah Medical Center at 3 years of age because of the multiple fractures. An odd, stiff-kneed gait was noted, along with muscular atrophy and weakness of both legs, thought to be secondary to disuse and prolonged immobilization for treatment of the fractures. There was full range of motion in both hips, but limitation of knee flexion and elbow extension bilaterally. In addition, a brown mottling of the teeth near the gums and a cardiac murmur, thought to be functional, were noted. He was receiving 11 units of NPH insulin daily with supplements of regular insulin. Laboratory tests revealed glucosuria, acetonuria, and hyperglycemia (490 mg. per 100 ml.). Blood urea nitrogen ranged from 20 to 49 mg. per 100 ml.; serum creatinine and creatinine
Brief clinical and laboratory observations
29 3
clearance were normal. Intravenous urogram and voiding cystourethrogram were also normal. Values for blood electrolytes, serum proteins, alkaline phosphatase, SGOT, calcium, and phosphorus were normal. Radiographs of the pelvis and extremities showed diffuse demineralization. The epiphyses were small, irregular, and poorly calcified. There was prominent beaking of the metaphyses of the distal femora and proximal radii. There was also a tubulation defect of the metacarpals and phalanges. Radiographs of the skull and chest were normal (Fig. I). Biopsy of the iliac crest showed the cartilage ceils at the epiphyseal line to have a narrow zone of vacuolation. The zone of provisional calcification was practically nonexistent. Bone trabeculae of irregular width and orientation abutted directly onto the hypoplastic epiphyseal line. The bone trabeculae in the metaphysis contained small foci of incomplete ossification (Fig. 2). The biopsy and radiologic findings were consistent with the diagnosis of multiple epiphyseal dysplasia. Re-examination at 4~2 years of age showed relatively little change. Muscular atrophy of the lower extremities was again noted. There was limited abduction of both hips. Bilateral genu valgus was present. The gait was lordotic and waddling. The liver was enlarged, and, although SGOT was elevated to 104 m/z per milliliter, no other evidence of liver disease was found. Urinary excretion of mucopolysaccharides was normal (total uronic acid was 8 rag. per gram of creatinine). Urinary IT-ketosteroids were 1.7 rag. per day, and 17-hydroxycorticosteroids were 1.6 mg. per day. Radiographs revealed irregularity of most of the epiphyses of the long bones with some fragmentation and coarse trabeculation. There was bilateral coxa magna and coxa valga. The acetabular roofs were somewhat irregular. Case 2. Patient J. S., a girl, was hospitalized at 8 weeks of age with a brief history of irritability, fever, and vomiting. Physical examination at the time of admission revealed an emaciated, dehydrated irritable infant. A blood sugar concentration of 1,000+ mg. per 100 ml., glucosuria, and acetonuria led to recognition of diabetes mellitus. The child was treated with regular insulin and fluids. Grand mal seizures, which occurred the morning following admission, responded poorly to intravenous administration of glucose, although the blood sugar concentration prior to
294
Brief clinical and laboratory observations
The Journal of Pediatrics February 1972
Fig. lB. Radiograph of Case 1 demonstrating normal healing of femoral fractures.
Fig. 2. Biopsy from iliac crest in Case 1 showing dysplastic bone growth. The area of cartilage vacuolation is narrow and the zone of provisional calcification is essentially nonexistent.
administration was 40 mg. per 100 ml. Blood electrolyte values were normal. Blood urea nitrogen was 23 mg. per 100 ml., calcium 9.6 rag. per 100 ml., and phosphorus 7.2 mg. per 100 ml. The cerebrospinal fluid was normal. The child improved thereafter and was discharged 13 days after admission, well regulated on 6 units of Lente ittsulin daily, and with no apparent residuaI neurologic damage. However, the child continued to have seizures and was treated with anticonvulsant medication. Three subsequent hospitalizations were necessary for insulin-induced hypoglycemia. The fifth and final admission at 2~e years of age was marked by refractory hypoglycemia and urinary tract
infection with hemolytic E. coil Decreasing urine output and rising blood urea nitrogen led to a diagnosis of renal failure. The child died 4 days following admission; permission for autopsy was denied. At no time during any of the hospitalizations were abnormalities of the extremities noted by the examiners, and no history of fractures was obtained. However, genu vaIgus (a common clinical manifestation of multiple epiphyseal dysplasia) was evident on family photographs; no radiologic studies were made. She was noted to have tooth discoloration as welI as scaliness and "erratic" pigmentation bands of the skin, which were diagnosed as ectodermal dysplasia.
