Gingival Enlargement in Klippel-Trenaunay-Weber

Rare Instance of Gingival Enlargement in Klippel-Trenaunay-Weber Syndrome

Case Report

Pradeep S. Anand, MDS; T. Roshna, MDS

Abstract

Klippel-Trenaunay Syndrome is a rare congenital malformation that may include port-wine stain, soft tissue and bony hypertrophy, and venous malformations and lymphatic abnormalities. Although it usually involves the limbs, it may also rarely involve the head, neck, and orofacial regions. Despite its rarity, Klippel-Trenaunay Syndrome should be considered in the differential diagnosis of gingival enlargement. The condition can be easily recognized clinically, but further investigations including imaging studies have to be carried out in order to better understand the nature of the lesion. This report describes a case of gingival enlargement in Klippel-Trenaunay Syndrome in a 16-year-old female patient. The diagnosis of the condition was made based on the patient history, clinical and radiographic examination, computed tomography (CT), and angiogram.

Keywords: Gingival hyperplasia, Klippel Trenaunay disease

Citation: Anand PS, Roshna T. Rare Instance of Gingival Enlargement in Klippel-Trenaunay Syndrome: A Case Report. J Contemp Dent Pract 2006 July;(7)3:092-098.

Introduction

Klippel-Trenaunay Syndrome was first described by two French doctors, Klippel and Trenaunay, in 1900. The Klippel-Trenaunay Syndrome is a rare congenital malformation that may include the following, which are described as a triad of symptoms affecting one or more limbs:1

Port-wine stain or "birthmark" (cutaneous capillary malformations)
Soft tissue and bony hypertrophy (excessive growth of the soft tissue and/or bones)
Venous malformations and lymphatic abnormalities

The terms Klippel-Trenaunay Syndrome and Klippel-Trenaunay-Weber Syndrome have been used interchangeably. But at present, Klippel-Trenaunay Syndrome is described as hypertrophy and varicosity associated with port-wine staining; Klippel-Trenaunay-Weber Syndrome (more correctly called Parkes-Weber Syndrome) is similar but includes significant arteriovenous malformations with shunting. Klippel-Trenaunay Syndrome generally affects a single extremity, although cases of multiple affected limbs have been reported. The lower limb is the most common site, with involvement seen in about 95% of the patients2,3, followed by the arms and the trunk. The condition rarely involves the head and the neck. All three signs of the clinical syndrome-port-wine stain, varicose veins, and bony and soft tissue hypertrophies are seen in most patients. There have been very few reports of Klippel-Trenaunay Syndrome involving the orofacial region.4,5 When the condition involves the oral cavity, the characteristic findings include an enlarged maxilla, displacement of teeth, and malocclusion.4 Premature tooth eruption has also been reported.5 There has been one earlier report of gingival enlargement occurring in Klippel-Trenaunay Syndrome.6 Another report described the occurrence of hereditary gingival fibromatosis in association with Klippel-Trenaunay-Weber Syndrome.7 Some authors suggest Sturge-Weber Syndrome and Klippel-Trenaunay-Weber are two manifestations of one single entity.8 Patients with port-wine stain are said to have Sturge-Weber Syndrome if they also show “tram-line” calcifications on radiographs of the skull and the presence of angiomas along the distribution of the ophthalmic branch of the trigeminal nerve.9 Patients with Klippel-Trenaunay Syndrome show no intra-cranial calcifications, and hence, unlike Sturge-Weber syndrome patients, do not have a history of seizures. Although the two conditions rarely coexist, Reich and Wiatrak reported two patients with both of these angiomatoses.10

This report describes a case of gingival enlargement occurring in Klippel-Trenaunay Syndrome in a 16-year-old female patient.

Case Report

A 16-year-old female patient presented at the Department of Periodontics with the complaint of pain and swelling of the gingiva in relation to the right upper posterior teeth of two weeks duration. She had received antibiotics for the complaint from a general dentist. She had undergone extraction of the mandibular left first molar six months previously. Extra-orally, the patient had a diffuse port-wine staining on the right side of the face over the cheek extending from the midline to the external ear and from the forehead to the upper lip (Figure 1). The pigmentation was present from birth. The face showed asymmetry with the right side showing hypertrophy compared to the left side. There was no history of seizures, which suggested absence of intra-cranial calcifications seen in Sturge-Weber Syndrome.

Intra-oral examination showed enlargement of the buccal and palatal gingiva in relation to the right maxilla (Figures 2 and 3). The enlargement extended from the maxillary right second molar up to the midline (Figure 4). The enlargement was diffuse, bright red in color, and pebbly in appearance. On gentle palpation, the tissue was found to be soft and edematous. The gingiva in relation to the right mandible appeared normal. The maxillary right first premolar exhibited grade I mobility, while the second premolar, first, and second molars exhibited grade II mobility. The mandibular right second molar showed caries with exposure of the pulp.

Intra-oral periapical and panoramic radiographs were taken which did not show significant changes in the bone structure. The patient was referred to Department of Radiodiagnosis for further investigation.

Computed tomography (CT) was done which showed enlargement of the soft tissues overlying the right maxilla (Figure 5). It also showed definite enlargement of the right maxilla (Figure 6).

