Milroy Disease
Summary
Clinical 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 pathogenic variants 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 the following findings:
- Lower-limb swelling that is:
- Usually but not always bilateral
- Present at birth or develops soon afterNote: 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 2000, 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 multigene panel that includes FLT4 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in Milroy Disease
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant Detectable by This Method |
|---|---|---|
| FLT4 | Sequence analysis 2 | ≤75% in well-phenotyped cohorts 3 |
| Unknown 4 | NA | NA |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.
- 2.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon 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 Characteristics
Clinical Description
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].
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:
- Consultation with a clinical geneticist and/or genetic counselor
- 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 overexpressing VEGF-C, the ligand for FLT4, have been successful in producing functional lymphatics in mice [Karkkainen et al 2001]. This is now in clinical trial in Finland for human breast cancer-related lymphedema.
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.