Methylmalonic acidemia presenting as persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) results from disruption of the normal fetal-neonatal circulatory transition and may be associated with meconium aspiration, group B streptococcal sepsis, pneumonia, respiratory distress syndrome, congenital diaphragmatic hernia and pulmonary hypoplasia. Seventeen percent of cases are considered idiopathic since there is no identifiable cause. Although it is recognized that acidosis and hypoxia from any cause in neonates may produce pulmonary vasoconstriction and maintain pulmonary hypertension, PPHN has not been reported in inborn errors of metabolism (IEM) associated with metabolic acidosis like methyl malonic acidemia (MMA). We report the first case in the literature of MMA presenting concomitantly with PPHN. Undiagnosed IEMs, like MMA, could represent a subset of idiopathic cases of PPHN. Infants and neonates have a limited repertoire with which to respond to an overwhelming illness. Because metabolic diseases are rare, they are considered only after excluding more common causes of neonatal distress. PPHN is therefore more likely to be attributed to meconium aspiration, sepsis, pneumonia or respiratory distress syndrome than to an IEM. The advent of expanded newborn screening has made pre-symptomatic diagnosis of several IEMs including MMA possible. However, not all IEMs are identified, and in some instances, an infant who has an IEM may become ill before the results of the newborn screen become available. Early diagnosis of IEM is crucial to prevent catastrophic consequences and the awareness of an association with PPHN would lead to an aggressive search of an underlying IEM and its management.

High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors.

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

Pediatric renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and clinicopathologic associations.

Renal cell carcinomas (RCCs) are rare in children and studies of their subtypes and clinicopathologic associations are limited to small series. We identified 8 patients with RCC treated at our institution between 1981 and 2003, reviewed their clinicopathologic features, cytogenetics findings, and evaluated the status of TFE3 expression by immunohistochemistry and numerical chromosomal alterations by interphase fluorescent in situ hybridization on paraffin-embedded tissue. These 8 patients (5 female and 3 male) had diploidy, and 5 had morphologic features compatible with the recently described RCC associated with Xp11.2 translocations/TFE3 gene fusions and demonstrated nuclear labeling for TFE3 protein by immunohistochemistry. The translocation was confirmed in 2 of these 5 patients by conventional cytogenetics. One case was a high-grade nonpapillary RCC and the other was compatible with type 2 papillary RCC. Four patients showed at least 1 chromosomal gain including trisomy 7 and/or trisomy 17. None of the tumors from male patients showed evidence of loss of the Y chromosome, but 2 patients showed numerical abnormalities of X chromosome +add(X). Two patients had sickle cell disease, and 1 of these also had stage IV-S neuroblastoma. This study suggests that many cases of RCC in children reported under the terms "papillary" and "clear cell" likely represent Xp11.2 translocation/TFE3 gene fusion-associated RCC. It also emphasizes the unusual associations of RCC with neuroblastoma and sickle cell hemoglobinopathy, which need further study.

Otolaryngologic manifestations of Rosai-Dorfman Disease.

PURPOSE: To describe an unusual head and neck occurrence of Rosai-Dorfman Disease (RDD) and to review the otolaryngologic manifestations of this rare entity. METHODS: A case presentation with review of the literature describing Rosai-Dorfman Disease and its head and neck involvement. SETTING: A tertiary care, urban children's hospital. RESULTS: This is the first description, to the best of our knowledge, of RDD [Sinus Histiocytosis with Massive Lymphadenopathy (SHML)] involving bilateral external auditory canals and middle ear in a 12 year old patient previously diagnosed with 'asthma' and hearing loss. This patient also had extensive involvement of the tracheobronchial tree. Representative clinical, radiographic and histological findings are presented. Its etiology, diagnosis and management are also reviewed. CONCLUSION: This is the first reported case of middle ear and external auditory canal involvement of RDD in a patient with hearing loss and associated tracheobronchial lesions. RDD, although rare, may be considered in the differential diagnosis of unusual histiocytic lesions of the external auditory canal, especially with findings of similar or comparable lesions involving the respiratory tract. Confirmation is with identification of emperipolesis and appropriate immunohistochemical staining (S-100 positive, CD-68 positive and CD-1a negative). Intervention is recommended in cases where there is increased risk of mortality, as in severe obstruction of the tracheobronchial tree. Otherwise, since these lesions are self-limiting, the patients can be observed closely.

Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome.

Three full-term infants died in the first month of life with hypoplastic left heart syndrome (HLH) and persistent pulmonary hypertension (PPH). At postmortem examination, they were found to have alveolar capillary dysplasia with misalignment of pulmonary veins (ACD with MPV). The association of HLH syndrome, and ACD with MPV with intestinal malrotation and/or obstruction, is unique. Decreased blood flow in the ascending aorta in fetuses with left outflow tract obstruction might cause vasoconstriction of pulmonary arterioles to maintain cerebral perfusion. Vasoconstriction early during embryogenesis might lead to decreased growth and development of alveolar capillaries and pulmonary veins. This results in pulmonary hypertension, and the arterial blood is forced to bypass the deficient capillary bed and can drain only via the anomalous bronchial veins.

Ewing sarcoma vs lymphoblastic lymphoma. A comparative immunohistochemical study.

