Birgit Borgström

Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study

CONTEXT The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment. OBJECTIVE To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden. DESIGN Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands). PATIENTS All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation. MAIN OUTCOME MEASURE Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed. RESULTS Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect. CONCLUSIONS In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.

Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes

Background Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller–Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller–Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. Methods Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. Results Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3ε). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. Conclusions The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.

Growth and Growth Hormone in Children after Bone Marrow Transplantation

Growth and growth hormone (GH) were investigated every year in 24 children after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA) or leukemia. Conditioning included total body irradiation (TBI) in all cases of leukemia. The young leukemic children grew poorly. At 4 years after BMT, the mean standard deviation score for attained height had decreased from 0 to -1.73. GH deficiency was diagnosed with provocation tests. Three years after BMT, 10/18 children had a subnormal response. Ten children were further investigated with 24-hour GH profiles. Children with SAA had normal growth and GH levels. TBI seemed to be the major factor responsible for impaired growth.

Histologic changes in dental morphology induced by high dose chemotherapy and total body irradiation

Disturbances in dental development were studied with the use of radiography and histology in a patient with acute lymphoblastic leukemia who was treated with induction chemotherapy at 2.3 years of age and bone marrow transplantation at 4.3 years of age. The follow-up 9.5 years after bone marrow transplantation showed evidence of short tapered roots, enamel hypoplasia, microdontia, and aplasia. A histologic examination of two extracted permanent teeth showed that the crown of the maxillary lateral incisor exhibited numerous incremental lines that corresponded closely to the treatment periods with cytotoxic drugs. The maxillary second premolar exhibited regularly spaced incremental lines in the enamel and dentine. A gross hypoplasia was seen in the cervical part of the crown corresponding to the time of administration of 10 Gy total body irradiation. The results indicate that chemotherapy mainly induces qualitative disturbances in dentine and enamel, whereas total body irradiation induces both qualitative and quantitative changes.

Growth Hormone Induces Low-Density Lipoprotein Clearance but not Bile Acid Synthesis in Humans

Objective—Growth hormone (GH) induces hepatic low-density lipoprotein (LDL) receptors and lowers plasma cholesterol. We characterized the influence of GH treatment on plasma LDL clearance in normal humans and investigated the relative role of LDL receptor (LDLR) activity and stimulation of bile acid synthesis in subjects with different LDLR expression. Methods and Results—Plasma clearance of autologous 125I-LDL was measured before and during 3 weeks of treatment with GH (0.1 IU/kg per day) in 9 healthy young males. Plasma LDL cholesterol was reduced by 13% and the fractional catabolic rate of LDL increased by 27%. More marked changes were seen in a patient with hypopituitarism substituted with GH (0.07 IU/kg per day) for 3 months. In a second study, GH dose-dependently reduced LDL cholesterol and increased Lp(a) levels in 3 groups of males: younger and elderly healthy subjects and heterozygous familial hypercholesterolemia (FH). No effect on bile acid synthesis measured by the plasma marker 7&agr;-hydroxy-4-cholesten-3-one was observed. In an LDLR-deficient FH homozygote, LDL cholesterol was not affected by GH. Conclusions—GH treatment reduces plasma LDL cholesterol by inducing LDL clearance. In humans, LDLR expression is a prerequisite for this effect, whereas it is not related to stimulation of bile acid synthesis.

Outcome in six children with mucopolysaccharidosis type IH, hurler syndrome, after haematopoietic stem cell transplantation (HSCT)

Aim: To follow‐up six children with severe mucopolysaccharidosis type IH, Hurler syndrome, who were treated before 24 months of age with haematopoietic stem cell transplantation.

Craniomandibular dysfunction in children treated with total-body irradiation and bone marrow transplantation

The prevalence of pain and dysfunction in the stomatognathic system was studied in a group of 19 long-term survivors after pediatric bone marrow transplantation (BMT), conditioned with total-body irradiation (TBI). Compared with the control group, the children and adolescents in the BMT group had a significantly reduced mouth opening capacity. A reduced translation movement of the condyles was diagnosed in 53% of children treated with TBI, compared with 5% in the control group. Signs of craniomandibular dysfunction were found in 84% of children in the BMT group, compared with 58% in the control group. Both irradiation and chemotherapy induce long-term alterations in connective and muscle tissues resulting in inflammation and eventually fibrosis. These changes in tissue homeostasis and concomitant growth retardation may lead to the observed malocclusion and reduced mobility of the temporomandibular joint, with subsequent muscle pain and headaches, which were found in this study.

