Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis characterized by a poikilodermatous rash starting in infancy, small stature, skeletal abnormalities, juvenile cataracts, and predisposition to specific cancers. We have identified a contemporary cohort of 41 patients to better define the clinical profile, diagnostic criteria, and management of patients with RTS. Patients with the diagnosis of RTS were ascertained by referrals from dermatology, ophthalmology, genetics, and oncology or from direct contact with the patient's family. Medical information was obtained from interviews with physicians, patients, and their parents and a review of medical records. The age range at ascertainment was 9 months to 42 years (28 males and 13 females; M:F, 2:1). All subjects displayed a characteristic rash. Thirteen subjects had osteosarcoma (OS) (32%), eight had radial defects (20%), seven had gastrointestinal findings (17%), two had cataracts (6%), and one had skin cancer (2%). Twenty-two of 28 patients without OS were less than 15 years old and thus remain at significant risk for this tumor. This case-series study reveals a clinical profile of RTS that includes a higher prevalence of OS and fewer cataracts, compared with historical reports. These differences may reflect either allelic or genetic heterogeneity. This study documents the frequency of clinical anomalies in a contemporary cohort of RTS patients and revises guidelines for diagnosis and management of RTS.

Staphylococcal toxins bind to different sites on HLA-DR.

Staphylococcal enterotoxins (SE) and toxic shock syndrome toxin 1 (TSST-1) bind to MHC class II molecules and the toxin-class II complexes induce proliferation of T cells bearing specific V beta sequences. We have previously reported that these toxins display varying binding affinities for HLA-DR1. We now investigated whether these differences simply reflected differences in binding affinity for a single class II binding site or, at least in part, the engagement of different binding sites on the HLA-DR complex. Through competitive binding studies we show that SEB and TSST-1, which are not closely related by their amino acid sequences, bind to two different sites on HLA-DR. Both of these sites are also occupied by staphylococcal enterotoxin A (SEA), enterotoxin D (SED), and enterotoxin E (SEE) which exhibit more than 70% amino acid sequence homology. SEB and TSST-1 failed to inhibit SEA binding to HLA-DR. These studies suggest that there may be three distinct, although perhaps overlapping, binding sites on HLA-DR for these toxins. Further, although SED and SEE are similar to SEA in structure, and appear to bind the same sites on HLA-DR as SEA, they displayed significantly lower binding affinities. T cell proliferative responses to SED required a higher concentration of the toxin than SEA, probably reflecting its lower binding affinity. SEE, however, elicited T cell responses at very low concentrations, similar to SEA, despite its much lower binding affinity. Therefore, although the affinities of these toxins to MHC class II molecules appear to significantly influence the T cell responses, the effective recognition of the toxin-class II complex by the TCR may also contribute to such responses.

Treatment of essential thrombocythemia with anagrelide.

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by persistent elevation in platelet count. It is a rare disorder in children, and children who have symptoms require treatment. We report the successful use of anagrelide, with few toxic effects, in the treatment of three children with ET.

Pancytopenia with chromosomal fragility: vitamin B12 deficiency.

PURPOSE: Pancytopenia in children may have many etiologies. Chromosomal abnormalities with pancytopenia is of particular concern because clonal abnormalities indicate a neoplastic process. We describe three children who had vitamin B12 deficiency and who displayed pancytopenia with multiple chromosomal breaks, rearrangements, and deletions consistent with chromosomal fragility. Severe vitamin B12 deficiency is rare in children and should be considered in the differential diagnosis of a child with pancytopenia, dyserythropoiesis, and multiple chromosomal abnormalities. PATIENTS AND METHODS: Three children displayed pancytopenia with dyserythropoiesis in the bone marrow. Routine cytogenetic analyses in all three patients were performed and chromosome breakage study was performed on the peripheral blood of one patient after vitamin B12 supplementation. RESULTS: All three patients had severe vitamin B12 deficiency. Spontaneous chromosomal fragility was seen in routine cytogenetic analyses in all three patients. Vitamin B12 supplementation resolved the pancytopenia in all three patients and spontaneous and diepoxybutane-induced breakage rates in chromosomes were well within normal rates after therapy in one patient. CONCLUSION: The presence of pancytopenia with cytogenetic abnormalities in a child is worrisome. However, careful interpretation of dyserythropoiesis and megaloblastic changes in bone marrow in the aforementioned clinical situation would result in the correct diagnosis of a disorder that is easily cured.

