Growth and growth hormone secretion in children after bone marrow transplantation

Long-term sequelae of bone marrow transplantation (BMT) are a major concern among long-term survivors since the procedure has been considerably developed over the past decade. In this study, linear growth and growth hormone (GH) secretion were evaluated in 25 children (14 males and 11 females) with various neoplastic or non-neoplastic hematological disorders who had survived for more than 3 years after BMT. Impaired linear growth after BMT, as defined by a change in height standard deviation score (SDS) by more than ? 1.0 SD, was observed in 14 patients (56%). Four children showed severe growth suppression with a decrease in SD score by more than 2.0, and 10 exhibited a moderate reduction by between 1.0 and 2.0 SD. A recovery of normal height velocity was observed in those who had received BMT at a younger age. The type of disease, a difference in preconditioning regimen, the presence of chronic graft-versus-host disease or a GH secretory capacity 1 year after BMT were not contributing factors for impaired growth. A serial examination of GH secretion with insulin-induced hypoglycemia demonstrated that poor GH secretion was not necessarily a prerequisite for impaired growth. These results indicate that the secretory status of GH does not predict the future growth pattern of children who received BMT.     

Defective growth hormone secretion in children with pycnodysostosis and improved linear growth after growth hormone treatment

Short stature is a characteristic feature of pycnodysostosis. We report defective growth hormone secretion in response to provocation and low insulin-like growth factor-I (IGF-I) concentration in five out of six patients with pycnodysostosis. Physiological replacement with growth hormone increased IGF-I concentration and improved linear growth in these children.     

Prepubertal growth and growth hormone secretion in children after treatment for hematological malignancies, including autologous bone marrow transplantation

Prepubertal growth standards were used to assess growth in 20 children who had undergone autologous bone marrow transplantation (ABMT) as part of their treatment for hematological malignancy. Most of the patients (16 of 20) were transplanted after a relapse of their disease. A negative change in height standard deviation score (H-SDS) was seen only in the group of patients (n=7) who had received both cranial irradiation therapy (CRT) and 7.5-Gy single-fraction total body irradiation (TBI). Height changes in this group were observed from the time of diagnosis. In contrast, the groups of patients conditioned with chemotherapy only (n=3) or both chemotherapy and TBI, without preceding CRT (n=10), did not demonstrate a significant loss in H-SDS. Weight related to height demonstrated large individual differences over time. Spontaneous growth hormone (GH) secretion, as measured by a four-point sleep curve, was followed longitudinally and an increasing proportion of patients with low peak levels was seen in all patient groups. In summary, prepubertal growth was suppressed only in patients who received cranial irradiation before ABMT. Despite low GH peak levels, normal prepubertal growth was found in patients with no CRT before ABMT.     

Hyperuricemia after liver transplantation in children

Uric acid may be involved in the development and progression of kidney diseases. Hyperuricemia is a common feature in adult liver transplant recipients but there is limited information in children. In order to estimate the incidence, predictors of hyperuricemia in pediatric liver transplant recipients, and to assess whether hyperuricemia may impact long-term renal function determined by measured GFR, we reviewed data of 70 children who received a first liver transplant between 1991 and 2005 (median follow-up 7.1 yr). Renal function tests performed annually included uric acid concentration, inulin and uric acid clearances. The cumulative incidence of hyperuricemia was 32% at 10-yr post-transplantation, mainly because of decreased urate excretion. The only factor significantly associated with an increased risk of hyperuricemia was older age. After adjustment for donor and recipient age, gender, primary liver disease, immunosuppression, and post-operative acute renal failure, hyperuricemia as time dependent variable tended to predict (p = 0.05) subsequent CRI. The control of serum urate concentration in eight of the 21 hyperuricemic patients either by nutritional management or by allopurinol was not followed by a significant GFR improvement. Hyperuricemia after liver transplantation in children is a frequent problem which needs further investigation.     

Evaluation of catch-up growth after liver transplantation in children with biliary atresia