The brain showed no evidence of involvement, and there was no evidence of intra-cranial calcifications (Figure 7). There was no evidence of Sturge-Weber Syndrome.

Later, an angiogram was performed at the Department of Radiology, Sri Chitra Thirunal Institute of Medical Sciences and Technology in Trivandrum, India. The angiogram showed there was no arteriovenous malformation. The aortogram showed the feeder vessel for the hemangioma was the right internal maxillary artery as evidenced by the “blush” seen in the view when the dye was injected into the artery (Figure 8). When the dye was injected into the facial and lingual arteries, there was no such “blush” indicating the blood vessels did not contribute to the hemangioma.

As the condition warranted surgical management under hospital facilities, the patient was then referred to the Department of Plastic Surgery, Government Medical College, in Trivandrum, India for further management. The surgical procedure was planned to be performed in multiple stages for both the treatment of gingival enlargement and for cosmetic reasons as well. The first stage surgery planned was a debulking procedure to remove the hemangioma on the right side of the face by an intra-oral approach with the incision placed on the upper labial mucosa. The surgical procedures for the management of the gingival enlargement were to be performed in subsequent stages. Prior to all the surgical procedures, the feeder vessel, the right internal maxillary artery, would be embolised with gel foam. The treatment plan and the surgical procedure were explained to the patient and the patient’s parents, and the patient opted not to undergo the surgical procedure.

Discussion

Klippel-Trenaunay Syndrome involving the orofacial tissues is rare. Involvement of the oral cavity can result in an enlarged maxilla, displacement of teeth, and malocclusion.4 Although the diagnosis can be made on clinical grounds, further investigations need to be carried out.
The exact cause of Klippel-Trenaunay Syndrome/Klippel-Trenaunay-Weber Syndrome remains to be elucidated, although several theories exist. Among the various theories, one suggests Klippel-Trenaunay Syndrome may be caused by mesodermal abnormalities during fetal development, while another medical opinion suggests the cause could be the result of a gene mutation. According to Bliznak and Staple, intrauterine damage to the sympathetic ganglia or intermediolateral tract leading to dilated microscopic arteriovenous anastomoses is the cause.11 Servelle suggested deep vein abnormalities, with resultant obstruction of venous flow, lead to venous hypertension, the development of varices, and limb hypertrophy.12 Baskerville et al. opined that a mesodermal defect during fetal development causes maintenance of microscopic arteriovenous communications.13 According to McGrory and Amadio, an underlying mixed mesodermal and ectodermal dysplasia is likely to be responsible for the development of Klippel-Trenaunay-Weber Syndrome.14 Most cases are sporadic, although a few cases in the literature report an autosomal dominant pattern of inheritance.15

Complications may arise either due to hemangiomas or due to varicosities. Complications of hemangiomas include skin breakdown and ulceration, bleeding, and secondary infection. Complications due to varicosities include thromboembolism16, paresthesia, stasis ulcers, pulmonary emboli, thrombophlebitis, stasis dermatitis, and hemorrhage.

When complications are present, imaging studies can be useful. A CT can be a useful diagnostic. Evaluation of the deep venous system can be completed with duplex scanning contrast venography, ultrasonography, contrast venography and arteriography, and nuclear magnetic resonance imaging (MRI) studies.17

Management of this syndrome can be divided into medical and surgical interventions.

Medical Care

Treatment is conservative and symptomatic. Complications such as cellulitis and thrombophlebitis can be managed with analgesics, elevation, antibiotics, and corticosteroids.18 Intermittent or prophylactic antibiotics can be considered for patients with a history of recurrent cellulitis. Anticoagulant therapy is indicated in acute thrombosis and prophylactically prior to surgical procedures. Given the risk of thrombotic events, women with Klippel-Trenaunay-Weber Syndrome should avoid using oral contraceptive pills.
When the condition involves the gingiva, as in the present case, care should be taken not to traumatize the gingival tissues during examination or treatment. Periodontal probing should not be done as even probing can result in uncontrolled bleeding. Non-surgical management includes oral hygiene instructions and plaque control with the aid of mouthwashes.

Surgical Care

Surgery should be considered in cases where skin ulcerations lead to persisting and recurrent bleeding or where significant deformities or overgrowth leads to both functional and psychological impairment.18 Laser treatment of the hemangioma can be effective in lightening the color of the port-wine stain.19,20 Laser treatment is also indicated in the case of ulceration. Ulceration of hemangiomas can be painful and can impair functional abilities. When treated with laser, ulcers often heal more quickly. Laser treatment is most effective when performed early, as it can improve the long-term appearance of the port-wine stain and, thereby, also improve function. Lasers have been used for gingivectomy in patients with Sturge-Weber Syndrome.21 Typically, several treatments are required to achieve the desired effect. Laser treatment only helps with the superficial component of the hemangioma.

