The tissue now has a spongy consistency and is considered non-pitting: when pressed by the fingertips, the affected area bounces back without indentation. Fibrosis found in Stage 2 lymphedema marks the beginning of the hardening of the limbs and increasing size. Stage 3: Swelling is irreversible and usually the limb(s) or affected area becomes increasingly large. The tissue is hard (fibrotic) and unresponsive; some patients consider undergoing reconstructive surgery, called "debulking". This remains controversial, however, since the risks may outweigh the benefits and the further damage done to the lymphatic system may in fact make the lymphedema worse. Stage 4: The size and circumference of the affected limb(s) become noticeably large. Bumps, lumps, or protrusions (also called knobs) on the skin begin to appear. Stage 5: The affected limb(s) become grossly large; one or more deep skin folds is prevalent among patients in this stage. Stage 6: Knobs of small elongated or small rounded sizes cluster together, giving mossy-like shapes on the limb. Mobility of the patient becomes increasingly difficult. Stage 7: The person becomes "handicapped", and is unable to independently perform daily routine activities such as walking, bathing and cooking. Assistance from the family and health care system is needed. Grades
Lymphedema can also be categorized by its severity (usually referenced to a healthy extremity):
Grade 1 (mild edema): Involves the distal parts such as a forearm and hand or a lower leg and foot. The difference in circumference is less than 4 cm and other tissue changes are not yet present.
Another form of hereditary lymphedema is Milroys disease caused by mutations in the VEGFR3 gene. Hereditary lymphedema is frequently syndromic and is associated with Turner syndrome, lymphedema–distichiasis syndrome, yellow nail syndrome, and Klippel–Trénaunay–Weber syndrome.One defined genetic cause for hereditary lymphedema is GATA2 deficiency. This deficiency is a grouping of several disorders caused by common defect, viz., familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the genes product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are deficient and individuals develop over time hematological, immunological, lymphatic, and/or other disorders. GATA2 deficiency-induced defects in the lymphatic vessels and valves underlies the development of lymphedema which is primarily located in the lower extremities but may also occur in other places such as the face or testes (i.e. hydrocele). This form of the deficiency, when coupled with sensorineural hearing loss which may also be due to faulty development of the lymphatic system, is sometimes termed the Emberger syndrome.Primary lymphedema has a quoted incidence of approximately 1-3 births out of every 10,000 births, with a particular female preponderance to male ratio of 3.5:1 In North America, the incidence of primary lymphedema is approximately 1.15 births out of every 100,000 births Compared to secondary lymphedema, primary lymphedema is relatively rare.