Anemia and autoimmunity markers in an adolescent with Castleman disease

We describe herein the case of an adolescent girl with anemia non‐responsive to oral iron, associated with low‐grade fever, diminished appetite and fatigue. A palpable mass below the xiphoid was noted. Laboratory findings were consistent with anemia of inflammation. Direct antiglobulin test was positive without any other evidence of autoimmune anemia. Other autoantibodies, such as anti‐thyroid and anti‐nuclear antibodies, were also positive. After thorough investigation, Castleman disease was the most likely diagnosis on the basis of high serum interleukin (IL)‐6 and the magnetic resonance imaging findings. ¹⁸ F‐FDG positron emission tomography–computed tomography showed a localized hypermetabolic mass, which was resected. Castleman disease of plasma type was identified on histology. Hemogloblin and IL‐6 gradually returned to normal, whereas positive autoantibodies became negative. This case emphasizes the need to investigate thoroughly for the underlying cause of anemia of inflammation and to include Castleman disease in the differential diagnosis, on the measurement of IL‐6.     

Studies of malformation syndromes of man XL VII: Disappearance of spermatogonia in the fanconi anemia syndrome

A 15 year old boy with the Fanconi malformation-aplastic anemia syndrome developed erythroleukemia and died of multiple arterial thromboses and hemorrhage. He was one of 10 siblings including 3 affected sisters. He was short of stature and had hypoplastic thumbs; his testes were small and secondary sexual characteristics were inadequately developed. At autopsy he was found to have very few spermatogonia, i.e., a histological picture compatible with the Sertoli-cell-only defect. Male hypogonadism in other chromosome breakage syndromes (the Bloom syndrome and ataxia telangiectasia) may have a similar pathogenesis.Supported, in part, by DHEW/USPH Grant GM 20130 from the National Institute of General Medical Sciences. Paper No. 2088 from the Laboratory of Genetics, University of Wisconsin, Madison, WI 53706, USA     

Pseudohypoparathyroidism with normal serum calcium level.

A mildly obese 15-year-old boy had short stature with rounded facies and short, stubby hands and toes. He had the fully expressed syndrome of pseudohypoparathyroidism but was the only member of his family who had all the somatic characteristics of this disease. The serum parathyroid hormone level was substantially elevated. Urinary excretion of cyclic adenosine monophosphate and phosphate failed to increase following intravenous infusion of parathyroid hormone. However, he did not have hypocalcemia. The present entity is probably a transient form of pseudohypoparathyroidism with partial responsiveness of skeletal adenyl cyclase to parathyroid hormone.     

A boy with psychosocial short stature followed up from infancy to adulthood

A boy with psychosocial short stature who has been followed up from the age of 11 months to adulthood is described. The boy was the product of an unwanted pregnancy. The emaciated short boy gained weight and height markedly during a short-term stay at hospital, but lost weight and experienced minimal height gain at home. On the fourth hospital admission at the age of 6 years 3 months the boy weighed 10 kg and measured 85.7 cm, he was malnourished and exhibited strange behavior and had a voracious appetite. He was examined endocrinologically and provocative tests performed early after admission showed insufficient growth hormone secretion, although this recovered later at a time of catch-up growth. The boy was reared in an orphanage from the age of 6 years 5 months until the age of 15 years 3 months. His growth rapidly caught up to a normal rate, his abnormal behavior disappeared, and he demonstrated an increased IQ. He attained 169.5 cm at the age of 17.5 years and possessed normal secondary sexual characteristics. After graduating from senior high school the patient has been living happily by himself without intervention from his mother, and is working in a Chinese restaurant. The impaired relationship between the boy and mother has never been restored. The record of growth and development described in this case is the longest ever reported.     

Paraneoplastic syndrome and intrathoracic Castleman disease

We report two cases of intrathoracic Castleman disease presenting with paraneoplastic syndrome. Patient 1 was a 10-year-old girl with short stature. She was found to have delayed bone age, slow growth velocity, and iron-deficiency anemia, which was refractory to treatment. Thrombocytosis and hypergammaglobulinemia were later detected. Chest X-ray revealed a hilar mass. Patient 2 was a 14-year-old boy who had severe cough, progressive mucocutaneous erosion, and dermatitis. Chest X-ray showed a mediastinal mass. Sections of skin biopsy showed findings consistent with pemphigus disease. In each case, the histological diagnosis of Castleman disease was made.     

Growth and endocrine function after renal transplantation.