To develop a practical immunohistochemistry panel for distinguishing lymphoblastic lymphoma from Ewing sarcoma (ES), we evaluated 17 ES and 27 lymphoblastic lymphoma and leukemia cases with antibodies to CD99, terminal deoxynucleotidyl transferase (TdT), leukocyte common antigen (LCA), CD43, CD79a, CD20, CD3, vimentin, and neuron-specific enolase (NSE). Three cases were bone lymphomas, 2 initially misdiagnosed as ES. All cases were CD99+. All lymphomas and leukemias were TdT+ compared to none of the ESs. None of the ESs expressed other lymphocytic markers, which were inconsistently expressed in the lymphomas and leukemias: CD43, 33%; LCA, 30%; CD79a, 19%; CD3, 19%; and CD20, 7%. Of the ESs, 88% were vimentin positive compared with 23% of lymphomas and leukemias. Vimentin was stronger and more diffuse in ES. NSE did not reliably stain any cases. When faced with the differential diagnosis of ES vs lymphoblastic lymphoma, an immunohistochemical panel that includes antibodies to CD99 and TdT is useful. Both epitopes are well preserved in fixed and decalcified tissue. A panel composed of antibodies to CD99 and TdT, in conjunction with other lymphocytic markers and vimentin, is highly sensitive and specific.

Myocardial infarction due to coronary abnormalities in pulmonary atresia with intact ventricular septum.

We describe the clinical course, angiography, and histopathology of a newborn male with pulmonary atresia and intact ventricular septum who succumbed to a myocardial infarction. Angiography demonstrated right ventricular-dependent coronary circulation and focal areas of coronary narrowing. His clinical course was characterized by attacks of sudden irritability, consistent with ischemia. Histology demonstrated significant coronary artery narrowing secondary to fibromuscular dysplasia as well as evidence of new and old infarction. This case illustrates the severity of coronary lesions in pulmonary atresia and the potential for progression of coronary obstruction and insufficiency, and it provides correlation between angiography, ischemic symptoms, and pathology.

Bile duct size does not predict success of portoenterostomy for biliary atresia.

BACKGROUND/PURPOSE: Presence of large bile ducts (>200 microm) at the portal end-plate has been suggested to predict success after portoenterostomy. The authors reviewed their patients with biliary atresia to test the hypothesis that bile duct size in patients with successful portoenterostomy was no different than in the patients with unsuccessful portoenterostomy. METHODS: The authors reviewed the patients at their institution from 1989 to 1998 who had the diagnosis of biliary atresia (n = 38). A pathologist blinded to the results of the operation confirmed the measurements of the bile duct remnants. RESULTS: Five of the 38 patients did not have a portoenterostomy. They underwent cholangiogram and liver biopsy and were evaluated for liver transplantation. All patients who underwent surgery (n = 33) had a Roux-en-y hepaticojejunostomy. Twenty-one patients had successful surgery (64%) and 12 patients (36%) had unsuccessful surgery. The average age at operation in the successful group was 50.9 +/- 3 days and in failures, 57.9 +/- 4 days (P = .16). Duct size at the portal end-plate was not different between the successes and failures. Two of the patients in the success group had no evidence of bile ducts grossly or histologically. CONCLUSION: Children presenting early in infancy (<3 months) with biliary atresia should undergo a portoenterostomy regardless of the size of the bile ducts at the time of exploration.

Unilateral lobectomy for Hurthle cell adenoma.

Considerable controversy exists regarding the ability to predict the biologic behavior of Hurthle cell tumors. Some have found the clinicopathologic criteria used to differentiate benign from malignant lesions to be unreliable and have advocated total thyroidectomy for all Hurthle cell neoplasms. From January 1980 to December 1995, 39 patients had surgery for Hurthle cell tumors of the thyroid. The surgical pathologic findings were reviewed by an experienced pathologist (JP). Eight patients had histologic findings of capsular or vascular invasion consistent with carcinoma and had total thyroidectomy. Four of these patients had postoperative evidence of residual disease and were treated by radiation ablation. No evidence of invasion was found in 31 patients diagnosed with Hurthle cell adenoma. Twenty-three of these patients had unilateral lobectomy; total thyroidectomy was done in the remaining 8 patients, 5 of whom were found to have an associated papillary carcinoma at the time of operation. There were no operative deaths or significant morbidity. Twenty-two adenomas (71%) were found in females, whereas males had malignant tumors in 6 of 8 cases (P = 0.025). The mean age of adenoma patients is 54.1 years, and that of the carcinoma patients is 55.8 years. Mean size of benign tumors was 2.8 cm and of malignant tumors 4.1 cm (P = 0.04). Four of seven (57%) carcinomas were larger than 4 cm as compared with 6 of 30 (20%) adenomas (P = 0.069). Follow-up has ranged from 1 month to 15 years, with a mean of 3.2 years. There have been no deaths, and no patients with Hurthle cell adenoma have had evidence of recurrence or metastases during follow-up. Our data suggest that carcinoma patients tend to be male and tumor size is larger. An association was found when trying to predict malignancy by using 4 cm as a threshold size. We conclude that pathologic evidence of capsular or angioinvasion can accurately differentiate benign from malignant tumors. Unilateral thyroid lobectomy is adequate therapy for the treatment of Hurthle cell adenoma, with total thyroidectomy reserved for those patients with histologically proven carcinoma.

Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson's disease.

One month of adjunct treatment with naltrexone (100 mg/day) was compared with placebo in a double-blind, randomized, cross-over design in two groups of patients with Parkinson's disease. The first group was composed of 10 patients with a moderate motor impairment insufficiently controlled by monotherapy with bromocriptine. The second group was composed of eight patients with L-dopa-induced peak-dose dyskinesia. Naltrexone as compared with placebo did not demonstrate any significant change in motor function in either group. These negative clinical results do not support a significant role of endogenous opioid systems in the pathophysiology of motor impairment in Parkinson's disease.