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Ggh_23_2b.inddVolume 23 Number 2 Growth, Genetics & Hormones
ISSN 0898-6630 (Print) ISSN 1932-9032 (Online) In This Issue
Reviews & Comments
GROWTH IN OSTEOGENESIS IMPERFECTA Childhood Hypopituitarism HORACIO PLOTKIN, MD, FAAP
may even be a different degree of severity 24 after Traumatic Brain Injury Departments of Pediatrics and
in different members of the same family.4,5 Clinical features that may be present 25 Value of Clinical
Radiological Expertise in University of Nebraska Medical Center include bone fragility, joint hyperlaxity, Mutation Screening and Children's Hospital muscle weakness, chronic unremitting bone Omaha, Nebraska pain, and skul deformities (eg, posterior 26 Height Determinants in
ﬂattening) due to bone fragility in infants Turner Syndrome – KIGS with severe OI. Fractures may stil occur 27 Focusing Ilusion: Wealth,
Osteogenesis imperfecta (OI), or brittle bone after puberty,6 with bone fragility persisting Height, and Happiness disease, is a rare disorder with congenital throughout life. Individuals with mild forms bone fragility caused by mutations in the of the disease may have normal stature with genes that codify for type I pro-col agen no deformities or fractures at al , and the GH Therapy in Cystic production in osteoblasts (COL1A1 and condition would be diagnosed only when 29 Fibrosis
COL1A2), located in chromosomes an x-ray is obtained for other reasons. MC2R Loss in Salt-losing 7 and 17.1 Numerous mutations have been People with severe OI may have extreme 30 Adrenal Hypoplasia
described as causing the condition.2 In short stature and severe deformity of the the vast majority of cases, OI is inherited long bones. Exercise tolerance and muscle 30 Mutant IGF-1R as Cause for in a dominant fashion, or caused by a new strength are signiﬁcantly reduced in patients
Familial Growth Failure mutation. The prevalence of OI is estimated with OI, even in the mild forms.7 31 Final Height in GHD Patients
to be 1 in 20 000 to 50 000 infants.3 With Normalized Pubertal GH Osteogenesis imperfecta can affect several Besides brittle bones, clinical characteristics organs and systems. For example, hearing E-Reviews & Comments
and severity of OI are widely variable. There loss may be present in about 50% of the Anorchia and Micropenis in Infancy and Testosterone Treatment From The Editor's Desk
Cancer Survivors, GH Treatment and Second Neoplasms You may be aware that our former sponsor, Insmed, settled a patent infringement dispute and CRTAP - Cartilage Deﬁciency in OI no longer promotes IGF-I/IGFBP-3 to patients with severe primary IGF-I deﬁciency or other short Guidelines for Turner Syndrome stature indications. Therefore, they no longer provide an educational grant to the GGH journal. Consequently, Pediatric Sunshine Academics, Inc., a 501(c)(3) non-proﬁt organization, is funding Highlights: International Congress the cost of this issue of GGH without prior anticipation or alternative funding sources available. of the GRS and the IGF Society However, I am committed to seek new grants that wil al ow us to continue publishing this journal. Leukemia Survivors: GHD, QOL, I am grateful to the editorial board for their strong support; they have al pledged to contribute with and Neuropsychological Function their usual efforts and expertise while we seek more stable times. Since its inception 23 years ago, Neonatal Dexamethazone, GGH has improved and expanded; it is held in high regard and enjoys over 11 000 subscribers. We Growth, and Bone Accretion al feel obliged not to let you down. In order to forge ahead GGH wil need the support of its readers while we elicit educational grants. You Novel FGFR3 Mutations in can help us during this transition by contributing to Pediatric Sunshine Academics, Inc. an organization whose mission is to support research and education in pediatric endocrinology and nutrition. Your Prenatal CAH Treatment and ful y tax deductible donation to Pediatric Sunshine Academics, Inc., P. O. Box 3208, Tallahassee,
Cognitive Function FL 32315-3208, either by check or online atwil be used entirely for the
Prepubertal Gynecomastia Linked continued publication of GGH. Pediatric Sunshine Academics, Inc.'s federal EIN is 65-0854085. to Lavender and Tea Tree Oils On behalf of the editorial board, I thank you in advance for your donations and support. I wil Sleep-related Disturbances in keep you apprised of our quest to elicit new grants and sponsorships for the continuation of the Prader-Wil i Syndrome publication of GGH.
