Milroys Disease: Symptoms, Types, Causes and Treatment

Milroy’s disease, also known as primary congenital lymphedema, is a rare genetic disorder that affects the lymphatic system, leading to chronic swelling—most often in the lower limbs. Understanding this disease requires a closer look at its symptoms, types, underlying causes, and treatment options. This article brings together the latest scientific findings to provide a comprehensive guide for patients, families, and healthcare professionals.

Symptoms of Milroys Disease

Milroy’s disease presents with a range of clinical symptoms that can impact daily life and well-being. Recognizing these early signs is crucial for diagnosis and management.

Symptom	Frequency/Prevalence	Typical Presentation	Source(s)
Lower limb edema	~90%	Swelling from birth, usually confined to legs	1, 2, 5
Cellulitis	~20%	Recurrent skin infections	1
Large leg veins	~23%	Prominent superficial veins	1, 5
Hydrocele (males)	~37%	Scrotal swelling in males	1, 5
Upslanting toenails	~10%	"Ski jump" or upslanting appearance	1, 5
Papillomatosis	~10%	Warty skin lesions	1
Abdominal symptoms	Rare	Diarrhea, abdominal pain	8

Table 1: Key Symptoms of Milroy's Disease

Lower Limb Edema: The Hallmark

The most consistent and defining feature of Milroy’s disease is chronic, usually painless swelling—edema—of the lower limbs. About 90% of individuals with a confirmed VEGFR-3 mutation experience this symptom, and for most, it appears at or soon after birth. The swelling is typically bilateral, though it can sometimes affect one leg more than the other. In rare cases, the edema may extend to the feet and toes, causing shoes to fit poorly 1, 2, 5.

Associated Features

Beyond limb swelling, Milroy’s disease can present with several associated symptoms:

• Cellulitis: Up to a fifth of patients may suffer from episodes of cellulitis, a painful skin infection that requires prompt treatment 1.
• Large Veins: Approximately 23% of patients develop unusually prominent leg veins, possibly due to impaired lymphatic drainage 1, 5.
• Toenail Changes: "Ski jump" toenails, or upslanting toenails, are seen in about 10% of cases and can be a diagnostic clue 1, 5.
• Hydrocele in Males: A significant number of males (around 37%) exhibit a hydrocele, or painless scrotal swelling, due to lymphatic involvement 1, 5.
• Papillomatosis: This refers to the formation of small, wart-like skin growths, present in roughly 10% of affected individuals 1.

Gastrointestinal and Other Rare Symptoms

Though much rarer, gastrointestinal symptoms such as diarrhea and abdominal pain can occur if the intestinal lymphatics are affected. These symptoms are typically resistant to standard treatments but may respond to specialized interventions, as described in rare case reports 8.

Types of Milroys Disease

While Milroy’s disease is fundamentally a genetic lymphatic disorder, its clinical expression varies. Understanding these types helps with accurate diagnosis and family counseling.

Type	Key Features	Family History	Source(s)
Typical Milroy Disease	Classic lower limb edema, congenital onset	Often present but not always	2, 4, 5
Atypical Milroy Disease	Variable symptoms, may include non-classic presentation	Sometimes	2
Milroy-like Lymphedema	Similar clinical signs, caused by other gene mutations (e.g., VEGFC)	May be present	3
Complex Primary Lymphedema	Involvement of multiple regions, not classic Milroy	Rare	2

Table 2: Clinical Types of Milroy's Disease

Typical Milroy Disease

This is the classic form, marked by congenital or early-onset bilateral lower limb swelling, sometimes with additional features such as upslanting toenails, prominent veins, and hydrocele. The majority of these patients have a family history of similar symptoms, reflecting the autosomal dominant inheritance pattern. However, a family history is not essential for diagnosis; cases with no clear family history can still be genetically confirmed 2, 4, 5.

Atypical Milroy Disease

Some patients present with symptoms that do not fit the classic pattern—perhaps the swelling is not strictly limited to the lower limbs, or the onset is later in childhood. These cases are referred to as "atypical." Genetic testing can help clarify the diagnosis, as many atypical cases do not carry VEGFR-3 mutations 2.

Milroy-like Lymphedema

Recent discoveries have identified mutations in genes other than VEGFR-3, such as VEGFC, that can cause a similar clinical picture. These cases may be considered Milroy-like lymphedema and highlight the genetic heterogeneity of the disorder 3.

Complex Primary Lymphedema

This rare category includes cases where lymphedema is present in multiple body regions or is associated with additional anomalies. Such cases often require extensive genetic and clinical evaluation to distinguish them from classic Milroy’s disease 2.

Causes of Milroys Disease

Milroy’s disease is primarily a genetic disorder, but its causes can be surprisingly complex. Understanding the molecular basis of the condition provides insight into its inheritance and variability.