Volume 80 Number 2
Brie[ clinical and laboratory observations
295
Fig. 3. A and B, Radiographs of Case 3 demonstrating smaIl, dysplastic epiphyses.
Case 3. Patient C. S. was hospitalized at 6 weeks of age with the history of frequent urination since birth. Physical examination was normal. Laboratory tests revealed a mild anemia (volume packed red ceils 27 per cent, hemoglobin 10.5 Gm. per cent). Urinalysis showed glucosuria with no acetonuria. Fasting blood sugar values ranged from 102 to 155 rag. per I00 ml. Treatment with NPI-t insulin resulted in good control of hyperglycemia and glucosuria. I-Ie was seen at the University of Utah Medical Center at 14 months of age, The liver was
palpable 4 cm. below the right costal margin and the skin over the fingers, hams, toes, and dorsum of the feet was dry, smooth, and shiny. Hemogram was normal. Urinalysis showed no glucosuria or acetonnria, although the fasting blood sugar concentration was 300 rag. per 100 ml. Values for serum electrolytes, calcium, phosphorus, blood urea nitrogen, creatirfine, and blood proteins were normal. SGOT was 75 mu. per milliliter. Urinary excretion of mucopoly* saccharides was normal (total uronic acid was 17.7 rag. per gram of creatinine).
296
Brie[ clinical and laboratory observations
Skeletal survey revealed symmetrically small epiphyses. At the distal femur and proximal tibia, they were noted to be irregular in outline and poorly calcified (Fig. 3), consistent with the diagnosis of multiple epiphyseal dysplasia. FAMILY
HISTORY
Both parents were Caucasian with no history of consanguinity. Both were of above average height with no bony deformities. The mother had 7 pregnancies. T h e first, of 34 weeks' gestation, resulted in an infant who died at 2 months of age from a cerebral hemorrhage. The second and third pregnancies yielded normal female infants who are living and well. The fourth pregnancy resulted in Case 2. The fifth child was born prematurely and died shortly after birth. The mother's sixth and seventh pregnancies resulted in Cases 1 and 3. T w o maternal aunts and the maternal great-grandmother, now deceased, had diabetes mellitus. T h e paternal grandfather was said to have had "sugar in the urine." Oral glucose tolerance tests and skeletal surveys performed on both parents were normal. Skeletal surveys of the two living nondiabetic siblings were also normal. DISCUSSION
Diabetes mellitus is rarely found under the age of one year? Imerslund 2 found only 13 patients among the 3,847 juvenile diabetic patients followed by the Joslin Clinic from 1922 to 1956. True diabetes mellitus (as seen in our three patients) is insulin dependent, permanent, and has a predisposition for ketosis. Imerslund 2 found a positive family history in 51 per cent of the children diagnosed before one year of age. By contrast, in 20 cases of transient neonatal diabetes reviewed by Kloss 3 in 1967, in only one was there a family history of diabetes mellitus. We were not able to determine the etiology of the bone demineralization in Case 1. It was present at the time of his initial fracture and has persisted. Blood calcium and phosphorus values were normal, and there was no evidence, either by physical examination or laboratory determinations, to suggest a diag-
The Journal of Pediatrics February 1972
nosis of Cushing's syndrome, which might account for both diabetes and bone deroineralization. Multiple epiphyseal dysplasia is not characterized by osteoporosis or fractures. We found no evidence of osteoporosis in the surviving diabetic sibling, the nondiabetic siblings, or the parents. Two of the siblings had tooth discoloration and two had skin abnormalities, suggesting a possible link to ectodermal dysplasla. Multiple epiphyseal dysplasia may occur sporadically or may be inherited as an autosomal dominant trait. I n either case, it is characterized by symmetrical involvement of the epiphyses of the long bones and of the primary ossification centers of the tarsal and carpal bones. The epiphyses have irregular outlines, are often fragmented or stippled, and ossification centers are small. There may be some metaphyseal irregularity. The spine and skull are usually normal. T h e parents and the two nondiabetic siblings did not have radiologic or clinical evidence of this disorder, but we were able to demonstrate it in two of the diabetic siblings. No radiographs were obtained of Case 2 before her death, but she did have genu valgus. One case of multiple epiphyseal dysplasia and hyperglycemia associated with mental retardation has been reported by Norman. * The patient was a 15-year-old child with spatulate fingers, sparse coarse hair, large joints, and dwarfing. T h e glucose tolerance test was abnormal, and there were elevated levels of glycine, ornithine, and asparagine in the urine. The association of the diabetes and multiple epiphyseal dysplasia was thought to be coincidental. From the information which we have gathered, we can offer no unifying biochemical or physiologic mechanism to explain the simultaneous occurrence of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia~ and elements of ectodermal dysplasla in this family, but suggest that this may be a new syndrome. SUMMARY
Three siblings with onset of diabetes mellitus in infancy are reported. Two (and pos-
Volume 80 Number 2
sibly all three) of the c h i l d r e n also h a d m u l t i p l e epiphyseal dysplasia. Demineralization o f bone with m u l t i p l e fractures, t o o t h discoloration, a n d skin abnormalities were also observed. A unifying biochemical or physiologic m e c h a n i s m for the simultaneous a p p e a r a n c e of diabetes, epiphyseal dysplasia, a n d possible e c t o d e r m a l dysplasia has not suggested itself, b u t this m a y represent a new syndrome.
