What Is a Lymphatic Malformation? Causes, Inheritance, and Diagnosis

📍Key Takeaways

• Lymphatic malformation, cystic hygroma, and lymphangioma refer to the same disease group, classified by ISSVA as a low-flow vascular malformation.
• Most cases are not inherited from parents; a somatic mosaic PIK3CA mutation arising during development is the most common cause.
• Because the somatic variant may exist only in the lesion tissue, blood-based testing alone can miss it — a key consideration when planning diagnosis.

What is a lymphatic malformation?

A lymphatic malformation is a congenital vascular malformation made up of abnormally dilated lymphatic channels and cysts. It was historically called a lymphangioma, and the large-cyst form in the neck was called a cystic hygroma. The three terms essentially describe the same disease group. It is categorized by cyst size into macrocystic, microcystic, and mixed types.

Under the International Society for the Study of Vascular Anomalies (ISSVA) classification, a lymphatic malformation is grouped not as a proliferative vascular tumor but as a low-flow vascular malformation. The starting point for understanding it is that it is a structural anomaly of development, not a tumor.

Is a lymphatic malformation a rare disease?

Yes, it is an uncommon congenital anomaly. Robust prevalence data are limited, but roughly 75% of superficial lymphatic malformations are reported to occur in the head and neck. Most are identified in  infancy or childhood.

Is a lymphatic malformation inherited?

This is the most common question, and the answer is clear: isolated lymphatic malformations are usually not inherited. The cause is not a germline variant passed down from a parent, but a somatic mosaic mutation that occurs only in a subset of cells during development.

The most common causative gene is PIK3CA, which over-activates the PI3K/AKT/mTOR signaling pathway that governs cell growth. PIK3CA variants also underlie the PIK3CA-related overgrowth spectrum (PROS). Because this is a somatic variant, the risk of passing it to a child is very low — a point that can reassure families.

Why does genetic testing matter for diagnosis?

Evaluation of a lymphatic malformation usually begins with imaging such as ultrasound and MRI. Confirming the underlying variant, however, requires genetic testing — and there is an often-overlooked pitfall here.

A somatic variant such as PIK3CA frequently exists only in the lesion tissue, so a standard blood-based germline test may not detect it. This makes lesion tissue the appropriate sample and adequate sequencing depth important, so that low variant allele frequencies (VAF) can be captured. The insight that sample type and assay sensitivity must be considered together — or a false negative may follow — is especially useful when working with lymphatic malformations.

When you need an accurate molecular diagnosis

Lymphatic malformations are often mistaken for an “inherited disease,” but in reality most cases are non-inherited and driven by somatic variants. An accurate molecular diagnosis can ease unnecessary family anxiety and clarify the underlying gene. 3billion provides  genetic testing based on WES and WGS. If you are considering genetic testing for a lymphatic malformation or another vascular malformation, you can consult with us.

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References

1. Kunimoto K, et al. ISSVA Classification of Vascular Anomalies and Molecular Biology. 2022. https://doi.org/10.3390/ijms23042358
2. Mahajan P, et al. The genetics of vascular birthmarks. 2022. https://doi.org/10.1016/j.clindermatol.2022.02.006
3. Greene AK, Goss JA. Vascular Anomalies: From a Clinicohistologic to a Genetic Framework. 2018. https://doi.org/10.1097/PRS.0000000000004294
4. Hughes M, et al. PIK3CA vascular overgrowth syndromes: an update. 2020. https://doi.org/10.1097/MOP.0000000000000923
5. Brouillard P, et al. Non-hotspot PIK3CA mutations are more frequent in CLOVES than in common or combined lymphatic malformations. 2021. https://doi.org/10.1186/s13023-021-01898-y
6. Diarra D, et al. Cystic lymphangioma of the upper limb: Clinical case and literature review. 2022. https://doi.org/10.1259/bjrcr.20210206