Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Wednesday, January 31, 2007

Blau Syndrome

Blau syndrome--a chronic granulomatous, genetic disease

Ugeskr Laeger. 2006 Oct 16;168(42):3612-4.

Milman N,
Byg KE.
H:S Rigshospitalet, Hjertecentret, Medicinsk Afdeling B, Afsnit for Lungetransplantation, Kobenhavn O.

Blau syndrome is a rare hereditary granulomatous disease presenting in patients of young age with exanthema, granulomatous arthritis and uveitis. Genetic analysis has shown an autosomal dominant inheritance and a number of specific mutations on chromosome 16q in codon 334, of which the most predominant are R334W and R334Q. Blau syndrome exists in Caucasian, Asian and Afro-American families, and de novo mutations have been reported. The estimated minimum incidence in Denmark is 0.05 per 100,000 person-years. Blau syndrome has pathological, clinical and therapeutic features in common with sarcoidosis but rarely involves the lungs or other parenchymatous organs. Discrimination between Blau syndrome and early-onset sarcoidosis should rely on chromosome analysis.

PMID: 17069723 [PubMed - indexed for MEDLINE]

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Paratuberculosis in Blau Syndrome tissues

Dow CT.

University of Wisconsin, Madison, Wisconsin, USA

Blau syndrome is familial, juvenile, systemic granulomatosis with primary clinical findings of uveitis, arthritis, and dermatitis. Although rare, Blau syndrome shares aspects of the more common diseases sarcoidosis and Crohn's disease. The clinical findings of Blau syndrome are similar to those of juvenile sarcoidosis and mutations of Blau syndrome are on the same chromosome 16 gene that confers susceptibility to Crohn's disease, CARD15. The product of this gene is a component of the innate immune system involved in bacterial pathogen surveillance. Mycobacterium avium subsp. paratuberculosis (MAP) has been implicated as a causative agent of sarcoidosis and Crohn's disease. The presence of MAP in Blau syndrome tissue was postulated and archival tissues of individuals with Blau syndrome were acquired to test for the DNA of MAP. Six tissues of five patients representing three kindred were tested. The tissues were granulomatous lesions of skin, synovium, liver and kidney. Paratuberculosis was detected in all tissues. Its presence in these multi-system disease tissues expands the argument for the disease-causing role of MAP beyond the gut and positions MAP for consideration as a “superantigen”.


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Analysis of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis

S. A. Raphael, E. B. Blau, W. H. Zhang and S. H. Hsu Department of Pediatrics, Temple University School of Medicine, Philadelphia, PA.

OBJECTIVE--To determine whether HLA and autoimmunity contribute to the pathogenesis of Blau syndrome (familial granulomatous arthritis, uveitis, and rash) and evaluate whether this condition is related to sarcoidosis. DESIGN--Large family survey. SETTING--General community, Green Bay, Wis, and two tertiary care medical centers in Philadelphia, Pa.

PARTICIPANTS--Thirty-six family members and spouses from a large kindred with Blau syndrome.

SELECTION PROCEDURES--Volunteer and convenience sample.


MEASUREMENTS AND RESULTS--Ten affected and many unaffected subjects were personally examined. Medical records and previous biopsy reports and specimens, when available, were reviewed. Two affected subjects had skin biopsies performed and three affected adult subjects were tested with Kveim skin-test reagent. Serologic and genomic class I and class II HLA typing was performed on 27 affected and unaffected subjects. All 13 living affected subjects and the one obligate carrier had the following assays performed; antinuclear antibody titer, rheumatoid factor, serum angiotensin converting enzyme level, quantitative immunoglobulins of the IgG, IgM, and IgA classes, and clinical chemistry profiles. Several had complete blood cell counts and erythrocyte sedimentation rates performed. Four affected subjects, one possibly affected subject, and one obligate carrier were newly identified. Flexion contractures of the fingers and toes (camptodactyly) were found, for the first time, to be a phenotype characteristic.

