HGF and MET Mutations in Primary and Secondary Lymphedema.

Lymphat Res Biol. 2008
Finegold DN, Schacht V, Kimak MA, Lawrence EC, Foeldi E, Karlsson JM, Baty CJ, Ferrell RE.

Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania., Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania., DNF, CJB, and REF contributed equally to this work.

Abstract Background: Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance.

Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes.

Methods and Results: The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals.

Conclusions:The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.

Mary Ann Liebert

Congenital Lymphedema-lymphangiectasia Associated With Scrotal Angiokeratoma (Fordyce Type) and Hear

Congenital Lymphedema-lymphangiectasia Associated With Scrotal Angiokeratoma (Fordyce Type) and Hearing Impairment.

J Clin Gastroenterol. 2008 May

Pavone P, Lucenti C, Fraggetta F, Micali G, Incorpora G, Ruggieri M.

Departments of *Paediatrics §Dermatology, University of Catania †Department of Paediatrics, AUSL 3, Caltagirone ‡Pathology Unit, AUSL 3, Cannizzaro Hospital ∥Institute of Neurological Science, National Research Council, Catania, Italy.

Congenital lymphangiectasia-lymphedema is a rare disorder that presents with edema of the lower half of the body, the face, hands, and scrotum, or with protein-losing enteropathy owing to structural anomalies in the endothelium of the lymphatic system. We describe a biopsy-proven case of severe lymphangiectasia-lymphedema in a 16-year-old boy who was born to consanguineous parents and who, in addition, had mild (20 to 40 dB), early onset, sensorineural deafness and skin abnormalities, consisting of angiokeratomas of the face, hands, and feet, and also a large, localized angiokeratoma of the scrotum and the penis (Fordyce type). Both of the proband's parents had profound (>80 dB), congenital, mixed conductive/sensorineural, nonsyndromic deafness to low-mid frequencies. To the best of our knowledge, this constellation of lymphatic, skin, hearing, and systemic abnormalities seen in the proband has not been previously reported.

PMID: 18496391 [PubMed - as supplied by publisher]

Utility of double-balloon enteroscopy for the evaluation of malabsorption.

Utility of double-balloon enteroscopy for the evaluation of malabsorption.

Dig Dis. 2008

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, Magdeburg, Germany.

INTRODUCTION: Occasionally, patients with malabsorption represent a diagnostic challenge. Double-balloon enteroscopy (DBE) allows deep and detailed examination of the small bowel.

AIM: To determine the diagnostic value of DBE in patients with malabsorption of unclear origin.

METHODS: DBE was performed in a total of 12 patients with clinical malabsorption. Biopsy specimens were taken from macroscopic lesions or from examined small bowel at three different levels of scope insertion depth. Tissue specimens were evaluated with standard hematoxylin and eosin, the modified Marsh classification and, when indicated, special stains for amyloidosis.

RESULTS: Fifteen DBEs were successfully performed in 12 patients without complications. DBE with small bowel biopsies yielded a diagnosis in 8 patients (67%). A new diagnosis was reached in 4 patients (33%). The new diagnoses included: Crohn's disease, primary intestinal lymphangiectasia and jejunal amyloidosis. In none of these 4 patients did the duodenal biopsies yield a diagnosis. Also, DBE excluded enteropathy-associated T-cell lymphoma (EATL) and/or ulcerative jejunitis in symptomatic celiac disease patients.

CONCLUSIONS: DBE had a diagnostic value of 42% in patients with malabsorption of unclear origin. In addition, DBE was useful to rule out complications of long-standing celiac disease such as ulcerative jejunitis or EATL. DBE should be reserved for patients with unexplained malabsorption. DBE with jejunal and ileal biopsies appears to have a diagnostic value in patients with malabsorption, even when duodenal biopsies are histologically normal. 2008 S. Karger AG, Basel.

Key Words

• Double-balloon enteroscopy
• Malabsorption
• Celiac disease
• Lymphoma
• Sprue

Karger

Primary intestinal lymphangiectasia (Waldmann's disease).

Primary intestinal lymphangiectasia (Waldmann's disease).

Feb 2008 Orphanet J Rare Dis.

Vignes S, Bellanger J.

ABSTRACT:

Primary intestinal lymphangiectasia (PIL) is a rare disorder characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. Prevalence is unknown. The main symptom is predominantly bilateral lower limb edema. Edema may be moderate to severe with anasarca and includes pleural effusion, pericarditis or chylous ascites. Fatigue, abdominal pain, weight loss, inability to gain weight, moderate diarrhea or fat-soluble vitamin deficiencies due to malabsorption may also be present. In some patients, limb lymphedema is associated with PIL and is difficult to distinguish lymphedema from edema. Exsudative enteropathy is confirmed by the elevated 24-h stool alpha-1 antitrypsin clearance. Etiology remains unknown. Very rare familial cases of PIL have been reported. Diagnosis is confirmed by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of intestinal biopsy specimens. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Differential diagnosis includes constrictive pericarditis, intestinal lymphoma, Whipple's disease, Crohn's disease, intestinal tuberculosis, sarcoidosis or systemic sclerosis. Several B-cell lymphomas confined to the gastrointestinal tract (stomach, jejunum, midgut, ileum) or with extra-intestinal localizations were reported in PIL patients. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL medical management. The absence of fat in the diet prevents chyle engorgement of the intestinal lymphatic vessels thereby preventing their rupture with its ensuing lymph loss. Medium-chain triglycerides are absorbed directly into the portal venous circulation and avoid lacteal overloading. Other inconsistently effective treatments have been proposed for PIL patients, such as antiplasmin, octreotide or corticosteroids. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. The need for dietary control appears to be permanent, because clinical and biochemical findings reappear after low-fat diet withdrawal. PIL outcome may be severe even life-threatening when malignant complications or serous effusion(s) occur.

Orphanet

Lymphamgiogenesis, Lymphangiectasia and Crohn's Disease