Orthotopic liver transplantation (Tx) has improved survival in infants with extrahepatic biliary atresia (BA) when portoenteroanastomosis fails. Symptoms leading to Tx include liver failure, poor quality of life and growth failure. The objective of the study was to determine catch-up growth in children with BA. Medical records and growth data of 36 patients (24 girls) who received a Tx due to BA were analyzed. Thirty-two patients completed 3 yr and 15 patients 7 yr of follow-up after Tx. At Tx, the median age was 2.7 yr (range 0.7-12.6) and mean height Z score (+/-s.d.) was -1.56 (+/-1.3). Patients were divided in two groups according to age at Tx: group I (n = 10), younger than 1.0 yr, and group II (n = 26) older than 1.0 yr. Median age (range) at Tx in group I was 0.8 yr (0.7-1.0) and in group II it was 3.35 yr (1.25-12.6). Thirteen patients (nine in group I) were receptors of living related donors. We evaluated linear growth, liver and renal function, immunosuppressive regimen and allograft rejection episodes. We did not find any significant differences in allograft or renal function, immunosuppressive therapy and number of acute rejection episodes or height Z score at Tx, second and third year post-Tx between both groups. The mean height Z score at Tx in group I was -1.61 and in group II -1.54; at the second year, group I -0.66 and group II -1.08; at the third year, group I -0.17 and group II -0.85; and at the seventh year (total group) -0.3. However, the height gain at the third year was better in group I than in group II (p < 0.01, t-test). Height Z score at the third year improved more than 1 SDS in seven out of eight patients in group I and in only nine out of 24 in group II (odds ratio 11.6). We also found a correlation between height gain at the third year and age at Tx (r-0.65) and between height gain at the third year and height Z score at Tx (r-0.54) (Pearson, p < 0.05). Children with BA who are transplanted before 12 months of age presented better catch-up growth without change survival and morbidity. Orthotopic liver Tx improves survival and also enables height gain in these children.     

Changes with growth hormone treatment in growth hormone deficient children

A total of 54 previously untreated patients (15 girls, 39 boys) with poor growth due to idiopathic growth hormone deficiency (IGHD) were treated with human growth hormone (hGH), continuously up to 4 years. All of the patients had a peak hGH level which was below 10 ng/mL after at least two pharmacological tests and/or blunted physiologic hGH secretion, and their height was below ?2.5 s.d. for age and gender. After the 1st year of therapy, height velocity (HV) increased significantly when compared with baseline (from 3.18 ±0.76 cm/year to 9.17±1.03 cm/year; P <0.001), declined during the 2nd year and then remained significantly higher than pretreatment HV. When considering improvement in height expressed by height standard deviation score (SDS), during the therapy all of the patients showed a significant gain ± 1.72±1.09 (from ?4.11±0.61 to ?2.21±0.48). The height values were significantly higher than pretreatment, but remained below ?2 s.d. after 4 years of hGH therapy in our patients. Increased height velocity has been sustained, but height improvement after therapy was inversely correlated to height SDS for chronological age of patients at the start of therapy. In conclusion post-treatment height has been shown to be related to height deficit at the beginning of therapy. Therapy was well tolerated with no local or systemic adverse effects or acceleration of bone age.     

Adenovirus infection and treatment with cidofovir in children after liver transplantation

Abstract:  In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real-time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life-threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow-up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 × 10⁹ copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 × 10⁴ copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.     

生长激素治疗造血干细胞移植后生长障碍儿童的疗效观察

目的　 观察重组人生长激素对造血干细胞移植后生长障碍儿童的疗效和安全性。方法 　用分泌型重组人生长激素 ,剂量为 1u/kg·w ,分 6～ 7次 ,于晚上睡前3 0分钟皮下注射 ,在治疗前后对比生长指标的变化 ,并随访不良反应。结果 　经治疗6个月后身高增长率较治疗前明显提高 ,血清胰岛素样生长因子 -1亦明显升高 ,未发现有严重的不良反应。结论 　生长激素能明显促进造血干细胞移植后生长障碍儿童的身高增长 ,使用安全。     

Follow-up height after discontinuation of growth hormone treatment in children with intrauterine growth retardation

Growth hormone (GH) treatment has been used in children with intrauterine growth retardation (IUGR) to promote growth with success in several short- and long-term clinical trials. Intermittent GH therapy has also been advocated in children with IUGR. This study was designed to evaluate the growth of children with IUGR after discontinuation of a two-year trial of GH treatment. Sixteen children (12 F, 4 M) who had received GH (Genotropin) at age 5.3 (1.3) years at a dose of 0.2 IU/kg/day for 2 years (Group 1) and 10 (6 F, 4 M) controls of age 4.3 (1.7) years without treatment (Group 2) were followed after completion of the trial over a median period of 4 years. Height SDS of the GH-treated group showed an increase from -3.0 (0.5) to -1.9 (0.7) (p <0.001) over 2 years of therapy. Off therapy, height SDS decreased to -3.5 (0.5) at a mean age of 11.2 (1.6) years. The difference between the initial and recent height SDS in this group was significantly different (p = 0.02). Height SDS of the control group, -2.7 (1.4) initially, did not change over the two-year observation period. At follow-up, seven control children received GH in a similar fashion for one year. In spite of an insignificant increase in height SDS on one year of GH, it decreased to -2.9 (1.6) at age 11.0 (2.1) years at the latest visit. There was no significant difference between the recent heights of the two groups at final examination. One girl in Group 1 developed acanthosis nigricans and type 2 diabetes mellitus at age 13.3 years, after the follow-up period. A second patient developed osteosarcoma in the left tibia at age 9.9 years, for which she received chemotherapy and surgery. In conclusion, height SDS showed a significant increase on GH therapy for 2 years in children with IUGR; however, it decelerated after discontinuation of therapy. At the final visit, GH therapy did not seem to have had any effect on height prognosis. This finding shows that GH should be given continuously to improve final height in children with IUGR.     