Surgical procedures can be performed for the treatment of varicosities and venous malformations, but it is controversial. One might consider surgery for either significant cosmetic deformity or the symptoms of pain, bleeding, or infectious complications. Venous stripping, ligation, excision, or sclerotherapy are contraindicated unless the surgery involves the superficial system and the underlying deep system is normal or demonstrates only mild-to-moderate reflux. Woods22 reported the sclerosing agent sodium tetradecyl sulfate, used appropriately, is a safe and frequently effective agent in the treatment of hemangiomas and a number of similar or related problems. It is especially useful in the management of cavernous hemangiomas where there are no arterio-venous malformations. Debulking procedures can be done but have limited use and may damage venous and lymphatic structures, leading to increased edema in the affected site. Symptomatic superficial varicosities can be removed without harm and with benefit to the patient when an adequate preoperative examination is performed. Although Baskerville et al.13 demonstrated that some 90% of treated varicosities redevelop, treatment can provide lasting improvement for years.

Although patients with severe chronic venous insufficiency, disturbing cosmetic appearance, or complications of hemangioma may benefit from surgical treatment, detailed preoperative imaging to understand the nature of the vascular lesion is needed to decrease complications.23 Inadequate evaluation prior to excision increases surgical complications. Embolisation of the hemangioma should be done. The agents used for embolisation include gelfoam and polyvinyl alcohol. The potential risks and benefits must be carefully weighed before attempting surgical intervention.

Conclusion

In conclusion, although it rarely involves the orofacial region, Klippel-Trenaunay Syndrome should be included in the differential diagnosis of severe gingival enlargement. In view of the potentially dangerous complications that can arise, it is imperative the dental surgeon has a thorough knowledge about the condition. Although the condition can be recognized clinically, further investigations including imaging studies have to be carried out in order to better understand the nature of the lesion. The condition can be managed in a conservative manner or by a surgical approach depending upon the nature of the patient’s complaints.

References

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Meine JG, Schwartz RA, Janniger CK. Klippel-Trenaunay-Weber syndrome. Cutis 1997; 60: 127-132.

Al-Salman MM. Klippel-Trenaunay syndrome: Clinical features, complications, and management. Surg Today 1997; 27: 735-740.

Berry SA, Peterson C, Mize W, Bloom K, Zachary C, Blasco P, Hunter D. Klippel-Trenaunay syndrome. Am J Med Genet 1998; 79: 319-326.

Steiner M, Gould AR, Graves SM, Kuerschner TW. Klippel-Trenaunay-Weber syndrome. Oral Surg Oral Med Oral Pathol. 1987; 63: 208-215.

Mueller-Lessmann V, Behrendt A, Wetzel WE, Petersen K, Anders D. Orofacial findings in the Klippel-Trenaunay syndrome. Int J Paediatr Dent. 2001; 11: 225-229.

Bathi RJ, Agarwal N, Burde KN. Klippel-Trenaunay syndrome (angio osteohypertrophy syndrome): a report of 3 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002; 93: 276-280.

Hallett KB, Bankier A, Chow CW, Bateman J, Hall RK. Gingival fibromatosis and Klippel-Trenaunay-Weber syndrome. Case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995; 79: 578-582.

Happle R. Sturge-Weber-Klippel-Trenaunay syndrome: What's in a name? Eur J Dermatol. 2003; 13: 223.

Soft Tissue Tumors. In: Neville BW, Dam DD, Allen CM, Bouquot JE, eds. Oral and Maxillofacial Pathology. WB Saunders Company; 1995: 362-415.
Reich DS, Wiatrak BJ. Upper airway obstruction in Sturge-Weber and Klippel-Trenaunay-Weber syndromes. Ann Otol Rhinol Laryngol. 1995; 104: 364-368.

Bliznak J, Staple TW. Radiology of angiodysplasias of the limb. Radiology 1974; 110: 35-44.

Servelle M. Klippel and Trenaunay's syndrome. 768 operated cases. Ann Surg 1985; 201: 365-373.

Baskerville PA, Ackroyd JS, Browse NL. The etiology of the Klippel-Trenaunay syndrome. Ann Surg 1985; 202: 624-627.

McGrory BJ, Amadio PC. Klippel-Trenaunay syndrome: orthopaedic considerations. Orthop Rev 1993; 22: 41-50.

Aelvoet GE, Jorens PG, Roelen LM. Genetic aspects of the Klippel-Trenaunay syndrome. Br J Dermatol 1992; 126: 603-607.

Aggarwal K, Jain VK, Gupta S, Aggarwal HK, Sen J, Goyal V. Klippel-Trenaunay syndrome with a life-threatening thromboembolic event. J Dermatol. 2003; 30: 236-240.

Williams DW, Elster AD. Cranial CT and MR in the Klippel-Trenaunay-Weber syndrome. AJNR Am J Neuroradiol. 1992; 13: 291-294.

Capraro PA, Fisher J, Hammond DC, Grossman JA. Klippel-Trenaunay syndrome. Plast Reconstr Surg. 2002; 109: 2052-2060; quiz 2061-2062.

Spicer MS, Goldberg DJ, Janniger CK. Lasers in pediatric dermatology. Cutis 1995; 55: 270-272, 278-280.

Yamauchi PS, Soriano TT, Lask GP. Treatment of port wine stains using the pulsed-dye laser at 585 nm with the dynamic cooling device. J Cutan Laser Ther 2000; 2 : 33-36.

Hylton RP. Use of CO2 laser for gingivectomy in a patient with Sturge-Weber disease complicated by dilantin hyperplasia. J Oral Maxillofac Surg. 1986; 44: 646-648.

