New JAG1 Mutation Causing Alagille Syndrome Presenting With Severe Hypercholesterolemia: Case Report With Emphasis on Genetics and Lipid Abnormalities.

Context: Alagille syndrome is a rare autosomal-dominant genetic disorder caused by defects in the Notch signaling pathway, which involves multiple organ systems. Bile duct paucity is the main characteristic feature of the disease, which often leads to cholestatic hypercholesterolemia. Case Description: We report the case of a male infant who had developed failure to thrive, jaundice, intermittent pruritus, and multiple diffuse symmetrical skin xanthomas at 1 year of age. He was diagnosed with pulmonary stenosis, butterfly vertebrae of T4, T6, and T8; horseshoe kidney, and embryotoxon in the left eye. Laboratory workup revealed severe hypercholesterolemia. Alagille syndrome was suspected and confirmed by genetic testing, which identified a previously undescribed frameshift pathogenic heterozygous variant in the JAG1 gene, p.Arg486Lysfs*5. Conclusions: Here, we report a unique case of a patient diagnosed with Alagille syndrome who was found to have a previously undescribed frameshift pathogenic mutation in the JAG1 gene and who presented with xanthomatosis and levels of hypercholesterolemia more than 2 times higher than those previously reported in the literature. We also provide a review of the different pathophysiologic mechanisms associated with the increase in serum cholesterol and low-density lipoprotein cholesterol concentrations seen in cholestatic liver disease in general and in Alagille syndrome in particular.

Diabetic lipemia presenting as eruptive xanthomas in a child with autoimmune polyglandular syndrome type IIIa.

Diabetic lipemia, although common in type 2 diabetes, is rare in type 1 diabetes mellitus. It may manifest as lipemia retinalis, eruptive xanthomas, fatty liver, and pancreatitis. We describe a 6-year-old girl diagnosed with autoimmune poly-glandular syndrome type IIIa, who presented with diabetic lipemia manifesting as eruptive xanthomas. Probable metabolic derangements causing such severe lipid abnormalities and its treatment are discussed.

Xantogranuloma multiple del adulto: reto diagnostico y terapeutico / Multiple adult xanthogranuloma: a diagnostic and therapeutic challenge

El xantogranuloma m£ltiple del adulto (XMA) es una variante muy pocofrecuente y de inicio tard¡o del xantogranuloma juvenil. A diferencia del xantogranuloma juvenil que se presenta en ni¤os peque¤os y se localiza preferentemente en cabeza y cuello, el XMA se presenta en personas de 20 a 30 a¤os, sin mostrar predilecci¢n por sexo. Las lesiones del xantogranuloma tienden a ser £nicas en un 87% de casos, sin embargo, el paciente que se presenta manifest¢ lesiones m£ltiples y diseminadas en diferentes estadios evolutivos. Se presenta el caso de una paciente mujer de 20 a¤os con un tiempo de enfermedad de cuatro meses que presenta m£ltiples lesiones papulares al inicio eritematosas con superficie brillante, el sticas, no dolorosas que con el tiempo van torn ndose amarillentas a nivel central; las lesiones se diseminan a nivel de extremidades, t¢rax, abdomen y cara, caus ndole gran molestia est‚tica.

Multiple adult xanthogranuloma (XMA) is a rare variant oflate onset of the juvenile xanthogranuloma. Unlike Juvenile xanthogranuloma occurs in young children and is preferentially located in head and neck, the XMA occurs in people 20 to 30 years, showing no sex predilection. Xanthogranuloma lesions tend to be unique in 87% of cases, but our patient showed multiple lesions and scattered in dijferent developmental stages. We report the case of a woman in her 20s who presents for 4 months multiples erythematous papular witli shiny surface, elastic, painless that eventually go at turning yellowisli central lesions spread to the extremities, chest, abdomen and face, causing great discomfort aesthetic.

Juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis: case report and literature review.

The synchronous or metachronous development of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in the same patient is rare. To date, only seven cases of xanthogranulomas developing in young patients with a history of Langerhans cell histiocytosis and systemic therapy have been reported in the literature. As of yet, the pathogenesis and the clinical significance of this phenomenon are unclear. We report the case of a 3 year old boy who developed juvenile Xanthogranulomas on the forehead and right upper eye lid 1.5 years after systemic therapy for monosystemic Langerhans cell histiocytosis of the bone and complete disease remission.