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 ± 1.1 years). Pre-transplantation serum GH levels (7.5 ± 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 ± 0.5 ng/ml). However, post-transplantation levels (1.8 ± 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 ± 9.4 vs 190 ± 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 ± 96 ng/ml). In comparison with pre-transplantation data (z− 2.70), there was an increase in height 4 years postoperatively (z− 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z−1.58 ± 1.63 vs 2.59 ± 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.     

Emotional adaptation in children after liver transplantation

The emotional adaptation of 25 children who had undergone successful liver transplantation at least 1 year previously was evaluated and compared with that of a control group of 26 children with diabetes mellitus, matched for age, gender, and socioeconomic status, and with reported normative values. With the use of parent- and self-report measures, emotional adaptation was assessed in terms of behavioral adjustment (Child Behavior Checklist), depressive experiences (Children's Depression Inventory), anxiety (State-Trait Anxiety Inventory for Children), and self-concept (Piers-Harris Children's Self-concept Scale). Similar variables were also assessed by a projective personality measure (Rorschach). We found minimal differences in emotional adjustment between liver transplant and diabetic groups; on self-report measures, the adjustment of those with liver transplants was as good as, or better than, that of normative samples. However, on other tests, children with transplants differed from normative samples. On projective measures, liver transplant recipients had an increased number of depressive experiences, situationally related internal distress, and a greater tendency toward negative self-focus and evaluation. We conclude that in pediatric liver transplant recipients, behavioral and emotional adjustment is as good as in children with another chronic illness; in comparison with physically well children, the transplant recipients have subtle signs of emotional difficulties.     

Long-term outcome after liver transplantation in children

Children (defined as under 18 yr of age) account for approximately 12.5% of all liver transplants in the United States. Even though the annual number of liver transplantation procedures remains relatively constant, the population of long-term survivors of liver transplantation has grown. Presently, the population of long-term survivors of liver transplantation is 10-fold greater then the number of transplantations carried out each year. For long-term survivors of liver transplantation, the goal is to maintain graft function and wellness while decreasing the morbidity associated with long-term immunosuppression. The primary diagnosis leading to liver transplantation in children do not recur in the allograft. Consequently, many of the complications of liver transplantation, both early and long term, relate to the need for immunosuppression. Children may be at increased risk to develop significant end-organ damage as a result of increased serum lipid levels, elevated blood pressure, altered glucose metabolism, decreased renal function, cancer, and diminished bone accretion that occur as a result of immunosuppressive therapy or complications of therapy. As survival rates have increased, health care providers have begun to assess health-related quality of life. We will review our current knowledge of long-term outcome following pediatric liver transplantation in children.     

Ascites after orthotopic liver transplantation in children

Ascites is a poorly understood postoperative complication of orthotopic liver transplantation (OLT). It is associated with additional morbidity and can prolong hospitalization considerably. The incidence, the factors predictive of occurrence and the etiology of this complication are not known. The charts of 118 patients with 138 OLT were analyzed according to the following criteria: ascites lasting longer than the first 10 postoperative days, assessed by loss of ascitic fluid through drainage tubes, surgical wounds or paracentesis, with a peak volume of > or =10 mL/kg/day. Patients were divided into three groups: Group 1, no ascites; Group 2, ascites associated with postoperative complications, including chylus ascites; and Group 3, ascites not associated with postoperative complications. Postoperative ascites occurred in 43 of 138 OLT (31.2%). Patients with biliary atresia, preoperative portal hypertension, postoperative pleural effusion or at retransplantation had ascites significantly more often. In 32 of 138 (23.2%) OLT, ascites was associated with postoperative complications, including thrombosis, abdominal infections, intestinal perforation, biliary leak, pancreatitis, and chylus ascites. In 11 of 138 (7.9%) OLT, ascites was the only postoperative complication (group 3). Group three patients were significantly older, and had lower preoperative platelet counts and preoperative ascites more often than group 1 patients. The primary liver diseases were mainly cystic fibrosis of the pancreas, congenital hepatic fibrosis, and North American Indian childhood cirrhosis. The serum-ascites albumin gradient suggested a hepatic origin of ascites. Postoperative ascites is associated with the duration and degree of preoperative portal hypertension. We speculate that the mechanism involved includes a disproportion between venous blood volume and liver uptake capacity of the donor organ.     

