Volume 86 Number 3
6. Ehlers KH, Engle MA, Levin AR, and Deely WJ: Eccentric ventricular hypertrophy in familial and sporadic instances of 46 XX, XY Turner phenotype, Circulation 45:639, 1972. 7. Phornphutkul C, Rosenthal A, and Nadas AS: Cardiomyopathy in Noonan's syndrome, Br Heart J 35:99, 1973. 8. Ellis FR, Keaney NP, Harriman DGF, Sumner DW, Kyei-Mensah K, Tyrrell JH, Hargreaves JE, Parikit RK, and Mulrooney PL: Screening for malignant hyperpyrexia, Br Med J 3:559, 1972.
Agents responsiblefor infection in chronic granulomatous disease of childhood George M. Lazarus, M.D., and Harold C. Neu,
M.D.,* New York, N. Y.
CHRONIC GRANULOMATOUS DISEASE of childhood is characterized by the inability of polymorphonuclear leukocytes to destroy ingested microorganisms which possess catalase. 1 Various metabolic defects have been proposed to explain the functional disorder. Chronic granulomatous disease may be inherited as a sex-linked or autosomal recessive trait. Patients have recurrent infections caused by Staphylococcus aureus, certain fungi, and many gram-negative organisms. 2 The most comm o n i n f e c t i o n s are s u p p t i r a t i v e adenitis and pneumonia, b u t o s t e o m y e l i t i s , hepatic and s u b p h r e n i c a b s c e s s e s , and s e p t i c e m i a are not u n c o m m o n . The quantitative nitroblue tetrazolium dye reduction test and in vitro tests of bacter!cidal capacity of phagocytes have made the diagnosis of the disease relatively simple. There is no effective therapy for CGD and most patients die b e f o r e a d o l e s c e n c e . T h e r a p e u t i c m e a s u r e s which have been employed in an attempt.to prevent infection have i n c l u d e d the a d m i n i s t r a t i o n o f g a m m a globulin, leukocyte transfusions, busulfan, female sex h o r m o n e s , a n t i t u b e r c u l o u s and antifungal agents, From the Babies Hospital, The Children's Medical and Surgical Center, and the Departments of Pediatrics, and Medicine, College of Physicians and Surgeons, Columbia University. *Reprint address: Department of Medicine, Columbia University, 630 W, 168thSt., New York, N. Y. 10032.
Brief clinical and laboratory observations
415
9. Kyei-Mensah K, Tyrrell JH, and Sumner DW: Clinical and genetic aspects of malignant hyperpyrexia, Proc R Soc Med 66:63, 1973. 10. Bradley WG, and Murchison D: Screening for malignant hyperpyrexia, Br Med J 4:108, 1972. 11. Ellis FR, and Harriman DGF: A new screening test for susceptibility to malignant hyperpyrexia, Br J Anaesth 45:638, 1973.
methylene blue, vitamin A, corticosteroids, irradiation, and immunizations with bacterial "toxoids." Recently, c o n t i n u o u s p r o p h y l a c t i c a n t i b i o t i c t h e r a p y with a penicillinase-resistant penicillin has been advocated for CGD p a t i e n t s ) Prophylactic treatment with a penicillinase-resistant penicillin can be expected to encourage infection with gram-negative bacilli, including Salmonella, and fungi by altering the normal bacterial flora#, s If most serious and fatal infections in CGD patients were actually due to gram-negative bacteria and fungi, such prophylactic therapy might be inadvisable. This study was undertaken to evaluate this risk. Abbreviation used CGD: chronic granulomatous disease
PATIENT
MATERIAL
We have surveyed all previously reported cases of CGD, and reviewed our own experience with nine patients. Only reports of infections from which the causative agent was clearly identified were utilized. Infection was considered fatal if it contributed directly to the patient's death. Our nine patients were seen between March 1958 and July 1971. They came from six white families, each of which had histories typical for CGD. The ages of the patients when first seen ranged from 17 days to 22 months. In six patients the diagnosis of C G D was confirmed by quantitative NBT test a n d / o r in vitro s t u d i e s of phagocytic function. A seventh patient, who died at age 17 days from d i s s e m i n a t e d aspergillosis, had two brothers with proved CGD. The remaining two patients were brothers; one died at 10 months of age from pneumonia caused by a paracolon bacillus; at autopsy generalized granulomas were noted. Three patients are well at 3, 4, and 16 years of age,
4 16
Brief clinical and laboratory observations
The Journal of Pediatrics March 1975
Table I. Organisms producing sepsis or death in CGD patients Published reports*
Babies Hospital
Sepsis [ Fatal Sepsis [ Fatal Salmonella Staphylococcus aureus Pseudomonas Escherichia coli Serratia Klebsiella Paracolon bacillus Enterobacter A lkaligenesfecalis Chromobacteriumjanthinum Herellea Candida Aspergillus Nocardia Totals