Bone marrow transplantation in children using unrelated donors at Huddinge Hospital

Twenty‐eight out of 31 children that underwent bone marrow transplantation (BMT) from unrelated donors between 1984 and 1995 received HLA‐A, HLA‐B and HLA‐DR matched unrelated donor (MUD) marrows as defined by serologic HLA class I and genomic HLA class II typing. Compared with 28 case‐matched controls transplanted with HLA identical sibling donors, MUD patients received a more intensive conditioning. Twenty‐six patients (93%) engrafted while two died of septicaemia during the aplastic phase. Two patients rejected their grafts and four developed Evans syndrome. All controls engrafted without incidents of rejection or Evans syndrome. The probability of acute graft‐versus‐host disease (GVHD) of grade II or above was 27% after MUD‐BMT and 7% in the controls. The 5‐year probability of survival was 60% in MUD patients and 89% after sibling BMT (p= 0.03). Leukaemia‐free survival was 60% with one relapse in the MUD patients, and 59% with five relapses in the sibling group. Three children who received a mismatched donor marrow died, two of severe GVHD and one after graft rejection. In conclusion, today, a matched unrelated donor BMT is an acceptable alternative for many children who need a BMT but lack a suitable related donor.

Ovarian function after allogeneic hematopoietic stem cell transplantation in childhood and adolescence

OBJECTIVE The aim of the study was to evaluate long-term ovarian function after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence. SUBJECTS AND METHODS Predictive factors for ovarian function were evaluated among 92 adult or pubertal female survivors transplanted at Huddinge and Helsinki University Hospital during 1978-2000, at a mean age of 9±4.3 years (range 1-19). At the time of the study a mean±s.d. of 13±5.5 years (range 6-27) had elapsed since the HSCT and the mean age of the participants was 22±6.3 years (range 9-41). RESULTS Spontaneous puberty based on breast development occurred in 40 and menarche in 30 of the 70 girls who were prepubertal at transplantation. Six out of 20 girls who received HSCT after initiation of pubertal development recovered their ovarian function. Younger age at HSCT, conditioning without total body irradiation (TBI), and a non-leukemia diagnosis predicted the spontaneous menarche. The incidence of menarche was higher after fractioned vs single fraction TBI (P<0.05), cyclophosphamide (Cy) vs busulfan (Bu)-based conditioning (P<0.05), and among leukemia patients transplanted at first remission vs later remissions (P<0.01) and with no cranial irradiation (cranial radiotherapy, CRT) vs given CRT (14-24 Gy) (P<0.01). The majority of recipients conditioned with only Cy vs TBI (P<0.001) or vs Bu-based regimens (P<0.01) showed preserved ovarian function and required no estrogen replacement at their latest follow-up visit at a mean age of 23±6.3 years (range 15-41). Ten women became pregnant. CONCLUSIONS Patients conditioned with TBI or Bu-based regimes are at high risk of ovarian failure. Intensive anti-leukemia therapy before HSCT including CRT especially among relapsed patients may further decrease the possibility of spontaneous menarche.

Adverse health events and late mortality after pediatric allogeneic hematopoietic SCT-two decades of longitudinal follow-up.

Treatment-related late toxicities after pediatric allogeneic hematopoietic SCT (allo-HSCT) are increasingly important as long-term survival has become an expected outcome for many transplanted children and adolescents. In a retrospective cohort study, we assessed long-term health outcomes in 204 allo-HSCT survivors transplanted in childhood or adolescence (<20 years) between 1978 through 2000 after a median follow-up time of 12 (range 4–28) years. Data on conditioning regimen, adverse health events (AE) and growth and hormonal substitutions (hormone replacement therapies (HRTs)) were obtained from medical records. AEs were graded retrospectively according to Common Terminology Criteria for Adverse Events v3.0. Late deaths (⩾48 months after allo-HSCT) were evaluated separately. Multivariate analysis demonstrated that chronic GVHD (P<0.000) and longer follow-up time (P<0.05) correlated with AEs, whereas CY-based conditioning was inversely correlated (P<0.002). TBI and longer follow-up duration predicted more severe AEs (P<0.001 and P<0.001, respectively). HRTs were more frequent after TBI. Diabetes type II, dyslipidemia and hypertension were detected in 9, 7 and 7% of the survivors, respectively. Late deaths (n=22) were most frequently due to pulmonary failure (n=7), followed by secondary malignancy (n=5). The occurrence of AEs after pediatric allo-HSCT is high and likely to increase during extended follow-up, particularly in patients who have received TBI.