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The lymphatic anomalies in primary lymphedema can be morphological or functional or a combination of both. Lymphedema can occur at any level of the lymphatic system. The morphological changes of the lymphatic system in primary lymphedema can be clearly demonstrated with magnetic resonance lymphangiography (MRL) and are classified into three major subtypes. Dysfunction of lymph collectors, including valve deficiency and transporting delay, can be demonstrated by indocyanine green lymphography (ICG) in patients with lymphedema distichiasis syndrome (LDS) and Milroy’s disease.

Introdução:O linfedema primário consiste num edema crónico dos tecidos, mais comumente presente nos membros inferiores. Caso:Lactente de um mês do sexo masculino, previamente saudável, observado por edema firme da perna e pé esquerdos e hidrocelo bilateral recente. Sem sinal de godet, outros sinais inflamatórios ou limitação articular. Apresentava sobreposição dos dedos e alterações tróficas das unhas dos pés. Aos cinco meses surge edema semelhante no pé direito. Bisavó com edema bilateral dos membros inferiores desde a infância. Apresentação consistente com Doença de Milroy. Posteriormente, necessidade de internamentos por celulite. Eco-doppler dos membros inferiores sem alterações vasculares. Estudo do gene FLT4 negativo. Iniciada drenagem linfática com franca melhoria. Atualmente, clinicamente estável. Comentários/Discussão: Doença rara, caracterizada por anaplasia/hipoplasia dos vasos linfáticos e edema dos membros inferiores, geralmente bilateral, podendo cursar com hidrocelo, celulite recorrente e alterações nas unhas. Transmissão autossómica dominante, mas mutação encontrada em apenas 70% dos indivíduos afetados.vv, NASCER E CRESCER - BIRTH AND GROWTH MEDICAL JOURNAL, Vol 26, No 1 (2017)

We present a case of congenital lymphedema in a 7-year-old boy in Sierra Leone with active filarial infection and penile edema. The genital edema with onset at 6 months of age may have been due to a congenital abnormality in lymphatic drainage. Other possible causes of childhood lymphedema, including Milroy's disease, are discussed.

Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and "idiopathic" hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of hereditary lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary lymphedema, with sometimes antenatal features. Hereditary lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.

Milroy's disease is a hereditary congenital lymphedema caused by lymphatic obstruction. The legs are most commonly affected, but impaired intestinal lymphatic flow can cause loose bowel movements. Here, we report the use of the Kampo extract of shinbuto for successful treatment of and abdominal pain in a patient with Milroy's disease. Milroy's disease was diagnosed because of left leg lymphedema with onset at birth. Conservative therapy with a compression bandage was applied. However, when the patient moved to Manila at 35 years of age, she was exposed to drastic temperature changes between the air-conditioned cold environment in her room and the hot and humid environment outside. She developed a constitutional state of coldness as in hiesho. Then sudden lower abdominal pain and diarrhea began to occur 3 times per week and lasted at least 1 hour, sometimes accompanied by vomiting. It happened particularly when she was exposed to the cold environment and was not related to meals. Conventional anti-cholinergic or antidiarrhetic drugs had no therapeutic effect. These attacks continued in the same frequency for 3 years, so the patient visited a Kampo (traditional Japanese medicine) clinic, where her diagnosis of Milroy's disease-associated diarrhea and abdominal pain was augmented by the Kampo diagnosis of hiesho, suitai (body fluid retention). She was prescribed 7.5 g of shinbuto extract per day (TJ-30; Tsumura Co, Tokyo, Japan). The shinbuto extract significantly reduced abdominal pain and refractory diarrhea to about 2 days per month, and it tapered of completely in 3 months. Shinbuto is usually used against cold-induced diarrhea. Rewarming and water movement by shinbuto resulted in significant improvement in symptoms induced by hiesho and suitai triggered by the cold environment, though the patient's leg swelling did not change.