Essential thrombocythemia in a child: management with anagrelide.

Essential thrombocythemia (ET) is a rare disorder in children. An 11-year-old white boy was first seen in January 1986 with symptoms of abdominal pain. His platelet count was 1.5 million/mm3. Other hematological values and coagulation studies, including bleeding time, were normal. There was laboratory evidence of mild platelet dysfunction. Using the criteria of the Polycythemia Vera Study Group, a diagnosis of ET was made. He developed frequent headaches. Aspirin was prescribed for the next 2 years at varying doses and frequency. During the period, platelet counts ranged between 1 and 3 million/mm3. In view of progressive headaches and evidence of increasing platelet dysfunction, further treatment was indicated. The use of a new agent, anagrelide, reported effective in adults with ET, resulted in amelioration of symptoms and improvement in quantitative and qualitative platelet control with no significant untoward effects.

Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1.

Optic pathway tumors (OPT) occur in about 15% of individuals with Neurofibromatosis Type 1 (NF1) and may effect substantial visual loss. Because their growth is not predictable at the time of discovery, neuroimaging for OPT in asymptomatic NF1 patients remains controversial. We evaluated the outcomes of systematic screening by both MRI and ophthalmic examinations for OPT in young children with NF1 seen at multi-disciplinary clinics for Neurofibromatosis and Genetics at one institution between 1996 and 2001. We report on 84 children who presented with NF1 under age 6 years, of whom 13 children presented with either known OPT or abnormal MRI findings and 11 children had OPTs identified by neuroimaging, including two children with abnormal eye examinations at presentation (one with strabismus and one with optic atrophy). Nine OPTs were detected in asymptomatic subjects with normal ophthalmic examinations. Three children with chiasmal lesions enlarging on subsequent MRI were treated with carboplatin and vincristine. After treatment, the vision in each involved eye was intact. In contrast, the 13 children with OPT diagnosed outside of screening guidelines included five children with substantial visual loss. Our observations suggest that early recognition of NF1 promotes appropriate surveillance and allows early intervention to reduce complications of OPT. This analysis supports prospective studies to compare the outcomes of systematic screening with neuroimaging to screening with ophthalmic examinations alone in children with NF1.

Chronic relapsing thrombotic thrombocytopenic purpura in infants with large von Willebrand factor multimers during remission.

We studied two children with recurrent schistocytic hemolytic anemia and thrombocytopenia beginning in the neonatal period. One patient had a stroke during one of the episodes of thrombotic thrombocytopenic purpura. The presence of unusually large von Willebrand factor multimers was demonstrated in both children during clinical and hematologic remissions. Treatment with corticosteroids and intravenous injections of immune globulin was unsuccessful in the one patient who received it. Immediate improvement occurred in both patients after the infusion of fresh-frozen plasma. Symptoms of thrombocytopenia continue to recur at regular intervals in the absence of periodic fresh-frozen plasma infusions. One of these children apparently has chronic relapsing thrombotic thrombocytopenic purpura; the second has a chronic relapsing disorder similar to thrombotic thrombocytopenic purpura.

Hodgkin's disease associated with central pontine myelinolysis.

We describe a 12-year-old black male who presented with cervical lymphadenopathy, hepatosplenomegaly of 3 months duration, and ataxia and incoordination of recent onset. Hodgkin's disease, stage IVB, was diagnosed. An MRI of the head demonstrated a nonenhancing, well-defined pontine lesion. The pontine lesion and the associated neurologic symptoms were consistent with central pontine myelinolysis. Treatment of Hodgkin's disease resulted in complete remission and complete disappearance of the pontine abnormality.

Mixed neuronal-glial tumors (gangliogliomas) in children.

Mixed tumors account for about 10% of the childhood central nervous system tumors. Studies of the most common tumor, the ganglioglioma, in patients of all ages suggest that optimal therapy is total gross resection. There are few studies on these tumors in children. In our institution between 1984 and 1993, 28 children with gangliogliomas (4 of which were anaplastic) and 4 children with dysembryoplastic neuroepithelial tumors were treated and followed. Fourteen had local subarachnoid involvement. Total gross resection was usually curative, regardless of histology. Subarachnoid involvement was not indicative of a poorer prognosis.

