Graniofacial growth in bone marrow transplant recipients treated with growth hormone after total body irradiation GORAN DAHLLOF', CARL-MAGNUS FORSBERG^ MARGARETA NASMAN', TORSTEN MATTSSON^ THOMAS MODEER', BIRGIT B O R G S T R O M * , PER BOLME* AND OLLE RINGDEN' Departments of'Pedodontics, ^Orthodontics, ''Oral Surgery, School of Dentistry, and Departments of''Pediatrics, ^Clinical Immunology and ^Transplantation Surgery, Huddinge Hospital, Karolinska Institutet, Stockholm, Sweden

Dahllof G, Forsberg C-M, Nasman M, Mattsson T, Modeer T, Borgstrom B, Bolme P, Ringden O: Craniofacial growth in bone marrow transplantation recipients treated with growth hormone after total body irradiation. Scand J Dent Res 1991; 99: 44-7. Abstract The efTect of growth hormone (GH) treatment on craniofacial development was studied in five children exhibiting growth retardation following bone marrow transplantation. Linear and angular measurements were made on lateral radiographic cephalograms taken prior to the start of GH treatment and after an average treatment time of 1,2 yr. The results showed that the mean growth increments of mandibular length in the GH treated children, exceeded the corresponding value.s of the control group by 150% during the period of investigation. It is suggested that this dimensional increase in the patients was due to GH stimulation on the chondral growth process in the mandibular condyles. Key words: bone marrow transplantation; cephalometry; growth; growth hormone; radiation, Goran Dahllof, Department of Pedodontics, Odontological Glinics, PO Box 4064, S-141 04 Huddinge, Sweden, Accepted for publication 22 July 1990,

Multiagent chemotherapy and 10 Gy total treatment on eraniofacial development in body irradiation (TBI) administered to chil- children with growth retardation following dreii during bone marrow tran.splantation BMT. (BMT) may result in diminished growth, a reduction in the production of growth hormone (,GH) (1) and severe disturbances in Patients and methods denial development (2). I n the area o f c r a n i -

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ofacial development, mandibular length and the height of the alveolar processes in particular are redueed as a consequence of TBI (3). This report deals with the effect of GH

^^.i.i^ ^^^ ^^^ ^oy) who had been treated with B M T at a mean age of 9.1 ± 1.0 yr (Table 1). Four patients were treated because of acute leukemia and one as a result ofa combined immunodeficien-


GROWTH HORMONE AND CRANIOFACIAL GROWTH Table 1 Age and sex distribution of the patients

Age in yr at Patient





Bone marrow transplantation

Start of growth hormone treatment

Follow-up examination


12.0 12.1

13.1 14.1 13.3 15.2 16.6

9.2 9.1 10.0 8.0

cy. At the time of BMT their mean standard deviation score (SDS) for standing height was -0.72. Growth in subsequent years was poor and 3.6 yr ailer BMT the mean SDS was - 1.96. Growth hormone (OH) secretion, before start of treatment with synthetical GH, was investigated with provocation tests. Insulin and arginine provocation tests were used in combination (4). In our group of patients the peak GH values ranged from 4.3 to 6.6 jig/L. Peak values above 10 |Jg/L are considered normal. At a mean age of 13.2 + 1.5 yr of age, treatment was commenced with synthetic GH, which was administered suhcutaneously with 0.1 IU/kg body wfight per day (5). After BMT with TBI girls get a total ovarian failure (1), and fail to enter puberty without medication. In two of the girls very iow doses (2.5 [.Ig/ day) of ethinylestradiol was administered as substitutional therapy. TBI also causes damage to the thyroid gland and some children develop hypothyroidism (1). One of the present children exhibited a high thyroid stimulating hormone level, suggesting insufficient thyroid function. In this case a low dose of thyroid hormone (0.05 mg/day) was given as substitution. Bone age was examined once a year after BMT, using radiographs of the hand according to the




ious ages reported by RJOLO el al. (7). The value for radiographical magnification was not given by RiOLO et al. (7), and the linear measurements in their material were not corrected for this factor. In order to obtain comparable dimensional data, therefore, all linear measurements were converted to indices. In the patient group these were calcuated by dividing the linear measurements for each subjeet by the sella-nasion distance determined for t!ie same subject and multiplying the quotient by 100. Corresponding indices in the control group were based on the mean values recorded by RIOLO et al. ( 7 ) .

method applied by GREULIGH & PYLE (6).