Fima Lifshitz, MD Stature and Status: Height, Ability, and Labor Market Outcomes Where Does the Genome Live? GGH is supported by an unrestricted educational grant from Pediatric Sunshine Academics, Inc.
GROWTH, GENETICS & HORMONES individuals with mild forms of OI after the third decade of very short stature, whereas individuals with type IV OI life.8 The incidence of congenital malformations of the heart may have mild-to-moderate short stature. Furthermore, in children with OI is probably similar to that of the normal according to some authors, individuals with type IV OI population,9,10 but respiratory complications secondary to may have normal stature.21 This highlights the inaccuracy kyphoscoliosis are common in individuals with severe OI.11 of classifying this disease into 4 types.22 I wil , therefore, Joint hyperlaxity is also a common occurrence in patients refer to OI "severity" throughout this article, instead of with OI,12 and may lead to dislocation of hips and radial heads, sprains, and ﬂat feet. Constipation and hernias are also a common complication of OI.13 Dentinogenesis The mean standing height of patients with OI is lower imperfecta (DI), caused by an abnormal dentin while than that of their unaffected ﬁrst degree family members, enamel remains normal,14,15 is prevalent in about 28% of regardless of severity. Truncal height is reduced and OI patients.16 Life expectancy in subjects with non-lethal OI head size increased in one third of the patients, more appears to be the same as that in the normal population,17 so in individuals with moderate or severe OI (Sil ence's with the exception found in cases of very severe OI with types IV and III). During childhood, there appears to be respiratory or neurological complications.18 no difference between the standing heights of girls and boys, but women had lower height z-scores than men. Histomorphometric analysis of the bone in patients with The reduction in arm span z-score general y fol ows the OI shows decreased trabecular bone volume, possibly same pattern as for height: individuals with moderate or secondary to the formation of fewer trabeculae, and to severe OI tend to have lower z-scores than individuals a lack of thickening of trabeculae with growth. There with mild OI. The arm span/height ratio appears to be is evidence of defects in modeling of external bone increased in children with moderate or severe OI, but not size and shape, production of secondary trabeculae in those with mild OI. Mean concentrations of insulin-like by endochondral ossification, and thickening of growth factor (IGF)-I and IGF binding protein (IGFBP)-3 are secondary trabeculae by remodeling.19 Contrary to the general y normal, in the low range of age-speciﬁc reference common conception of attributing the defect in OI to the values.10,21 Growth hormone (GH) deﬁciency is very rare in osteoclast, OI should be regarded as a disease of the patients with OI. In a group of 22 children tested by Marini osteoblast. Col agen plays an essential role in forming et al,23 none fulﬁl ed the standard criteria for GH deﬁciency. an interactive network between the cel s by making A few children in that study had a blunted response to extracel ular matrix and noncollagenous proteins that GH-releasing hormone or failed to double their serum IGF-I lead to proper mineralization of the bone. When the in a 5-day somatomedin generation test. However, there fundamental structure of the col agen helix is disturbed was no consistent relationship between those responses by a mutation, a complex series of secondary changes to or between the responses and type of OI. the bone develops, leading to increased bone fragility.
The etiology of the growth restriction in children with GROWTH IN CHILDREN WITH OI
moderate and severe OI is not entirely clear. It has been Severely affected patients may be short because of suggested that it could be viewed as a self-protective vertebral compression fractures, severe scoliosis, lower mechanism: a given mechanical load creates smal er limb deformities, and disruption of growth plates.20 stresses in a short bone than in a long bone, thus a short However, growth can also be delayed in the absence bone wil break less easily.24 People with severe OI have of these abnormalities. The most commonly used a typical deformity of the growth cartilage, deﬁned as classiﬁcation divides OI into 4 types. Type I patients "popcorn" appearance of the metaphysis. Microfractures do not have bone deformities and may have normal of the growth cartilage may play a role in the growth height, but fractures may range from very few to dozens problems experienced by these patients. There are no over a lifetime. Type II is the most severe, with patients reports on the effects of puberty and hormonal changes usually not surviving the perinatal period. Patients with on growth in children with OI.