We highlight a case of Milroy’s disease in a 28-year-old man. He originally presented with fleshy, exophytic coliform lesions that carpeted his scrotum and penile shaft (figure 1). His prior treatments included laser therapy and electrocautery, but the lesions recurred. Ultimately, he underwent a complex scrotal and phalloplasty, excision of coliform lesions and split thickness skin grafting. Postoperative findings are demonstrated in figure 2. Gross pathology revealed yellow-pink friable coliform excrescences (figure 3). H&E stained microscopic sections showed papillary outgrowths of dermis with overlying epidermal hyperplasia and hyperkeratosis. The deeper dermis was oedematous and fibrotic with a dense chronic inflammatory infiltrate and lymphangiectasia (figures 4⇓⇓–7). The histological findings were consistent with chronic lymphatic obstruction. Figure 1 Presentation of diffuse coliform lesions …

Genetic studies of inherited lymphedema have provided the starting point for the molecular dissection of lymphatic development and disease. Here, we update the recent contribution of the study of inherited lymphedema and discuss the parallels between mouse models of lymphedema and inherited lymphedema. That the known mutations leading to lymphatic phenotypes explain fewer than half the cases of lymphedema means that the continued study of these disorders may reveal new pathways in lymphatic biology.

Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with hereditary lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele. In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of hereditary lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of lymphedema in their children. Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for hereditary lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.

Hereditary lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known "classic" phenotype of HL-I.

Milroy's primary congenital lymphedema (PCL) (hereditary lymphedema type I, Milroy disease) is present at birth, and mostly affects the dorsal aspects of feet. It is mostly a life-long condition but does not affect longevity. Complications are rare except for chronic discomfort and warmness of affected areas. PCL is an autosomal dominant disease with incomplete penetrance due to a mutation in the gene locus encoding for VEGFR3 with resultant dysgenesis of microlymphatic vessels. We report on two fetuses where ultrasonographic examination at 15 weeks of gestation showed significant edema of the dorsal aspects of both feet with no evidence of other major malformations. Whereas in one fetus the edema resolved completely, it persisted in the second fetus and proved after birth to be of lymphedematous nature. To the best of our knowledge, this is the first report of early prenatal diagnosis of primary congenital lymphedema via fetal ultrasonographic examination and of spontaneous resolution of lymphedema during fetal life.

Hereditary lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with hereditary lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital hereditary lymphedema linked to 5q34-q35.

An 8-year-old girl referred to our Department for a two-month worsening of congenital primary lymphedema of the lower limb and for the appearance of several purpuric lesions on the right thigh and knee. We diagnosed a lichenoid pigmented purpura of Gougerot and Blum in a patient with Milroy disease, complicated by an insufficiency of anterior saphena. We treated the patient with topical steroids and compression stockings, until surgical intervention of phlebectomy. We report this case for the rarity of the disease, for the even more rare association with lichenoid pigmented purpura and for cutaneous immunopathological findings.

The authors describe the case of a newborn and their family with Nonne-Milroy disease (hereditary lymphedema type I), a genetic disease that is usually characterized by lymphedema, that most often affects the lower extremities or less frequently the back of the hands. We discuss etiology, inheritance pattern, differential diagnosis and follow-up.

In cases of congenital lymphoedema the finding of ulceration, violaceous nodules or papules, or apparent traumatic ecchymoses 1 should act as a diagnostic beacon warning of dangers. A case is reported of a high-grade angiosarcoma developing in a patient with congenital hereditary lymphoedema (Milroy's disease). This is the second paper to report this complication, the third case report and the first case in which the diagnosis is substantiated by immunohistochemistry and lectin histochemistry. A review of cases of angiosarcoma complicating congenital hereditary and non-hereditary lymphoedema is also presented

Lymphoedema in children is rare and poorly recognized. Children with lymphoedema have great difficulty accessing appropriate services and treatment. The long term global consequences of living with this incurable condition are under-estimated. This article outlines the causes, effects and treatment of lymphoedema in children. Recommendations are made that all children with lymphoedema should be referred to a lymphoedema specialist as soon as swelling develops.

The phenotypic entities of primary lymphedema vary in age of onset, site of edema, associated features, inheritance patterns, and underlying genetic cause. Determining the representative phenotype for different types of genetically determined primary lymphedema has been successfully achieved with Milroy's disease and the lymphedema-distichiasis syndrome. Here we describe and illustrate their well-delineated phenotypes. Phenotype characterization facilitates the identification of causative genes, as has been demonstrated with VEGFR3 and FOXC2, in Milroy's disease and lymphedema-distichiasis respectively. Other forms of primary lymphedema are discussed.