Woods JE. Extended use of sodium tetradecyl sulfate in treatment of hemangiomas and other related conditions. Plast Reconstr Surg. 1987; 79: 542-549.

Gloviczki P, Stanson AW, Stickler GB, Johnson CM, Toomey BJ, Meland NB, Rooke TW, Cherry KJ Jr. Klippel-Trenaunay syndrome: the risks and benefits of vascular interventions. Surgery 1991; 110: 469-479.

Journal of Contemporary Dental Practice

Primary Intestinal and Thoracic Lymphangiectasia: A Response to Antiplasmin Therapy

Primary Intestinal and Thoracic Lymphangiectasia: A Response to Antiplasmin Therapy

Abstract

Lymphangiectasia is a congenital or acquired disorder characterized by abnormal, dilated lymphatics with a variable age of presentation. We describe a case of lymphangiectasia with intestinal and pulmonary involvement in an adolescent female, who presented with many of the classic features including chylous pleural effusions, lymphopenia, hypogammaglobinemia, and a protein-losing enteropathy. She also presented with recurrent lower gastrointestinal bleeding, which is infrequently described. The patient did not improve with bowel rest and a low-fat medium-chain triglyceride diet and had little improvement with octreotide acetate therapy. However, she had a clinical response to antiplasmin therapy, trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid) in terms of serum albumin and gastrointestinal bleeding. She continues to have exacerbations of her condition, as well as persistent lymphopenia and chronic pleural effusions.

Key Words: lymphangiectasia • anti-plasmin • gastrointestinal bleeding

Introduction

Primary lymphangiectasia is a congenital disorder of the lymphatic system characterized by marked ectasia of the lymphatic vessels resulting in obstruction and leakage of lymph fluid.1 Intestinal lymphangiectasia is characterized by a protein-losing enteropathy and is diagnosed definitively by small bowel biopsy demonstrating dilated lymphatics in the mucosa, submucosa, and serosa in the absence of coexistent inflammation.2–4 Symptoms include diarrhea, peripheral edema, lymphedematous limbs, general malaise, and weight loss.2,5 In pulmonary or thoracic lymphangiectasia, dilation of lymphatics in the visceral pleura as well as interlobular septa result in chylothoraces, which may lead to respiratory compromise or failure.1 Intestinal and thoracic lymphangiectasia may occur in isolation or simultaneously in the same patient as part of a generalized lymphatic dysplasia.6

Treatments described for lymphangiectasia have included corticosteroids for patients with primary inflammatory conditions,7 dietary modifications,8 surgical resection for isolated lesions,9 octreotide,10,11 and antiplasmin therapy.12 Successful management with these treatment modalities has been variable with no evidence of specific groups of patients responding to a particular treatment. We report a case of lymphangiectasia associated with intestinal bleeding, a finding that is not commonly described.13 The protein-losing enteropathy was refractory to total parenteral nutrition and a low-fat medium-chain triglyceride diet as well as octreotide, with improvement after starting antiplasmin therapy.

Case Report

A 14-year-old previously healthy girl was transferred from a peripheral hospital with a microcytic anemia requiring transfusion and a large left-sided pleural effusion. She had a 3-week history of fatigue, abdominal pain, nausea, and vomiting, accompanied by a 3-kg weight loss and grossly bloody stools.

On physical examination, her heart rate was 119 beats/min, respiratory rate 36 breaths/min, blood pressure 97/46 mm Hg, and oxygen saturation 99% in room air. She had marked pallor and periorbital edema. Chest examination revealed decreased breath sounds on the left side. A grade II/VI systolic ejection murmur was heard over the left lower sternal border with normal heart sounds. Abdominal examination revealed evidence of ascites with no organomegaly. There was notable peripheral edema but no evidence of lymphadenopathy.

Initial laboratory investigations showed a hemoglobin of 58 g/L and platelets of 248 x 109/L. White blood cell count was 5.9 x 109/L with lymphopenia (0.36 x 109/L lymphocytes). Albumin was 19 g/L with a total protein of 34 g/L and immunoglobulins G, A, and M of 2.4 g/L (normal range: 7.2–15.8 g/L), 0.5 g/L (normal range: 0.5–3.5 g/L), and 0.7 g/L (normal range: 0.2–2.6 g/L), respectively. Urinalysis showed no evidence of proteinuria. The erythrocyte sedimentation rate, amylase, urate, lactate dehydrogenase, transaminases, bilirubin, and -fetoprotein levels were normal with stools positive for blood and markedly elevated stool -1-antitrysin levels.

Chest radiograph showed a large left-sided pleural effusion and a small right-sided effusion (Fig 1). Computerized tomography and magnetic resonance imaging of the chest and abdomen revealed diffuse abnormalities in the mediastinal fat, thickened bowel loops, and mild ascites but no focal mass or lymphadenopathy. An echocardiogram was normal. An endoscopic examination of the small bowel showed diffuse bowel wall thickening with distal nodularity of the ileum. A lymphangiogram demonstrated delayed transit with normal subdiaphragmatic nodal architecture and no entry into the cisterna chyli or thoracic duct.

