Clinical characteristic.

Milroy disease is characterized by lower-limb lymphedema, present as pedal edema at (or before) birth or developing soon after. Occasionally it presents 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 the early years. Other features sometimes associated with Milroy disease include hydrocele (37% of males), prominent veins below the knees (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.

The diagnosis of Milroy disease is established in a proband with congenital or infantile-onset lower-limb lymphedema accompanied by lack of uptake of radioactive colloid in the ilioinguinal lymph nodes on lymphoscintigraphy and/or by identification of a heterozygous pathogenic variant in FLT4 by molecular genetic testing.

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. Standard treatment for cellulitis, hydroceles, and urethral abnormalities.

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.

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

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: Evaluation of apparently asymptomatic at-risk relatives of an affected individual is appropriate in order to identify those who would benefit from properly fitted compression hosiery and advice on how to reduce the risk of cellulitis of the legs and feet.

Genetic counseling.

Milroy disease is inherited in an autosomal dominant manner. Most individuals diagnosed with Milroy disease have an affected parent. If a parent of the proband is affected and/or has an FLT4 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability and reduced penetrance are observed in Milroy disease; a heterozygous sib may be more or less severely affected than the proband. Once the FLT4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. 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 (fetal hydrops) in an affected fetus.

Suggestive Findings

Milroy disease should be suspected in individuals with the following clinical features, radiographic findings, and family history.

Clinical features

• Lower-limb swelling that is:
  • Usually (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 below-knee region (rarely extending above the knees).
• Large-caliber veins below the knees
• Upslanting and small, dysplastic toenails
• Deep interphalangeal creases of the feet
• Hydroceles in males
• No internal clinically significant lymphatic issues (e.g., intestinal lymphangiectasia, pleural or pericardial effusions)

Radiographic findings. Lymphoscintigraphy typically demonstrates a lack of uptake of tracer into peripheral lymphatics. Consequently, no drainage channels are visualized nor is there any uptake in the ilio-inguinal nodes. This is referred to as "functional aplasia" and is characteristic of Milroy disease.

Note: The lymphoscintigraphic findings are characteristic and useful for diagnosis, but this test is not absolutely required (see Clinical Description for more detail).

Family history shows similarly affected individuals consistent with an autosomal dominant inheritance pattern.

Note: Absence of a known family history of Milroy disease does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Milroy disease is established in a proband with congenital or infantile-onset lower-limb lymphedema accompanied by lack of uptake of radioactive colloid in the ilioinguinal lymph nodes on lymphoscintigraphy and/or identification of a heterozygous pathogenic variant in FLT4 (VEGFR3) by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Milroy is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with lymphedema are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The most common finding in Milroy disease is congenital bilateral, lower-limb lymphedema. The edema is usually present from (or before) birth. Rarely, prenatal pleural effusion and fetal hydrops have been reported [Daniel-Spiegel et al 2005, Boudon et al 2015], but in general Milroy disease is not associated with more widespread lymphatic abnormalities. In neonates the swelling tends to affect primarily the dorsum of the feet (pedal edema). Anecdotal evidence suggests that on rare occasions it develops later in life (see Penetrance).

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:

• Hydrocele (37% of males)
• Prominent veins (23%) below the knees (with or without venous reflux seen on duplex imaging) [Mellor et al 2010]
• Upslanting (spoon-shaped and/or dysplastic) toenails (14%)
• Papillomatosis located on the toes and/or forefoot (10%)
• Urethral abnormalities, such as hypospadias or urethral stricture, 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.

Lymphoscintigraphy is a common method of distinguishing Milroy disease from other lymphatic conditions. 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. Milroy disease and other forms of lymphedema can have differing patterns on lymphoscintigraphy [Connell et al 2013, Sarica et al 2019]. In cases of unilateral swelling, lymphoscintigraphy can determine if lymphatic drainage is impaired in the "unaffected" leg.

Genotype-Phenotype Correlations

No genotype-phenotype correlation for Milroy disease has been reported. Most pathogenic variants are missense variants that occur in the tyrosine kinase domain of FLT4 (see Molecular Genetics).

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.

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.

Milroy disease may also be referred to as Milroy congenital lymphedema.

Prevalence

The prevalence of Milroy disease is not known but it appears to be one of the more common causes of primary lymphedema, occurring in all ethnic groups.

Chromosomal Disorders and Hereditary Disorders of Unknown Genetic Cause

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 1:2,500 to 1:3,000 live female births [Sybert & McCauley 2004] and should always be considered in a female with congenital lymphedema particularly if hands and feet are affected.

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. The disorder is thought to be autosomal dominant or non-genetic/acquired [Hoque et al 2007, Maldonado et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Milroy disease, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Prevention of Secondary Complications

Secondary cellulitis is prevented through the following measures:

• Prevention of foot infections, particularly athlete's foot or infected ingrown toenails
• 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 250 mg 2x daily for 1-2 years). The dose may need to be adjusted for pediatric or obese individuals [British Lymphology Society / Lymphoedema Support Network 2016] (full text).

