Numbness and paresthesias in the median nerve distribution are the hallmark neuropathic symptoms (NS) of carpal tunnel entrapment syndrome. Weakness and atrophy of the thumb muscles may occur if the condition remains untreated, because the muscles are not receiving sufficient nerve stimulation. Discomfort is usually worse at night and in the morning. Most cases of CTS are of unknown cause. Risk factors include obesity, repetitive wrist work, pregnancy, genetics, and rheumatoid arthritis. There is tentative evidence that hypothyroidism increases the risk. Diabetes mellitus is weakly associated with CTS. The use of birth control pills does not affect the risk. Types of work that are associated include computer work, work with vibrating tools and work that requires a strong grip. Trauma may also place a role, as may genetics. Carpal tunnel is a feature of a form of Charcot-Marie-Tooth syndrome type 1 called hereditary neuropathy with susceptibility to pressure palsies. Other causes of this condition include intrinsic factors that exert pressure within the tunnel, and extrinsic factors (pressure exerted from outside the tunnel), which include benign tumors such as lipomas, ganglion, and vascular malformation. Severe carpal tunnel syndrome often is a symptom of transthyretin amyloidosis-associated polyneuropathy and prior carpal tunnel syndrome surgery is very common in individuals who later present with transthyretin amyloid-associated cardiomyopathy, suggesting that transthyretin amyloid deposition may cause carpal tunnel syndrome in these people. The median nerve can usually move up to 9.6 mm to allow the wrist to flex, and to a lesser extent during extension. Long-term compression of the median nerve can inhibit nerve gliding, which may lead to injury and scarring. When scarring occurs, the nerve will adhere to the tissue around it and become locked into a fixed position, so that less movement is apparent. Normal pressure of the carpal tunnel has been defined as a range of 2–10 mm, and wrist flexion increases this pressure 8-fold, while extension increases it 10-fold. Repetitive flexion and extension in the wrist significantly increase the fluid pressure in the tunnel through thickening of the synovial tissue that lines the tendons within the carpal tunnel. Genetic factors are believed to be the most important determinants of who develops carpal tunnel syndrome. A genome-wide association study (GWAS) of carpal tunnel syndrome identified 16 genomic loci significantly associated with the disease, including several loci previously known to be associated with human height.