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Milroy Disease

Hereditary Lymphedema, Type I; Milroy Congenital Lymphedema

, RGN BSc (Hons), , FRCP, , PhD, , MBChB, MRCPCH, MD, , PhD, and , MD, FRCP.

Author Information
, RGN BSc (Hons)
SW Thames Regional Genetics Department
St George's, University of London
London, United Kingdom
, FRCP
Consultant Geneticist, SW Thames Regional Genetics Department
St George's, University of London
, PhD
Medical Genetics Unit, Clinical Developmental Sciences
St George's, University of London
London, United Kingdom
, MBChB, MRCPCH, MD
SW Thames Regional Genetics Department
St George's, University of London
London, United Kingdom
, PhD
Medical Genetics Unit, Clinical Developmental Sciences
St George's, University of London
London, United Kingdom
, MD, FRCP
Department of Cardiac and Vascular Sciences (Dermatology)
St George's, University of London
London, United Kingdom

Initial Posting: ; Last Update: July 23, 2009.

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. FLT4 (VEGFR3) is the only gene known to be associated with Milroy disease.

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.

Evaluation 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. Prenatal testing is possible for pregnancies at increased risk if the disease-causing mutation in the family is known; however, it is rarely requested.

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

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].

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%.

Table 1. Summary of Molecular Genetic Testing Used in Milroy Disease

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method
FLT4Sequence analysis Sequence variants 3Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

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.

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.

Penetrance

Approximately 85%-90% of individuals who have a mutation in FLT4 develop lower-limb lymphedema by age three years; conversely, 10%-15% of individuals with an FLT4 mutation are clinically unaffected.

Anticipation

Anticipation has not been observed.

Nomenclature

Milroy disease is named after William Milroy, who described 97 members of a family, of whom 26 had leg edema [Milroy 1892]. In the family described by Milroy, the edema was painless, non-progressive, and confined to the lower limbs.

Hereditary lymphedema of the legs was also described by Nonne [1891]; hence, the term Nonne-Milroy disease has been used in the past.

Prevalence

The prevalence of Milroy disease is not known but it appears to be one of the more common causes of primary lymphedema.

Differential Diagnosis

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.

Disorders in the differential diagnosis

Congenital lymphedema secondary to a congenital abnormality of the lymphatic system is not always caused by Milroy disease or mutations in FLT4.

Lymphedema-distichiasis syndrome is characterized by lower-limb lymphedema and distichiasis. Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis. Distichiasis, which may be present at birth and is observed in 94% of affected individuals, describes the presence of aberrant eyelashes arising from the Meibomian glands ranging from a full set of extra eyelashes to a single hair. About 75% of affected individuals have ocular findings resulting from the aberrant eyelases including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include early-onset varicose veins (50%), congenital heart disease (8%), and ptosis (30%). About 25% of individuals are asymptomatic. FOXC2 is the only gene known to be associated with lymphedema-distichiasis syndrome. Inheritance is autosomal dominant.

Meige disease presents with pubertal-onset lymphedema. No other features appear to be associated. Women are more commonly affected than men. No genes have been identified as yet. Inheritance appears to be autosomal dominant with reduced penetrance.

Hypotrichosis-lymphedema-telangiectasia syndrome is the association of childhood-onset lymphedema in the lower limbs, loss of hair, and telangiectasia, particularly on the palms. Inheritance is either autosomal dominant or autosomal recessive. Mutations in SOX18 are causative [Irrthum et al 2003].

Turner syndrome is the combination of a characteristic phenotype in females who have one normal X chromosome and either (1) absence of the second sex chromosome (X or Y) with or without mosaicism or (2) partial deletion of the X chromosome. The Turner syndrome phenotype includes short stature, stature disproportion, primary amenorrhea, neck webbing, congenital lymphedema of the hands and feet, high-arched palate, short metacarpals, scoliosis, Madelung deformity, hearing difficulties, cardiac and renal anomalies, hypothyroidism, and glucose intolerance [Batch 2002, Sybert & McCauley 2004]. Lymphedema in this syndrome affects the extremities and often improves over time. Turner syndrome occurs in 1:2500 to 1:3000 live female births [Sybert & McCauley 2004] and should always be considered in a female with congenital lymphedema.

