Diencephalic syndrome: a cause of failure to thrive and a model of partial growth hormone resistance

Diencephalic syndrome is a rare but potentially lethal cause of failure to thrive in infants and young children. The diencephalic syndrome includes clinical characteristics of severe emaciation, normal linear growth, and normal or precocious intellectual development in association with central nervous system tumors. Our group initially described a series of 9 patients with diencephalic syndrome and found a reduced prevalence of emesis, hyperalertness, or hyperactivity compared with previous reports. Also, the tumors were found to be larger, occur at a younger age, and behave more aggressively than similarly located tumors without diencephalic syndrome. We have been able to extend our follow-up of the original patients, as well as describe 2 additional cases. Because the mechanism of the growth and endocrinologic findings in diencephalic syndrome has not been explained, we report on these patients in light of current research on hypothalamic factors that affect growth and weight. This study emphasizes diencephalic syndrome as a model for additional study of growth hormone resistance and metabolic regulation of adiposity.     

Diencephalic Syndrome of Emaciation Report of a Case

A new case with diencephalic syndrome of emaciation is reported. The first symptoms occurred when the patient was 2 months old. Ventriculography demonstrated a probable tumour in the third ventricle. The patient is described and the findings shortly commented on.     

Diencephalic syndrome revisited.

This report details the histories of five patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. A review of an additional 67 patients indicates that the observations are not unique. The anatomic variability combined with the fact that the course of those who are treated is infinitely better than those left untreated adds urgency to the establishment of precise anatomic diagnosis. These considerations led to a critical review of the histories of the 72 patients. From this it can be stated that anteriorly and posteriorly placed tumors do exhibit subtle but significant differences in their clinical course, and roentgenograms of the optic foramina and analysis of the CSF cell and protein content appear warranted early in the investigation of emaciation from unknown cause. Further, an evaluation is made of the role of various radiologic techniques and of endocrine studies in establishing the diagnosis. Similarly, the relative merits of radiotherapy and/or surgery in the treatment of the disease are defined. Finally, the adequacy of the term diencephalic syndrome is discussed.     

STUDIES ON GROWTH HORMONE SECRETION IN A PATIENT WITH THE DIENCEPHALIC SYNDROME OF EMACIATION

A girl with a large optic glioma, and the typical features of diencephalic syndrome of emaciation (Russell) was followed up from ¹/₂ to 2 ¹/₂ years of age. She had very high levels of growth hormone (GH) in the plasma, which were not influenced by hyperglycaemia, by hypoglycaemia or by dexamethasone, reserpine or chlorpromazine. Interference by the glioma with GH releasing factor or more likely with GH inhibiting factor is suggested. In spite of the elevated plasma GH, linear growth was markedly retarded. Sulfation factor activity (Somatomedin) was low with no significant response to injections of HGH. The patho-genesis of the profound metabolic disturbances in this syndrome is not properly understood. The endogenous GH obviously exerts its full adipokinetic effect, whereas the synthesis of the sulfation factor (Somatomedin) must be defective. This case illustrates a type of retardation of linear growth, not seen in any other known syndrome.     

Diencephalic cachexia (A. Russel's syndrome). Apropos of 3 cases. Importance of transfontanelle ultrasonography

Three children with diencephalic tumours are described. In these cases, the main clinical features are extreme emaciation and nystagmus. Ultrasonography and computed tomography demonstrated the tumour. In one case, high levels of growth hormone were observed. In the three cases, the tumour was a glioma.     

Targeted therapy for infants with diencephalic syndrome: A case report and review of management strategies

Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low‐grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.     