type III have a characteristic triangular face, very short stature, and severe bowing of long bones; they typically USE OF BISPHOSPHONATES IN CHILDREN WITH OI
suffer many fractures throughout their life. Type IV is not Bisphosphonates are synthetic drugs with a chemical clearly deﬁned. Patients with this type of OI are general y structure based on pyrophosphate,25 and have been used short, although there is no consensus regarding the to treat osteopenia of primary and secondary origin in speciﬁc characteristics of this type. Other types have both children and adults.26 Effects on both osteoblasts27,28 been described, but there is controversy because they and osteoclasts29,30 have been shown, although the actual y represent syndromes resembling OI.1 According mechanism through which bisphosphonates increase to one study, during the ﬁrst 10 years of life the number bone mineral density (BMD) is not clear (Figure 1). of fractures, extent of skeletal deformities, and growth Likewise, effects of bisphosphonates on growth retardation do not differ between OI types III and IV.10 This have been documented, but the mechanism of those is surprising, as individuals with type III OI usually have effects has not been elucidated. There are differences 18 GGH Vol. 23, No. 2 June 2007
GROWTH, GENETICS & HORMONES decreases as wel . Fracture healing does not appear Increase osteoclast apoptosis?
Decrease osteoblast apoptosis
to be impaired in patients with OI when compared to untreated OI patients.37,38 There is a striking disappearance of bone pain and decreased fracture incidence noted with intravenous treatment. This may contribute to greater mobility,39,40 an essential factor for the development of the skeletal system.41 A lower fracture incidence, despite higher risk of injury due to increased mobility, suggests a direct effect of the therapy. These effects contribute to an improvement in the quality of life of patients with OI who are receiving treatment.
A side effect of high doses of pamidronate (9 mg/kg/yr) is retention of calciﬁed cartilage within Interfere with osteoclast function?
secondary spongiosa in children with OI.30 Higher Figure 1. Possible mechanisms of action of bisphosphonates on bone.
doses have caused osteopetrosis in a patient with no diagnosis.42 Retention of calciﬁed cartilage within among the bisphosphonates that may inﬂuence their secondary spongiosa is a hal mark of osteopetrosis, mechanisms for binding and inhibiting bone crystal this suggests a dose-related effect of pamidronate. growth and dissolution. This may explain differences Studies using oral bisphosphonates for the treatment of in potency among different bisphosphonates, such as OI (olpadronate,43 alendronate) showed no differences the apparently more prolonged duration of action of between the drugs and placebo on functional outcome, alendronate and zoledronic acid, compared with the more anthropometrics, fracture incidence, or vertebral height, readily reversible effects of risedronate.31 although it has been suggested that oral alendronate may improve quality of life in this group of patients.44 Different treatment protocols recommend the use of different bisphosphonates (ie, pamidronate, risedronate, EFFECTS OF BISPHOSPHONATE TREATMENT ON
alendronate, olpadronate, neridronate), and at different GROWTH IN CHILDREN WITH OI
dose regimens for the pediatric population. For example, The effect of treatment with bisphosphonates on pamidronate doses range from 4.5 mg/kg/yr32,33 (Tables 1 longitudinal bone growth in children has been a concern and 2) to 9 mg/kg/yr.34,35 Children treated with high-dose among clinicians.45 Bone resorption is an essential part pamidronate experience dramatic increase in BMD, with of the normal endochondral ossification process,46 changes of as high as 200% per year.35,36 Other positive and of the bone modeling and remodeling process. effects observed include increase of the cortical width Despite the fact that the mechanism of long bone of the metacarpals, and increased vertebral height in growth relies upon clonal expansion and subsequent previously fractured vertebrae. The incidence of fractures hypertrophy of chondrocytes, endochondral bone growth requires resorption of the septa of calciﬁed cartilage at the chondro-osseous junction of the growth plate Table 1. Protocol for administration of low-dose IV
by chondroclasts, permitting vascular invasion of the hypertrophic cell lacunae.47 Drugs interfering with this Age group
mechanism could potentially cause impairment of the 0.37 mg/kg/day for 2 days bone elongation process. Bisphosphonates interfere with osteoclast function29 or survival,48 and could, therefore, 0.56 mg/kg/day for 2 days have a deleterious effect on bone growth. This undesired 0.75 mg/kg/day for 2 days effect has actually been shown in animal studies.49 High doses of alendronate (>2.5 mg/kg/wk) inhibited long bone length in the OIM mice (a model of OI) through alteration Table 2. Suggested dilution and infusion rates for IV
of the growth plate and possibly reduced resorption at the chondro-osseous junction.50 Furthermore, lower mg of pamidronate
mL of normal saline
doses of alendronate do not appear to have a detrimental effect on growth in oim/oim mice,51 suggesting another dose-related effect of bisphosphonates. On the other hand, bisphosphonates do not appear to be detrimental for growth in human subjects at the doses currently used (Figure 2).24,52-55 Each time a patient receives a pamidronate infusion, a new sclerotic line appears in the GGH Vol. 23, No. 2 June 2007 19
GROWTH, GENETICS & HORMONES Figure 2. Lower limbs x-ray of a child with severe OI before (a) and after 12 months (b) of treatment with low-dose pamidronate
(4.5 mg/kg/yr). Treatment was started at 18 months of age. Note longitudinal growth. Fractures do occur under treatment as evident in the
panel on the right, but at much lower rate than before treatment.