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 a reduced resistance to infection
• Long periods of immobility with the legs in a dependent position (e.g., on a long airplane flight)
• Medications that can cause increased leg swelling in some individuals (particularly calcium channel-blocking drugs)

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of 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.

Evaluations can include:

• Molecular genetic testing if the causative pathogenic variant in the family is known;
• Physical examination if the causative pathogenic variant in the family is not known.

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 [Gordon et al 2013b]. Very rarely, fetal hydrops is present.

If the mother is affected by Milroy disease there may be an increase in the mother's swelling during the pregnancy.

Therapies Under Investigation

Attempts at overexpressing VEGF-C, the ligand for FLT4, have been successful in producing functional lymphatics in mice [Karkkainen et al 2001]. This treatment approach (in combination with microsurgical lymph node transfer surgery) is now being studied in humans in a clinical trial for breast cancer treatment-related secondary lymphedema [Hartiala et al 2020].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Treatment with diuretics is of no proven benefit.

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.
• An individual diagnosed with Milroy disease may have the disorder as the result of a de novo FLT4 pathogenic variant. Approximately 10% of individuals with Milroy disease represent simplex cases (i.e., a single affected family member) [Ghalamkarpour et al 2006, Carver et al 2007, Connell et al 2009, Gordon et al 2013b]. However, the proportion of these individuals who have Milroy disease as the result of a de novo pathogenic variant (as opposed, for example, to inheritance of a pathogenic variant from a heterozygous parent with reduced penetrance or a parent with germline mosaicism) is not known because parental testing has not been performed in all reported families.
• If a molecular diagnosis has been established in the proband, molecular genetic testing for the FLT4 pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ cells.
• The family history of some individuals diagnosed with Milroy disease may appear to be negative because of failure to recognize the disorder in family members as a result of variable expression or reduced penetrance.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or has an FLT4 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability and reduced penetrance are observed in Milroy disease; a heterozygous sib may be more or less severely affected than the proband.
• If the proband has an FLT4 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• If the genetic status of the parents is unknown but they 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 possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with Milroy disease has a 50% chance of inheriting the FLT4 pathogenic variant. Intrafamilial variability is observed in Milroy disease; a heterozygous child may be more or less severely affected than the proband.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have a Milroy disease-causing pathogenic variant, 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 and Preimplantation Genetic Testing

Molecular genetic testing. Once the FLT4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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 (fetal hydrops) in an affected fetus [Franceschini et al 2001, Makhoul et al 2002, Daniel-Spiegel et al 2005].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The normal gene product of FTL4, VEGFR-3 (vascular endothelial growth factor receptor 3), is a dimeric transmembrane receptor for the ligands VEGFC and VEGFD. The binding of the ligands activates the intracellular kinase domains of the dimer, which then autophosphorylate each other. The trans-autophosphorylation results in recruitment of adaptor proteins such as CRK, SHC, and GRB2, which in conjunction with phosphatidylinositol-3-kinase (PI3K) activate downstream signaling pathways that include the mitogen-activated protein kinase (MAPK) family members AKT, ERK1/2, and JNK (c-Jun N-terminal kinase) [Monaghan et al 2020].

VEGFR-3 is a lymphatic endothelial cell-specific receptor and, when stimulated by the VEGFC ligand, is the key regulator of lymphatic vessel growth and function. The abnormal gene products will form either mutant/mutant type homodimers showing no tyrosine kinase activity or mutant/wild type heterodimers showing some TK activity, leading to an overall decrease in downstream signaling [Irrthum et al 2000, Karkkainen et al 2000]. Studies have shown that the proportion of dimers including a mutant receptor is higher than expected. This is due to a greater stability at the plasma membrane and slower rate of degradation of the mutant receptor compared to wild type receptors, leading to a dominant-negative effect.

Mechanism of disease causation. Dominant negative [Karkkainen et al 2000, Monaghan et al 2020]. All pathogenic variants identified to date have been in exons encoding tyrosine kinase domains. See Gordon et al [2013b] for discussion of variants reported in the literature.

Author Notes

Acknowledgments

The authors would like to thank the following organizations: the Medical Research Council, the British Heart Foundation, and the National Institute for Health Research.

Author History

Glen W Brice, RGN BSc (Hons); St George's, University of London (2005-2021)
Fiona Connell, MBChB, MRCPCH, MD; Guy's Hospital (2009-2021)
Kristiana Gordon, MD, FRCP (2021-present)
Steve Jeffery, PhD; St George's, University of London (2005-2021)
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)
Malou Van Zanten, PhD (2021-present)

Revision History

• 18 February 2021 (ma) Comprehensive update posted live
• 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 live
• 19 July 2005 (gb) Original submission

Published Guidelines / Consensus Statements

• British Lymphology Society / Lymphoedema Support Network. Consensus document on the management of cellulitis in lymphoedema. 2016. Available online. Accessed 2-10-21.

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