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Milroy Disease

Synonyms: 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
Guy’s Genetics Service
Guy’s Hospital
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: September 25, 2014.

Summary

Disease characteristics.

Milroy disease is characterized by lower-limb lymphedema, present as pedal edema at (or before) birth 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 and well-fitting, supportive shoes. Toe gloves may be of benefit and good skin care is essential.

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 pathogenic variant. Although de novo mutation has been reported, the proportion of cases caused by de novo mutation is not known. Ultrasonography during pregnancy may detect swelling of the dorsum of the feet, mild pleural effusions which often resolve and (very rarely) more extensive edematous states (hydrops fetalis) in an affected fetus. Prenatal testing is possible for pregnancies at increased risk if the pathogenic variant in the family is known; however, it is rarely requested.

Diagnosis

Suggestive Findings

Milroy disease should be suspected in individuals with:

  • Lower-limb swelling that is:
    • Usually but not always bilateral;
    • Present at birth or develops soon after.
      Note: 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.
  • Large-caliber veins;
  • Upslanting, ‘ski-jump’ toenails.

Evaluation of the limb swelling can include 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 [Connell et al 2013]. 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.

Lymphoscintigraphy is not essential to make the diagnosis and one can proceed directly to molecular testing.

Establishing the Diagnosis

The diagnosis of Milroy disease is established in a proband with identification of a pathogenic variant in FLT4 (VEGFR3), 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] (see Table 1).

One genetic testing strategy is molecular genetic testing of FLT4 by sequence analysis of exons 17 to 26.

An alternative genetic testing strategy is use of a multi-gene panel that includes FLT4 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in Milroy Disease

Gene 1 Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
FLT4Sequence analysis 2Up to 75% in well-phenotyped cohorts 3
Unknown 4NANA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Connell et al [2009] suggest that a pathogenic variant is detected in 75% of those clearly affected and with a positive family history and in 68% of those with typical Milroy features but without a family history.

4.

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 pathogenic variant is found in only 75% of affected individuals, suggesting that other genes may be involved [Connell et al 2009]. Rare cases may be caused by pathogenic variants in VEGFC [Gordon et al 2013a].

Clinical Description

Natural History

The most common finding in Milroy disease is lower-limb lymphedema. The edema is usually present from (or before) 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, but can be 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.

Rarely, prenatal pleural effusion and hydrops fetalis have been reported [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 pathogenic variant in FLT4 develop lower-limb lymphedema by age three years; conversely, 10%-15% of individuals with an FLT4 pathogenic variant 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 and occurs in all ethnic groups.

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.

A list of differential diagnoses can be found in Connell et al [2013].

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) (OMIM 152950). This autosomal dominant condition is caused by mutation of KIF11. The edema seen in individuals with a pathogenic variant in KIF11 is indistinguishable from that associated with FLT4 pathogenic variants. Features associated with KIF11 pathogenic variants (and not seen in Milroy disease) include microcephaly, chorioretinopathy, and (in most individuals) learning difficulties. However, the pattern on lymphoscintigraphy in affected individuals is identical for the two disorders [Ostergaard et al 2012, Jones et al 2014].

VEGFC-related lymphoedema. Two families with a phenotype resembling Milroy disease have been shown to have pathogenic variants in VEGFC. Clinically, it is not possible to distinguish these individuals from those with FLT4 pathogenic variants and testing of VEGFC should be considered if FLT4 testing is negative. The pattern on lymphoscintigraphy in individuals with VEGFC pathogenic variants is different from that in patients with Milroy disease [Gordon et al 2013a].

Other disorders in the differential diagnosis may be distinguished by age of onset.

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 particularly if hands and feet are affected

Noonan syndrome is characterized by short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, 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. Pathogenic variants in PTPN11 are observed in 50% of affected individuals, SOS1 in approximately 13%, RAF1 in 3%-17%, and KRAS in fewer than 5%. Other genes in which pathogenic variants have been reported to cause Noonan syndrome in fewer than 1% of cases include NRAS, BRAF, and MAP2K1. Inheritance is autosomal dominant. People with Noonan syndrome may present with congenital lymphedema of the feet and legs. They may also present later with lower-limb and genital edema, chylous reflux, intestinal lymphangiectasia, and/or chylothoraces.