Thorascopic biopsy of the mediastinal lesion showed grossly fatty vascular tissue that appeared necrotic microscopically without evidence of malignancy. Upper gastrointestinal endoscopy revealed gross white nodules consistent with lymphangiectasia. No focal bleeding sites were seen. Microscopically, there was focal lymphangiectasia in the duodenal cap and gastric antrum. Thoracentesis of the left hemithorax drained 1.8 L of serous fluid with pH 7.0, protein of 20 g/L, glucose of 5.4 mmol/L, and elevated triglycerides of 0.92 mmol/L with chylomicrons present. The white blood cell count of the fluid was elevated at 231 cells/mm3 with a lymphocytic predominance. Routine and mycobacterial cultures were sterile. Cytology showed no malignant cells. Bilateral bone marrow aspirates and biopsy were normal. A gallium scan was normal.

The patient was started on total parenteral nutrition and complete bowel rest. Her albumin remained persistently low despite weekly albumin infusions, and her chest tube continued to drain 1 to 2 L daily. Persistent gastrointestinal bleeding resulted in blood transfusions approximately every 2 weeks. A red blood cell scan and Meckel’s scan were negative with repeat upper and lower intestinal endoscopies showing no signs of active bleeding. Subcutaneous octreotide therapy was initiated 30 days into hospitalization. Although the chest pathology improved with decreased output from the chest tubes, the enteropathy persisted. Repeat endoscopy 5 weeks into hospitalization revealed some pathologic improvement in the duodenum, but multiple focal areas of lymphangiectasia were seen in the terminal ileum. A low-fat medium-chain triglyceride diet was instituted for 4 weeks but did not lead to any improvement. Based on a report showing benefit with antiplasmin therapy, a trial of tranexamic acid (1000 mg by mouth, 3 times daily) was initiated 2.5 months after presentation (Fig 2). At the time, D-dimer levels were elevated at 1770 ng/mL (normal: 0–449 ng/mL) with normal partial thromboplastin time and international normalized ratio. One month later, her albumin had improved to 24 g/L and her immunoglobulin G level was 5.4 g/L. She remained clinically stable for 10 months with normal levels of serum albumin and immunoglobulin G, and she did not have additional intestinal bleeding. Fourteen months after her initial presentation, an exacerbation of her condition occurred with recurrent transfusion dependent lower gastrointestinal bleeding and hypoalbuminemia requiring daily albumin infusions. Repeat endoscopic biopsies again demonstrated lymphangiectasia throughout the small bowel as well as multiple areas of mucosal petechiae. After a 1-month period of parenteral nutrition and bowel rest, increasing the dose of octreotide, and increasing the dose of tranexamic acid to 6 g/d, her condition stabilized with resolution of the intestinal bleeding.

Discussion

Lymphangiectasias are disorders characterized by abnormal, dilated lymphatics. There is wide variation in the age of onset and extent of disease. Primary lymphangiectasia is a congenital malformation, with the age of presentation ranging from in utero onset to early adulthood. Lymphangiectasia may also be secondary to lymphatic damage from other processes including lymphoma, radiotherapy, and constrictive pericarditis. Although lymphangiectasia can be isolated to the gastrointestinal or pulmonary systems, generalized disease usually shows a predominance of intestinal manifestations.14

We describe a case showing some of the classic features of lymphangiectasia including chylous pleural effusions, lymphopenia, hypoalbuminemia with enteric protein loss, and hypogammaglobulinemia. A thorough investigation excluded potential underlying causes. This case also describes an association with intestinal bleeding thought to be related to latent lymphatic-venous anastomoses, which can rupture under abnormally high lymphatic pressure.13 There was marked clinical improvement, as measured by serum albumin, immunoglobulin levels, and resolution of intestinal bleeding, with the initiation of antiplasmin therapy.

The rarity of lymphangiectasia and the wide variation in its clinical presentation provides a challenge in identifying appropriate therapy. Supportive therapy including albumin infusions, diuretics, thoracentesis, and paracentesis provides transient relief of symptoms. Surgical resection is an option for limited disease of the small bowel.9,15 Dietary modifications are aimed at controlling symptoms and consequences of lymphatic obstruction but not at modifying the underlying disease process. Restriction of dietary fat results in reduction in lymph flow and subsequent leak of protein. Low-fat medium-chain triglyceride diets have been used as sole therapy as well as a part of other treatment regimens. These triglycerides are not reesterified within intestinal cells, thereby bypassing enteric lymphatics. In most patients, dietary modifications need to be continued indefinitely to control symptoms.8 Although it is generally accepted that corticosteroids do not have a role in the treatment of lymphangiectasia, they have been used with success in patients with elevated acute phase reactants, suggesting that there may be a subset of patients with underlying inflammatory disease who may respond to corticosteroids.7,16

Octreotide acetate is a long acting somatostatin analog that may aid in the reduction of lymphatic losses in lymphangiectasia through a variety of mechanisms including reduction of thoracic duct lymph flow17 and reducing lymph fluid excretion in enteric vasculature.18 Octreotide has been reported to be successful in 2 cases refractory to other therapeutic modalities.10,11

Increased fibrinolytic activity, which causes intestinal protein loss, has been proposed as a mechanism responsible for several conditions characterized by protein-losing enteropathy. In a rat protein-losing enteropathy model as well as in patients with Menetrier’s disease and hypertrophic gastritis, Kondo et al19 demonstrated increased tissue fibrinolytic activity in gastric mucosa biopsy specimens. Treatment with antiplasmin therapy, tranexamic acid, led to a resolution of symptoms, laboratory evidence of enteric protein loss, and, in animal models, a normalization of tissue fibrinolytic activity.20