Cause	Key Mechanism	Genetic Component	Source(s)
VEGFR-3 Mutation	Impaired lymphatic vessel development	FLT4 gene (autosomal dominant)	1, 2, 4, 5, 6
VEGFC Mutation	Disrupted ligand-receptor signaling	VEGFC gene (rare)	3
Incomplete Penetrance	Variable symptom expression	Modifier genes/environment	4, 5
Other/Unknown Genes	Not fully understood	Possible genetic heterogeneity	2, 3

Table 3: Genetic and Molecular Causes

VEGFR-3 (FLT4) Mutations: The Main Cause

Most cases of Milroy’s disease are caused by mutations in the FLT4 gene, which encodes the vascular endothelial growth factor receptor 3 (VEGFR-3). This receptor plays a critical role in the formation and maintenance of the lymphatic system. When VEGFR-3 is dysfunctional due to a mutation, lymphatic vessels in the skin fail to develop properly, leading to hypoplasia and impaired lymph drainage 1, 2, 4, 5, 6.

• Autosomal Dominant Inheritance: Only one mutated copy of the gene is needed for the disease to manifest. However, not everyone who inherits the mutation develops symptoms, a phenomenon known as incomplete penetrance 2, 4, 5.
• Mutation Spectrum: The majority are missense mutations, but deletions and splicing variants have also been identified. Most pathogenic changes occur in the tyrosine kinase domains of the receptor 4, 5.

VEGFC Mutations: Expanding the Genetic Landscape

In rare cases, mutations in VEGFC, which encodes a ligand for VEGFR-3, have been found to cause a Milroy-like form of lymphedema. These mutations disrupt the signaling required for normal lymphatic vessel development. This finding illustrates the genetic complexity and heterogeneity of primary lymphedema syndromes 3.

Variable Expression and Incomplete Penetrance

The same mutation can lead to varying symptom severity among affected family members, and some may show no symptoms at all. This variability suggests the influence of other modifier genes or environmental factors 4, 5.

Other Genetic and Unknown Causes

About 30% of patients with classic clinical features do not have detectable mutations in the known genes, indicating the likelihood of additional, as yet unidentified, genetic causes 2, 3.

Treatment of Milroys Disease

While there is no cure for Milroy’s disease, a variety of treatments can help manage symptoms, improve quality of life, and prevent complications. The best approach is often a combination of conservative, medical, and, in select cases, surgical therapies.

Treatment	Purpose/Approach	Effectiveness/Notes	Source(s)
Compression therapy	Reduce swelling, support lymph flow	Mainstay of management	9, 8
Physical therapy	Decompressive massage, exercise	Symptom relief	9
Infection control	Antibiotics for cellulitis	Prevent complications	1
Surgical intervention	Lymph node transfer, lipectomy	For severe, refractory cases	7
Pharmacological	Symptom-specific (e.g., shinbuto for diarrhea)	Case-dependent	8
Experimental	VEGF-C gene therapy (animal models)	Potential future option	6

Table 4: Treatment Approaches for Milroy's Disease

Conservative Management

The cornerstone of Milroy’s disease treatment is conservative management:

• Compression Garments: Special stockings or wraps help reduce swelling by promoting lymph drainage 9, 8.
• Manual Lymphatic Drainage: Gentle massage techniques can further assist fluid movement 9.
• Exercise: Regular, low-impact exercise helps maintain mobility and lymphatic function.

Preventing and Managing Infections

Because the affected limbs are prone to cellulitis, prompt treatment of skin infections with antibiotics is essential. Good skincare and hygiene can reduce infection risk 1.

Surgical Options

When conservative treatments fail to control severe swelling, surgical approaches may be considered:

• Vascularized Lymph Node Transfer (VLNT): Transferring healthy lymph nodes to the affected limb can restore some lymphatic function.
• Therapeutic Lipectomy: Removing excess fat and fibrous tissue can help reduce limb size and improve mobility. These surgical options are typically reserved for select, challenging cases 7.

Pharmacological and Symptom-Specific Treatments

Medications can address certain symptoms:

• For Refractory Diarrhea: Traditional herbal medicines like shinbuto have shown benefit in rare cases with gastrointestinal involvement 8.
• Pain Management: Analgesics or other symptom-specific medications may be used as needed.

Experimental Treatments and Future Directions

Gene therapy, particularly using VEGF-C to stimulate lymphatic vessel growth, has shown promise in animal models and may one day be an option for humans 6.

Conclusion

Milroy’s disease is a rare but impactful genetic disorder. Here’s a summary of the key points covered:

• Symptoms: Chronic lower limb swelling is the hallmark, with possible associated features like cellulitis, hydrocele in males, and upslanting toenails 1, 5.
• Types: Most cases are classic (typical) Milroy’s, but atypical presentations and Milroy-like forms due to other gene mutations exist 2, 3, 4.
• Causes: The main cause is VEGFR-3 (FLT4) mutations, but genetic heterogeneity is increasingly recognized, including rare VEGFC mutations 1, 2, 3, 4, 5, 6.
• Treatment: Management focuses on compression, physical therapy, infection control, and, in severe cases, surgery. New therapies, including gene therapy, are being explored 6, 7, 9.

With ongoing research, our understanding of Milroy’s disease continues to grow, offering hope for improved treatments and outcomes in the future.