重组人生长激素治疗生长激素缺乏症患儿影响生长速度疗效的因素

自1993年10月我们开始采用基因重组人生长激素（rhGH）治疗生长激素缺乏症（GHD）患儿,部分患儿疗程达7年半。现将治疗半年以上的患儿生长发育情况总结如下。     

Factors affecting growth and strategies for treatment in children after renal transplantation

Growth failure is a frequent side effect of long-term high-dose glucocorticoid therapy in children. Pharmacological doses of glucocorticoids interfere at different levels with the integrity of the somatotropic hormone axis. The majority of patients on chronic corticosteroid medication present with overt GH hyposecretion, apparently due to enhancement of hypothalamic somatostatin release. Glucocorticoids also inhibit IGF bioactivity by the induction of IGF inhibitors and stimulate the production of certain IGFBPs. In addition, glucocorticoids inhibit growth directly at the tissue level by suppressing local growth factors and skeletal tissue matrix production. In children post renal transplantation, concomitant treatment with cyclosporin A for immunosuppression allows low-dose glucocorticoid medication. Reduction of glucocorticoids, in particular when given as alternate-day therapy, improves growth in some but not all children. The new glucocorticoid deflazacort appears to have fewer side effects regarding steroid-induced osteopenia and cushingoid appearance. A beneficial effect on longitudinal growth has not been clearly established. Recent experimental and clinical data indicate that the catabolic and growth-depressing effects of glucocorticoids can be counterbalanced by concomitant anabolic treatment with rhGH. The potential role of rhIGF-I is less well investigated. Treatment with rhGH is able to antagonize several side effects of long-term glucocorticoid administration, such as growth failure, protein-wasting and osteoporosis. If catch-up growth cannot be achieved by an alternate-day steroid regimen and discontinuation of glucocorticoids appears to be an intolerable risk for graft survival, rhGH therapy may be initiated. However, rhGH therapy in this setting must still be considered experimental, because the possible interference of rhGH with the immunosuppressive action of glucocorticoids in children after organ transplantation is still incompletely defined.     

Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure

We studied the effect of recombinant human growth hormone treatment on five boys, aged 4.6 +/- 1.8 years, who had chronic renal failure secondary to congenital renal diseases (mean creatinine clearance (+/- SD): 18.3 +/- 6.3 ml/min/1.73 m2 (0.32 +/- 0.11 ml/sec/1.73 m2]. Patients received 0.125 mg/kg of growth hormone three times per week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 4.9 +/- 1.4 cm/yr (range 3.0 to 6.3 cm/yr), with a mean standard deviation score for a height of -2.98 +/- 0.73 (range -2.16 to -3.59). At the end of therapy, the mean growth velocity had increased to 8.9 +/- 1.2 cm/yr (range 7.5 to 10.7 cm/yr), and the mean height standard deviation score improved to -2.36 +/- 0.83 (range -1.15 to -3.18). Bone age advancement was consistent with the period of growth. Routine laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels. These preliminary data indicate that growth-retarded children with chronic renal failure can respond to exogenous growth hormone therapy with a marked acceleration in growth velocity.     

Incidental pineal cysts in children who undergo 3-T MRI

Background

Pineal cysts, both simple and complex, are commonly encountered in children. More cysts are being detected with MR technology; however, nearly all pineal cysts are benign and require no follow-up.

Objective

To discover the prevalence of pineal cysts in children at our institution who have undergone high-resolution 3-T MRI.

Materials and methods

We retrospectively reviewed 100 consecutive 3-T brain MRIs in children ages 1 month to 17 years (mean 6.8 ± 5.1 years). We evaluated 3-D volumetric T1-W imaging, axial T2-W imaging, axial T2-W FLAIR (fluid attenuated inversion recovery) and coronal STIR (short tau inversion recovery) sequences. Pineal parenchymal and cyst volumes were measured in three planes. Cysts were analyzed for the presence and degree of complexity.

Results

Pineal cysts were present in 57% of children, with a mean maximum linear dimension of 4.2 mm (range 1.5–16 mm). Of these cysts, 24.6% showed thin septations or fluid levels reflecting complexity. None of the cysts demonstrated complete T2/FLAIR signal suppression. No cyst wall thickening or nodularity was present. There was no significant difference between the ages of children with and without cysts. Cysts were more commonly encountered in girls than boys (67% vs. 52%; P?=?0.043). There was a slight trend toward increasing pineal gland volume with age.

Conclusion

Pineal cysts are often present in children and can be incidentally detected by 3-T MRI. Characteristic-appearing pineal cysts in children are benign, incidental findings, for which follow-up is not required if there are no referable symptoms or excessive size.