Based on these studies and case reports, Mine et al12 treated a 35-year-old woman with intestinal lymphangiectasia and increased plasma fibrinolytic activity, as measured by euglobin lysis time, with tranexamic acid. The mechanism of action of tranexamic acid has been shown to involve inhibition of conversion of plasminogen to plasmin as well through weak noncompetitive inhibition of plasmin. This patient showed a dramatic clinical response within 6 weeks that was sustained over 8 years, with clinical exacerbations occurring only with discontinuation of the drug and remitting with reinstituting therapy. Two different authors reported 3 subsequent patients, with and without increased plasma fibrinolytic activity, who did not benefit from antiplasmin therapy, and there has not been a subsequent reported case of lymphangiectasia that responded to this therapy. Mine concluded that there is a subset of patients with lymphangiectasia, who may have increased tissue or plasma fibrinolytic activity and may respond to antiplasmin therapy. Our case represents the second apparent beneficial use of this therapy. The elevated D-dimers in our patient may be reflective of increased fibrinolytic activity, which may have a causative role in the protein-losing enteropathy. Tranexamic acid has been used successfully in hereditary hemorrhagic telangiectasia,21 and this condition is also characterized by lesions with increased local fibrinolytic activity caused by an increase in tissue plasminogen activator.22 It is plausible that the multiple areas of mucosal bleeding in our patient represent lesions with increased fibrinolytic activity, and that tranexamic acid modulates the effect of tissue fibrinolysis in these areas. There may be a subset of patients with lymphangiectasia who have gastrointestinal bleeding from diffuse areas of local hyperfibrinolysis and may respond to antiplasmin therapy.

Although it can be argued that our patient’s initial improvement was coincidental to initiation of therapy with tranexamic acid as spontaneous remissions can occur, the timing and nature of the improvement was similar to Mine’s patient. The resolution of gastrointestinal bleeding and the lack of need for any red blood cell or albumin infusions are striking. Our patient has had an exacerbation of her condition which subsequently improved and ongoing lymphopenia which reflects the persistence of the anatomic abnormalities of the lymphatics despite therapy. D-dimers remain elevated, which may be indicative of a persistent fibrinolytic state. The side effect profile of tranexamic acid includes gastrointestinal upset and retinal changes,23 which have not been demonstrated in ongoing surveillance in our patient. Although the long-term outcome of our patient is unclear, it is evident that the improvement in her condition was most likely related to tranexamic acid therapy.

This case underscores the fact that lymphangiectasia is a heterogeneous and poorly understood condition. Some patients with this condition, particularly those with diffuse gastrointestinal bleeding, may respond to antiplasmin therapy. A multicenter surveillance study may aid in our understanding of this uncommon and heterogeneous disorder and provide a more systematic approach to treatment of this complex clinical problem.

Division of Paediatric Medicine The Hospital for Sick Children University of Toronto Toronto, Ontario, Canada M5G 1X8

-->Joanna E. MacLean, MD, Eyal Cohen, MD and Michael Weinstein, MD
Division of Paediatric Medicine The Hospital for Sick Children University of Toronto Toronto, Ontario, Canada M5G 1X8

Pediatrics

Pulmonary Cystic Lymphangiectasis

PULMONARY CYSTIC LYMPHANGIECTASIS

Alternative titles; symbols: LYMPHANGIOMATOSIS, PULMONARYLYMPHANGIECTASIA, PULMONARY

TEXT

Frank and Piper (1959) described 2 affected infants who were not related. One was stillborn and the other lived only about 2 hours. In 1 case there were similar lesions in the heart, pancreas, kidneys, and mesentery. Scott-Emuakpor et al. (1981) described the disorder in 2 sisters who showed acute respiratory distress soon after birth and died in the neonatal period. Changes at autopsy were limited to the lungs.

Moerman et al. (1993) reported on 7 perinatal autopsy cases of primary congenital pulmonary lymphangiectasis (CPL) with bilateral chylothorax. They demonstrated that primary CPL is often complicated by chylous pleural effusions with ensuing pulmonary hypoplasia. Conversely, CPL appears to be a constant pathologic finding in spontaneous congenital chylothorax. These observations indicated a common pathogenesis for the 2 disorders. The basic defect is not an intrinsic lung abnormality, but a developmental error of the lymphatic system resulting in a pulmonary lymphatic obstruction sequence.

Moerman et al. (1993) concluded that the cause of CPL is heterogeneous. Most cases are apparently sporadic occurrences. They reported the second instance of CPL in sibs. Thus, some cases are genetically determined with autosomal recessive inheritance. CPL may also be part of a multiple congenital anomalies (MCA) syndrome, such as Noonan syndrome (163950), Turner syndrome, and Down syndrome.

Njolstad et al. (1998) reported the cases of 3 sibs with nonimmune hydrops fetalis (236750); 2 of them had congenital pulmonary lymphangiectasia.