Gastrointestinal autonomic nerve tumors in the pediatric population: a report of four cases and a review of the literature.

BACKGROUND: Gastrointestinal autonomic nerve tumors (GANTs) are a subpopulation of gastrointestinal stromal tumors (GISTs) that are characterized by ultrastructural features resembling enteric autonomic nerve cells, without epithelial, Schwannian, or smooth muscle differentiation. Delineation of the clinicopathologic features of GANT in the pediatric population is lacking. METHODS: The clinicopathologic and outcome data for four pediatric patients with GANT are presented. The data from these patients and four previously reported pediatric patients are summarized and compared with data for GANT in adults. RESULTS: All four cases occurred in females at a mean age of 12.5 years. The primary tumor site was the stomach in all cases, and the mean tumor size was 6.3 cm. Immunocytochemical and ultrastructural examination were essential in distinguishing GANT from GIST in all cases by identifying features of neural origin (neuron specific enolase in all four cases, NFP in three cases, S-100 in two cases, dense core neurosecretory granules in all four cases, and neuritelike processes in all four cases), while failing to identify features of myogenic origin (no desmin, smooth muscle actin, myofilaments, or dense bodies were found in any of the cases). Primary treatment was surgical, with chemotherapy administered to 1 patient at the time of recurrence. All patients are alive after a mean follow-up of 60 months (range, 8 months to 9 years). CONCLUSIONS: Similarities of pediatric GANT to GANT in adults include the need for a high index of suspicion for diagnosis; comparable histopathologic, immunohistochemical, and ultrastructural features; and surgery as the primary therapy. Distinguishing features in children may be a prevalence among females in the second decade, a predominance of smaller gastric tumors, and a positive prognostic value of younger age.

Malignant melanoma of soft parts involving the head and neck region: review of literature and case report.

Malignant melanoma of soft parts (MMSP) was originally described as a distinct entity by Enzinger in 1965 and was termed "clear cell sarcoma of tendons and aponeuroses" because of its association with tenosynovial structures. It has been shown immunophenotypically and ultrastructurally that this tumor is derived from neuroectoderm and shares a number of features with cutaneous melanoma. Over 95% of MMSPs present in the extremities, with the head and neck region (1.9%) being an unusual site. This study presents an additional case of MMSP of the head and neck region involving the posterior cervical region in a 15-year-old Hispanic male and reviews the literature on MMSP. Ultrastructural examination showed rudimentary cell attachments, smooth cell membranes, discontinuous basal lamina, scanty glycogen, and occasional premelanosomes in some tumor cells. Cytogenetic analysis showed a reciprocal translocation between the long arms of chromosomes 12 and 22 [t(12:22)(q13;q12.2)], characteristic for MMSP and not seen in cutaneous melanoma. Survival in MMSP has been correlated with tumor size, tumor necrosis, and ploidy status. Overall reported clinical outcome for this tumor is as follows: died of disease, 45%; alive with disease, 23%; no evidence of disease, 30%; and died of other causes, 2%. MMSP represents a distinct entity with a characteristic ultrastructural appearance and a tumor defining cytogenetic translocation.

Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer.

The risk of malignancies among persons with neurofibromatosis 1 (NF1) is higher than in the general population, but the excess risk has not been precisely estimated. The effects of gender and inheritance pattern on cancer risk are unclear. Therefore, we conducted a historical cohort study to determine cancer risk factors by contacting 138 Caucasian NF1 patients originally seen at Baylor College of Medicine (BCM) in Houston between 1978 and 1984. A total of 304 patients of all ethnic groups were evaluated at BCM during this period. We successfully located 173 patients, 138 of who were Caucasian. We computed standardized incidence ratios (SIRs) with the age-, gender-, and time period-specific rates from the Connecticut Tumor Registry for 2,094 person-years of observation (median follow-up = 16 years). Eleven incident tumors were reported. Females were at much higher risk of cancer than males (SIR = 5.6, 95% confidence interval (CI) 2.7-10.3 and SIR = 0.6; 95% CI, 0.0-3.0, respectively). We found no elevated cancer risk in unaffected first-degree relatives, regardless of whether the proband had cancer or not (SIR = 1.1 95% CI, 0.6-1.8 and SIR = 1.0, 95% CI, 0.6-1.5, respectively). Our results suggest that malignancy in the proband is not the result of a modifying gene that has a significant impact on general cancer risk.