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CLINICAL AND LABORATORY OBSERVATIONS Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency Vijaya Prasad, MB,BS, Fenella Greig, MD, DPhil,* William Bastian, MD, Salvador Castells, ME), Christina Juan, MS, and Theodore W. AvRuskin, ME) From the Divisions of Pediatric Endocrinology and Metabolism, Department of Pediatrics, The Brookdale Hospital Medical Center and the State University of New York Health Science Cen- ter at Brooklyn Slipped capital femoral epiphysis occurs most commonly in children during the peripubertal period and is associated with trauma or obesity I or, less frequently, with endocrine imbalance, including growth hormone deficiency 25 and hypothyroidism.6 In a retrospective study of children with GH deficiency, 21 children with SCFE were identified among 7719 patients on GH registries. This cumulative in- cidence of 272 per 100,000 significantly exceeded the expected values (45/100,000 girls and 123/100,000 boys5,7). The majority of cases previously described had GH deficiency associated with brain tumors, structural ab- normalities, or trauma. 24 All of 11 children with additional endocrine data were described as having multiple pituitary deficiencies.4, 5 Pituitary-derived GH was available for only the most severely affected patients. Currently, children with partial GH deficiency or other forms of short stature may receive GH treatment. We report two patients with isolated, idiopathic GH deficiency and one with Turner syndrome in whom SCFE developed during treatment with recombinant GH. METHODS Evaluation for short stature included one or more stan- dard GH provocative tests with arginine, 0.5 gm/kg administered as an intravenous infusion for 30 minutes, in- sulin-induced hypoglycemia, 0.l U/kg administered as an intravenous bolus, or levodopa, 500 mg administered orally. Deficiency of GH was defined as a peak GH response _< 10.0 Supported in part by the HANID Foundation (Dr. AvRuskin). Submitted for publication July 11, 1989; accepted Oct. 6, 1989. Reprint requests: Vijaya Prashd, MB, BS, Interfaith Medical Center, 1545 Atlantic Ave., Brooklyn, NY 11213. *Current address: Mount Sinai Medical Center, Box 1198, One Gustave L. Levy Place, New York, NY 10029. 9/22/17101 ng/ml, measured by double-antibody radioimmunoassay. Spontaneous GH secretion was evaluated by continuous blood withdrawal by pump, with collection of samples every 30 minutes for 24 hours. Deficient response was defined by this integrated concentration of GH of <3.2 ng/ml. 8 Bone age radiographs were interpreted by a single pediatric ra- diologist. Bone density measurement was performed by ra- diographic photodensitometry 9 by R. S. Bachtell, Clinical Radiology Testing Laboratory, Yellow Springs, Ohio. This method measures the ratio of bone mineral mass to bone image area of the second, third, and fourth middle phalan- ges of a hand radiograph scanned by computer-controlled microdensitometer; the result is compared with a large group of age- and sex-matched normal subjects,9 and is ex- pressed as a standard deviation score for chronologic and SCFE Slipped capital femoral epiphysis GH Growth hormone See related article, p. 400. bone age. Bone density was measured before treatment in patients 1 and 2 and at diagnosis of SCFE in patient 3. All three patients had heights below the 3rd percentile for age and for mid-parental height; bone age was delayed >2 SD for chronologic age, and growth rates were ~<4.1 cm/yr (Table). Apart from short stature, all three patients had no evidence of other systemic disease, and they denied previ- ous bone or joint injury. Periodic blood cell count and serum chemistry values were normall CASE REPORTS Patient I. Patient 1 had isolated, idiopathic GH deficiencywith peak GH responses of 4.1 ng/ml (arginine) and 10.0 ng/ml (insulin), and integrated GH concentration of 1.1 ng/ml. At the 397

Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency

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Page 1: Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency

CLINICAL AND LABORATORY OBSERVATIONS

Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency

V i j a y a Prasad, MB,BS, Fene l la Gre ig , MD, DPhil,* Wi l l iam Bast ian, MD, S a l v a d o r Caste l ls , ME), Chr is t ina Juan , MS, a n d T h e o d o r e W. AvRuskin, ME)

From the Divisions of Pediatric Endocrinology and Metabolism, Department of Pediatrics, The Brookdale Hospital Medical Center and the State University of New York Health Science Cen- ter at Brooklyn

Slipped capital femoral epiphysis occurs most commonly in children during the peripubertal period and is associated with trauma or obesity I or, less frequently, with endocrine imbalance, including growth hormone deficiency 25 and hypothyroidism. 6 In a retrospective study of children with

GH deficiency, 21 children with SCFE were identified among 7719 patients on GH registries. This cumulative in- cidence of 272 per 100,000 significantly exceeded the expected values (45/100,000 girls and 123/100,000 boys 5,7). The majority of cases previously described had GH deficiency associated with brain tumors, structural ab- normalities, or trauma. 24 All of 11 children with additional endocrine data were described as having multiple pituitary deficiencies.4, 5 Pituitary-derived GH was available for only

the most severely affected patients. Currently, children with partial GH deficiency or other forms of short stature may receive GH treatment. We report two patients with isolated, idiopathic GH deficiency and one with Turner syndrome in whom SCFE developed during treatment with recombinant GH.

