b'Early examples in the genetics of primary lymphedemaanxiety and depression. Major contributing factors to involve genes such as FLT4 and FOXC2, identified inthe psychosocial effects of lymphedema may include Nonne-Milroy disease and lymphedema-distichiasisphysical symptoms, lack of social and emotional syndrome, respectively. These genes were discoveredsupport, time-consuming medical care, lack of through classical human genetic approaches usingsensitivity and awareness amongst the public, linkage studies in large families with a history ofinadequate health insurance, and associated financial lymphedema. Later findings in mice (PROX1, burdens 147 . Additionally, body image-related concerns ANGPT1, ANGPT2) and zebrafish allowed us tomay manifest as problems with sexual well-being, enlarge the number of genes possibly involved inincluding sexual pain and dysfunction 148 . Specialist primary lymphedema. services may be of use in terms of effectively The core of the lymphatic pathway is the VEGF-C/ addressing such concerns. Consultative services may VEGFR3 axis. However, other ligand-receptor signalinginclude but are not limited to:pathways are progressively identified. These newpsychiatry and psychology for mental-emotionalpathways include ANGPT2-TIE1 or TIE2, HGF-MET.disorders and relational counseling services for the There are also phenotypes that carry a pathogenicdevelopment of effective coping strategies,variant in one of the RAS/MAPK pathway proteins. gynecology for problems with sexual pain andAs many as 31 loci and genes have nowadays beendysfunction,confirmed as involved in primary lymphedema.oncology for cancer-related pain,Eighteen other genes have been suggested as dermatology or wound care for skin-relatedlymphedema genes and need to be confirmed either in additional patients or through a functional validationchanges and infections,of the variants. These genes are involved in theOccupational therapy when LD affects the ability initiation of lymphatics, lymphatic valve formation,to work, andexpansion, and proliferation of lymphatics.other referrals for the improvement of quality Chromosomal disorders are also associated withof life.lymphedema, such as Turner syndrome, Prader-Willi syndrome, and more rare diseases such as Phelan- B. MENTAL HEALTHMcDermid syndrome. There are also overgrowthAuthors: Kay T. Pham, MD, Alexander M.syndromes that involve lymphatics, such as PIK3CA Kaplan, MD, MPHor AKT1 mutations 146 . IntroductionMolecular diagnosis is nowadays a routine exam Lymphedema, lipedema, and vascular andin referral centers taking care of patients with lymphatic anomalies are chronic conditions thatprimary lymphedema. In most cases, gene panels impact a persons physical, psychological, and social are performed; however, with the increasing number functioning. A comprehensive understanding of of new genes discovered in primary lymphedema,biopsychosocial factors in lymphatic disease andwhole exome sequencing might become a mosttheir impact on mental health will help providers interesting option. address patients unmet psychosocial needs and Being able to precisely describe the phenotype empower patients to better manage their conditionof our patients is the core of genotype-phenotypeto experience a higher quality of life (QoL). Here,correlations, as genetic testing will increase ourwe review the physical, psychological, and social experience and our knowledge both in variableeffects of lymphatic disease as it pertains to mental expressivity and incomplete penetrance. Genetichealth. We discuss psychotherapeutic approachescounseling will, therefore, be improved by the betteras they relate to the aforementioned factors.stratification of the lymphatic subtypes of the patients.In closing, we discuss psychotropic medicationsAs the use of genetic testing as a diagnostic tooland potential adverse effects relevant to patientscontinues to rise, enabling more precise molecularwith lymphatic disease.diagnosis and family screening, it will be important toPhysical Effectsset up personalized support for family members toThe physical effects of lymphedema and other prevent lymphedema if it is still infraclinical and tolymphatic diseases vary, given a wide range of treat it if already diagnosed. manifestations and severity. Symptoms may include Others pain, upper or lower extremity disability, progressive The visible accumulation of fluid seen in lymphedemadyspnea, shortness of breath, and abdominal patients may negatively impact psychosocial well- distention due to pericardial effusions, pleural being due to diminished quality of life and theeffusions or ascites, and impediments in speechdevelopment of psychological problems such asand swallowing, to name a few. These effects can | Standardized Approach for the Diagnosis and Management of Lymphedema (LE) and Lymphatic Diseases (LD)|38'