Compound heterozygosity for a variably penetrant variant and a variant of unknown significance in FLT4 causes fully penetrant Milroy's lymphedema.

Milroy disease, known as primary congenital lymphedema, is characterized by chronic tissue swelling due to impaired lymphatic drainage and is inherited in an autosomal dominant manner. This study reports a rare case of Milroy disease affecting siblings from unaffected parents. A one-month-old female infant presented with swelling of the bilateral calf and the dorsum of the feet which had been present since birth. Her 14-month-old brother had a similar presentation since birth with swelling of the bilateral calf and the dorsum of the feet. Milroy disease was diagnosed based on the clinical findings of bilateral lower limb swelling and confirmed by molecular genetic testing. The patient and her family, including her brother, parents, and maternal grandfather, were genetically tested, and two novel missense mutations (NM_182925.4: c.2534T>C; p.Leu845Pro, c.4006G>A; p.Glu1336Lys) were found in the Fms-related tyrosine kinase (FLT4) gene. Mutations segregated by the parents who carried each mutation in the heterozygous state were identified in the patient and her brother. The present case report in which Milroy disease developed in all offspring of parents with a normal phenotype suggests the possibility of a compound heterozygous mutation or non-penetrance during the process of inheritance of Milroy disease.