Earlier onset and worsening of symptoms in succeeding generations (anticipation) were observed. Sixteen HLA haplotypes were identified. No conclusive evidence for linkage between these haplotypes and phenotype expression could be demonstrated. All 13 affected subjects, however, carried the DR2 (DR beta 1*1501) and/or DR4 (DR beta 1*0401) allele. There was no evidence of hypercalcemia, hypergammaglobulinemia M, rheumatoid factor production, or abnormal blood cell counts. Two affected subjects had low-titer antinuclear antibody screening tests, five had mild to moderately elevated IgG and/or IgA levels, two had raised serum angiotensin converting enzyme levels, and three had mild elevation of the erythrocyte sedimentation rate. All three subjects tested with Kveim skin-test reagent showed no reactivity by visual inspection. Both subjects who had had skin biopsies performed had evidence of granulomatous inflammation.

CONCLUSIONS--This family's illness is distinct from both classic and early-onset sarcoidosis. There is minimal evidence for autoimmunity and systemic inflammation. Camptodactyly should be added to the list of syndrome-defining characteristics. Although HLA haplotypes do not appear to segregate with affected subjects, HLA-DR2 and HLA-DR4 subtypes may play a permissive role in phenotype expression. This family represents a unique opportunity to define the molecular mechanisms involved in the initiation of arthritis and uveitis in humans. Genetic linkage studies to determine the chromosomal location of the Blau syndrome gene are in progress.

Archives of Pediatrics

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Friday, January 26, 2007

Liver involvement in hereditary hemorrhagic telangiectasia (HHT).

Liver involvement in hereditary hemorrhagic telangiectasia (HHT).

1: J Hepatol. 2007 Jan 2

Garcia-Tsao G.

Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine and VA CT Healthcare System, 333 Cedar Street - 1080 LMP, P.O. Box 208019, New Haven, CT 06520, USA.

Liver involvement in hereditary hemorrhagic telangiectasia (HHT) consists of extensive intrahepatic vascular malformations associated with blood shunting (arteriovenous, arterioportal and/or portovenous). It is a rare disorder that nevertheless can result in significant systemic and hepatobiliary abnormalities. Although hepatic vascular malformations are present in a majority of patients with HHT, symptoms occur in a only a minority with a clear predominance for the female gender. Symptoms from liver vascular malformations are often misdiagnosed and this can lead to potentially harmful interventions. In this review article, clinical findings of liver involvement in HHT and their pathophysiology are discussed as well as diagnostic methodologies, therapies used and their outcome.

Data presented is based on a review of the literature performed in October 2006 using the following MEDLINE search terms: (hereditary hemorrhagic telangiectasia [ALL] OR Rendu-Osler-Weber [ALL]) AND (liver OR hepatic [ALL]). Papers were considered if they were published in English and if they included specific cases that were sufficiently described.


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Hereditary hemorrhagic telangiectasia.

Peng YF,Chen LK,Chou YH,Chang FC,Hwang SJ.

Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a rare disorder characterized by arteriovenous communications in visceral organs. The diagnosis of HHT consists of recurrent epistaxis, mucocutaneous telangiectasis, visceral vascular lesion and familial occurrence. HHT can be definitely diagnosed with the presence of all these three criteria. The prevalence of liver involvement of HHT was reported to range from 8 to 31%. Herein, we present a 75-year-old male who was diagnosed as having HHT with liver involvement, based on the findings of recurrent epistaxis, mucosal telangiectasis on the lower lip and hepatic arteriovenous malformation. The clinical presentations of this patient are discussed, and the literature is reviewed.

PMID: 12636208 [PubMed - indexed for MEDLINE]

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Monday, January 22, 2007

Treatment of cystic lymphatic vascular malformations with OK-432 sclerotherapy.

Treatment of cystic lymphatic vascular malformations with OK-432 sclerotherapy.
Plast Reconstr Surg. 2006 Nov;118(6):1441-6.

Peters DA,
Courtemanche DJ,
Heran MK,
Ludemann JP,
Prendiville JS.
Vascular Anomalies Clinic, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.