Noonan syndrome is characterized by short stature; congenital heart defect; broad or webbed neck; unusual chest shape with superior pectus carinatum, inferior pectus excavatum, and apparently low-set nipples; developmental delay of variable degree; cryptorchidism; and characteristic facies. Varied coagulation defects and lymphatic dysplasias are observed with onset at birth or in childhood. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or appear in infancy or childhood. Mutations in PTPN11 are observed in 50% of affected individuals, SOS1 in approximately 13%, RAF1 in 3%-17%, and KRAS in fewer than 5% [Tidyman & Rauen 2008]. Inheritance is autosomal dominant.

Lymphedema with yellow nails (yellow nail syndrome, YNS) often presents after age 50 years. The nails in YNS are very slow growing, with transverse over-curvature and hardening of the nail plate. The nail changes are different from the typically discolored nails that are often associated with chronic lymphedema of any cause. Inheritance is said to be autosomal dominant; however, most cases are not associated with a family history [Hoque et al 2007, Maldonado et al 2008].

Management

Treatment of Manifestations

Referral should be made to a lymphedema therapist regarding management of edema (e.g., fitting stockings, massage). Although the edema cannot be cured, some improvement is usually possible with the use of properly fitted compression hosiery and/or bandaging. These treatments may improve the cosmetic appearance of the limb, decrease the size of the limb, and reduce the risk of complications.

Prevention of Secondary Complications

Secondary cellulitis is prevented through the following measures:

  • Prevention of foot infections, particularly athlete's foot/infected eczema
  • Prompt treatment for early cellulitis with appropriate antibiotics. It may be necessary to give the first few doses intravenously.
  • Prophylactic antibiotics in recurrent cases (e.g., penicillin V 500 mg daily)

Surveillance

Routine follow up in a clinic specializing in the care of lymphedema is appropriate.

Agents/Circumstances to Avoid

The following should be avoided:

  • Wounds to the swollen limbs, because of their reduced resistance to infection
  • Long periods of immobility with the legs in a dependent position, for example, on a long flight on an airplane
  • Medications, particularly calcium channel-blocking drugs, that can cause increased leg swelling in some individuals

Evaluation of Relatives at Risk

If the disease-causing mutation in a family is known, molecular genetic testing of at-risk relatives ensures identification of those who will benefit from treatment early in the disease course and identifies unaffected heterozygotes who warrant genetic counseling as their offspring are at a 50% risk of Milroy disease.

If the disease-causing mutation in a family is not known, evaluation of relatives at risk by physical examination is appropriate in order to identify those who will benefit from treatment early in the course of the disease. The use of properly fitted compression hosiery and advice to reduce the risk of cellulitis of the legs and feet can be beneficial.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Attempts at over-expressing VEGF-C, the ligand for FLT4, have been successful in producing functional lymphatics in mice [Karkkainen et al 2000b], suggesting that growth factor gene therapy may be applicable to human lymphedema in the future.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Treatment with diuretics is of no proven benefit.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Milroy disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with Milroy disease have an affected parent.
  • A proband with Milroy disease may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is not presently known, as a clinical delineator for Milroy disease has, in the past, included a family history of the disorder. Of the 15 mutations discovered in the authors' laboratory to date (seven of these unpublished data), three represent de novo mutations [Carver et al 2007]. Previously, one de novo mutation was reported [Ghalamkarpour et al 2006].
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical examination and lymphoscintigraphy if the diagnosis is in doubt and molecular genetic testing if the mutation in the family is known.

Note: Although most individuals diagnosed with Milroy disease have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance. Somatic mosaicism for mutations in FLT4 has not been demonstrated but should be considered.

