RESUMEN
Germline mutations in the gene CBL (Casitas B-lineage lymphoma), involved in the RAS-MAPK signaling pathway, have been found as a rare cause of the neuro-cardio-facial-cutaneous syndromes. Somatically acquired homozygous CBL mutations were initially identified in association with myeloproliferative disorders, particularly juvenile myelomonocytic leukemia (JMML). We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL. She developed an ovarian mixed germ cell/teratoma with later occurrence of mature liver, omental, and ovarian teratomas. Copy neutral loss of heterozygosity for the CBL mutation due to acquired segmental uniparental disomy of 11q23 was observed in three teratomas, suggesting a specific association of CBL mutations in germ cell tumor predisposition.
Asunto(s)
Cromosomas Humanos Par 11 , Mutación de Línea Germinal , Linfedema/genética , Neoplasias Ováricas/genética , Proteínas Proto-Oncogénicas c-cbl/genética , Teratoma/genética , Disomía Uniparental/genética , Adolescente , Femenino , Heterocigoto , HumanosRESUMEN
Sertoli-Leydig cell tumors are rare ovarian neoplasms. We report two unusual cases with bilateral SLCTs suggesting evidence of genetic predisposition and at high risk of recurrence. To reduce this risk, we exploited the use of GnRH analog to lower gondadotropin and potentially directly inhibit the tumors through expressed GnRH receptors. We used it as maintenance antitumor therapy for 2 years after completion of chemotherapy, to cover the period of risk for recurrence. Both patients remain in complete remission at >2 years after completing leuprorelin therapy. Of note, both patients carry DICER1 mutations, frequently found in pleuropulmonary blastoma syndrome.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Leuprolida/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Tumor de Células de Sertoli-Leydig/tratamiento farmacológico , Niño , Femenino , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Tumor de Células de Sertoli-Leydig/patologíaRESUMEN
Osteopathia striata with cranial sclerosis (OSCS) is an X-linked disease caused by truncating mutations in WTX. Females exhibit sclerotic striations on the long bones, cranial sclerosis, and craniofacial dysmorphism. Males with OSCS have significant skeletal sclerosis, do not have striations but do display a more severe phenotype commonly associated with gross structural malformations, patterning defects, and significant pre- and postnatal lethality. The recent description of mutations in WTX underlying OSCS has led to the identification of a milder, survivable phenotype in males. Individuals with this presentation can have, in addition to skeletal sclerosis, Hirschsprung disease, joint contractures, cardiomyopathy, and neuromuscular anomalies. A diagnosis of OSCS should be considered in males with macrocephaly, skeletal sclerosis that is most marked in the cranium and the absence of metaphyseal striations. The observation of striations in males may be indicative of a WTX mutation in a mosaic state supporting the contention that this sign in females is indicative of the differential lyonization of cells in the osteoblastic lineage.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/patología , Osteosclerosis/patología , Fenotipo , Proteínas Adaptadoras Transductoras de Señales/genética , Huesos/patología , Análisis Mutacional de ADN , Cartilla de ADN/genética , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Luciferasas , Masculino , Megalencefalia/patología , Osteosclerosis/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
The authors report a case of a neonate with gastroschisis, which, after repair, was further complicated by the diagnosis of Hirschsprung's disease. The authors discuss the diagnostic and management dilemmas posed by the coexistence of these two conditions for the clinician.
Asunto(s)
Anomalías Múltiples/cirugía , Gastrosquisis/complicaciones , Gastrosquisis/cirugía , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/cirugía , Anomalías Múltiples/diagnóstico , Procedimientos Quirúrgicos del Sistema Digestivo , Gastrosquisis/diagnóstico , Enfermedad de Hirschsprung/diagnóstico , Humanos , Recién Nacido , Masculino , Enfermedades Raras , Resultado del TratamientoRESUMEN
We report the clinical features and pathological findings in 9 cases of intrapartum and early neonatal death associated with embolism of brain tissue to the pulmonary and systemic circulation following difficult delivery. All except 1 of the cases in this series were born at, or near to, term, were vertex presentations, and were normally grown. All followed instrumental delivery and in 5, at least one mode of assisted delivery had failed. Whilst some evidence of cranial trauma was present in 7 cases, only 3 had skull fractures and 7 showed intracranial hemorrhage, although this was described as minor in 3. Emboli of brain tissue were identified in the pulmonary circulation in all cases. Fragments of brain were also seen in vessels of other organs, in particular the heart, in 6 cases. Emboli were highlighted by immunostaining for glial fibrillary acid protein. Brain emboli should be sought in all post mortems of unexplained intrapartum or early neonatal death following difficult delivery, even in the absence of overt cranial trauma. Disseminated intravascular coagulation is a frequent association. Extensive sampling for histology, particularly of the lungs and coronary vessels, is essential if this condition is not to be missed.