11 5 2
5 2 3
1 1 1
1 l 1
1 1 1 1
4
1
1 1
1
1
1
7
4
1 1 1 1
2 1
1
26
20
*Seventy patients reported previously. "]'Brotherof patient. respectively. Three patients left our care at ages 2, 2, and 8 years, respectively. In addition to the two deaths noted above, a third death caused by Salmonella septicemia occurred in an l l - y e a r - o l d child. His brother, not admitted to our hospital, died of generalized nocardiosis at another hospital at a g e 4 89 months. A t autopsy generalized granulomas were noted. RESULTS Patients at Babies Hospital. The causative agent was identified in 50 infections in our nine patients. The most common infection was suppurative adenitis (20 out of 50), but there were also seven episodes of sepsis, three hepatic abscesses, two cases of osteomyelitis, two perinephric abscesses, and one brain abscess. Sixteen different organisms were cultured from these 50 infections. Staph. aureus was recovered most often, b u t from l y m p h a d e n i t i s . N o n e o f the p a t i e n t s had staphylococcal sepsis. Four of the seven episodes of sepsis (Table I), were due to Salmonella; one each was due to enterobacter, aspergillus, and paracolon organisms. Three of the episodes of Salmonella sepsis occurred in patients who were receiving oxacillin. One patient had been receiving oxacillin for 6 weeks after discharge from the hospital when he developed sepsis due to S. typhimurium. One had been receiving oxacillin for two weeks and was admitted to the hospital with S. typhimurium septicemia and died with dissemi-
nated intravascular coagulation. The third patient had b e e n receiving oxacillin for 5 months when he developed sepsis with S. oranienberg. Cases reported in the literature. Pertinent culture information was available for 70 patients with CGD previously reported. In 202 infections the causative a g e n t s were identified. The most common infection was suppurative lymphadenitis (93/202), b u t more serious infections occurred frequently. There were 24 episodes of sepsis, 20 episodes of hepatic abscess, 17 patients with osteomye'litis, and 15 pneumonias for which the causative agent was known. Infections led directly to death in 20 patients. Eighteen different organisms were recovered. Staph. aureus was cultured from the site in 53% of infections, primarily from patients with suppurative adenitis. A n organism other than Staph. aureus was cultured in 52% of the infections; salmonella was isolated from ten percent and Escherichia eoli from eight percent. Eleven different organisms were isolated from the 24 cases o f septicemia. S a l m o n e l l a was c u l t u r e d in 11 episodes.2, 6, 8There were only five cases of Staph. aureus sepsis; 79% of the septicemias were due to other organisms. Salmonella was responsible for 25% of the fatal infections (5 of 20), and 90% of fatal infections were caused by organisms other than Staph. aureus. DISCUSSION Although Staph. aureus is the organism cultured most frequently from patients with CGD, life-threatening infections in these patients are more often caused by other organisms. Staph. aureus was responsible for 52% of all the infections reviewed, but this organism was m o s t o f t e n isolated f r o m s u p p u r a t i v e l y m p h n o d e s , which can be treated adequately with incision, drainage, and an appropriate antibiotic. Staph. aureus was the agent involved in 16% of sep 7 ticemias and 9% of fatal infections; whereas gram-negative bacteria accounted for 80% of fatalities. Salmonella was responsible for more episodes of sepsis and fatalities than any other organism. W e t h i n k that the use of p r o p h y l a c t i c a n t i s t a p h ylococcal therapy may have contributed to the three episodes of Salmonella bacteremia that our CGD patients developed. The use of the penicillinase-resistant penicillin may have not been of any importance, since published reports of C G D patients indicate that gramnegative sepsis has been common. However, the reports do not detail the p r e c e d i n g a n t i b i o t i c t h e r a p y which was employed. W e propose that there are insufficient data to prove that prophylactic antibiotic therapy for CGD patients is beneficial, and we suggest that each
Volume 86 Number 3
B r i e f cfinical and laboratory observations
episode of infection should be treated with an appropriate antibiotic chosen on the basis of Gram stains, cultures, and bacterial sensitivities. We wish to thank Drs. R. E. Behrman, R. S. Asnes, and J. Silverman for suggestions.
