Congenital lymphedema as a rare and first symptom of tuberous sclerosis complex

Lymphedema are characterized by interstitial edema leading to swelling of extremities. They can be divided into primary and secondary lymphedema. Developmental abnormalities of the lymphatic system are responsible for the primary form of lymphedema. The secondary form of lymphedema is caused by damage of the lymphatic system due to external factors. Lymphedema can rarely be observed in patients with tuberous sclerosis complex (TSC), which is a neurocutaneous syndrome caused by pathogenic variants in the genes TSC1 or TSC2. Patients with TSC usually present with neurological manifestations and the development of multiple benign tumors of ectodermal origin. Typical onset for several symptoms is during the first year of life and in some cases lesions can be detected prenatally. Epilepsy is one of the most common manifestations, affecting up to 90% of TSC patients, and is associated with developmental delay. Early pharmacotherapy improves long term patient outcome. Trio exome sequencing was performed in a 3 weeks old girl with congenital lymphedema of the right lower extremity. Using a filter for de novo variants, the heterozygous missense variant c.2524C>T, p.(Gln842Ter) in TSC1 (NM_000368.4) could be identified. After the first onset of infantile spams at age 7 months treatment with vigabatrin was started immediately. We propose to include TSC1 and TSC2 analysis in the diagnostic work-up of patients with (isolated) congenital lymphedema as early diagnosis facilitates consequent treatment strategies potentially improving the prognosis of TSC patients.

Keywords: Exome sequencing; Lymphedema; TSC; TSC1; TSC2; Tuberous sclerosis complex.