Hypotrichosis-lymphedema-telangiectasia syndrome (OMIM 607823) 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. Pathogenic variants in SOX18 are causative [Irrthum et al 2003].

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 than females. 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 eyelashes including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include early-onset varicose veins (50%), congenital heart disease (7%), 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 (OMIM 153200) 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.

Lymphedema with yellow nails (yellow nail syndrome, YNS) (OMIM 153300) 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].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Milroy disease, the following evaluations are recommended:

  • Medical genetics consultation
  • Referral to a lymphedema therapist
  • Lymphoscintigraphy

Treatment of Manifestations

Guidance by a lymphedema therapist regarding management of edema (e.g., fitting stockings, massage) is important. Although the edema cannot be cured, some improvement is usually possible with the use of properly fitted compression hosiery and/or bandaging and well fitting, supportive shoes. Toe gloves may be of benefit and good skin care is essential. Such treatment measures 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 (e.g., on a long airplane flight)
  • Medications, particularly calcium channel-blocking drugs, that can cause increased leg swelling in some individuals

Evaluation of Relatives at Risk

If the FLT4 pathogenic variant 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.

If the pathogenic variant 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.

Pregnancy Management

Ultrasound scanning during pregnancy may indicate if a fetus is affected if swelling of the dorsum of the feet is noted in the second or third trimester. The fetus may have mild pleural effusions which frequently resolve before birth [S Mansour, personal communication]. Very rarely, the fetus may present with hydrops fetalis. If the mother is affected by Milroy disease there may be an increase in swelling during the pregnancy.

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]. This is now in clinical trial in Finland for human breast cancer-related lymphedema.

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 de novo FLT4 mutation. The proportion of cases caused by de novo mutation 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 pathogenic variants discovered in the authors' laboratory to date (7 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 pathogenic variant 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. Germline mosaicism has been observed [Author, personal communication] but remains uncommon.

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 pathogenic variants in FLT4 is rare but has occurred [Author, personal communication].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has an FLT4 pathogenic variant, the risk to the sibs is 50%.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low, but greater than that of the general population because of the possibilities of non-penetrance and germline mosaicism.

Offspring of a proband. Each child of an individual with Milroy disease has a 50% chance of inheriting the FLT4 pathogenic variant.

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

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the FLT4 pathogenic variant in the family.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the FLT4 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Milroy disease) do not affect intellect and have some treatment available 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 during pregnancy may detect swelling of the dorsum of the feet, mild pleural effusions which often resolve, and (very rarely) more extensive edematous states (hydrops fetalis) 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 FLT4 pathogenic variant has 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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FLT45q35​.3Vascular endothelial growth factor receptor 3FLT4 databaseFLT4

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; LMPH1A

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Normal variants include the following:

  • 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].

Pathogenic allelic variants. All pathogenic variants identified to date have been in exons encoding tyrosine kinase domains. Identification of pathogenic variants 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 pathogenic variants outside the tyrosine kinase domains. See Gordon et al [2013b] for discussion of variants reported in the literature.

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 mutant/mutant type homodimers 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 pathogenic variants 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. 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]
  4. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, Mansour S, Ostergaard P. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet. 2013;84:303–14. [PubMed: 23621851]
  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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  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]
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  12. Gordon K, Spiden SL, Connell FC, Brice G, Cottrell S, Short J, Taylor R, Jeffery S, Mortimer PS, Mansour S, Ostergaard P. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat. 2013b;34:23–31. [PubMed: 23074044]
  13. 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]
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  19. 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]
  20. 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]
  21. Makhoul IR, Sujov P, Ghanem N, Bronshtein M. Prenatal diagnosis of Milroy's primary congenital lymphedema. Prenat Diagn. 2002;22:823–6. [PubMed: 12224079]
  22. Maldonado F, Tazelaar HD, Wang CW, Ryu JH. Yellow nail syndrome: analysis of 41 consecutive patients. Chest. 2008;134:375–81. [PubMed: 18403655]
  23. Milroy WF. An undescribed variety of hereditary oedema. NY Med J. 1892;56:505–8.
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  25. Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet. 2012;90:356–62. [PMC free article: PMC3276660] [PubMed: 22284827]
  26. Sybert VP, McCauley E. Turner's syndrome. N Engl J Med. 2004;351:1227–38. [PubMed: 15371580]

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

  • 25 September 2014 (me) Comprehensive update posted live
  • 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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