4.
5.
REFERENCES 1. Good RA, Quie PG, Windhorst DB, Page AR, Rodey GE, White J, Wolfgon J J, and Holmes BH: Fatal (chronic) granulomatous disease of childhood: a hereditary defect of leukocyte function, Semin Hematol 5:215, 1968. 2. Johnston RB Jr, and Baehner RL: Chronic granulomatous disease: correlation between pathogenesis and clinical findings, Pediatrics 48:730, 1971. 3. Philippart AI, Colodny AH, and Baehner RL: Continuous
Fontanel size and epiphyseal ossification in neonatal twins discordant by weight Alistair G. S. Philip, M.B., M.R.C.P.(E.), D.C.H., Burlington, Vt.
IN A PREVIOUS STUDY, infants who were born with intrauterine growth retardation had delayed epiphyseal ossification at the knee when anterior fontanel size was large, 1which confirmed the report by Scott and Usher 2 that m a n y i n f a n t s with I U G R have no epiphyseal ossification at the knee. The present report is confined to infants who were discordant by weight at birth, 3 where the smaller twin can definitely be regarded as small for date ( I U G R ) , and the larger twin acts as a "normal" control (although occasionally also undernourished). One may assume that the genetic pool from which the twins draw, and socioeconomic, demographic, and other factors (e.g., parity, gestation) are comparable, but that the prenatal e n v i r o n m e n t may have b e e n different w i t h i n their respective fetoplacental units. MATERIALS
AND METHODS
Thirteen pairs of discordant twins in whom the smaller twin was at least 20% lighter than the larger twin were examined. In all cases the gestational age was conFrom the University o f Hawaii Medical School Reprint address:Medical CenterHospitalof Vermont,,~,lary Fletcher Unit, Burlington, Vt. 05401.
6. 7.
8.
417
antibiotic therapy in chronic granulomatous disease: Preliminary communication, Pediatrics 50:923, 1972. McCurdy RS, and Neter E: Effects of penicillin and broad spectrum antibiotics on the emergence of a gram-negative bacillary flora in the upper respiratory tract of infants, Pediatrics 9:572, 1952. Hook EW: Salmonellosis: Certain factors influencing the interaction of salmonella and the human host, Bull NY Acad Med 37:499, 1961. Johnston RB, and McMurry JS: Chronic familial granulomatosis, Am J Dis Child 11,1:370, 1967. Azimi PH, Bodenbender JG, Hintz RL, and Kontras SB: Chronic granulomatous disease in 3 fem~ile siblings, JAMA 206:2865, 1968. Balfour HH, Shehan J J, Speicker CE, and Kauder E: Chronic granulomatous disease of childhood in a 23-yearold man, JAMA 217:960, 1971.
firmed as term (38-42 weeks), except for one twin pair born at 36 weeks' gestation but examined at age one month. All babies were evaluated by the scoring system of Dubowitz and associates.4 Weight was determined on arrival in the nursery, but other measurements were performed on the second or third day, as described previously. 1T h e size of the anterior fontanel was obtained by outlining the fontanel on pliable paper placed over the scalp. The diamond shape formed by tangential lines provides the area of the fontanel.1 Abbreviation used IUGR: intrauterine growth retardation RESULTS Details of the infants are given in Table I. The term infants included in this investigation had a wide range of birth weights. The difference in mean weight, between twin pairs was 794 gm, with the range of 426 to 1,092 gm (21-51%). Five infants with fontanel area greater than 4 cm 2 had greatly reduced epiphyseal ossification, and this finding was also noted in nine of ten infants with fontanel area greater than 3 cm 2. Analysis of all infants revealed a highly significant negative correlation of anterior fontanel size and epiphyseal ossification at the knee (p (0.01). If only the lighter of a discordant twin pair is considered, nine of 13 had markedly retarded epiphyseal ossification, and the four with adequate ossification had a fontanel area less than 2.5 cm 2. There was a significant positive correlation (p ( 0 . 0 5 ) b e t w e e n epiphyseal ossification and birth weight.
