Dominant negative mutations: Most individuals with Li–Fraumeni syndrome are heterozygous for a mutant TP53 gene, and some p53 mutants can inhibit the function of the wild-type p53 in a dominant negative manner. Mutated p53 proteins are typically more stable than wild-type, and can inhibit the activity of the wild-type protein in suppressing cell proliferation and in inducing cell cycle arrest. Due to the mutant p53 being able to inhibit some wild-type p53, damaged cells are at an even greater susceptibility to proliferate and become transformed, resulting in cancer.LFS2: mutations in CHEK2
Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene; it regulates the action of p53 and is activated by ATM, which detects DNA damage, and in this way, DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death). LFS-L:
Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like". LFS-like individuals generally do not have any detectable p53 mutations, and tend to be diagnosed on either the Birch or Eeles criteria. A third locus has been mapped to the long arm of chromosome 1 (1q23), but no gene has yet been identified.Another locus that has been linked to this syndrome is CDKN2A-CDKN2B.
Anterior cutaneous nerve entrapment syndrome (ACNES) is a nerve entrapment condition that causes chronic pain of the abdominal wall. It occurs when nerve endings of the lower thoracic intercostal nerves (7–12) are entrapped in abdominal muscles, causing a severe localized nerve (neuropathic) pain that is usually experienced at the front of the abdomen. ACNES is frequently overlooked and unrecognized, although the incidence is estimated to be 1:2000 patients.The relative unfamiliarity with this condition often leads to significant diagnostic delays and misdiagnoses, often resulting in unnecessary diagnostic interventions and futile procedures. Physicians often misdiagnose ACNES as irritable bowel syndrome or appendicitis as symptoms of the condition are not unique to this syndrome. Signs and symptoms
Affected individuals typically experience limited relief from standard pain relieving medication, with the exception of some neuroleptic agents. Patients frequently experience pseudovisceral phenomena or symptoms of altered autonomic nervous system function including nausea, bloating, abdominal swelling, loss of appetite with consecutively lowered body weight or an altered defecation process.Pain is typically related to tensing the abdominal wall muscles, so any type of movement is prone to aggravate pain. Lying quietly can be the least painful position. Most patients report that they cannot sleep on the painful side. Diagnosis
Once ACNES is considered based on the patients history, the diagnosis can be made via a thorough physical examination: looking for a painful spot, which worsens by tensing the abdominal muscles with lifting the head and straightened legs (Carnetts sign).