REFERENCES

1. Frank, J.; Piper, P. G. :
Congenital pulmonary cystic lymphangiectasis. J.A.M.A. 171: 1094-1098, 1959.PubMed ID : 13824507
2. Moerman, P.; Vandenberghe, K.; Devlieger, H.; Van Hole, C.; Fryns, J.-P.; Lauweryns, J. M. :
Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality. Am. J. Med. Genet. 47: 54-58, 1993.PubMed ID : 8368253
3. Njolstad, P. R.; Reigstad, H.; Westby, J.; Espeland, A. :
Familial non-immune hydrops fetalis and congenital pulmonary lymphangiectasia. Europ. J. Pediat. 157: 498-501, 1998.PubMed ID : 9667408
4. Scott-Emuakpor, A. B.; Warren, S. T.; Kapur, S.; Quiachon, E. B.; Higgins, J. V. :
Familial occurrence of congenital pulmonary lymphangiectasis: genetic implications. Am. J. Dis. Child. 135: 532-534, 1981.PubMed ID : 7234788

CONTRIBUTORS

Victor A. McKusick - updated : 2/20/1999Victor A. McKusick - updated : 8/21/1998

CREATION DATE

Victor A. McKusick : 6/4/1986

EDIT HISTORY

carol : 2/23/1999terry : 2/20/1999terry : 8/21/1998mimadm : 3/12/1994supermim : 3/17/1992supermim : 3/20/1990ddp : 10/27/1989marie : 3/25/1988reenie : 6/4/1986
Copyright © 1966-2004 Johns Hopkins University

Pub Med

.................................

Pulmonary cystic lymphangiectasis

Clinical Signs:

abnormal pleura/hydrothorax (Very frequent sign) autosomal recessive inheritance (Very frequent sign) respiratory distress (Very frequent sign) stillbirth/neonatal death (Very frequent sign) liver enlargement (excl. storage dis.) (Occasional sign) lymphoedema/oedema (Occasional sign) splenomegaly (Occasional sign)

Outpatient clinic(s)

Dysmorphology clinicGenetic counselling clinic

Any outpatient pneumology clinic.

Orphanet

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Congenital pulmonary lymphangiectasis.

Report of four cases (author's transl)]

[Article in Spanish]

Fidalgo I, Ortega F, Alustiza J, Pastor E, Cabrera A.

Four cases of congenital pulmonary lymphangiectasis were observed during a five year period. This represents an incidence of 1.11 per 10,000 cases among alive newborns and of 53 per 10,000 cases among pediatric necropsias performed during the same period. One case was observed in the clinical context of a generalized hemangiolymphangiomatosis, another was associated to tetralogy of Fallot and the remaining two cases were associated to obstruction of pulmonary venous return. Although one of the pathogenic theories generally accepted in the formation of pulmonary lymphangiectasis points to the presence of either hypertension or obstruction of pulmonary venous drainage, it is possible that such situation is only circumstantial. Among 40 personal cases of obstruction of pulmonary venous return proved anatomically, only in the two cases presented were pulmonary lymphangiectasis demonstrated. The presence of dysplastic elements in pulmonary tissue in cases of lymphangiectasis suggests that a more possible mechanism is a primary defect in the development of pulmonary lymphatics.

Publication Types:

Case Reports

PMID: 7224372 [PubMed - indexed for MEDLINE]

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Congenital pulmonary lymphangiectasis

[Article in German]

Wockel W, Dietrich M.

3 cases of congenital pulmonary lymphangiectasis are described. A girl, now 3 years old, underwent at the age of 4 weeks a resection of the left superior lobe of the lung which was singularly involved. A male newborn died 4 h after birth and showed the typical affection of both lungs. A second male infant died 19 d after birth and had an isolated involvement of the left lung. Post-mortem examination additionally revealed in both boys a cardiovascular malformation. Histologically, we especially observed a papillar endothelial hyperplasia in a dilated lymph vessel in case 1 and multinuclear giant cells of the foreign-body type in case 3. In the literature, there are reported 99 cases of congenital pulmonary lymphangiectasis. Including our case, a unilobar or unilateral involvement is described in only 8 cases.

The congenital pulmonary lymphangiectasis occurs more often in males than in females (1.8 : 1). 90 out of 93 life-born children suffering from this malformation died, 57 of them during the perinatal period. However, cardiovascular malformations, which were observed in 53 cases, are playing an important role as the cause of death. The aetiology of the congenital pulmonary lymphangiectasis remains unknown. There are 4 different theories concerning the pathogenesis, namely, a persistence of early-fetal lymphatic vessels, a missing connection between primitive lymphatic vessels, a hyperplasia of lymphatic ducts and, last but not least, a passive dilatation of the lymph vessels because of venous or lymphatic congestion.

Publication Types:

Case Reports

PMID: 6485606 [PubMed - indexed for MEDLINE]

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Bilateral symmetrical lymphangiomas of the gingiva: case report

Bilateral symmetrical lymphangiomas of the gingiva: case report

Case Report

Pouria Motahhary1 , Babak Sarrafpour1 and Afshin Abdirad2 1Department of Oral Pathology, Dental School, Tehran University of Medical Sciences, Iran2Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, IranDiagnostic Pathology 2006, 1:9 doi:10.1186/1746-1596-1-9

© 2006 Motahhary et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Lymphangioma is a benign lesion that is related to proliferation of lymphatic vessels. Lymphangioma of the gingiva is a rare lesion that manifest as a pebbly hyperplasia on gingiva. The purpose of this study is to report a case of bilateral symmetrical lymphangioma of the gingiva.