metaphysis of long bones. The distance between these in those with more severe forms of the condition when lines reﬂects longitudinal bone growth (Figure 3).
receiving therapy with alendronate or pamidronate.57 Pamidronate in high doses (9 mg/kg/yr) does not appear One study showed that patients treated with high doses of to negatively affect growth. Height z-score actually pamidronate (9 mg/kg/yr) had similar growth plate width but increased in a group of patients wider metaphyses when compared with with OI who had started treatment untreated OI patients who were matched before 3 years of age.35 After one for OI type and age, despite the lack of year of pamidronate therapy, height detrimental effects of bisphosphonates z-scores increased signiﬁcantly in a on longitudinal growth,58 suggesting group of children with severe OI and an effect of the high dose on bone did not change in children with mild remodeling. A different study showed and moderate OI.24 After 4 years of that metaphyseal modeling in the therapy with the same dose regimen distal femur is constant in children on of pamidronate, mean height z-scores bisphosphonates—with slight variation increased signiﬁcantly in children with between sexes—resulting in a similar moderate OI, whereas non-signiﬁcant shape of the distal femur throughout trends to increase were seen in childhood when looking at the modeling patients with mild and severe OI.24 process.59 Noteworthy, the observed Low doses of pamidronate appear positive effect of pamidronate on bone to have a similar effect (data not growth does not appear to be secondary published) (Figure 3).
to acceleration of bone age.24 Low doses of pamidronate elicited Infants with OI appear to grow better no short-term evidence of growth when treatment with neridronate is impairment in children with a variety of started soon after birth, rather than at pathologies leading to osteoporosis, 6 months of age.60 Older children with including OI. A median annualized Figure 3. Distal femur of a pediatric OI receiving neridronate grew faster
change in height SDS of 0 (range, patient with OI receiving treatment with than controls in one study.61 At the
–0.4 to 0.5) was noted in that group.56 IV pamidronate. Note the sclerotic lines, microscopic level, the size of iliac crest
each representing an infusion. The distance As expected, growth changes are between lines reflects longitudinal bone bone biopsies is not signiﬁcantly different greater in children with milder OI than growth in a 2-month period.
before or after treatment in children 20 GGH Vol. 23, No. 2 June 2007
GROWTH, GENETICS & HORMONES with OI. Changes are seen in cortical in patients with moderate OI, and width, which increased by about 90%. 9 cm in patients with severe OI Cancel ous bone volume increases can be expected at 15 years of by about 45% with treatment. This age. These results suggest that change is due to higher trabecular acceleration of growth is not just a number, with no change in trabecular transitory effect, but rather a lasting thickness.30 Importantly, there is no outcome on height in children with evidence for a mineralization defect OI who are receiving pamidronate in children with OI treated with high intravenously. As mentioned doses of pamidronate.30 Growth in above, it is not entirely clear how children continues after treatment pamidronate treatment might with pamidronate is stopped, and the improve growth. Part of the effects newly-formed bone wil be unprotected of bisphosphonates on growth in and prone to fractures (Figure 4).