Longitudinal height data and physical development were assessed in 45 boys and 34 girls after renal transplantation. All children received alternate day steroids and either azathioprine or cyclosporin A for immunosuppression. There was a significant increase in growth velocity after transplantation in prepubertal children. Growth velocity declined at the expected age of the normal pubertal growth spurt, however, with delay in the appearance of secondary sexual characteristics. Overnight hormone profiles in 17 adolescent subjects with short stature or maturational delay, or both, showed blunting of growth hormone and gonadotrophin pulsatility. It is likely that long term steroid treatment after renal transplantation induces the clinical and endocrine picture of delayed puberty. Failure of growth to accelerate at this time is a cause of short stature, which may have an effect on adult height.     

Short stature and failure of pubertal development in thalassaemia major: evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin secretion

In patients with β-thalassaemia major, frequent blood transfusions combined with desferrioxamine chelation therapy lead to an improved rate of survival. Endocrine disorders related to secondary haemosiderosis such as short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. A total of 32 patients with β-thalassaemia major undergoing treatment at the Children's Hospital, University of Göttingen were examined. Fourteen of these were short in stature. Growth hormone (GH) secretion was investigated in 13 patients exhibiting either a short stature or reduced growth rate. The stimulated GH secretion of 10 patients in this subgroup lay within the normal range. Studies of their spontaneous GH secretion during the night revealed that these patients had a markedly reduced mean GH and reduced amplitudes in their GH peaks. Low insulin-like growth factor (IGF)-I levels were seen in the growth-retarded thalassaemic patients. Eight were subjected to an IGF generation test and showed a strong increase in both IGF-I and insulin-like growth factor binding protein (IGFBP)-3 levels indicating intact IGF-I generation by the liver. Hypogonadotropic hypogonadism was found to be present in both the male and female patients with impaired sexual development. After priming with LH-releasing hormone (GnRH) per pump in 2 female and 5 male patients, no change in either their serum oestradiol or testosterone levels or in LH/FSH response to GnRH was observed suggesting that they were suffering from a severe pituitary gonadotropin insufficiency. Three male patients at the age of puberty but exhibiting short stature, low GH, low IGF-I and hypogonadism received low dose long-acting testosterone. After 3–12 months of therapy there was a marked growth spurt, higher nocturnal GH levels and an increase in both IGF-I and IGFBP-3. Conclusion Reduced GH secretion and low IGF-I in thalassaemic patients are related to a neurosecretory dysfunction due to iron overload rather than to liver damage. Hypogonadotropic hypogonadism is caused by the selective loss of pituitary gonadotropin function. In patients with both GH deficiency and hypogonadism, low dose sexual steroid treatment should be considered either as an alternative or an additional treatment before starting GH therapy.     

Children with short‐limbed short stature in pediatric endocrinological services in Japan

Short‐limbed short stature is a heterogeneous condition that can result from many diseases such as bone disorder, metabolic disease, and multiple malformation syndrome. We conducted a questionnaire survey of council members of the Japanese Society of Pediatric Endocrinology and doctors of affiliated hospitals in 2010 to investigate short‐limbed short stature. Among 91 hospitals, responses were obtained from 61 hospitals (67% response rate). This study also examined data of 193 short‐limbed short stature patients, among whom FGFR3‐related chondrodysplasia such as achondroplasia (n = 109; 56.5%) was found the most frequently. Second to achondroplasia, hypochondroplasia (n = 47; 24.4%) was the most frequently observed. Along with achondroplasia and hypochondroplasia, 31 patients with disorders of 13 other kinds and six undiagnosed patients were identified. Genetic testing for hypochondroplasia was conducted for only 27.7% of all hypochondroplasia patients, although hypochondroplasia is a heterogeneous condition with many causes, only one of which is FGFR3 mutation. We conducted a genetic analysis of 25 patients who had been clinically diagnosed as having “hypochondroplasia”. In these patients, other diseases such as acromicric dysplasia, geleophysic dysplasia, and Aarskog–Scott syndrome were included in addition to FGFR3‐related hypochondroplasia (n = 10). Clinical diagnosis of each disorder causing short‐limbed short stature is difficult. Therefore, not only clinical diagnosis but also genetic diagnosis play an important role in the diagnosis of short‐limb short stature. Diagnostic strategies must be created for each disorder.     