Hereditary lymphedema type I (Milroy disease) is a rare autosomal dominant disease resulting from mutations of FLT4 encoding the vascular endothelial growth factor receptor-3. Patients develop edema of the legs and feet, resulting in chronic swelling of the lower extremities from the neonatal period. Here we report a Japanese family with 10 affected members of five generations of hereditary lymphedema type I. We identified a previously reported missense mutation of G857R in one allele of FLT4 from three affected individuals of three generations, the mother of whom presented only hemi-lymphedema of the left foot. Thus, the clinical features of hereditary lymphedema type I caused by a FLT4 mutation are heterogeneous and it would be appropriate to consider FLT4 mutations even in a patient with hemi-lymphedema of the foot.

A pedal complication of Milroy's disease has been presented. With a history of multiple debridement procedures as in this case, there is the risk of recurrent infections and the possibility of permanent vascular compromise, particularly with respect to the thin pedal skin on the dorsal aspect. When the toes are recurrently involved with infection, a patient may be best served with a transmetatarsal amputation using a skin flap on the plantar aspect.

Kaposiform infantile hemangioendothelioma (KHE) is a rare recently characterized, locally aggressive, endothelial-derived neoplasm that occurs exclusively in the pediatric age group. Milroy-Nonne disease (primary hereditary lymphedema) is an uncommon congenital entity with familiar history of lower limb edema as typical clinical features. An 8-year-old boy developed a hard painless mass in the right leg 7 years after the diagnosis of congenital primary lymphedema of the right lower extremity. Histopathological analysis of the tumor showed the typical findings of the KHE. To our knowledge this is the first reported case of a KHE engrafting on this infrequent benign lymphatic anomaly.

The term lymphangioma circumscriptum (LC) was first used by Morris in 1889. It is a benign disorder of lymphatic channels which is localized to an area of skin, subcutaneous tissue or sometimes muscle. It is considered to be a circumscribed developmental defect of lymphatic tissue in the dermis. In Milroy’s disease (MD), there is primary lymphoedema due to the total absence of skin lymphatics and it is characterized by peripheral œdema of the lower extremities at birth or in early childhood. The occurrence of LC and MD was thought to be interesting and is presented here.

Milroy hastalığı başlıca klinik özelliği alt ekstremitelerin bir veya ikisinde kronik lenfödem olan nadir bir durumdur. Yeni doğan döneminde tanı koyduğumuz ve 12 ay izlediğimiz bir Milroy hastalığı olgusu sunuldu ve kaynaklar taranarak tartışıldı. Milroy's disease is rare condition with the principal clinical manifestation of chronic lymphedema of one or both lower extremities. We describe a neonatal infant and he followed for a 12 month. This case with Milroy's disease was presented and discussed.

A rare hereditary primary lymphoedema (Milroy′s disease) affecting three generations of a family involving males only, starting at the age of 15 years is reported.

Milroy’s disease is an old term used to describe hereditary congenital lymphedema. It is the rarest of the inheritedlymphedema. The cause is a mutation in the VEGFR3 gene and is inherited in an autosomal dominant manner. Thisgene has been mapped to the telomeric part of the chromosome 5q in the region 5q34-q35. It is characterized bylower limb lymphedema, present at birth or developing soon after. It may be associated with intestinal lymphangiectasiaand cholestasis. Here we report a 57 years old male who had been suffering from bilateral leg swelling since birth andfinally leveled as a case of Milroy’s disease by positive family history and excluding other causes of lymphedema. Wepresent this case due to the rarity of its occurrence.Keywords: Milroy’s Disease; LymphedemaDOI: 10.3329/jom.v11i2.5471J MEDICINE 2010; 11 : 189-192

Summary Two cases of Milroy's disease have been reported and short review of the literature has been written, analyzing and describing the condition. The small number of cases reported in the literature and the lack of a satisfactory theory of the etiology and the absence of an effective treatment justify the publication of all available material. The laboratory reports of our cases, all being within normal limits, substantiate the fact, that this is not a constitutional disorder. The histologic examination of the foreskin of our patient (Case 1), proves the presence of definite tissue changes, ruling out the mere stasis of the lymphatic fluid or blood.

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