Surgical treatment of Milroy disease.

BACKGROUND AND OBJECTIVES: Milroy disease is a form of congenital primary lymphedema affecting the lower limbs. When conservative management is ineffective, surgical treatment becomes necessary. The purpose of this study was to investigate the efficacy of vascularized lymph node transfer (VLNT) associated with extensive therapeutic lipectomy in the treatment of these patients. METHODS: In China Medical University Hospital, four patients have been diagnosed with Milroy disease and treated over an 8 year-period time. All patients presented with hereditary bilateral legs swelling since birth. All patients were treated with VLNT from the gastroepiploic region bilaterally associated with extensive therapeutic lipectomy. RESULTS: All procedures have been executed bilaterally and have been successful, without complications. The average follow-up of the patients was 20.2 ± 2.8 months. The limbs treated presented an average circumference reduction of a 4.0 ± 2.1 cm and patients did not experience cellulitis during follow-up. Patients expressed satisfaction with the procedure. CONCLUSIONS: VLNT together with therapeutic lipectomy proved to be a reliable technique in moderate cases of Milroy disease, providing an alternative path for lymph drainage, and reducing the lymph load and the excess of subcutaneous adipose tissues, thus improving patients' quality of life.

Atypical retiform hemangioendothelioma arising in a patient with Milroy disease: a case report and review of the literature.

Retiform hemangioendothelioma (RH) is a rare vascular neoplasm with a high rate of local recurrence and low metastatic potential. We describe an unusual case of RH in a 45-year-old patient with Milroy disease, with a prominent solid component diffusely involving a chronic lymphedematous leg. This case is consistent with the postulated relationship between lymphedema and vascular neoplasms developing as a result of local immune dysfunction, and highlights the need to closely monitor patients with Milroy disease for pathologic changes. Our case highlights a unique example of RH with atypical features. There are several noteworthy unusual clinical and histologic findings including diffuse involvement of an entire limb, solid component with cytologic atypia, D2-40 expression, and first-time-reported association with Milroy disease. Given the atypical histologic presentation of cytologic atypia, solid areas and atypical immunohistochemical profile with D2-40 positivity, this case could cause diagnostic difficulty, especially in the setting of such a broad clinical differential.

Two novel variations p.(Ser1275Thr) and p.(Ser1275Arg) in FLT4 causing prenatal hereditary lymphedema type 1.

BACKGROUND: Hereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. CASES: In our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. CONCLUSION: Cystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.

Compound heterozygosity for a variably penetrant variant and a variant of unknown significance in FLT4 causes fully penetrant Milroy's lymphedema.

Milroy disease, known as primary congenital lymphedema, is characterized by chronic tissue swelling due to impaired lymphatic drainage and is inherited in an autosomal dominant manner. This study reports a rare case of Milroy disease affecting siblings from unaffected parents. A one-month-old female infant presented with swelling of the bilateral calf and the dorsum of the feet which had been present since birth. Her 14-month-old brother had a similar presentation since birth with swelling of the bilateral calf and the dorsum of the feet. Milroy disease was diagnosed based on the clinical findings of bilateral lower limb swelling and confirmed by molecular genetic testing. The patient and her family, including her brother, parents, and maternal grandfather, were genetically tested, and two novel missense mutations (NM_182925.4: c.2534T>C; p.Leu845Pro, c.4006G>A; p.Glu1336Lys) were found in the Fms-related tyrosine kinase (FLT4) gene. Mutations segregated by the parents who carried each mutation in the heterozygous state were identified in the patient and her brother. The present case report in which Milroy disease developed in all offspring of parents with a normal phenotype suggests the possibility of a compound heterozygous mutation or non-penetrance during the process of inheritance of Milroy disease.

Recurrent Left-Sided Pleural Effusions in a Patient With Chronic Lymphedema.

Chronic lymphedema can lead to several long-term complications. The causes of lymphedema can be primary, due to a genetic source, or secondary to procedures, trauma, or other conditions. Primary hereditary lymphedema, as in the case of Milroy's disease, is rare. Because of the condition's rarity, case reports mostly involve presentations to monitor for. Here we document a case of Milroy's disease in a 70-year-old woman with recurrent left lung effusions.

A family with Milroy disease caused by the FLT4/VEGFR3 gene variant c.2774 T > A.

BACKGROUND: Milroy disease (MD) is a rare, autosomal-dominant disorder. Variants in the Fms-related tyrosine kinase 4 (FLT4/VEGFR3) gene cause the symptoms of this disease. In this report, we investigated the variant in a large Chinese family with MD. METHODS: We conducted Sanger sequencing of exons 17-26 of FLT4/VEGFR3 (NM_182925.4). We assessed its pathogenicity based on the ACMG criteria and predicted it with an in silico program. RESULTS: A heterozygous substitution (NM_182925.4 (FLT4/VEGFR3):c.2774 T>A, p. (Val925Glu)) was detected in all patients with MD but not in any healthy controls. The variant was evaluated as pathogenic according to the ACMG criteria and was predicted to be pathogenic using an in silico program. CONCLUSIONS: In this report, we described a large family with MD caused by a missense variant in FLT4/VEGFR3 (NM_182925.4 (FLT4/VEGFR3_v001):c.2774 T>A, p. (Val925Glu)). There are phenotypic heterogeneities among family members, and further research should be conducted to explore the possible reasons.

FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease.

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

Investigation on the role of biallelic variants in VEGF-C found in a patient affected by Milroy-like lymphedema.

BACKGROUND: Milroy-like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing for FLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF-C variations found in a female proband born with congenital edema consistent with Milroy-like disease. METHODS: The proband underwent next-generation sequencing-based genetic testing for a panel of genes associated with known forms of hereditary lymphedema. Segregation analysis was performed on family members by direct sequencing. In vitro studies were performed to evaluate the role of a novel identified variant. RESULTS: Two VEGF-C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148-3_148-2delCA, of paternal and maternal origin, respectively. Functional characterization of the p.(Ser65Arg) variation in vitro showed alterations in VEGF-C processing. CONCLUSIONS: Our findings reveal an interesting case in which biallelic variants in VEGF-C are found in a patient with Milroy-like lymphedema. These data expand our understanding of the etiology of congenital Milroy-like lymphedema.

Lymphoscintigraphic Abnormalities Associated with Milroy Disease and Lymphedema-Distichiasis Syndrome.

Background: Primary lymphedema is genetically heterogeneous. Two of the most common forms of primary lymphedema are Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS). This study aims to look further into the pathogenesis of the two conditions by analyzing the lymphoscintigram images from affected individuals to ascertain if it is a useful diagnostic tool. Methods and Results: The lymphoscintigrams of patients with MD and LDS were analyzed, comparing the images and transport parameters of the two genotypes against a control population. Lymphoscintigrams were available for 12 MD and 16 LDS patients (all genetically proven diagnoses). Eight of the 12 (67%) lymph scans performed on patients with MD demonstrated little or no uptake from the initial lymphatics and poor visualization of the inguinal lymph nodes. These changes were consistent with a "functional aplasia," that is, the lymphatic vessels were present but appeared to be ineffective in absorbing the interstitial fluid into the lymphatic system. In patients with LDS the lymphoscintigraphic appearances were different. In 12 of the 16 scans (75%), the lymph scans were highly suggestive of lymphatic collector reflux. Quantification revealed a significantly reduced uptake of tracer within the inguinal lymph nodes and a higher residual activity in the feet at 2 hours in MD compared with LDS and compared with controls. Conclusion: Lymphoscintigraphic imaging and quantification can be characteristic in specific genetic forms of primary lymphedema and may be useful as an additional tool for in-depth phenotyping, leading to a more accurate diagnosis and providing insight into the underlying mechanism of disease.

Immunohistochemical Evaluation of Histological Change in a Chinese Milroy Disease Family With Venous and Skin Abnormities.

Background: Milroy disease (MD) is rare and autosomal dominant resulting from mutations of the vascular endothelial growth factor receptor-3 (VEGFR-3 or FLT4), which leads to dysgenesis of the lymphatic system. Methods: Here we report a Chinese MD family with 2 affected members of two generations. We identified the mutation of c.3075G>A in one allele of FLT4 in Chinese population firstly. The father and child presented lymphedema under knees both. Unfortunately, the child was premature delivered for a car accident of the mother and then died of asphyxia. Then we gathered the tissue of the lower-limb from the child with permission from the parents and ethic committee. We stained the tissue with lymphatic marker D2-40 and hematoxylin-eosin to explore the histological changes. Afterwards, we compared the results with a normal child who unfortunately died of premature delivery also. Results: It is firstly identified the mutation of FLT4: c.3075G>A in Chinese population, and the mutation Inherited in the lineage. The histological evaluation indicated: (1) The number of lymphatic vessels decreased; (2) The morphology and structure of lymphatic vessels was abnormal. And what is added to our knowledge: (1) Capillary hyperemia and phlebectasia is severe; (2) Vascular malformations; (3) The number of vascular endothelial cells and vascular smooth muscle cells decreased; (4) Large sheets of epidermis desquamated; (5) The numbers of cutaneous appendages reduced in MD. Conclusions: Based on the new findings, we assume that mutation of FLT4 not only affect the lymphogenesis, but also the angiogenesis, and epidermis structure.

[Primary congenital lymphedema: Milroy disease: the first case observed in the Department of Pediatrics at the University Hospital Yalgado Ouedraogo, Ouagadougou]. / Le lymphœdème congénital primaire: la maladie de Milroy: à propos du premier cas observé dans le Département de Pédiatrie du Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou.

Congenital lymphedema is the accumulation of lymphatic fluid in the child's interstitial spaces. Milroy disease is a rare, hereditary, autosomal dominant condition showing incomplete penetrance. We report the case of a 7-year old little girl with Milroy disease examined for erysipelas on congenital big right leg. A family history of large congenital member existed. Physical examination showed big oedematous right leg painful to palpation, with skin lichenification and erysipelas. Paraclinical assessment objectified cutaneous lymphedema with vascular involvement suggestive of ectasia of the right saphenous vein. Female karyotype showed no abnormalities, despite the small chromosomal rearrangements. Treatment was based on physiotherapy, bandages, compression stockings and psychotherapy. This first case in Burkina Faso testifies to the rarity of the pathology but especially to the diagnostic difficulties related to the inadequacy of paraclinical investigations.