M E T H O D S

Evaluation for short stature included one or more stan- dard GH provocative tests with arginine, 0.5 gm/kg administered as an intravenous infusion for 30 minutes, in- sulin-induced hypoglycemia, 0.l U/kg administered as an intravenous bolus, or levodopa, 500 mg administered orally. Deficiency of GH was defined as a peak GH response _< 10.0

Supported in part by the HANID Foundation (Dr. AvRuskin). Submitted for publication July 11, 1989; accepted Oct. 6, 1989. Reprint requests: Vijaya Prashd, MB, BS, Interfaith Medical Center, 1545 Atlantic Ave., Brooklyn, NY 11213. *Current address: Mount Sinai Medical Center, Box 1198, One Gustave L. Levy Place, New York, NY 10029. 9/22/17101

ng/ml, measured by double-antibody radioimmunoassay. Spontaneous GH secretion was evaluated by continuous blood withdrawal by pump, with collection of samples every 30 minutes for 24 hours. Deficient response was defined by this integrated concentration of GH of <3.2 ng/ml. 8 Bone age radiographs were interpreted by a single pediatric ra- diologist. Bone density measurement was performed by ra- diographic photodensitometry 9 by R. S. Bachtell, Clinical Radiology Testing Laboratory, Yellow Springs, Ohio. This method measures the ratio of bone mineral mass to bone image area of the second, third, and fourth middle phalan- ges of a hand radiograph scanned by computer-controlled microdensitometer; the result is compared with a large group of age- and sex-matched normal subjects, 9 and is ex- pressed as a standard deviation score for chronologic and

SCFE Slipped capital femoral epiphysis GH Growth hormone

See related article, p. 400.

bone age. Bone density was measured before treatment in patients 1 and 2 and at diagnosis of SCFE in patient 3.

All three patients had heights below the 3rd percentile for age and for mid-parental height; bone age was delayed >2 SD for chronologic age, and growth rates were ~<4.1 cm/yr (Table). Apart from short stature, all three patients had no evidence of other systemic disease, and they denied previ- ous bone or joint injury. Periodic blood cell count and serum chemistry values were normall

CASE REPORTS Patient I. Patient 1 had isolated, idiopathic GH deficiency with

peak GH responses of 4.1 ng/ml (arginine) and 10.0 ng/ml (insulin), and integrated GH concentration of 1.1 ng/ml. At the

3 9 7

Page 2: Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency

3 9 g Clinical and laboratory observations The Journal of Pediatrics March 1990

Table. Clinical and laboratory data (A) at start of GH treatment, (B) at visit before diagnosis of SCFE, and (C) after 1 year of GH treatment

Free Patient Age Height Weight Growth BA/CA Thyroxine" thyroxinet Testosteroner

No./gender Visit (yr) (cm) (kg) (cm/yr) (yr) (/~g/dl) (ng/dl) (ng/dl)

1/M A 15.4 140.2 52.0 3.8 10.0/14.8 8.2 50.1 Bw 15.6 141.4 52.7 7.8 C 16.4 148.3 54.0 8.1 12.5/16.4 8.4 152.7

2/M A 14.1 137.3 30.0 4.1 10.0/13.8 9.1 <10.0 BII 14.6 139.7 32.3 5.2 <10.0 C 15.1 143.8 34.0 6.5 10.5/15.t 10.3 29.4

3/F A 14.6 139.1 44.0 3.6 12.0/14.2 12.7 BII 15.1 142.1 46.4 5.5 1.4 C 15.6 143.1 46.0 4.0 13.0/15.4

BA. Bone age; CA, chronologic age. *To convert thyroxine measurement to nanomoles per liter, multiply by 12.87. fTo convert free thyroxine measurement to picomoles per liter, multiply by 12.87. ~To convert testosterone measurement to picomoles per liter, multiply by 34.67. w weeks of GH treatment. I]Six months of GH treatment.

start of GH treatment (authentic recombinant GH, 0. l mg/kg ad- ministered subcutaneously three times a week), the patient, a white, prepubertal boy, was 15.4 years of age and at 153% of ideal body weight for height. Bone density standard deviation scores for chronologic age and for bone age were -2.25 and -1.42 SD, respectively. After 15 weeks of GH therapy, the patient had pain in the left hip for 1 month, which was exacerbated by a jump of a few feet into water. The diagnosis of SCFE was confirmed radio- graphically and treated surgically with internal fixation of the epiphysis with the use of Knowles pins. Treatment with GH was continued. During the first year he advanced to Tanner stage 2 of puberty. After 14 months of GH therapy, without prior trauma, SCFE developed in the right hip and was similarly treated.