Diagnosis and management of infantile marfan syndrome

Marfan syndrome is infrequently diagnosed early in infancy. The experience of the authors with 22 severely affected infants diagnosed as having Marfan syndrome in the first 3 months of life is described and the literature on 32 additional infants with Marfan syndrome is reviewed. It was found that serious cardiac pathology (82% of the patients described in the article, 94% of those described in the literature) may be present at birth, and that congenital contractures (64% of our cases, 47% of literature cases) are often an associated finding. Other useful clinical findings included arachnodactyly, dolichocephaly, a characteristic facies, a high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodenesis, megalocornea, and dislocated lenses. Echocardiography was useful as a noninvasive method for defining the extent of cardiovascular involvement and following its course. Characteristic cardiac findings in early life included mitral valve prolapse, valvular regurgitation, and aortic root dilation. Cardiac function ranged from normal to poor, with a tendency to worsen. Of the 22 cases 3 infants died during the first year of life. Morbidity and mortality may be high when Marfan syndrome is diagnosed during infancy, and prompt recognition of this phenotype can facilitate management and counseling. Most such severe cases appear to be due to a sporadic mutation in a single germ cell of one parent. Many familial cases may have milder manifestations, be more difficult to detect during infancy, and have a better prognosis.     

Increased urinary catecholamines in an infant with the diencephalic syndrome.

In an infant of 15 months with the diencephalic syndrome, urinary excretion of norepinephrine was moderately raised and epinephrine greatly so. It is suggested that catecholamine secretion may be due to sympathetic stimulation at the level of the diencephalon, by a space-occupying lesion pressing on the thalamohypothalamic pathway. Some of the symptoms of the diencephalic syndrome such as euphoria, irritability, skin pallor, and hypertension may be the result of catecholamine secretion.     

Malignant transformation of a chiasmatic pilocytic astrocytoma in a patient with diencephalic syndrome

Chiasmatic gliomas with metastatic spread are rare in children and are usually associated with diencephalic syndrome. They are mostly pilocytic astrocytomas and their transformation to high-grade astrocytomas has never previously been reported in the pediatric population. We report leptomeningeal spread of a chiasmatic pilocytic astrocytoma in a child presenting with diencephalic syndrome. He was treated with chemotherapy and radiation. The tumor recurred with transformation into a high-grade astrocytoma. Radiation therapy may have played a role in transformation of the tumor, but more research is needed to further clarify the biological behavior of this tumor.     

Are Klinefelter boys hypogonadal?

Male hypogonadism implies decreased function of one or more testicular cell population, i.e. germ, Leydig and/or Sertoli cells. In the normal prepubertal boy, Sertoli cells are very active, as indicated by high anti-Müllerian hormone (AMH) and inhibin B secretion, whereas the functional activity of Leydig cells is minimal, as evidenced by low testosterone production, and germ cells do not undergo the full spermatogenic process. Klinefelter syndrome is the most frequent cause of hypogonadism in the adult male. In this review, we discuss whether the gonadal failure is already established during infancy and childhood. In Klinefelter syndrome, there is increased germ cells degeneration from mid-foetal life - resulting in a decreased number at birth - which persists during infancy and childhood and becomes dramatic during puberty. Controversial results exist in the literature regarding Leydig cell function in Klinefelter boys: while some authors have found normal to low testosterone levels in infancy and childhood, others have reported normal to high values. Sertoli cell products AMH and inhibin B are normal in prepubertal boys and only decline during mid- to late puberty. CONCLUSION: Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations. Germ cells are affected from foetal life, and a severe depletion occurs at puberty. Leydig cell function may be normal or mildly affected in foetal and early postnatal life. Sertoli cell function is not impaired until mid- to late puberty, as reflected by normal AMH and inhibin B in Klinefelter boys.     