Two lateral cephalograms were taken of each patient, one before administration of GH and the other after 1-2 yr of treatment. The variables evaluated were hased on standard cephalometric reference points and lines (Fig. 1). Growth changes in the patient group were compared with mean increments calculated from the average dimensions of relevant craniofacial measurements at var-

Fig. I. Reference points and lines



Results The effect of GH on growth was evaluated at a mean of 1.2 ±0.4 yr after initiation of GH therapy. The standard deviation score (SDS) for standing height was - 1.96 at the time of start of GH treatment and — 1.86 at the follow-up examination. Bone age according to GREULICH & PYLE (6) increased 0.8 + 0.8 yr during the observation period. The differences between actual and expected craniofacial growth changes were small (Table 2). The only exception was seen in mandibular length (cd-pgn), which exceeded the expeeted increase by 150% (range 75-474%) in children on GH therapy. The changes in all other variables measured were consistently smaller than expected in the BMT group.

Table 2 Linear cephalometric measurements. Variables were converted to indices by dividing linear measurements for each subject by sella-na.sion (s-n) distance for the same subject and multiplying quotient hy 100. Results are expressed as mean index values for two groups

Growth changes


-0.47 6.0.^

0.72 2.43

-1.19 3.60

0.95 -0.22 -0,18 0.37

1.03 -0.08 0.63 1.10

-0.08 -0.14 -0.81 -0.73

0,18 0.97 0.47 0.27

0.64 1.36 0.82 0.48

-0.46 -0.39 -0.35 -0.21

Variable pns-sn cd-pgn ri-gn n-ans se-pns ans-gn pr-NL! UJ6-NL! id-ML! 1J6-ML!

Discussion The standard deviation score for standing height showed a minor increase during the observation period. In a study of children with brain tumors receiving craniospinal irradiation, the initial standing height SDS was —2.4, while after 4 yr of GH treatment there had been a decrease to —3.4 (8). The results of this study confirm that the role of exogenous GH is to prevent further loss in growth potential in irradiated patients. This is in contrast to the effeet of GH therapy in cases with classical GH deficiency in whom the expected outcome is to induce a catchup growth. Growth hormone therapy may have a stimulating influence on mandibular growth in bone marrow transplant reeipients treated

Table 3 Angular

Controlgroup expected change*


An anterior rotation of the mandible (ML/ NSL) as well as an increased vertical growth of the condyles (cd-pgn/ML) was also recorded (Table 3).

cephalometric measurements. Growth changes (degrees) in 5 patienls treated with GH

Growth changes in degrees


GH-group (« = 5)

Controlgroup expected change*



0.04 0.38 -0.38

0.10 0.28 -0.26

-0.06 0.10 -0.12


-0.80 0,30 -1,12

-0.48 0.46 -0.94

CL/ML cd-pgn/ML

-1.50 1.50

-0.32 -0.16 -0.18 ** **

* Values of expected growth are calculated from mean values (RiOLO et al. {!)) relevant for healthy * Values of expected growth are calculated from mean values (RIOLO el al. (7) relevant for healthy children of corresponding age. ! Perpetidicular distance from ihe point to the children of corresponding age. ** Not listed in RIOLO et al. (7). line.