Celiac disease with various presentations

BACKGROUND: Celiac disease (CD) has a wide clinical spectrum from malabsorption syndrome to extra intestinal presentations. A total of 45 children with CD presented with mainly chronic diarrhea (n :23), anemia (n: 12), and short stature (n: 10) were evaluated in this study. The aim was to find common parameters of CD with various presentations. METHODS: Basic anthropometric, biochemical and hematological parameters in cases with CD with various presentations were compared. RESULTS: It was found that children with CD presenting with chronic diarrhea were younger. There was no significant difference in hemoglobin levels in children with CD presenting with anemia. Children with CD with short stature had significantly lower serum vitamin B(12) levels and lower levels of height standard deviation scores, bone age delay, and alkaline phosphatase. CONCLUSIONS: It was concluded that children, especially infants with chronic diarrhea with CD, may not be affected with generalized malabsorption. Anemia and short stature are frequent findings in cases with CD whether they are main presenting symptoms or not. Children with CD presenting with short stature may have lower levels of vitamin B(12) than other presentations.     

Constitutional delay of growth and pubertal development: growth hormone secretory pattern and possible therapy

Constitutional delay of growth and pubertal development is a frequent cause of short stature. These children have a significant retardation of skeletal age and delayed sexual development. They generally maintain a normal growth curve and tend to attain normal adult height. Although children with constitutional delay of growth are believed to have no medical or endocrine abnormality to explain their short stature, some controversy regarding their growth hormone secretory status has recently surfaced; some authors have reported low growth hormone levels to provocative stimuli and decreased growth hormone secretion during sleep, as well as low somatomedin C values in some children with constitutional delay of growth. Others, however, have found the growth hormone secretory status to be normal and similar to that of a control population. The implications of these findings, particularly in regard to possible forms of therapy, are discussed in some detail.     

Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3–7 days and recurring every 4–6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C‐reactive protein are elevated during the episode, and in addition, high levels of interleukine‐1 (IL‐1), IL‐6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF‐alpha inhibitor, and three children with anakinra, IL‐1 receptor antagonist. Conclusion: This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5‐year‐old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented.     

The role of insulin like growth factor (IGF) — 1 and IGF — binding protein-3 in diagnosis of Growth Hormone Deficiency in short stature children

Objective  The purpose of this study was to evaluate the role of IGF-1 and IGFBP-3 in diagnosis of short stature children and adolescents in whom Growth Hormone Deficiency (GHD) was found. Methods  In this cross sectional study the referred short stature children and adolescents to Namazi Hospital in Shiraz- Iran, in 2003–2005 were studied. The inclusion criteria were proved short stature based on the physical examination, weight, height, standard deviation score (SDS) of height < −2, with considering stage of puberty and predicted height in children without any genetic or chronic disorders. The exclusion criteria were any positive physical or laboratory data suggesting hypothyroidism, rickets or liver disorders. For all patients a provocative growth hormone test was performed with propranolol and L-dopa and serum IGF-1 and IGFBP-3 were measured. GHD defined as peak(cutoff) serum GH level under 10 ìg/L and low IGF-1 and IGFBP-3 considered as cutoff serum level under −2 standard deviation. Results  Eighty one short stature patients (39 boys and 42 girls) with mean age of 10.6 ± 3.5 years completed the study. Seventeen patients with GHD were found and in 18 patients IGF-1 level were low. Only in 6 patients both GH and IGF-1 were low and 2 of them had low IGFBP-3. There were no correlations between the levels of GH,IGF-1 and IGFBP-3 in children with short stature due to GHD. The sensitivity and specifity of IGF-1 and IGFBP-3 in assessment of GHD were 35% and 81% for IGF-1 and 12% and 94% for IGFBP-3, respectively. Conclusion  No correlations were found between GH level and serum levels of IGF-1 and IGFBP-3 in short patients and the sensitivity of those tests in assessment of GHD were poor.     

Asymmetrical closure of epiphyses in a patient with sickle cell anemia

There is a high incidence of delayed sexual development and short stature during childhood in children with sickle cell anemia (SCA). We report a 15 year-old male with SCA who presented with significant short stature after a near death event (involving seizures and prolonged hypoxia). His evaluation showed growth hormone (GH) deficiency with low insulin-like growth factor-I (IGF-I), low IGF binding protein-3, and low GH response to stimulation. He was started on GH replacement with poor response in height gain although with normal response in terms of elongation of his arm span. Further studies showed premature closure of the epiphyses of the femora and tibiae bilaterally. This report demonstrates that children with SCA may present with growth failure not only due to nutritional and GH abnormalities but also due to abnormal growth plates, probably due to local anoxic events. Children with SCA should always have their arm span measured carefully.     