Diencephalic syndrome: An uncommon cause of malnutrition

Diencephalic syndrome (DS) is a complex of signs and symptoms related to hypothalamic dysfunction. Its main features are emaciation despite normal energy intake and an alert appearance. This syndrome has been described in association with space-occupying lesions of the hypothalamic-optic chiasm region, mainly low-grade glioma, and less often with tumors in the proximity of the IV ventricle. Two patients with DS are reported. The first patient was an 8-month old boy with classical features of DS. Extensive investigation of malabsorption revealed no abnormalities and the first neurologic sign was a rotatory nystagmus. Magnetic resonance imaging (MRI) showed evidence of a hypothalamic tumor, which was identified after surgical resection as a pilocytic astrocytoma. The second patient was an adolescent boy who presented a 20-kg weight loss over a 6-month period and psychological disturbances. Gastrointestinal disease was ruled out as a cause of malnutrition. Because of a polydipsia-polyuria syndrome, manifest while the patient was hospitalized with a suspected diagnosis of anorexia nervosa, MRI of the brain was performed. Multiple intracranial lesions were revealed, mainly in the hypothalamus, and were identified as a disseminated disgerminoma. No neurologic signs or symptoms were present. The patients died 2 years and 1 year after diagnosis, respectively. Although DS is rare, it should be considered in severe failure to thrive or emaciation despite adequate food intake and normal absorptive function of the small bowel.     

Sjogren-Larsson syndrome

Sjogren-Larsson Syndrome is a rare autosomal disorder which occurs with 100% penetrance and is classically characterized by ichthyosis, spasticity and mental handicap. This has rarely been described in people of Indian origin, case reports mainly being restricted to Caucasians. We have described’a 6-year-old girl with classical features of this syndrome, the symptoms having started in infancy. The spasticity is mainly diplegic in nature. Skin changes of ichthyosis are generalized and more in the flexural areas. Mental retardation is severe. Management is supportive.     

Successful mechanical circulatory support for 251 days in a child with intermittent severe neutropenia due to Barth syndrome

Barth syndrome is an X‐linked recessive disorder that is characterized by cardiomyopathy, variable neutropenia, skeletal myopathy, growth delay, and organic aciduria. The cardiac involvement typically results in a high risk of severe heart failure in infancy or early childhood. While Berlin Heart EXCOR is widely accepted as ventricular assistance in pediatric patients with end‐stage cardiac failure, infections remain a frequent and potentially severe complication. Therefore, the extended use of the device in the setting of intermittent or severe neutropenia is challenging. We present the case of a three‐yr child with Barth syndrome who was bridged successfully to transplant with a Berlin Heart EXCOR assist device for eight months (251 days) without major infectious complication, despite several episodes of severe neutropenia. This case demonstrates that prolonged mechanical circulatory support for a patient with neutropenia is feasible without important morbidity, with careful monitoring and a multidisciplinary approach. G‐CSF provides an excellent support in managing neutropenia.     

The use of vitamin E in childhood

The essential effects of Tocopherol are based on its antioxidative capacity. Tocopherol, however, is just one in a group of antioxidants, which are important for the organism. Established indication for therapeutical application of vitamin E in infancy is only vitamin-E-malabsorption in connection with chronic cholestasis, pancreatic insufficiency (cystic fibrosis) and short bowel syndrome. In emergency therapy vitamin E is suggested with high dosage in case of shock lung and haemolytic-uraemic syndrome. Positive effects of daily vitamin E application in connection with prophylaxis of retinopathy prematurity, bronchopulmonary dysplasia and intraventricular encephalorrhagia of premature infants of severe underweight are not established. Very questionable therapeutic or prophylactic efficiency is opposed to the risk of higher incidence of severe complications in caring for premature infants of severe underweight, such as enterocolitis necroticans and neonatal septicaemia.     

Growth Hormone and Adrenocorticotropic Hormone Levels Increased in a Child with Diencephalic Syndrome

A Japanese male child with diencephalic syndrome due to suprasellar tumor was treated in our department. There were no symptoms suggestive of hyper-adrenalism despite an increased adrenocorticotropic hormone (ACTH), nor was there an excessive growth even in the presence of high fasting levels of growth hormone (GH). After radiation therapy, both ACTH and GH levels reverted to normal. Thus, the abnormal hypothalamic control following destruction of a certain area of the diencephalon may have led to increases in the levels of ACTH and GH. This may be the first documentation of increased ACTH levels in a patient with diencephalic syndrome.     