GROWTH HORMONE AND CRANIOFACIAL GROWTH with total body irradiation. The administration of ethinylestradiol and thyroid hormone as substitutional therapy for deficiencies caused by TBI were given in low doses and probably did not interfere with GH treatment. The increase in mandibuiar length, the anterior rotation of the mandible, and tbe vertical growth of the condyles indicates that the condylar cartilage is the most likely site for the mandibular growth activity. The results of this study are in accordance with the hypothesis concerning the dual effect of GH treatment (9). According to these authors GH encourages longitudinal bone growth directly by stimulating the difFerentiation of epiphyseal growth plate precursor cells, and indirectly by increasing the responsiveness to insulin-like growth factor-1 (IGF-1). Furthermore, MAOR et al. (10) demonstrated that growth hormone administration to an organ culture system of neonatal condylar cartilage from mouse enhanced the overall growth of the cartilage explant and stimulated differentiation of its cells. In epiphyseal cartilage, proliferation and matrix synthesis occur in differentiated chondroblasts, which arc surrounded by cartilaginous matrix apparently isolated from external stimuli. In mandibular condylar cartilage, however, proliferation only occurs in a zone of non-differentiated prechondroblasts located directly under the fibrous articular layer (11). Unlike primary cartilage the condylar cartilage does not function as a principal determinant of the amount and direction of growth. Rather, it functions more passively as a response to growlh conditions determined elsewhere, and grows adaptively superiorly and posteriorly in order to maintain an optimal relationship to the developing temporal squama. With the exeepdon of mandibular length all other variables in the patient group exhibited deficient growth. As regards the reduction in growth of the alveolar processes a contributing factor may be the disturbed


root development of the teeth seen in children conditioned with TBI (2). Since the root disturbances are irreversible, the stimulating effect of the dental development on the growth of the alveolar processes is absent. Acknowledgment — This study was supported by grants from the Swedish Dental Society. References 1. SANDERS JE, PITCHARD S, MAHONEY P, et al.

Growth and development foUowing marrow transplantation for acute leukaemia. Blood 1986; 68: 1129-35, 2. DAHLLOF G , BARR M , BOLME P, et al. Distur-

bances in denial development after total body irradiation in bone marrow transplant recipients, Orul SuTg Oral Med Oral Pathol 1988; 65; 41-3, 3. DAHLLOF G , FORSBERG G - M , RINGDEN O , et

al. Facial growth and morphology in longterm survivors after bone marrow transplantation. Eur J Orthod 1989; 11: 332-40. 4. FRAZIER SD, A review of growth bomone stimulation tests in children. Pediatrics 1974; 53: 929-37. 5. BoRGSTROM B, BoLME P, Growth and growth hormone in children after bone marrow transplantation, Horm Res 1988; 30: 98-100. 6. GREULICH W W , PYLE SL Radiographic atlas of

skeletal development of the hand and wrist. Stanford, CA: Stanford University Press, 1959. 7. RiOLo ML, MoYERs RE, MGNAMARA JA, HUNTER W S . An atlas of eraniofacial growth. The center for human growth and development. University of Michigan, Ann Arbor, MI, 1974, 8. CLAYTON PE, SHALET S M , PRICE DA. Growth

response to growth hormone therapy following craniospinal irradiation, Eur J Pediatr 1988; 147: 597-601. 9. GREEN H , MORIKAVA M , NIXOM T . A dual

effector theory of growth hormone action. Differentiation 1985; 29: 195-8. 10. MAOR, JF, HOCHBERG


Growth hormone stimulates the growth of mouse neonatal condylar cartilage in vitro. Aeta Endocrinology 1989'; 120: 526-32. 11. DuRKiN JF, HEELY JD, IRVING JT. The carti-

lage of the mandibular condyle. Oral Sci Ren 1973; 2: 29-99.

Craniofacial growth in bone marrow transplant recipients treated with growth hormone after total body irradiation.

The effect of growth hormone (GH) treatment on craniofacial development was studied in five children exhibiting growth retardation following bone marr...
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