The use of a Berlin Heart EXCOR LVAD in a child receiving chemotherapy for Castleman's disease

We present the unique case of a pediatric patient who received chemotherapy for a diagnosis of CD, while mechanically supported with a Berlin EXCOR LVAD secondary to restrictive cardiomyopathy. A four‐yr‐old previously healthy male with restrictive cardiomyopathy required MCS after cardiac arrest but was diagnosed with multicentric CD, a non‐malignant lymphoproliferative disorder fueled by excessive IL‐6 production. Treatment with IL‐6 blockade (tocilizumab) every two wk and methylprednisolone had no effect on his lymph nodes or cardiac function while on temporary RotaFlow. A Berlin LVAD was placed for treatment with rituximab, COP, vincristine, and methylprednisolone. After three courses of chemotherapy, his inflammatory markers normalized and his lymphadenopathy decreased but cardiac function remained severely depressed. He tolerated chemotherapy on the Berlin but required frequent titrations of his anti‐coagulation regimen and he did suffer a hemorrhagic stroke. His clinical status improved significantly with rehabilitation, and he tolerated heart transplantation without further complications. MCS is a feasible option as a bridge to recovery or heart transplant eligibility for patients with hemodynamic collapse requiring chemotherapy but it does necessitate close titration of the anti‐coagulation regimen to coincide with changes in the inflammatory state.     

儿童甲状腺功能减低并发垂体增生8例报告

目的：探讨甲状腺功能减低致垂体增生的内分泌激素的改变及治疗效果。方法：回顾性分析8例甲状腺功能减低致垂体增生儿童（3例男性,5例女性,年龄5～9岁）的临床资料,治疗随访1～6年。结果：8例患儿的甲状腺激素水平均降低,促甲状腺素（TSH）及血浆泌乳素（PRL）水平增高,予以甲状腺素替代治疗,用药2～6月后,血清游离三碘甲腺原氨酸(FT3)、游离四碘甲腺原氨酸(FT4)、TSH及PRL恢复正常,垂体体积恢复正常大小。其中6 例身高增长由治疗前3.1±0.5 cm/年,提高到治疗后11.6±1.7 cm/年,差异有显著性(P<0.01)。另外2例儿童甲状腺素替代治疗后身高增长不理想,予以基因重组人生长激素（rhGH）治疗后,随访身高增长为11 cm/年。8例均无垂体增生复发。结论：对于身材矮小儿童进行甲状腺功能及垂体检查十分必要,甲状腺素替代治疗是儿童甲状腺功能减低致垂体增生的有效手段。在垂体增生恢复后仍然合并生长激素缺乏的患儿予以生长素治疗可以获得满意的身高增长。［中国当代儿科杂志,2010,12（1）：17-20］     

Young patients with both type 1 diabetes mellitus and asthma have a unique IL-12 and IL-18 secretory pattern

Rachmiel M, Bloch O, Shaul AA, Ben‐Yehudah G, Bistritzer Z, Weintrob N, Ofan R, Rapoport MJ. Young patients with both type 1 diabetes mellitus and asthma have a unique IL‐12 and IL‐18 secretory pattern. Background: The expression of the regulatory cytokines interleukin (IL)‐12 and IL‐18 in patients with both Th1‐ and Th2‐mediated diseases, type 1 diabetes mellitus (T1DM) and asthma, is unknown. Objective: To investigate the in vivo and in vitro IL‐12 and IL‐18 secretion patterns in patients with both T1DM and asthma. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 44 patients. Mean age 19.4 ± 4.7 yr (10.5–28 yr), divided into four paired groups: T1DM and asthma, asthma only, T1DM only, and healthy controls. T‐cell proliferative response was assessed. IL‐12 and IL‐18 serum levels and expression by PBMC following in vitro stimulation by lipopolysaccharide (LPS) were determined by enzyme‐linked immunosorbent assay (ELISA). Results: Patients with T1DM and asthma had higher serum levels of both IL‐12 and IL‐18 compared to controls: 146.2 ± 69.2 and 109.7 ± 34.6 pg/mL, p = 0.038 and 436.1 ± 117.9, 320.2 ± 99.1 pg/mL, p = 0.028, respectively. Stimulated IL‐12 secretion was significantly lower in these patients compared to those with one disease only: 809 ± 426.4, 2111.6 ± 2214.3, 3188.1 ± 2692.9 pg/mL and after 48 h: 956.3 ± 489.3, 2429.8 ± 2394.6, 3874.5 ± 2820.3 pg/mL, respectively, p < 0.03 for all. The IL‐18/IL‐12 serum ratio was also significantly higher in patients with both diseases compared to those with asthma only, p = 0.017. Conclusion: Patients with both T1DM and asthma display a different pattern of IL‐12 and IL‐18 expression compared to patients with one disease only and controls.     