Diagnosis and follow-up of Russel's diencephalic cachexia by echography, x-ray computed tomography and nuclear magnetic resonance

A diencephalic astrocytoma was diagnosed by ultrasonography in a 5 months old girl with nystagmus and emaciation. A 27 months follow-up with ultrasonography, computed tomography and magnetic resonance imaging, showed an initial improvement after irradiation and afterwards the development of complications with ventricular dilatation and parenchymal calcifications.     

慢性病贫血患儿肿瘤坏死因子α、白介素6与红细胞生成素的关系

目的　探讨小儿慢性病贫血 (ACD)血清红细胞生成素 (EPO)水平与肿瘤坏死因子α(TNF α)、白介素 6 (IL 6 )的关系以及体外重组TNF α(rhTNF α)对EPO产生的影响。方法　住院患儿6 0例 ,其中ACD组 2 0例 ,慢性病无贫血组 (NA) 19例 ,缺铁性贫血组 (IDA) 2 1例。TNF α、IL 6采用ELISA方法检测 ,EPO应用化学发光法测定 ,对人肝癌细胞株HepG2进行体外培养 ,应用逆转录 聚合酶链反应 (RT PCR)半定量方法 ,探讨rhTNF α对EPO生成的影响。结果　三组患儿血清EPO水平差异有显著性 (F =4 4 6 8,P <0 0 1) ,ACD患儿血清EPO水平高于NA患儿 ,但在相同Hb值时 ,ACD患儿EPO低于IDA患儿。三组患儿血清TNF α水平差异有显著性 (F =2 5 12 ,P <0 0 1) ,血清TNF α水平 ,ACD组高于NA组和IDA组 ;三组患儿血清IL 6水平差异有显著性 (F =13 2 6 ,P <0 0 1) ,血清IL 6水平ACD组高于NA组和IDA组。ACD患儿血清TNF α及血清IL 6与EPO无相关性 (r=- 0 35 ,P >0 0 5 ;r=- 0 0 5 ,P >0 0 5 )。体外实验中 ,rhTNF α抑制低氧状态下EPOmRNA的表达 ,且随着rhTNF α剂量的增大而对EPO抑制作用增强 (F =6 4 2 0 ,P <0 0 1)。结论　ACD患儿EPO虽存在代偿性增高但代偿生成不足 ,是小儿ACD的发病原因之一 ;血清TNF α、IL 6与EPO     

婴儿恶性游走性部分性癫癎综合征研究进展

婴儿恶性游走性部分性癫癎综合征是在婴儿期发病的一种严重的癫癎性脑病,1995年由Coppola等首次报道,目前世界共有近80例报道,国内暂无报道.目前该综合征病因不明,早期诊断困难,传统抗癫癎药物疗效不佳.该文就婴儿恶性游走性部分性癫癎综合征可能的病因、临床特点、诊断、治疗进行综述.     

Hyper IgE Syndrome in Japan: A Summary of the Clinical and Immunological Features of 40 Patients

The authors analyze and discuss the clinical and immunological features of hyper IgE syndrome in 40 patients suffering from the disease in Japan. There was no geographical difference observed and the sexual difference was in a ratio of 2 men to 1 woman. The syndrome appears early in infancy and begins mostly with skin lesions. The age at diagnosis is given in Fig. 1. Staphylococcus aureus is detected in every case as the pathogenic microorganism. Although the majority of the cases are of superficial infections, some cases are severe or of deep infections which become critical. The serum IgE levels are above 1,000 IU/ml in all cases and often allergic diseases are a complication. Neutrophil chemotactic defect is considered a secondary defect because a decreased in vitro chemotaxis may turn to normal skin window tests in vivo. These results indicate that lesions in lymphocytes and polymorphonuclear cells (PMNs) are not a complete defect but an incomplete defect or quantitative decline. While lymphocyte and PMN functions are damaged to various extents, the decrease or defect in the specific protective function against staphylococcus aureus is discussed. With the abnormal IgE production, specific IgE antibodies to staphylococcus aureus are produced as well as IgE antibodies to other allergens with frequent chances of sensitization.