Thalidomide therapy for aggressive histiocytic lesions in the pediatric population.

Aggressive histiocytic lesions are uncommon in the pediatric population. These neoplasms occur in isolation or after therapy for other types of hematopoietic malignancy such as T-cell acute lymphoblastic leukemia. The etiology of these lesions is poorly understood, and no definitive standard of care has been established for patients with these diagnoses. Here, we report the success of thalidomide treatment for 2 subtypes of histiocytic proliferation--metastatic histiocytic sarcoma and extracutaneous juvenile xanthogranuloma--in pediatric patients. Our findings highlight the importance of considering thalidomide therapy in this unique and difficult to treat patient population.

Juvenile xanthogranuloma with lichenoid appearance.

Juvenile xanthogranulomas are benign histiocytic cell tumors that develop mainly in infancy and early childhood and then spontaneously regress. We report a 2-year-old boy who presented with generalized eruption of a mixture of micronodular and macronodular juvenile xanthogranuloma with a large number of widely distributed lichenoid papules. Light microscopic and immunocytochemical analyses of the lesion were consistent with juvenile xanthogranuloma. Abdominal ultrasonography did not detect any visceral lesions, and brain magnetic resonance imaging did not detect any mass lesions. We decided to observe the course without treatment in this case because there are no internal masses of juvenile xanthogranuloma. Regular follow up has therefore been scheduled. To our knowledge, this is the third report of a case demonstrating juvenile xanthogranuloma with lichenoid appearance. Future analyses of various cytokines such as granulocyte-macrophage colony-stimulating factor and/or tumor necrosis factor-α in juvenile xanthogranuloma lesions should be of great help in elucidating the pathogenesis of this disease.

Rathke's cleft cyst with xanthogranulomatous change--case report.

A 58-year-old man presented with a rare case of Rathke's cleft cyst (RCC) manifesting as headache and visual disturbance. Goldman's perimeter showed he had bitemporal hemianopia. Magnetic resonance imaging revealed a solid intrasellar lesion. He underwent surgery via a right pterional approach. The lesion was red, solid, and fibrous. Histological examination revealed a few columnar epithelial cells with poor cilia in a xanthogranulomatous lesion. Only 13 cases of RCC with granulomatous change have been diagnosed by pathological examination, including 4 xanthogranulomatous cases. Xanthogranuloma of the sellar region is relatively rare. The etiology is still unknown. We speculate that xanthogranulomas of the sellar region may be caused by reaction to the presence of RCC.

Cutaneous xanthogranulomas, hepatosplenomegaly, anemia, and thrombocytopenia as presenting signs of juvenile myelomonocytic leukemia.

The development of xanthogranulomas has been linked to hematologic malignancies in children and adults, based on a number of reports in the literature. In children, a specific association between juvenile xanthogranuloma, neurofibromatosis 1, and juvenile myelomonocytic leukemia has been described. We report a case of a 9-month-old child, without a known diagnosis of neurofibromatosis 1, who presented with hepatosplenomegaly, anemia, thrombocytopenia, and multiple cutaneous nodules, which were confirmed to be juvenile xanthogranulomas upon biopsy. A concurrent work-up showed that the child had juvenile myelomonocytic leukemia. Although cutaneous juvenile xanthogranulomas are benign lesions, in several reported cases they have been shown to herald leukemia. This association between xanthogranulomas and hematologic malignancy is poorly understood. Juvenile xanthogranulomas have a number of morphologic variants and clinical presentations that can be confused with the cutaneous lesions of Langerhans cell histiocytosis and dermatofibroma. Recognition of the broad clinicopathologic spectrum of juvenile xanthogranulomas is critical for proper diagnosis.

Xanthogranulomas associated with hematologic malignancy in adulthood.

