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.

Milroy disease with predominant preputial involvement.

Milroy disease is a form of congenital primary lymphedema that usually affects the lower limbs. Predominant genital lymphedema in Milroy disease is uncommon and disabling. When conservative management is ineffective, surgical treatment becomes necessary. Here, we present a rare case of congenital primary penile lymphedema in a 4-year-old child.

Dysfunction of dermal initial lymphatics of the arm and upper body quadrant causes congenital arm lymphedema.

OBJECTIVE: The objective of this study was to explore the pathologic process underlying primary lymphedema. METHODS: Twenty-seven patients with unilateral congenital arm lymphedema who visited our clinic from January 1, 2014, to May 30, 2019, were enrolled. The patients' clinical signs and the findings of indocyanine green (ICG) lymphography, skin tissue immunohistochemical staining, and whole exome sequencing of tissue and blood were evaluated. RESULTS: Among the 27 patients, 11 were diagnosed with stage II and 16 were diagnosed with stage III lymphedema. No lymphatic vessels were visualized in the affected arm in 25 of 27 (93%) patients who underwent ICG lymphography; likewise, no lymphatics were found in the territories of axillary lymph node drainage in the trunk, irrespective of any anomalies of the axillary lymph nodes. In only two (7%) patients, an unclear lymphatic trunk gradually appeared in the dorsum of the affected hand. The number of initial lymphatics was increased in the skin specimens of all nine patients in whom lymphatics were not demonstrated by ICG lymphography. Among 14 tested patients, we found compound heterozygote variants in the PIEZO1 gene in only one (7%) patient. Two missense variants, c.4072C>T; p.Arg1358Cys and c.5033C>T; p. Ala1678Val, were identified and found to have been inherited from the father and mother, respectively. No other pathogenic or likely pathogenic variants of currently known lymphedema-related genes were identified in the remaining 13 patients. No genetic difference was found between the lymphedematous and nonedematous healthy skin tissue of the same person. CONCLUSIONS: Segmental or regional dysfunction of the dermal initial lymphatics causes congenital arm lymphedema and may have implications for clinical treatment.

Congenital Lymphedema of the Foreskin in a 3-Year-Old Boy: A Case Report and Literature Review.

Congenital lymphedema of the external genitalia is a rare, disfiguring disorder. We describe here a case of a 3-year-old male with primary foreskin lymphedema persisting since birth. A compact, heterogenous swelling of the foreskin's distal third was observed, inhibiting preputial retraction (phimosis). Right lower extremity lymphedema was also observed in this case, while no further abnormalities were found. Surgery was performed, maintaining the foreskin, producing an excellent result with no recurrence at 10-month follow up.

Congenital Lymphatic Malformation and Aortic Aneurysm in a Patient with TSC2 Mutation.

We present a 7-year-old boy with tuberous sclerosis and congenital segmental lymphedema (CSL) of the left leg, as well as two aortic aneurysms. He was treated with everolimus (EVE) since the age of 14 months. His CSL regressed under treatment with EVE. His first aneurysms required operative intervention at age of 17 months. Four months afterward a new aortic aneurysm had been detected above the Dracon graft, but this one remained stable since that time. The patient didn't experience severe side effects. EVE has been well tolerated without disturbance of somatic growth or serious adverse effect.

Angiosarcoma arising from congenital primary lymphedema.

We herein report the case of a 3-year-old girl with atypical congenital right upper limb lymphedema who developed an angiosarcoma. Only a few cases have been reported following congenital form of lymphedema and only 4 in such a young child. We also summarize all cases of angiosarcoma associated with congenital lymphedema reported in the literature.

A novel mutation in the conserved sequence of vascular endothelial growth factor receptor 3 leads to primary lymphoedema.

Objective To investigate whether lymphoedema in a Chinese family showed the hereditary and clinical characteristics of Milroy disease, an autosomal dominant form of congenital lymphoedema, typically characterized by chronic lower limb tissue swelling due to abnormal lymphatic vasculature development, and to perform mutational analyses of vascular endothelial growth factor receptor ( VEGFR)3. Methods Individuals from a three-generation family affected by congenital lymphoedema were clinically assessed for Milroy disease. Mutation analysis of VEGFR3 was performed using DNA from family members and healthy controls. Results Out of 20 family members, eight were diagnosed with hereditary lymphoedema. Mutation analyses revealed a novel mutation site for c.3163 G>A, resulting in a p.1055D>N mutation in the second tyrosine kinase domain of VEGFR3, which was present in affected individuals only (absent in all unaffected family members and 130 healthy controls). Computed functional analyses showed the mutation may lead to structural alterations with a probability of 0.99999 of being disease causing. Conclusion A novel mutation associated with Milroy disease was identified in a Chinese family, expanding our knowledge of VEGFR3 gene function and providing a potential molecular target for treating hereditary lymphoedema.

[Lymphedema complicated with verrucous papillomatosis]. / Lymphœdème compliqué de papillomatose verruqueuse.

