Clinical application of molecular genetics in lymphatic malformations

Abstract

Objectives To describe the clinical presentation of lymphatic malformations (LM) and genotypically associated disorders and to summarize the recent literature regarding the genetic etiology of LM and provide a biologic correlation to medical and surgical management. Results LM are congenital lesions derived from a developmental abnormality of the lymphatic vessels. The severity of disease varies widely and complications can occur with higher staged disease and those associated with a known constellation of symptoms. Somatic mutations of the PIK3CA gene have been found to be an etiologic factor in the development of LM and associated overgrowth syndromes. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits the pathway downstream of PIK3CA . Preliminary studies in select groups of patients suggest that sirolimus has a role in the medical management of certain aspects of this disease. Conclusions Discovery of LM molecular genetics has led to the possibility of targeted therapies and highlights the importance of precision medicine in rare diseases. Identifying genetic mutations in larger cohorts of patients with LM will lead to additional insights. Knowledge of the genetic basis for disease can then lead to discovery of directed medical therapy. A specific molecular diagnosis can also help families understand better why their child is different and provide accurate counseling for subsequent pregnancies. Level of Evidence 6

Active Observation as an Alternative to Invasive Treatments for Pediatric Head and Neck Lymphatic Malformations

“…3,4 Now that the presence of genotypic mosaicism within HNLM cells is known, HNLM treatment algorithms need review. 5 Lymphatic malformations (LM) have an estimated incidence of 1.2 to 2.8 in 10,000 live births, and are often detected in-utero. 6,7 LM are most common in the head and neck, and their presence can compromise normal function, development, and quality of life.…”

“…Optimal HNLM treatment is debated and much of the existing medical literature does not provide high‐level evidence to support known treatment modalities 3,4 . Now that the presence of genotypic mosaicism within HNLM cells is known, HNLM treatment algorithms need review 5 …”

“…Now that there are novel medications that suppress PIK3CA activation and have HNLM treatment potential, understanding optimal treatment for specific types of HNLM is essential. 5,[14][15][16] Since invasive treatment of patients under 6 months of age increases procedure frequency and some HNLM regress without treatment, Seattle Children's vascular anomalies program adopted a conservative, shared decision-making model for HNLM not causing functional compromise in 2000; this is a significant change in our management philosophy. 11,12,17,18 At diagnosis, after thorough HNLM evaluation and staging, treatment plans are developed with patient family input with a goal of reducing the number of invasive procedures and episodes of anesthesia.…”

Intermittent Administration Regimen of Sirolimus for Refractory Cervicofacial Lymphatic Malformation

“…7 The most commonly associated mutation in cervicofacial LMs is a postzygotic somatic mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha gene. 8 Until now, sirolimus is becoming a rising star in the treatment of LMs with limited adverse events. 9 At present, there is no standard strategy for sirolimus in the treatment of complicated LMs.…”

“…Mammalian target of rapamycin is a serine/threonine kinase regulated by phosphoinositide-3-kinase, and it functions as a master switch of numerous cellular processes, including cellular catabolism and anabolism, cell motility, angiogenesis, and cell growth 7 . The most commonly associated mutation in cervicofacial LMs is a postzygotic somatic mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha gene 8 . Until now, sirolimus is becoming a rising star in the treatment of LMs with limited adverse events 9 …”