Brief clinical and laboratory observations
29 7
REFERENCES 1. Guest, G. M.: Diabetes mellitus in early infancy, treated without dietary restrictions, Acta Paediatr. 38: 196, 1949. 2. Imerslund, O.: The prognosis in diabetics with onset before age two, Acta Paediatr. 49: 243, 1960. 3. Kloss, J. L.: Transient diabetes in the newborn, Clin. Pediatr. 6: 303, 1967. 4. Norman, A. P.: Chondrodysplasia epiphysalis multiplex with diabetes mellitus and mental retardation, Proc. Roy. Soc. Med. 54: 333, 1961.
We are indebted to Dr. William McMain of Salt Lake City for referral of the cases for our study.
Pitfalls in prenatal diagnosis resulting from chromosomal mosaicism N a t a l i n e B. K a r d o n , M . D . , * P a t r i c e R. C h e r n a y , M.D.,* Lillian Y. Hsu, M.D.,
Joan L. M a r t i n , B.S., a n d K u r t Hirschhorn, M.D.,** N e w York, N. Y.
THE UTILIZATION of the technique of amniocentesis for purposes of p r e n a t a l diagnosis has achieved w i d e s p r e a d a c c l a i m ? W e r e p o r t here a n instance of p r e n a t a l cytogenetic studies in which a diagnosis of 45,X From the Division of Medical Genetics, Department of Pediatrics, Mount Sinai School of Medicine of the City University of New York. Supported by United States Public Health Service Grant HD-02552. Reprint address: Lilllan Y. Hsu, M.D., Division o] Medical Genetics, Department ot Pediatrics, Mount Sinai School o[ Medicine of the City University oI New York, lOOth St. and Fi#h Ave., New York, N. Y. 10029. ~Unlted States Public Health Service Postdoctoral Trainee in Human Genet~os (HD-O0210). **Career Scientist o[ the Health Research Council o[ the City o[ New York (1-513).
was m a d e on the first amniofic fluid specimen obtained by amnlocentesls, a n d subsequent culture of the amniotic fluid o b t a i n e d at t h e time of abortion revealed 46,XY.
CASE REPORT Patient E. E., a 36-year-old Caucasian woman with no previous miscarriages or stillbirths and two living children, was referred to our laboratory when she was 15 weeks' pregnant. Amniocentesis had been performed because the patient had a 2~-year-old daughter with Tay-Sachs disease. Subsequent assay for hexosaminidase-A performed on both uncultured and cultured amniotic fluid cells revealed that the fetus was not affected. Because of the advanced maternal age, the cultured cells of multiple flasks from the initial amniocentesis were harvested for chromosome analysis (See Results). Pertinent family history was that Mr. E., 41 years of age, had been exposed to heavy doses of radiation for the treatment of acne at the age of 14. In addition both he and the patient were of Eastern European ancestry. The couple elected to have a therapeutic abortion on the basis of the cytogenetic studies obtained from the first specimen. A "salting-out" procedure using hypertonic saline was performed at 22 weeks' gestation. A male fetus was expelled and amniotic fluid, as well as specimens from the fetus, were obtained for tissue culture. Postmortem examination of the fetus revealed a normal male, and hlstologlc sections of the- testes were reported as normal testicular tissue.