BACKGROUND: Cystic lymphatic vascular malformations are benign lesions that can cause disfigurement and functional impairment. Complete surgical resection is often difficult, and clinical recurrence is common. Sclerotherapy has been used as an alternative to excision. OK-432 is a lyophilized mixture of Streptococcus pyogenes and benzylpenicillin which, when injected into a lesion, has shown significant ability to reduce its size or obliterate it completely.

METHODS: The authors report a series of 12 patients treated in this fashion at the Vascular Anomalies Clinic, British Columbia Children's Hospital, between 1999 and 2004. All patients underwent imaging of the lesion: 10 had magnetic resonance imaging, one had a computed tomographic scan, and one had ultrasound examination. Six patients had macrocystic malformations (cysts > or = 2 cm) and six had microcystic or combined lymphaticovenous malformations. Patients were treated with intralesional injection of OK-432. The position of the injection was confirmed by angiography and/or ultrasound in 10 cases. Response to treatment was assessed clinically.

RESULTS: All patients with macrocystic malformations had complete resolution or good response to treatment. None required any additional treatment. In contrast, those with microcystic or combined malformations responded poorly. All of these patients underwent subsequent excision without adverse consequences. The size and location of the lesion did not correlate with response to treatment. Seventy-five percent of patients experienced pyrexia. Local swelling is an expected phenomenon and must be anticipated, particularly for lesions near the airway.

CONCLUSIONS: OK-432 is an excellent treatment for patients with macrocystic lymphatic malformations. However, it is ineffective for microcystic lesions.

PMID: 17051116 [PubMed - indexed for MEDLINE]

Tuesday, January 16, 2007

Radiofrequency ablation of microcystic lymphatic malformation in the oral cavity.

Radiofrequency ablation of microcystic lymphatic malformation in the oral cavity.

Arch Otolaryngol Head Neck Surg. 2006 Nov;132(11):1251-6

Grimmer JF,
Mulliken JB,
Burrows PE,
Rahbar R.

Division of Otolaryngology, Primary Children's Medical Center, University of Utah, Salt Lake City, UT 84113, USA.

OBJECTIVE: To determine the efficacy and safety of radiofrequency (RF) ablation of vesicles and the resulting symptomatic control of microcystic lymphatic malformation (LM) in the oral cavity.

DESIGN: An institutional review board-approved retrospective study with follow-up telephone interview.

SETTING: Tertiary pediatric medical center. Patients Eleven children (6 girls and 5 boys), aged 4 to 16 years, presenting between August 1, 2002, and December 1, 2004. Intervention Radiofrequency ablation of LM in the oral cavity.

MAIN OUTCOME MEASURES: Symptoms related to LM, postoperative oral intake, and postoperative antibiotic requirements.

RESULTS: Eleven patients presented with microcystic LM involving the lips, tongue, floor of the mouth, or buccal mucosa. Complaints included bleeding, infection, swelling, vesicle formation, and malocclusion. Patients underwent RF ablation (coblation) of oral cavity lesions. Seven (64%) of the 11 patients were able to tolerate oral intake in the recovery room. The need for antibiotics was reduced after RF ablation. All patients related diminished bleeding, pain, infection, or vesicle formation, with more than half reporting a significant improvement (6 patients) or complete resolution (1 patient). Five (62%) of 8 parents stated that the improvement after RF ablation was superior to that following previous procedures.

CONCLUSIONS: Subtotal RF ablation of LM appears to be safe, with early postoperative oral intake and minimal postoperative pain. Further studies are needed to determine long-term control of LM.

Full Text Article

Thursday, January 11, 2007

Mediastinal lymphangiomatosis coexisting with occult thymic carcinoma.

Mediastinal lymphangiomatosis coexisting with occult thymic carcinoma.

Ikeda JI,
Morii E,
Tomita Y,
Zhang B,
Tokunaga T,
Inoue M,
Minami M,
Okumura M,
Aozasa K.

Department of Pathology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita, 565-0871, Japan,

Mediastinal lymphangiomatosis in a 70-year-old woman was diagnosed on a medical checkup. The tumor was resistant to sclerotherapy with OK432 or bleomycin. The patient continued on a downhill course and died approximately 3 years after the initial diagnosis. Autopsy revealed a large tumor mass occupying the anterior mediastinum and firmly adhered to the pericardium and the pleura.