Sibs of a proband

Offspring of a proband. Each child of an individual with Milroy disease has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Timing for amniocentesis and/or CVS may vary slightly by country.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as Milroy disease are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Ultrasound examination. Ultrasonography in the third trimester may detect swelling of the dorsum of the feet and, rarely, more extensive edematous states in an affected fetus [Franceschini et al 2001, Makhoul et al 2002, Daniel-Spiegel et al 2005].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Lymphatic Research Foundation (LRF)
    40 Garvies Point Road
    Suite D
    Glen Cove NY 11542
    Phone: 516-625-9675
    Fax: 516-625-9410
    Email: lrf@lymphaticresearch.org
  • Lymphoedema Support Network (LSN)
    St. Luke's Crypt
    Sydney Street
    London SW3 6NH
    United Kingdom
    Phone: 020 7351 4480 (Information and Support); 020 7351 0990 (Administration)
    Fax: 020 7349 9809
    Email: adminlsn@lymphoedema.freeserve.co.uk
  • National Lymphedema Network (NLN)
    116 New Montgomery Street
    Suite 235
    San Francisco CA 94105
    Phone: 800-541-3259 (toll-free); 415-908-3681
    Fax: 415-908-3813
    Email: nln@lymphnet.org
  • Medline Plus
  • Lymphedema Family Study
    University of Pittsburgh, Department of Human Genetics
    A300 Crabtree Hall, GSPH
    Pittsburgh PA 15261
    Phone: 800-263-2152 (toll-free); 412-624-4659
    Email: genetics@pitt.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Milroy Disease: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Milroy Disease (View All in OMIM)

136352FMS-LIKE TYROSINE KINASE 4; FLT4
153100LYMPHEDEMA, HEREDITARY, IA

Normal allelic variants. The normal gene is about 45 kb in length; it has 31 exons and two mRNAs of 4.5 kb and 5.8 kb, the latter being the more predominant species. Normal allelic variants include:

  • p.Pro641Ser, p.Asn199Asp, p.Thr494Ala, p.Gln890His, p.Pro954Ser, p.Pro1008Leu, p.Arg1146His, p.Arg1342Leu
  • c.507G>T, c.3198T>C (silent); 17 intronic polymorphisms are detailed in Iljin et al [2001].

Pathologic allelic variants. All mutations identified to date have been in exons encoding tyrosine kinase domains. Identification of mutations only in these exons may in part be the result of a bias in ascertainment; however, Connell et al [2009] screened all exons of FLT4 and did not find any mutations outside the tyrosine kinase domains.

Pathologic variants include p.Pro1114Leu [Ferrell et al 1998]; p.His1035Arg [Irrthum et al 2000]; p.Gly857Arg, p.Arg1041Pro, p.Leu1044Pro [Karkkainen et al 2000a]; p.Gly933Arg, p.Gly845Ser, p.Ala915Pro, p.Cys916Trp, p.Arg1041Trp, delPhe1108, p.Pro1137Leu, p.Arg1041Gln [Evans et al 2003]; p.Glu1106Lys [Daniel-Spiegel et al 2005]; p.Gln1020Leu [Butler et al 2007] ; p.Asp1055Val [Yu et al 2007]; p.Arg844Pro, p.Gly852Ser, p.Gly852Arg, p.Gly854Arg, p.Arg943Pro, p.Gly1024Gln, p.Gly1024Arg, p.Asp1037Tyr, p.Asp1037His, p.Asn1042Ser, p.Asp1055Ala, p.Val1051Met, p.Tyr1115Cys, p.Gly1131Arg [Connell et al 2009]

Normal gene product. The normal gene product, VEGFR-3 (vascular endothelial growth factor receptor 3), is a dimeric receptor for the ligands VEGFC and VEGFD. VEGFR-3 is a lymphatic endothelial cell-specific receptor tyrosine kinase.

Abnormal gene product. The abnormal gene products are either homodimers of the mutation showing no tyrosine kinase activity or mutant/wild type heterodimers showing some TK activity [Irrthum et al 2000, Karkkainen et al 2000a]. However, the only mutations to have been tested in this way are p.Gly857Arg, p.His1035Arg, p.Arg1041Pro, p.Leu1044Pro, and p.Pro1114Leu.