Case presentation

A 32-year-old man was presented with bilateral hyperplasia of gingiva in upper canine regions. The lesions were resected completely and evaluated histologically. The microscopic evaluation revealed lymphangioma.

Conclusion

Bilateral lymphangioma of the gingiva is a very rare lesion which its origin is controversial.

Background

The lymphangioma is a well-known benign hamartomatous tumor of lymphatic vessels, which have a marked predilection for head and neck [1]. Oral lesions are most frequently found on the tongue and usually demonstrate a pebbly appearance as by their superficial location. Occurrence in other areas such as cheeks, lips, floor of the mouth, palate and gingiva has been reported [2]. Congenital alveolar lymphangioma is seen as a unique lesion on the alveolar mucosa of African-American neonates [1].

Two unusual cases of bilateral symmetrical lymphangiomas of the gingiva have been reported by Josephson and van Wyk [3] and McDaniel and Adcock [4]. The following report is another case of bilateral symmetrical lymphangioma of the gingiva which occurred in anterior maxillary gingiva as areas of hyperplastic gingivitis.

Case Presentation

A healthy 32-year-old man was referred to the Department of Periodontology of Tehran University of Medical Sciences complaining of gingival hyperplasia on the lateral and canine teeth of maxilla in both sides. The past medical history was unremarkable. In clinical examination clear vesicular asymptomatic lesions were found on the attached and marginal gingiva in canine area. He had no previous dental history relating to the lesion in those sites and lesions were appeared gradually from two years ago. No other lesion and alteration could be detected radiographically and clinically. Excisional biopsies were taken from both lesions and the specimens were sent to the Department of Oral Pathology of Tehran University of Medical Sciences for microscopic examination.

Microscopic evaluation revealed gingival tissue covered by parakeratinized squamous epithelium. Deep to the epithelium multiple dilated lymph vessels with different sizes were observed in a little loose fibrovascular tissue. These spaces were lined by a single layer of endothelial cells with flattened nuclei, and contained lymph with a few lymphocytes. Vessels just beneath the surface epithelium filled the connective tissue papilla. Both sides had similar appearance in histologic examination (figure 1 and 2). The diagnosis was lymphangioma.

The surgical wounds healed without scar formation in 4 weeks and no sign of recurrence was evident after 10 months.

Conclusion

Microscopically lymphangioma consist of capillary or cavernous lymphatic channels, which lined by endothelium and appeared empty or filled with proteinaceous material and occasional lymphocytes. Specific antibodies against vascular endothelial cells are used for detection of microvesseles. Pan-endothelial markers such as CD34 (an antibody targeting the transmembranous sialo protein), CD31 (an antibody targeting the platelet-derived cell adhesion factor that is present in endothelial cells) and CD105 (endoglin) are generally used for identification of microvessels [5,6]. But none of these factors are specific for lymphatic vessels. Recently several relatively specific antibodies for lymphatic endothelium, such as VEGR3 (vascular endothelial growth factor receptor 3), podoplanin, lymphatic vessel endothelial HA receptor-1 (LYVE-1), Prox1 and D2-40 have been identified [7] and It has been demonstrated that podoplanin and D2-40 monoclonal antibody can be used as reliable lymphatic endothelial cell marker for distinguishing blood vessels from lymphatic vessels [8].

It is often difficult to state whether lymphangioma are true neoplasms, hamartomas or lymphangiectasias. In the first two forms it is a malformation that arises from sequestration of lymphatic tissue that fails to communicate normally with the lymphatic system and have some capacity to proliferation. Lesions designated as acquired lymphangiectasia may develop as a result of infection or surgery that interferes with regional lymphatic drainage [9].

Bilateral and symmetrical distribution of lesions in this case, in addition to lacks of infection or surgery (that may cause localized lymphatic obstruction) rule out the possibility of acquired lymphangiectasia. On the other hand confined growth potential and bilateral distribution suggests a hamartomatous nature and probably a developmental origin. This point of view is in agreement with hypothesis of previous researchers [3,4] but the time of onset (30 years old) seems to be a little high for developmental lesions.

Traditionally lymphangiomas were divided into three groups: simplex (capillary), cavernous and cystic [9]. Although Bill and Sumner [10] suggested that histological differences in various lymphangiomas are attributed to the differences in anatomic location and therefore that histologic classification is of little benefit [9,10]. In according to this concept some authorities classify the cutaneous lymphangioma into superficial and deep types [11]. From this point of view this lesion can be considered as superficial lymphangioma.

Finally it can be concluded that in rare instances bilateral symmetrical lymphangioma, confined to the superficial lamina properia of gingiva may become clinically apparent. It is not possible to definitely determine the origin of this lesion but due to its behavior and location it may have developmental origin.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

Pouria Motahhary and Babak Sarrafpour were participated in preparing the material and drafting the manuscript equally and Afshin Abdirad was involved in sequence alignment.

Acknowledgements

Authors would like to express their sincere thanks to Dr. Khoshkhoonejad for surgical procedure.

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Diagnostic Pathology