Asunto(s)
Traumatismos del Nacimiento/complicaciones , Lesiones Encefálicas/complicaciones , Embolia Pulmonar/etiología , Traumatismos del Nacimiento/patología , Lesiones Encefálicas/patología , Femenino , Humanos , Embarazo , Embolia Pulmonar/patologíaRESUMEN
Familial non-Hodgkin lymphoma (NHL) is rare and in most cases, no underlying cause is identifiable. We report homozygous truncating mutations in the mismatch repair gene MSH2 (226C-->T; Q76X) in three siblings who each developed T-cell NHL in early childhood. All three children had hyperpigmented and hypopigmented skin lesions. Constitutional biallelic MSH2 mutations have previously been reported in five individuals, all of whom developed malignancy in childhood. Familial lymphoma has not been reported in this context or in association with biallelic mutations in the other mismatch repair genes MLH1, MSH6 or PMS2. In addition, hypopigmented skin lesions have not previously been reported in biallelic MSH2 carriers. Our findings therefore expand the spectrum of phenotypes associated with biallelic MSH2 mutations and identify a new cause of familial lymphoma. Moreover, the diagnosis has important management implications as it allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the proband, and the provision of cascade genetic testing and tumour screening for relatives.
Asunto(s)
Predisposición Genética a la Enfermedad , Linfoma de Células T/genética , Proteína 2 Homóloga a MutS/genética , Mutación/genética , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Hipopigmentación/etiología , Linfoma de Células T/complicaciones , Masculino , Datos de Secuencia Molecular , LinajeRESUMEN
The aim of our study was to compare the outcome of medical treatment vs. liver transplantation in infants with neonatal hemochromatosis (NH) referred to King's College Hospital from 1990-2002. We conducted a retrospective review of 19 children from 14 families. Fifteen children presented at birth and 4 during the first week of life. One child was diagnosed by cordocentesis at 30 weeks of gestation. NH recurred in 7 of 9 families with further children. In one family, 2 children from different fathers were affected. All patients had elevated ferritin levels, hypoalbuminemia, and coagulopathy. Liver histology showed parenchymal collapse, diffuse fibrosis, and moderate to severe hepatocyte hemosiderin deposition. Extrahepatic siderosis was demonstrated by magnetic resonance in 2 patients, lip biopsy in 3, and autopsy in 10. Ten patients received a chelation-antioxidant cocktail: 1 survived, 4 died, and 5 required liver transplantation, of whom 2 died. One of the 9 infants who did not receive the cocktail survived with medical support, 3 died, and 5 required transplantation, of whom 3 died. Seven children are alive, 5 after transplantation, at a median follow-up of 5.6 years, with excellent quality of life and no recurrence of the disease. In conclusion, chelation-antioxidant treatment does not appear to modify the prognosis of NH, at least in severe cases. Liver transplantation, with 50% long-term survival, remains the treatment of choice and should be promptly offered to those infants who do not improve with supportive medical treatment.
Asunto(s)
Antioxidantes/uso terapéutico , Quelantes/uso terapéutico , Hemocromatosis/tratamiento farmacológico , Hemocromatosis/cirugía , Trasplante de Hígado/métodos , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hemocromatosis/diagnóstico , Hemocromatosis/mortalidad , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/tratamiento farmacológico , Enfermedades del Recién Nacido/mortalidad , Enfermedades del Recién Nacido/cirugía , Trasplante de Hígado/efectos adversos , Masculino , Probabilidad , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Análisis de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
The outlook for children with cancer has improved substantially over the past 20 years, with over three-quarters of children now surviving in the long term. Better use of existing cytotoxic drugs and supportive care have made large contributions, but some of the improvement in survival is due to a greater knowledge of childhood cancer at the cellular and molecular levels. As in leukaemias, several childhood solid tumours carry balanced chromosomal translocations, resulting in fusion genes that encode chimeric proteins with new oncogenic properties. Many of these fusion genes, and other genetic aberrations are tumour specific and are related to outcome. Tumour biology now plays an important part in identifying appropriate treatment through more accurate diagnoses and new risk stratifications based on molecular markers.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias/genética , Niño , Terapia Combinada , Humanos , Neoplasias/terapia , Linaje , SobrevivientesRESUMEN
PURPOSE: Accurate frozen section interpretation of intraoperative biopsies is critical to the success of the Duhamel procedure. Errors during sampling or interpretation may result in an abnormal pull-through. The authors' aim was to determine the incidence and outcome of transitional zone pull-through (TZPT). METHODS: Ninety-six children who underwent a Duhamel procedure between January 1987 and May 2002 were followed up prospectively. The outcome of 18 children with TZPT was compared statistically with that of a cohort of 58 patients with a ganglionic pull-through. RESULTS: The incidence of TZPT was 18.8%. Concordance rate between frozen and paraffin-section analyses was 88.5%. The incidence of enterocolitis (P =.003) and intractable constipation (P =.02) was found to be significantly higher in TZPT. There was no significant difference in continence (P =.34), rectal sensation (P =.35), and control (P =.53). Five (27.8%) TZPT patients required a revisional surgery for failure of conservative management. The incidence of stoma placement and revision was significantly less in the ganglionic group (3.4%, P =.007). CONCLUSIONS: Up to one third of patients with TZPT will require revisional surgery for intractable symptoms. Vigilance is warranted in view of the greater risk of enterocolitis. Continence is not significantly affected.