children with moderate and severe OI could be due to prevention of long LONG-TERM EFFECTS OF
bone deformity and regeneration of BISPHOSPHONATES ON HEIGHT
vertebral fractures (Figure 5),35,62 In one study, mean height z-scores and to prevention of microfractures of subjects with all OI degrees of affecting growth cartilage.
severity tended to increase after 4 years of pamidronate therapy when EFFECTS OF GROWTH
compared with baseline. However, HORMONE IN CHILDREN WITH OI
the change in height z-scores was Growth hormone regulates post- signiﬁcant only for the group with Figure 4. Long bones continue growing after natal bone growth; IGF-I mediates
moderate OI, but not for mild or treatment with bisphosphonates is stopped the growth-promoting action of GH,
(arrow), causing susceptibility to fractures.
severe OI.24 It is of note that these although it has been shown that comparisons were done against normal growth charts GH may have independent, direct effects on growth.63 designed for healthy children. To more accurately Also, IGF-I has mitogenic effects in dividing cells and assess the growth rate of children with OI undergoing is closely associated with growth, although plasma treatment, the same group compared their growth with levels do not correlate with growth rates. It is known to that of a group of children with OI who were not receiving treatment with bisphosphonates. In that study, each height measurement of patients was expressed as a percentage of the mean value expected for untreated OI patients. During 4 years of pamidronate therapy, height significantly increased above the values expected for untreated patients.24 EFFECT OF PAMIDRONATE
ON FINAL HEIGHT
There is very little information
about ﬁnal height in children with
OI treated with bisphosphonates.
There is the description of only
8 patients who attained ﬁnal height
while receiving treatment with
pamidronate.24 In this study, ﬁnal
height, expressed as a percentage
of the expected height in untreated
patients, was signiﬁcantly higher than baseline height. This study Figure 5. Lumbar spine x-ray of a child with severe OI before (a) and after 12 months (b) of
suggests that an average gain of treatment with low-dose pamidronate (4.5 mg/kg/yr). Treatment was started at 18 months of 7 cm in patients with mild OI, 12 cm age. Note increased vertebral height with treatment.
GGH Vol. 23, No. 2 June 2007 21
GROWTH, GENETICS & HORMONES increase 1-α hydroxylase in kidneys, with subsequent and the largest bone strains, and those strains help to increased production of calcitriol (1,25 [OH]2 vitamin control the biological mechanisms that determine whole- D3). As calcitriol is the active form of vitamin D, IGF-I and bone strength (Figure 6).72 GH treatment can make calcium more available for bone mineralization,64 which could add to a possible beneﬁcial There are no large control ed studies of GH treatment in effect in patients with OI. Inversely, it has been suggested children with OI. Furthermore, there are no data in the that vitamin D, calcium, and protein supplements literature regarding ﬁnal height in OI patients treated with may elicit part of their effect on osteoporosis through GH. An increase of fracture rate during GH therapy has increased IGF-I levels.65 been reported in children with OI by different groups,73,74 although another group did not ﬁnd an increase in fracture IGF-I promotes longitudinal bone growth by ‘insulin- rate in a smal group of children with mild OI who were like' anabolic actions which augment chondrocyte treated with GH for 1 year.75 Extending treatment to 2 years hypertrophy.66 Chondrocyte differentiation, in turn, leads did not change the fracture risk either.76 Like al children to cartilage expansion and linear growth. Furthermore, who are initial y started on GH, children with OI experience osteoblasts and pre-osteoblasts secrete IGF-I, and an initial acceleration of growth rate,64,77 but a sustained bone resorption causes release of stored IGF-I. This effect has not been demonstrated. In one study, GH hormone appears to be a growth factor for osteoblasts. A (0.1- 0.2 IU/kg/d for 6 days/wk) was administrated for at homozygous molecular defect in the gene encoding IGF-I least 1 year to children with OI of different severity;78 about caused severe intrauterine growth failure, sensorineural one-half of the treated OI children sustained a 50% or deafness, and mild mental retardation in one individual.67 more increase in linear growth, compared to their baseline Treatment with IGF-I improved linear growth and insulin growth rate. It is of note that most responders (10 of 14) did sensitivity