6. Ehlers KH, Engle MA, Levin AR, and Deely WJ: Eccentric ventricular hypertrophy in familial and sporadic instances of 46 XX, XY Turner phenotype, Circulation 45:639, 1972. 7. Phornphutkul C, Rosenthal A, and Nadas AS: Cardiomyopathy in Noonan's syndrome, Br Heart J 35:99, 1973. 8. Ellis FR, Keaney NP, Harriman DGF, Sumner DW, Kyei-Mensah K, Tyrrell JH, Hargreaves JE, Parikit RK, and Mulrooney PL: Screening for malignant hyperpyrexia, Br Med J 3:559, 1972.
Agents responsiblefor infection in chronic granulomatous disease of childhood George M. Lazarus, M.D., and Harold C. Neu,
M.D.,* New York, N. Y.
CHRONIC GRANULOMATOUS DISEASE of childhood is characterized by the inability of polymorphonuclear leukocytes to destroy ingested microorganisms which possess catalase. 1 Various metabolic defects have been proposed to explain the functional disorder. Chronic granulomatous disease may be inherited as a sex-linked or autosomal recessive trait. Patients have recurrent infections caused by Staphylococcus aureus, certain fungi, and many gram-negative organisms. 2 The most comm o n i n f e c t i o n s are s u p p t i r a t i v e adenitis and pneumonia, b u t o s t e o m y e l i t i s , hepatic and s u b p h r e n i c a b s c e s s e s , and s e p t i c e m i a are not u n c o m m o n . The quantitative nitroblue tetrazolium dye reduction test and in vitro tests of bacter!cidal capacity of phagocytes have made the diagnosis of the disease relatively simple. There is no effective therapy for CGD and most patients die b e f o r e a d o l e s c e n c e . T h e r a p e u t i c m e a s u r e s which have been employed in an attempt.to prevent infection have i n c l u d e d the a d m i n i s t r a t i o n o f g a m m a globulin, leukocyte transfusions, busulfan, female sex h o r m o n e s , a n t i t u b e r c u l o u s and antifungal agents, From the Babies Hospital, The Children's Medical and Surgical Center, and the Departments of Pediatrics, and Medicine, College of Physicians and Surgeons, Columbia University. *Reprint address: Department of Medicine, Columbia University, 630 W, 168thSt., New York, N. Y. 10032.
Brief clinical and laboratory observations
415
9. Kyei-Mensah K, Tyrrell JH, and Sumner DW: Clinical and genetic aspects of malignant hyperpyrexia, Proc R Soc Med 66:63, 1973. 10. Bradley WG, and Murchison D: Screening for malignant hyperpyrexia, Br Med J 4:108, 1972. 11. Ellis FR, and Harriman DGF: A new screening test for susceptibility to malignant hyperpyrexia, Br J Anaesth 45:638, 1973.
methylene blue, vitamin A, corticosteroids, irradiation, and immunizations with bacterial "toxoids." Recently, c o n t i n u o u s p r o p h y l a c t i c a n t i b i o t i c t h e r a p y with a penicillinase-resistant penicillin has been advocated for CGD p a t i e n t s ) Prophylactic treatment with a penicillinase-resistant penicillin can be expected to encourage infection with gram-negative bacilli, including Salmonella, and fungi by altering the normal bacterial flora#, s If most serious and fatal infections in CGD patients were actually due to gram-negative bacteria and fungi, such prophylactic therapy might be inadvisable. This study was undertaken to evaluate this risk. Abbreviation used CGD: chronic granulomatous disease
PATIENT
MATERIAL
We have surveyed all previously reported cases of CGD, and reviewed our own experience with nine patients. Only reports of infections from which the causative agent was clearly identified were utilized. Infection was considered fatal if it contributed directly to the patient's death. Our nine patients were seen between March 1958 and July 1971. They came from six white families, each of which had histories typical for CGD. The ages of the patients when first seen ranged from 17 days to 22 months. In six patients the diagnosis of C G D was confirmed by quantitative NBT test a n d / o r in vitro s t u d i e s of phagocytic function. A seventh patient, who died at age 17 days from d i s s e m i n a t e d aspergillosis, had two brothers with proved CGD. The remaining two patients were brothers; one died at 10 months of age from pneumonia caused by a paracolon bacillus; at autopsy generalized granulomas were noted. Three patients are well at 3, 4, and 16 years of age,
4 16
Brief clinical and laboratory observations
The Journal of Pediatrics March 1975
Table I. Organisms producing sepsis or death in CGD patients Published reports*
Babies Hospital
Sepsis [ Fatal Sepsis [ Fatal Salmonella Staphylococcus aureus Pseudomonas Escherichia coli Serratia Klebsiella Paracolon bacillus Enterobacter A lkaligenesfecalis Chromobacteriumjanthinum Herellea Candida Aspergillus Nocardia Totals