Linfedema congénito primario bilateral. Reporte de caso / Bilateral primary congenital lymphedema. Case report

RESUMEN Fundamento: El linfedema congénito primario es una condición rara con un componente genético importante que se caracteriza por edema crónico de la zona afectada. Objetivo: Presentar un linfedema congénito primario bilateral y discutir su origen. Presentación de caso: Se presentó un caso de linfedema congénito primario bilateral en un niño de 2 años de edad, sin antecedentes patológicos familiares de la enfermedad. Se discutieron sus posibles causas genéticas ya que existen varias mutaciones que explican su origen. Aunque no se pudieron realizar estudios genéticos para conocer la etiología exacta, existen evidencias clínicas de que no se trata de una enfermedad de Milroy, a menos que se presente como una mutación de novo. Se le realizó al paciente un seguimiento desde su diagnóstico hasta la actualidad. Conclusiones: Existen múltiples mutaciones genéticas que explican el origen de un linfedema congénito primario, por lo que no necesariamente debe tratarse de enfermedad de Milroy cuando este se presente. Se destacó como elemento importante que en este caso no se evidenciaron antecedentes familiares. Se empleó el tratamiento conservador como conducta fundamental a seguir, se evidenció en el paciente una notable mejoría clínica.

ABSTRACT Background: Primary congenital lymphedema is a rare condition with an important genetic component characterized by chronic edema of the affected area. Objective: To present a bilateral primary congenital lymphedema and discuss its origin. Case report: A case of bilateral primary congenital lymphedema was presented in a 2-year-old boy with no any family background of the disease. Its possible genetic causes were discussed since there are several mutations that explain its origin. Although genetic studies could not be performed to know the exact etiology, there is clinical evidence that it is not a Milroy's disease, unless it presents as a de novo mutation. The patient was followed up from diagnosis to the present. Conclusions: There are multiple genetic mutations that explain the origin of a primary congenital lymphedema, so it should not necessarily be Milroy's disease when present. A highlighted and important element was that in this case no any family background was evidenced. Conservative treatment was used as the essential conduct to follow up, a remarkable clinical progress was evidenced in the patient.

Antenatal presentation of hereditary lymphedema type I.

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.

Lymphedema in a 7-year-old boy infected with Wuchereria bancrofti in Sierra Leone: a case report.

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.

Kampo Extract of Shinbuto Improved Refractory Diarrhea in Milroy's Disease.

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 lymph-edema 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 (え). 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 off 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.

La enfermedad de Milroy es un linfoedema congénito hereditario causado por la obstrucción linfática. Suele afectar a las piernas, pero los trastornos del flujo linfático intestinal pueden producir defecaciones blandas. En este texto notificamos el uso del extracto Kampo de Shimbuto (Zhen-Wu-Tang) para el éxito del tratamiento del dolor abdominal en una paciente con enfermedad de Milroy. Esta enfermedad se diagnosticó a causa del linfoedema de la pierna izquierda que había comenzado en el momento del nacimiento. Se aplicó un tratamiento conservador con un vendaje de compresión. Sin embargo, cuando la paciente se trasladó a Manila a los 35 años de edad, se vio expuesta a drásticos cambios de temperatura entre el entorno con aire acondicionado frío de su habitación y el ambiente cálido y húmedo del exterior. Comenzó a sufrir un estado constitucional de frialdad como en el trastorno conocido como hiesho «å†·ãˆç—‡¼. Posteriormente, comenzó a sufrir un dolor en la parte inferior del abdomen y diarrea tres veces por semana que duraban al menos 1 hora, en ocasiones acompañados de vómitos. Esto ocurría especialmente cuando se veía expuesta al entorno frío y no se relacionaba con las comidas. Los fármacos anticolinérgicos o antidiarréicos tradicionales no produjeron efecto terapéutico alguno. Estos ataques continuaron con la misma frecuencia durante 3 años, por lo que la paciente visitó una clínica Kampo (medicina tradicional japonesa) donde se aumentó su diagnóstico de diarrea y dolor abdominal relacionados con la enfermedad de Milroy con el diagnóstico Kampo de hiesho y suitai (retención de líquidos corporales). Se le recetaron 7,5 g de extracto de Shimbu-to al día (TJ-30; Tsumura Co, Tokio, Japón), con lo que se redujo de forma significativa el dolor abdominal y la diarrea resistente al tratamiento a unos 2 días al mes, para terminar desapareciendo gradualmente por completo en 3 meses. El extracto Shimbu-to suele usarse contra la diarrea provocada por el frío. El nuevo calentamiento y el movimiento del agua por parte del extracto Shimbu-to obtuvieron mejoras significativas en los síntomas provocados por hiesho y suitai desencadenados por el entorno frío, aunque la hinchazón de la pierna no ha cambiado.