The tumor consisted of two intermingled lesions: dilated vessels lined with D2-40-positive lymphatic endothelium and CD5-positive atypical cell nests with focal keratinization. The former was diagnosed as lymphangiomatosis and the latter as thymic squamous cell carcinoma. Vascular endothelial growth factor (VEGF)-C, a growth factor for lymphatic endothelial cells, was expressed by the carcinoma, and VEGF-C receptor was expressed by the endothelium of lymphangiomatosis.

These findings suggested that VEGF-C derived from the thymic carcinoma induced the lymphangiomatosis lesion in a paracrine manner.

Keywords: Lymphangiomatosis - Thymic carcinoma - VEGF-C

Springer Link

Friday, January 05, 2007

Inheritance in lymphoproliferative disorders

Inheritance in lymphoproliferative disorders

Ugeskr Laeger. 2006 Jun 12

Jonsson V,
Olsen JH.
Oslo Universitet, Aker Universitetssygehus, Haematologisk Afdeling, N-0514 Oslo.

Lymphoproliferative disorders, especially chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphomas, Hodgkin's lymphoma and multiple myeloma are regarded as a hereditary entity with pleiotropic clustering in families, although the genuine alleles have not been found so far. The world-wide highest incidence of CLL and the existence of a systematic cancer registration since 1943 make Denmark a perfect place for epidemiological and genealogical investigations in the search for the genetics of the lymphoproliferative disorders. In Scandinavia, we see no signs of anticipation but marked linkage between parents and children, where the combination CLL in parent and CLL in child is more predominant than CLL in parent and a child with any other type of lymphoproliferative disorder.

This same conservative pattern is also seen in parent-children transportation of non-Hodgkin's lymphomas and Hodgkin's lymphoma. That no certain linkage to other cancers can be significantly detected is discussed. A non-Mendelian mode of inheritance seems not unlikely in the familial clustering of the lymphoproliferative disorders.
PMID: 16822421

[PubMed - indexed for MEDLINE]

Monday, January 01, 2007

Imaging of the lymphatic system: new horizons.

Imaging of the lymphatic system: new horizons.

Contrast Media Mol Imaging. 2006 Nov;1
Barrett T, Choyke PL, Kobayashi H. Molecular Imaging Program, National Cancer Institute, Building 10, Room 1B40, Bethesda, MD 20892-1088, USA.

The lymphatic system is a complex network of lymph vessels, lymphatic organs and lymph nodes.

Traditionally, imaging of the lymphatic system has been based on conventional imaging methods like computed tomography (CT) and magnetic resonance imaging (MRI), whereby enlargement of lymph nodes is considered the primary diagnostic criterion for disease. This is particularly true in oncology, where nodal enlargement can be indicative of nodal metastases or lymphoma. CT and MRI on their own are, however, anatomical imaging methods. Newer imaging methods such as positron emission tomography (PET), dynamic contrast-enhanced MRI (DCE-MRI) and color Doppler ultrasound (CDUS) provide a functional assessment of node status. None of these techniques is capable of detecting flow within the lymphatics and, thus, several intra-lymphatic imaging methods have been developed.

Direct lymphangiography is an all-but-extinct method of visualizing the lymphatic drainage from an extremity using oil-based iodine contrast agents. More recently, interstitially injected intra-lymphatic imaging, such as lymphoscintigraphy, has been used for lymphedema assessment and sentinel node detection. Nevertheless, radionuclide-based imaging has the disadvantage of poor resolution. This has lead to the development of novel systemic and interstitial imaging techniques which are minimally invasive and have the potential to provide both structural and functional information; this is a particular advantage for cancer imaging, where anatomical depiction alone often provides insufficient information.

At present the respective role each modality plays remains to be determined. Indeed, multi-modal imaging may be more appropriate for certain lymphatic disorders. The field of lymphatic imaging is ever evolving, and technological advances, combined with the development of new contrast agents, continue to improve diagnostic accuracy.