11 5 2
5 2 3
1 1 1
1 l 1
1 1 1 1
4
1
1 1
1
1
1
7
4
1 1 1 1
2 1
1
26
20
*Seventy patients reported previously. "]'Brotherof patient. respectively. Three patients left our care at ages 2, 2, and 8 years, respectively. In addition to the two deaths noted above, a third death caused by Salmonella septicemia occurred in an l l - y e a r - o l d child. His brother, not admitted to our hospital, died of generalized nocardiosis at another hospital at a g e 4 89 months. A t autopsy generalized granulomas were noted. RESULTS Patients at Babies Hospital. The causative agent was identified in 50 infections in our nine patients. The most common infection was suppurative adenitis (20 out of 50), but there were also seven episodes of sepsis, three hepatic abscesses, two cases of osteomyelitis, two perinephric abscesses, and one brain abscess. Sixteen different organisms were cultured from these 50 infections. Staph. aureus was recovered most often, b u t from l y m p h a d e n i t i s . N o n e o f the p a t i e n t s had staphylococcal sepsis. Four of the seven episodes of sepsis (Table I), were due to Salmonella; one each was due to enterobacter, aspergillus, and paracolon organisms. Three of the episodes of Salmonella sepsis occurred in patients who were receiving oxacillin. One patient had been receiving oxacillin for 6 weeks after discharge from the hospital when he developed sepsis due to S. typhimurium. One had been receiving oxacillin for two weeks and was admitted to the hospital with S. typhimurium septicemia and died with dissemi-
nated intravascular coagulation. The third patient had b e e n receiving oxacillin for 5 months when he developed sepsis with S. oranienberg. Cases reported in the literature. Pertinent culture information was available for 70 patients with CGD previously reported. In 202 infections the causative a g e n t s were identified. The most common infection was suppurative lymphadenitis (93/202), b u t more serious infections occurred frequently. There were 24 episodes of sepsis, 20 episodes of hepatic abscess, 17 patients with osteomye'litis, and 15 pneumonias for which the causative agent was known. Infections led directly to death in 20 patients. Eighteen different organisms were recovered. Staph. aureus was cultured from the site in 53% of infections, primarily from patients with suppurative adenitis. A n organism other than Staph. aureus was cultured in 52% of the infections; salmonella was isolated from ten percent and Escherichia eoli from eight percent. Eleven different organisms were isolated from the 24 cases o f septicemia. S a l m o n e l l a was c u l t u r e d in 11 episodes.2, 6, 8There were only five cases of Staph. aureus sepsis; 79% of the septicemias were due to other organisms. Salmonella was responsible for 25% of the fatal infections (5 of 20), and 90% of fatal infections were caused by organisms other than Staph. aureus. DISCUSSION Although Staph. aureus is the organism cultured most frequently from patients with CGD, life-threatening infections in these patients are more often caused by other organisms. Staph. aureus was responsible for 52% of all the infections reviewed, but this organism was m o s t o f t e n isolated f r o m s u p p u r a t i v e l y m p h n o d e s , which can be treated adequately with incision, drainage, and an appropriate antibiotic. Staph. aureus was the agent involved in 16% of sep 7 ticemias and 9% of fatal infections; whereas gram-negative bacteria accounted for 80% of fatalities. Salmonella was responsible for more episodes of sepsis and fatalities than any other organism. W e t h i n k that the use of p r o p h y l a c t i c a n t i s t a p h ylococcal therapy may have contributed to the three episodes of Salmonella bacteremia that our CGD patients developed. The use of the penicillinase-resistant penicillin may have not been of any importance, since published reports of C G D patients indicate that gramnegative sepsis has been common. However, the reports do not detail the p r e c e d i n g a n t i b i o t i c t h e r a p y which was employed. W e propose that there are insufficient data to prove that prophylactic antibiotic therapy for CGD patients is beneficial, and we suggest that each
Volume 86 Number 3
B r i e f cfinical and laboratory observations
episode of infection should be treated with an appropriate antibiotic chosen on the basis of Gram stains, cultures, and bacterial sensitivities. We wish to thank Drs. R. E. Behrman, R. S. Asnes, and J. Silverman for suggestions.
