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--- milroys_syndrome 2008/06/01 11:26
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 http://www.thefetus.net/page.php?id=1035
 ===== Kaposiform hemangioendothelioma associated with Milroy's disease (primary hereditary lymphedema) =====
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 http://www.jpedsurg.org/article/PIIS0022346803002136/abstract
+=====Milroy's Syndrome from Gene Review======
+Summary
+Disease characteristics. Milroy disease is characterized by lower-limb lymphedema, present at birth as pedal edema or developing soon after. Occasionally it develops later in life. The severity of edema shows both inter- and intrafamilial variability. Swelling is usually bilateral but can be asymmetric. The degree of edema can progress but in some instances can improve, particularly in early years. Other features sometimes associated with Milroy disease include hydrocele (37% of males), prominent veins (23%), upslanting toenails (14%), papillomatosis (10%), and urethral abnormalities in males (4%). Cellulitis, which can damage the lymphatic vessels, occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females.
+Diagnosis/testing. Milroy disease is diagnosed by clinical findings and confirmed by molecular genetic testing. Lymphoscintigraphy can be performed; the characteristic finding is lack of uptake of radioactive colloid in the ilioinguinal lymph nodes caused by a paucity of lymphatic vessels or abnormal function of the vessels in the lower limbs. Molecular genetic testing for FLT4 (VEGFR3), the only gene known to be associated with Milroy disease, is available on a clinical basis.
+Management. Treatment of manifestations: A lymphedema therapist may utilize fitted stockings and massage to improve the cosmetic appearance or decrease the size of the limb and reduce the risk of complications. Improvement in swelling is usually possible with use of properly fitted compression hosiery and/or bandaging. Prevention of secondary complications: Frequency of cellulitis can be reduced through good skin hygiene, prompt treatment of infections with antibiotics, and prophylactic antibiotics for recurrent episodes. Agents/circumstances to avoid: wounds to limbs; long periods of immobility with the legs in a dependent position; and medications that can cause increased leg swelling. Testing of relatives at risk: Evaluating relatives at risk ensures identification of those who will benefit from treatment early in the disease course.
+Genetic counseling. Milroy disease is inherited in an autosomal dominant manner. Each child of an individual with Milroy disease has a 50% chance of inheriting the mutation. The proportion of cases caused by de novo mutations is not known. Ultrasonography in the third trimester of pregnancy may detect swelling of the dorsum of the feet and more extensive edematous states in an affected fetus.
+Diagnosis
+Clinical Diagnosis
+The clinical diagnosis of Milroy disease is based on the presence of lower-limb swelling, present at birth or developing soon after, large-caliber veins, and upslanting, ‘ski-jump’ toenails. The swelling is usually but not always bilateral. In neonates the swelling predominantly affects the dorsum of the feet. With age the swelling may improve or progress to affect the whole lower leg.
+Lymphoscintigraphy. Radioactive colloid is injected into the toe web spaces and uptake in the ilioinguinal nodes is measured at intervals. Lymphoscintigraphy is performed to determine if there is lack of uptake of radioactive tracer. This can help with the diagnosis of Milroy disease as other forms of lymphedema can have differing patterns on lymphoscintigraphy. In cases of unilateral swelling, lymphoscintigraphy can determine if lymphatic drainage is impaired in the 'unaffected' leg.
+Note: (1) Lymphoscintigraphy normally replaces lymphangiography (x-ray after direct injection of dye into the lymphatic vessels in the foot) as it is less invasive. (2) Lymphangiography is also technically more problematic because of difficulties locating lymphatic vessels for cannulation.
+Molecular Genetic Testing
+GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
+Gene. FLT4 (VEGFR3) is the only gene known to be associated with Milroy disease [Ferrell et al 1998, Irrthum et al 2000, Karkkainen et al 2000a, Evans et al 2003].
+Other loci. No other loci have been identified, but reports suggest that Milroy disease is genetically heterogeneous [Holberg et al 2001, Evans et al 2003]. Even when the individual has a clear clinical diagnosis, an FLT4 mutation is found in only 75% of affected individuals, suggesting that other genes may be involved [Connell et al 2009].
+Clinical testing
+Sequence analysis. The mutation detection frequency using sequence analysis is currently unknown as limited data are available. Connell et al [2009] suggest that with rigorous phenotyping a detection rate of up to 75% can be expected in those clearly affected and with a positive family history. If those with typical Milroy features but without a family history are included the mutation pick-up rate is around 68%.
+Testing Strategy
+Confirming/establishing the diagnosis in a proband
+Rigorous clinical phenotyping is essential.
+Lymphoscintigraphy is not essential to make the diagnosis and one can proceed directly to molecular testing.
+A family history makes it more likely that an FLT4 mutation will be found. In those with congenital lower-limb lymphedema but no family history, the pick-up rate is around 68% [Connell et al 2009].
+Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.
+Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
+Genetically Related (Allelic) Disorders
+No other phenotypes are known to be associated with mutations in FLT4.
+Clinical Description
+Natural History
+The most common finding in Milroy disease is lower-limb lymphedema. The edema is usually present from birth. In neonates the swelling tends to affect primarily the dorsum of the feet. Anecdotal evidence suggests that on rare occasions it develops later in life.
+The amount of edema varies both within and among families. Swelling is often bilateral, yet asymmetric.
+The degree of edema sometimes progresses but in some instances can improve, particularly in early years.
+Other features sometimes associated with Milroy disease include:
+Hydrocele (37% of males)
+Prominent veins (23%)
+Upslanting toenails (14%)
+Papillomatosis (10%)
+Urethral abnormalities in males (4%)
+Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [Brice et al 2005]. Cellulitis can damage the existing lymphatic vessels, resulting in an increase in the degree of swelling.
+Prenatal pleural effusion and chylous ascites have been reported rarely [Daniel-Spiegel et al 2005], but in general Milroy disease is not associated with more widespread lymphatic abnormalities.
+Genotype-Phenotype Correlations
+No genotype-phenotype correlation has been reported.
+Intra- and interfamilial variation in the phenotype is wide.
+Natural History
+The most common finding in Milroy disease is lower-limb lymphedema. The edema is usually present from birth. In neonates the swelling tends to affect primarily the dorsum of the feet. Anecdotal evidence suggests that on rare occasions it develops later in life.
+The amount of edema varies both within and among families. Swelling is often bilateral, yet asymmetric.
+The degree of edema sometimes progresses but in some instances can improve, particularly in early years.
+Other features sometimes associated with Milroy disease include:
+Hydrocele (37% of males)
+Prominent veins (23%)
+Upslanting toenails (14%)
+Papillomatosis (10%)
+Urethral abnormalities in males (4%)
+Cellulitis occurs in approximately 20% of affected individuals, with infection significantly more likely in males than females [Brice et al 2005]. Cellulitis can damage the existing lymphatic vessels, resulting in an increase in the degree of swelling.
+Prenatal pleural effusion and chylous ascites have been reported rarely [Daniel-Spiegel et al 2005], but in general Milroy disease is not associated with more widespread lymphatic abnormalities.
+Genotype-Phenotype Correlations
+No genotype-phenotype correlation has been reported.
+Intra- and interfamilial variation in the phenotype is wide.
+Milroy disease is suspected in individuals with 'woody' swelling of the dorsum of the feet with few associated features. Family history, if present, is consistent with autosomal dominant inheritance.
+[[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=milroy|Gene Review]] - complete article
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 Updated September 13, 2007