Limb lymphedemas are due to a malfunction of the lymphatic system responsible for lymph stasis in the interstitial tissue and secondarily to an increase in the volume of the affected limb. They are divided into primary lymphedema (PL) and secondary lymphedema (SL). SLs develop most frequently in lower limbs after breast cancer treatment while lymphedemas are either secondary (iatrogenic or infectious) or primitive, most often sporadic, sometimes familial or they can be part of syndromes resulting in malformations and/or more complex genetics in upper limbs. The diagnosis of lymphedema is essentially based on clinical examination. Erysipelas are the main complication of lymphedema. Other abnormalities are often visible: yellowish skin and nails, lymphangiectasias, keratotic papules with papillomatosis, lichenified plaques. The main differential diagnosis in patients with limb lymphedema is lipoedema, defined as body fat distribution from the hips up to the ankles and affecting almost exclusively obese women. We report the case of a 30 year old man with left lower limb lymphedema occurred at puberty complicated by verrucous papillomatosis. It is a late-revelation congenital lymphedema.

[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.

Vascularized lymph node transfer from thoracodorsal axis for congenital and post filarial lymphedema of the lower limb.

Vascularized lymph node transfer is becoming a popular method to treat lymphedema. We have performed vascularized lymph node transfer for two patients, one with congenital and the other with post filarial lymphedema of the lower limb. Lymph node transfer was performed from the thoracodorsal axis. Both cases exhibited improved results in both limb circumference and quality of life measurements. J. Surg. Oncol. 2017;115:78-83. © 2016 Wiley Periodicals, Inc.

An unusual case of Corynebacterium striatum endocarditis in a patient with congenital lymphedema and rheumatic heart disease.

Corynebacterium striatum (C. striatum) is a ubiquitous saprophyte with a potential to cause bacteremia. We report the first case of C. striatum endocarditis in a patient with congenital lymphedema and rheumatic heart disease.

Suction Assisted Protein Lipectomy (SAPL) Even for the Treatment of Chronic Fibrotic and Scarified Lower Extremity Lymphedema.

Chronic lymphedema results from the accumulation of adipose tissue and fibrotic solids and poses a significant challenge for the treating clinician. Despite its many challenges, chronic lymphedema can be safely and effectively treated using a minimally invasive technique known as suction assisted protein lipectomy (SAPL). We present the use of SAPL in a 65-year-old female with a history of chronic, congenital, non-compressible, solid predominant lymphedema for over 40 years. Her lymphedema was complicated by multiple episodes of severe cellulitis that often required hospitalization and treatment with intravenous antibiotics. The patient also had an excisional procedure designed to debulk the lymphedema swelling performed over 35 years prior by an outside provider. The procedure resulted in substantial scarring and fibrosis between the skin and underlying fascia over a significant area of the leg with only minimal improvement in symptoms. Following SAPL, a stable excess volume reduction of 86% was achieved along with a significant improvement in range of motion of the knee. Furthermore, the patient had no further episodes of recurrent cellulitis. We have found SAPL to be effective even in patients with complex, chronic lymphedema presentations with extensive preexisting scarring from prior surgery..

Congenital focal lymphedema as a diagnostic clue to tuberous sclerosis complex: report of two cases diagnosed by ultrasound.

Tuberous sclerosis complex (TSC) is a familial disorder characterized by benign hamartomas in the brain and other organs. Generally, the diagnosis of TSC is relatively easy, based on a medical history, a physical examination, and imaging findings. However, it can be difficult to consider a possibility of TSC in neonates and infants when congenital lymphedema is the sole external manifestation, because lymphedema associated with TSC is extremely rare. Herein, we report two cases of TSC showing congenital lymphedema at the initial presentation. Both patients were girls, and their sole complaint was congenital lymphedema. We diagnosed TSC using ultrasound focusing on the kidney, heart, and brain in addition to the extremity showing lymphedema. Awareness of a potential association of congenital lymphedema with TSC may assist in the diagnosis of TSC by ultrasound.

Generalized lymphedema associated with neurologic signs (GLANS) syndrome: a new entity?

BACKGROUND: Primary lymphedema in children, especially generalized disease with facial involvement, is rare. OBJECTIVE: We sought to report 3 childhood cases of lymphedema with associated neurologic findings and to provide a pathophysiologic explanation for this association. METHODS: Clinical observations, electroencephalography, and neuroimaging studies were evaluated. Microcomparative genomic hybridization was performed in 1 case. RESULTS: The 3 children had primary lymphedema of all 4 limbs and the face. This was confirmed by lymphoscintigraphy, which showed hypoplasia of vessels and hypofixation of lymph nodes. They had nonspecific neurologic disorders and electroencephalography abnormalities, without intellectual deficit. Neuroimaging revealed normal findings. Microcomparative genomic hybridization in 1 patient revealed no cytogenetic anomaly. The outcome was fatal in 1 case with development of visceral lymphedema and coma. LIMITATIONS: Genetic studies were performed in only 1 case. CONCLUSION: These observations suggest that neurologic assessment and electroencephalography are indicated for patients with lymphedema of the limbs and face to identify this syndrome.