Patient 2. Patient 2 had isolated, idiopathic GH deficiency with peak GH responses of 6.8 ng/ml (levodopa) and 4.8 ng/ml (insulin), and integrated GH concentration of 2.7 ng/ml. This black male patient was 14.1 years of age, at Tanner stage 2 of pu- berty, and at 100% of ideal body weight for height at the start of GH treatment (authentic recombinant GH, 0.1 mg/kg adminis- tered subcutaneously three times a week). Bone density standard deviation scores for chronologic age arid for bone age were -0.89 and -0.06 SD, respectively. After 7 months of treatment and no recognized trauma, pain developed in the right hip. The diagnosis of SCFE was confirmed radiographieally, and the condition was treated surgically with internal fixation of the epiphysis with the use of Knowles pins. Treatment with GH was continued. After 2 years treatment, when puberty had advanced to Tanner stage 3, SCFE developed in the left hip and was similarly treated.

Patient 3. Patient 3 had Turner syndrome (45,X). Intravenous administration of arginine produced a peak GH response of 9.5 ng/ml, and the integrated concentration of GH was 1.7 ng/ml. At the start of GH treatment (Protropin, 0.125 mg/kg administered subcutaneously three times a week), she was 14.7 years of age, at

Tanner stage 1 of puberty, and not clinically obese. Oxandrolone, 0.06 mg/kg administered orally once a day) was added after 2 months. After 10 months of GH therapy, a limp developed, because of pain in the left hip. The patient had been active in summer camp but denied specific trauma. The diagnosis of SCFE was confirmed radiologically, and the condition was treated surgically with inter- nal fixation of the epiphysis by means of Knowles pins. At diagno- sis of SCFE, bone density standard deviation scores for chronologic age and for bone age were -2.60 and -2.20 SD, respectively. Treatment with GH was resumed. SCFE had not developed in the contralateral hip by the time of epiphyseal fusion.

R E S U L T S

These three patients had isolated partial GH deficiency

by tests of stimulated and spontaneous G H secretion with-

out the suggestion of additional pituitary deficiencies. Thy-

roxine levels remained normal in all three patients. Patients

1 and 2 had onset or progression of puberty; adrenarche oc-

curred in patient 3 during t reatment with oxandrolone. Di-

agnosis of S C F E was made 15 weeks to 10 months after the

start of t reatment with GH. During 1 year of t reatment ,

each patient showed accelerated growth but without exces-

sive growth velocities (Table). Relative osteopenia was

suggested in patients 1 and 3, who had decreased bone den-

sity s tandard deviation scores.

D I S C U S S I O N

The growth plate of the femoral head and neck is a weak

point in the maturing human skeleton. An increased risk for

development of SCFE has been associated with GH

deficiency, 5 but the influence of isolated partial GH deft-

Page 3: Slipped capital femoral epiphysis during treatment with recombinant growth hormone for isolated, partial growth hormone deficiency

Volume 116 Clinical and laboratory observations 3 9 9 Number 3

ciency compared with multiple pituitary hormone abnor-

malities has not been addressed. The majority of children

previously reported had G H deficiency after t reatment for

craniopharyngioma or other brain tumors. 25 Although de-

tails of endocrine testing are not available for most of these

patients, in similar patients studied before the era of trans-

sphenoidal surgery, severe G H deficiency (maximum re-

sponse of GH <5 ng/ml) was described, and was associated

with deficiency of thyroid-stimulat{ng hormone in more

than 80% of cases. 1~ Thus the risk of S C F E development in

such patients might also be compounded by hypothy-

roidism. Diagnosis of S C F E has been made in some

GH-deficient children before GH therapy; of nine of those

reported, eight had also been treated for brain tumor or

midline brain abnormality, e, 5 Of 21 GH-deficient children,

S C F E developed in 12 during G H treatmentS; among those

with additional information, 6 of 10 probably had multiple

pituitary hormone deficiencies in addition. In contrast, our

patients had isolated, partial G H deficiency and lacked

other marked risk factors for SCFE.