in that patient.68 There is also some weak not have a severe form of OI. Incidental y, only the linear evidence that IGF-I has a role in declining BMD with growth responders had a signiﬁcant decrease in long aging. In patients with Laron syndrome, IGF-I treatment bone fractures. After 1 year of treatment, responders' iliac increases bone growth in the absence of GH.69 Low IGF-I crest biopsy showed signiﬁcant increases in cancel ous concentrations appear to be associated with low BMD bone volume, trabecular number, and bone formation in patients with cystic ﬁbrosis.70 rate, but no signiﬁcant increase in cortical thickness. Histomorphometric parameters of bone resorption were As discussed above, some children with OI have a blunted not signiﬁcantly changed in responders, whereas non- response to GH-releasing hormone or fail to double their responders had an 80% increase in the percentage of serum IGF-I in a 5-day somatomedin generation test (13 bone surface covered by osteoclasts. The incidence of 22 had less than a 2-fold stimulation of somatomedin-C of fractures was unchanged in non-responders. Bone by GH).71 There was no overlap between the group with formation parameters did not increase with treatment blunted IGF-I response and the group with decreased GH- in this group. Although progression of scoliosis was releasing hormone response, suggesting that there might unchanged compared with the National Institute of Child be 2 different mechanisms of GH resistance in children Health and Human Development (NICHD) OI population, with OI. GH is an anabolic hormone and, together with data on individual cases are not offered in the report. IGF-I, is a potent regulator of muscle mass. As such, there is potential for it to increase bone density. In the absence Recombinant human IGF-I, complexed with its of trauma, muscles are responsible for the largest loads predominant binding protein IGFBP-3 is currently being tested as a treatment for osteoporosis, alone or in combination with anti-resorptive drugs and GH.79 There appears to be a correlation between the dose of GH (and Direct action on growth
the obtained IGF-I plasma levels) and the increase in bone turnover markers and/or BMD in adults,80 although Increases
a different study found that 1 year of IGF-I treatment, at a dose sufﬁcient to elevate circulating IGF-I to young normal values, was not an effective means to alter body composition or blood parameters, nor to improve bone Increases Igf-I secretion
density, strength, mood, or memory in older women.81 CONCLUSION
Bisphosphonate treatment does not appear to have
a detrimental effect on linear growth in children and
adolescents with OI, regardless of the severity of the
condition. Long-term bisphosphonate therapy in children
Figure 6. Mechanisms for growth hormone stimulation of bone
with OI may be associated with a signiﬁcant height gain, growth and increase of bone mineral density.
as compared with untreated OI patients with the same 22 GGH Vol. 23, No. 2 June 2007 GROWTH, GENETICS & HORMONES disease severity. The use of GH in this population is stil controversial. It has been suggested that GH treatment should probably not be used as a ﬁrst-line therapy in OI.82 Combined protocols administering both bisphosphonates 39. Plotkin H, Gibis J, Glorieux FH. Bone. 2001;28:S78.
and GH are warranted. Other therapeutic options currently used or in research for patients with osteoporosis (PTH, IGF-I, strontium, RANK ligand) may have a role in the treatment of OI in the future.
Disclosures: The author discloses no conﬂicts of interest. Pamidronate
use for children with OI is off label.
46. Ross FP. Osteoclast biology and bone resorption. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6 ed. Washington, DC: ASBMR; 2006:30-5.
20. Plotkin H. Syndromes with brittle bones, hyperostotic bone diseases 66. Jie W, Jian Z, Bondy C. FASEB J. 1999;13:1985-90.
and ﬁbrous dysplasia of bone. In: Lifshitz F, ed. Pediatric Endocrinology. Vol 2, 5th edition. New York, NY: Informa;2007:559-70.
73. Kinugasa A, Fujita K, Inoue F, et al. Acta Ped Scan. 76. Antoniazzi F. Therapeutic approach with growth hormone. In: 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada; 1999:1-16.
36. Munns CF, Rauch F, Travers R, et al. J Bone Miner Res. GGH Vol. 23, No. 2 June 2007 23
Kno c he nmarke rkrankung e n Priv.-Do z. Dr. Ro land Re pp Me dizinis c he Klinik V Klinikum Bambe rg Was will ic h Ihne n e rzähle n … • Funktion des Knochenmarks • Welche Symptome werden durch ein gestörtes Knochenmark verursacht? • Was sind die häufigsten Erkrankungen des Knochenmarks? • Wie werden diese Erkrankungen