References

Literature Cited

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  2. Brice G, Child AH, Evans A, Bell R, Mansour S, Burnand K, Sarfarazi M, Jeffery S, Mortimer P. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet. 2005;42:98–102. [PMC free article: PMC1735984] [PubMed: 15689446]
  3. Butler MG, Dagenais SL, Rockson SG, Glover TW. A novel VEGFR3 mutation causes Milroy disease. Am J Med Genet A. 2007;143A:1212–7. [PubMed: 17458866]
  4. Carver C, Brice G, Mansour S, Ostergaard P, Mortimer P, Jeffery S. Three children with Milroy disease and de novo mutations in VEGFR3. Clin Genet. 2007;71:187–9. [PubMed: 17250670]
  5. Connell FC, Ostergaard P, Carver C, Brice G, Williams N, Mansour S, Mortimer PS, Jeffery S. Lymphoedema Consortium; Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet. 2009;124:625–31. [PubMed: 19002718]
  6. Daniel-Spiegel E, Ghalamkarpour A, Spiegel R, Weiner E, Vikkula M, Shalev E, Shalev SA. Hydrops fetalis: an unusual prenatal presentation of hereditary congenital lymphedema. Prenat Diagn. 2005;25:1015–8. [PubMed: 16231305]
  7. Evans AL, Bell R, Brice G, Comeglio P, Lipede C, Jeffery S, Mortimer P, Sarfarazi M, Child AH. Identification of eight novel VEGFR-3 mutations in families with primary congenital lymphoedema. J Med Genet. 2003;40:697–703. [PMC free article: PMC1735587] [PubMed: 12960217]
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  9. Franceschini P, Licata D, Rapello G, Guala A, Di Cara G, Franceschini D. Prenatal diagnosis of Nonne-Milroy lymphedema. Ultrasound Obstet Gynecol. 2001;18:182–3. [PubMed: 11547763]
  10. Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken JB, Boon LM, Vikkula M. Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Clin Genet. 2006;70:330–5. [PubMed: 16965327]
  11. Holberg CJ, Erickson RP, Bernas MJ, Witte MH, Fultz KE, Andrade M, Witte CL. Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families. Am J Med Genet. 2001;98:303–12. [PubMed: 11170072]
  12. Hoque SR, Mansour S, Mortimer PS. Yellow nail syndrome: not a genetic disorder? Eleven new cases and a review of the literature. Br J Dermatol. 2007;156:1230–4. [PubMed: 17459037]
  13. Iljin K, Karkkainen MJ, Lawrence EC, Kimak MA, Uutela M, Taipale J, Pajusola K, Alhonen L, Halmekyto M, Finegold DN, Ferrell RE, Alitalo K. VEGFR3 gene structure, regulatory region, and sequence polymorphisms. FASEB J. 2001;15:1028–36. [PubMed: 11292664]
  14. Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet. 2003;72:1470–8. [PMC free article: PMC1180307] [PubMed: 12740761]
  15. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000;67:295–301. [PMC free article: PMC1287178] [PubMed: 10856194]
  16. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet. 2000a;25:153–9. [PubMed: 10835628]
  17. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A. 2000b;98:12677–82. [PMC free article: PMC60113] [PubMed: 11592985]
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  19. Maldonado F, Tazelaar HD, Wang CW, Ryu JH. Yellow nail syndrome: analysis of 41 consecutive patients. Chest. 2008;134:375–81. [PubMed: 18403655]
  20. Milroy WF (1892) An undescribed variety of hereditary oedema. NY Med J Nov 5.
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Suggested Reading

  1. Meige H. Dystrophie oedemateuse hereditarie. Press Med. 1898;6:341–3.

Chapter Notes

Author History

Glen W Brice, RGN BSc (Hons) (2005-present)
Fiona Connell, MBChB, MRCPCH, MD (2009-present)
Steve Jeffery, PhD (2005-present)
Sahar Mansour, FRCP (2005-present)
Peter Mortimer, MD, FRCP (2005-present)
Pia Ostergaard, PhD (2009-present)
Carolyn Sholto-Douglas-Vernon, PhD; University of London (2005-2009)

Revision History

  • 23 July 2009 (me) Comprehensive update posted live
  • 6 April 2007 (gb) Revision: sequence analysis and prenatal testing clinically available
  • 27 April 2006 (me) Review posted to live Web site
  • 19 July 2005 (gb) Original submission
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