The force necessary to cause epiphyseal displacement

may be generated during exercise in an obese child. 11 Our

patients denied any marked a~tivity or specific trauma, and

only one was obese. Growth velocities during t reatment

were not excessive, and in patients 2 and 3 the responses

were actually disappointing. Patient I had a better response,

but his growth velocity was at less than the 50th percentile

for peak growth height velocity in late-maturing boys. 12

The epiphyseal growth plate, histologically divided into

zones of resting, proliferative, and hypertrophied chondro-

cytes, most often shows displacement and fracture at the

junction of the zone of hypertrophied, degenerating chon-

drocytes with the zone of provisional calcification in the

metaphysis.l i Widening of the cpiphyseal plate may reduce

its ability to resist shearing force.13 In untreated Snell dwarf

mice, lacking GH, thyroid-stimulating hormone, and pro-

lactin, the epiphyseal plate is very wide and has a broad

resting zone14; it is possible that this wide plate accounts for

S C F E development reported in some untreated, GH-defi-

cient patients. 4, 5 With G H treatment a significant increase

in the proliferative and hypertrophied cell zones occurs in

both Snell dwarf mice 14 and normal rats. 15 The force nec-

essary to displace the proximal tibial epiphysis is reduced in

the GH-treated rat.15 These animal studies suggest that G H

alone contributes to the widening of the weakest zone of the

epiphyseal plate and thus could increase the risk of S C F E

in GH-deficient children treated with GH. Relative os-

teopenia, as reported in GH-deficient children 16 and sug-

gested in two of our patients, may be an additional contrib-

uting factor in the development of SCFE. Bone density in-

formation determined in the hand (predominantly cortical

bone) may not reflect conditions in the trabecular bone of

the hip.

We suggest that children with milder forms of G H defi-

ciency or other forms of short stature treated with G H may

be at increased risk for S C F E development. Further study

involving many more such children would be needed to as-

sess the clinical significance of these observations.

R E F E R E N C E S

1. ChungSMK. Diseasesofthedeveloping hipjoint. Pediatr Clin North Am 1986;33:1457-73.

2. Rennie W, Mitchell N. Slipped femoral capital epiphysis oc- curring during growth hormone therapy. J Bone Joint Surg 1974;56B:703-5.

3. Fidler MW, Brook CGD. Slipped upper femoral epiphysis fol- lowing treatment with human growth hormone. J Bone Joint Surg 1974;56B:1719-22.

4. Heatley FW, Greenwood RH, Boase DL. Slipping of the up- per femoral epiphyses in patients with intracranial tumours causing hypopituitarism and chiasma! compression. J Bone Joint Surg 1976;58B:169-75.

5. Rappaport EB, Fife D. Slipped capital femoral epiphysis in growth hormon~dcficient patients. Am J Dis Child 1985; 139:396-9.

6. Hirano T, Stamelos S, Harris V, Dumbovic N. Association of primary hypothyroidism and slipped capital femoral epiphysis. J PEDIATR 1978;93:262-4.

7. Kelsey JL. The incidence and distribution of slipped capital femoral epiphysis in Connecticut. J Chron Dis 1971 ;23:567-78.

8. Zadik Z, Chalew SA, Raiti S, Kowarski AA. Do short children secrete insufficient growth hormone? Pediatrics 1985;76:355- 60.

9. Colbert C, Bachtell RS. Radiographic absorptiometry (photo- densitometry). In: Cohn SH, ed. Noninvasive measurements of bone mass and their clinical applications. Boca Raton, Fla.: CRC Press, 1981:51-84.

10. Newman CB, Levine LS, New MI. Endocrine function in children with intrasellar and saprasellar neoplasms. Am J Dis Child 1981;135:259-62.

11. Chung SMK, Batterman SC, Brighton CT. Shear strength of the hmnan femoral capital epiphyseal plate. J Bone Joint Surg 1976;58A:94-103.

12. Tanner JM, Davies PSW. Clinical longitudinal standards for height and height velocity for North American Children. J PEDIATR 1985;107:317-29.

13. Alexander CJ. Effect of growth rate on the strength of the growth plat~shaft junction. Skeletal Radiol 1976;1:67-76.

14. Smeets T, van Buul-Offers S. The influence of growth hor- mone, somatomedins, prolactin and thyroxine on the morphol- ogy of the proximal tibial epiphysis and growth plate of Snell dwarf mice. Growth 1983;47:160-73. Harris WR. The endocrine basis for slipping of the upper fem- oral epiphysis. J Bone Joint Surg 1950;32B:5-11. Shore RM, Chesney RW, Mazess RB, Rose PG, Bargman GJ. Bone mineral status in growth hormone deficiency. J PEDIATR 1980;96:393-6.

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16.