4.
5.
REFERENCES 1. Good RA, Quie PG, Windhorst DB, Page AR, Rodey GE, White J, Wolfgon J J, and Holmes BH: Fatal (chronic) granulomatous disease of childhood: a hereditary defect of leukocyte function, Semin Hematol 5:215, 1968. 2. Johnston RB Jr, and Baehner RL: Chronic granulomatous disease: correlation between pathogenesis and clinical findings, Pediatrics 48:730, 1971. 3. Philippart AI, Colodny AH, and Baehner RL: Continuous
Fontanel size and epiphyseal ossification in neonatal twins discordant by weight Alistair G. S. Philip, M.B., M.R.C.P.(E.), D.C.H., Burlington, Vt.
IN A PREVIOUS STUDY, infants who were born with intrauterine growth retardation had delayed epiphyseal ossification at the knee when anterior fontanel size was large, 1which confirmed the report by Scott and Usher 2 that m a n y i n f a n t s with I U G R have no epiphyseal ossification at the knee. The present report is confined to infants who were discordant by weight at birth, 3 where the smaller twin can definitely be regarded as small for date ( I U G R ) , and the larger twin acts as a "normal" control (although occasionally also undernourished). One may assume that the genetic pool from which the twins draw, and socioeconomic, demographic, and other factors (e.g., parity, gestation) are comparable, but that the prenatal e n v i r o n m e n t may have b e e n different w i t h i n their respective fetoplacental units. MATERIALS
AND METHODS
Thirteen pairs of discordant twins in whom the smaller twin was at least 20% lighter than the larger twin were examined. In all cases the gestational age was conFrom the University o f Hawaii Medical School Reprint address:Medical CenterHospitalof Vermont,,~,lary Fletcher Unit, Burlington, Vt. 05401.
6. 7.
8.
417
antibiotic therapy in chronic granulomatous disease: Preliminary communication, Pediatrics 50:923, 1972. McCurdy RS, and Neter E: Effects of penicillin and broad spectrum antibiotics on the emergence of a gram-negative bacillary flora in the upper respiratory tract of infants, Pediatrics 9:572, 1952. Hook EW: Salmonellosis: Certain factors influencing the interaction of salmonella and the human host, Bull NY Acad Med 37:499, 1961. Johnston RB, and McMurry JS: Chronic familial granulomatosis, Am J Dis Child 11,1:370, 1967. Azimi PH, Bodenbender JG, Hintz RL, and Kontras SB: Chronic granulomatous disease in 3 fem~ile siblings, JAMA 206:2865, 1968. Balfour HH, Shehan J J, Speicker CE, and Kauder E: Chronic granulomatous disease of childhood in a 23-yearold man, JAMA 217:960, 1971.
firmed as term (38-42 weeks), except for one twin pair born at 36 weeks' gestation but examined at age one month. All babies were evaluated by the scoring system of Dubowitz and associates.4 Weight was determined on arrival in the nursery, but other measurements were performed on the second or third day, as described previously. 1T h e size of the anterior fontanel was obtained by outlining the fontanel on pliable paper placed over the scalp. The diamond shape formed by tangential lines provides the area of the fontanel.1 Abbreviation used IUGR: intrauterine growth retardation RESULTS Details of the infants are given in Table I. The term infants included in this investigation had a wide range of birth weights. The difference in mean weight, between twin pairs was 794 gm, with the range of 426 to 1,092 gm (21-51%). Five infants with fontanel area greater than 4 cm 2 had greatly reduced epiphyseal ossification, and this finding was also noted in nine of ten infants with fontanel area greater than 3 cm 2. Analysis of all infants revealed a highly significant negative correlation of anterior fontanel size and epiphyseal ossification at the knee (p (0.01). If only the lighter of a discordant twin pair is considered, nine of 13 had markedly retarded epiphyseal ossification, and the four with adequate ossification had a fontanel area less than 2.5 cm 2. There was a significant positive correlation (p ( 0 . 0 5 ) b e t w e e n epiphyseal ossification and birth weight.