Elevated serum interleukin‐7 level in idiopathic steroid‐sensitive nephrotic syndrome

Background: Several cytokines have a pathological association with idiopathic steroid‐sensitive nephrotic syndrome (ISSNS) in inducing proteinuria or regulating T cells. Because interleukin (IL)‐7 plays important roles in regulating T‐cell proliferation and sustaining naïve or memory T cells, IL‐7 is one of the candidate cytokines in the pathogenesis of ISSNS. Very little is known, however, about the association of IL‐7 with ISSNS. To clarify the IL‐7 dynamics in children with ISSNS, serum IL‐7 level was investigated, from the nephrotic phase before steroid treatment (STx; group A1) to the remission phase with STx (group A2) and without STx (group A3). Methods: Eighteen children with ISSNS were included in the present study. A total of 25 paired samples were analyzed for groups A1 and A2, and a total of 10 paired samples for groups A1, A2, and A3 due to recurrence. Two control groups (with normal urinalysis, group B; or with nephrotic syndrome other than ISSNS, group C), matched for age and gender, were also included. Serum cytokine level was measured on bead‐based assay. Results: Each serum IL‐7 level in groups A1 and A3 was higher than each serum IL‐7 level of groups C and B, respectively. The group A2 serum IL‐7 level was higher than that of group A1. There was no statistical significance of serum IL‐7 level between group A1 and group A3. Conclusion: Serum IL‐7 level was elevated in children with ISSNS regardless of the status of the disease. This brings us one step closer to a better understanding of the pathophysiology of ISSNS in children.     

Exploring beyond viral load testing for EBV lymphoproliferation: Role of serum IL‐6 and IgE assays as adjunctive tests

Barton M, Wasfy S, Hébert D, Dipchand A, Fecteau A, Grant D, Ng V, Solomon M, Chan M, Read S, Stephens D, Tellier R, Allen UD and the EBV and Associated Viruses Collaborative Research Group. Exploring beyond viral load testing for EBV lymphoproliferation: Role of serum IL‐6 and IgE assays as adjunctive tests.
Pediatr Transplantation 2010: 14: 852–858. © 2010 John Wiley & Sons A/S. Abstract: We examined serum IL‐6 and IgE assays as adjuncts to VL monitoring for PTLD. Paediatric solid organ transplant recipients were followed with VL monitoring. VL, IL‐6, and IgE assays were compared between PTLD cases and non‐cases at <3, 3–6 and >6 months after transplantation. Median IL‐6 levels in PTLD cases were 15.5 (2.0–87.1) and 23.3 (2.1–276) pg/mL compared with 3.25 (0.92–114) and 3.5 (0.75–199.25) pg/mL in non‐cases at 3–6 and >6 months, respectively (p = 0.006 and p = 0.005). At >6 months, IL‐6 levels correlated with VL and PTLD occurrence (Spearman’s coefficients = 0.40; p = 0.001 and 0.32; p = 0.003) in univariate analyses. No benefit was derived from performance of IgE levels. The sensitivity and specificity of high VL as a test of PTLD were 76.3% and 92.5%, while the negative predictive value and PPV of VL were 94.9% and 68.4%, respectively. Combining elevated IL‐6 with high VL increased the PPV and specificity to 80% and 96.2%, respectively, and improved the receiver operating characteristic curve. Serum IL‐6 levels can improve the clinician’s ability to identify PTLD, among patients with elevated EBV viral loads.     

Cytokine profile in two siblings with neonatal lupus erythematosus

We studied the cytokine profile of two siblings with neonatal lupus erythematosus (NLE) born to a mother positive for serum anti‐Ro and ‐La antibodies, who did not receive any medication during the two pregnancies. The first sibling was found to have complete atrioventricular block in utero and became severely ill after birth. He fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis on day 2. The second sibling did not have any fetal symptoms. He was generally stable after birth, but with typical skin rash. Laboratory data suggested that they both had hypercytokinemia during the neonatal period, requiring corticosteroid treatment. Interleukin (IL)‐6, interferon‐γ, IL‐8 and monocyte chemotactic protein‐1 were elevated in both cases, while IL‐12, IL‐13 and IL‐17 were elevated only in the second sibling. Comparison of the cytokine profiles suggests the potential roles of different cytokines in the onset and clinical manifestations of NLE.