Although xanthogranulomatosis (XG), defined as multiple xanthogranulomas occurring simultaneously, was originally described in infants and children, a number of adult cases have been reported. Adult XG, which generally presents in the absence of hyperlipidemia, has many similarities to the childhood variant. Among the similarities are reports of the simultaneous development of XG and hematologic disorders. Herein we report a case of XG in a 45-year-old man with B-cell acute lymphoblastic leukemia and review the literature regarding the association of XG and hematologic disorders in adults. We propose that xanthogranulomas seen in children and adults bear many similarities, clinically and histopathologically, and share an association with hematologic malignancies.

[Neurofibromatosis type 1 and associated clinical abnormalities in 27 children]. / Neurofibromatose Typ 1 und assoziierte Krankheiten bei 27 Kindern und Jugendlichen.

Neurofibromatosis type 1 is the most common of the phakomatoses and the clinical follow-up is an interdisciplinary challenge. The data of 27 patients with NF1 were systematically reviewed and compared to data from the literature. All of our patients had clinical signs of NF1. Besides the classic criteria café-au-lait spots (100%), freckling (48,1%), positive family history (44,1%), neurofibromas (40,7%), Lisch nodules (22,2%) and optic pathway tumors (22,2%) there were developmental delay (40,7%), macrocephaly (33,3%), strabism (29,6%), scoliosis (18,5%), epilepsy (14,8%), pubertal anomalies (14,8%), short stature (11,1%) and tics. Morphologically, CNS hamartomas (55,5%), astrocytomas (22,2%) and one pheochromocytoma became apparent. Special findings consist of one aneurysm of internal carotic arteria, juvenile xanthogranulomas, a case of pulmonary stenosis and an intracardial tumor. Four new mutations in the NF1 gene were found. Regular screening of optic glioma with MRI had no clinical significance. In contrast to other authors, one of our patients with optic glioma showed clinical progress after twelve years of age. The detection of astrocytomas led only to therapeutic consequences, when clinical signs or symptoms occurred. As with other authors, we found no potential for CNS hamartoma to proliferate. In three cases with pubertal anomalies we found CNS gliomas, which indicates the need for MRI. The expense of screening, apart from clinical surveillance, seems inadequate in relation to clinical relevance and costs. We describe four new mutations in the NF1 gene; there have been no specific genotype-phenotype correlations. Neurofibromatosis type 1 and associated clinical abnormalities in 27 children.

Successful bone marrow transplantation for life threatening xanthogranuloma disseminatum in neurofibromatosis type-1.

A 2-yr and 9-month-old female patient with neurofibromatosis type-1 presented with hepatomegaly, anemia, thrombocytopenia, and croupy cough and diagnosed with xanthogranuloma disseminatum (XD). She failed chemotherapy consisting of steroids, 6-mercaptopurine and methotrexate. A partial response to HLH-94 therapy that included etoposide and cyclosporine A was initially observed. However, she continued to have significant organ dysfunction without further improvement at 6 months of therapy. She then received matched unrelated donor bone marrow transplantation (BMT) following carmustine, etoposide, cytarabine and melphelan conditioning with complete resolution of symptoms. BMT is an option in therapy-resistant, life threatening XD cases.

Juvenile xanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic malignancies.

The clinical features and natural history of juvenile xanthogranuloma (JXG) in 14 children affected by neurofibromatosis 1 (NF1) are reported. Mean follow-up in 11 of these patients was 4.3 years (range 1-10 years). None of the children developed hematologic malignancies during this period. The onset of JXG was in the first 2 years of life in 13 of the patients. In this series, the association between JXG and six or more café au lait spots more than 5 mm in diameter was a good marker for NF1 in the first few years of life. Overall the JXG in these patients did not show any features distinguishable from those of "classical" JXG.

Outcome of liver disease in children with Alagille syndrome: a study of 163 patients.

BACKGROUND AND AIMS: Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS). PATIENTS AND METHODS: We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit. RESULTS: At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004). CONCLUSIONS: The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life.

A case of juvenile xanthogranuloma arising on a nevus sebaceus.

Various epithelial and mesenchymal neoplasms can arise in nevus sebaceus (NS). Juvenile xanthogranuloma arising on an NS has not been reported previously. Juvenile xanthogranuloma, a disease characterized by reactive histiocytic proliferation, could be included in the list of secondary alterations arising on an NS.