MedGen

Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life. [from GeneReviews]

Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma The locus for susceptibility to familial cutaneous malignant melanoma-1 (CMM1) has been mapped to chromosome 1p36. Other CMM susceptibility loci include CMM2 (155601), caused by variation in the CDKN2A gene (600160) on chromosome 9p21; CMM3 (609048), caused by variation in the CDK4 gene (123829) on chromosome 12q14; CMM4 (608035), mapped to chromosome 1p22; CMM5 (613099), caused by variation in the MC1R gene (155555) on chromosome 16q24; CMM6 (613972), caused by variation in the XRCC3 gene (600675) on chromosome 14q32; CMM7 (612263), mapped to chromosome 20q11; CMM8 (614456), caused by variation in the MITF gene (156845) on chromosome 3p13; CMM9 (615134), caused by variation in the TERT gene (187270) on chromosome 5p15; and CMM10 (615848), caused by mutation in the POT1 gene (606478) on chromosome 7q31. Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (164757), STK11 (602216), PTEN (601728), TRRAP (603015), DCC (120470), GRIN2A (138253), ZNF831, BAP1 (603089), and RASA2 (601589). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (164757.0001) (Davies et al., 2002; Pollock et al., 2003). [from OMIM]

The signs and symptoms of PFIC2 are typically related to liver disease only; however, these signs and symptoms tend to be more severe than those experienced by people with PFIC1. People with PFIC2 often develop liver failure within the first few years of life. Additionally, affected individuals are at increased risk of developing a type of liver cancer called hepatocellular carcinoma.

In addition to signs and symptoms related to liver disease, people with PFIC1 may have short stature, deafness, diarrhea, inflammation of the pancreas (pancreatitis), and low levels of fat-soluble vitamins (vitamins A, D, E, and K) in the blood. Affected individuals typically develop liver failure before adulthood.

There are three known types of PFIC: PFIC1, PFIC2, and PFIC3. The types are also sometimes described as shortages of particular proteins needed for normal liver function. Each type has a different genetic cause.

Signs and symptoms of PFIC typically begin in infancy and are related to bile buildup and liver disease. Specifically, affected individuals experience severe itching, yellowing of the skin and whites of the eyes (jaundice), failure to gain weight and grow at the expected rate (failure to thrive), high blood pressure in the vein that supplies blood to the liver (portal hypertension), and an enlarged liver and spleen (hepatosplenomegaly).

Most people with PFIC3 have signs and symptoms related to liver disease only. Signs and symptoms of PFIC3 usually do not appear until later in infancy or early childhood; rarely, people are diagnosed in early adulthood. Liver failure can occur in childhood or adulthood in people with PFIC3.

Progressive familial intrahepatic cholestasis (PFIC) is a disorder that causes progressive liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals. [from MedlinePlus Genetics]

Cetuximab is a monoclonal antibody used in the treatment of metastatic colorectal cancer (mCRC) and cancer of the head and neck. Cetuximab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered as a weekly intravenous (IV) infusion, but in practice, is often given every other week to coincide with chemotherapy (for example, FOLFIRI or FOLFOX). Cetuximab has several off-label uses as well, which include non-small cell lung cancer, squamous cell carcinoma of the skin, and Menetrier’s disease. Interestingly, for colorectal cancer, the location of the primary tumor influences whether an individual with mCRC will respond to anti-EGFR therapy, and influences prognosis. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, currently only the mutation status of the tumor, and not the location of the tumor, is discussed in the drug label’s dosing recommendations. Resistance to cetuximab is associated with specific RAS mutations. The RAS family of oncogenes includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and are associated with resistance to anti-EGFR drugs such as cetuximab. In addition, mutations in NRAS and another gene, BRAF, have been associated with poor response to anti-EGFR therapy; however, BRAF mutation does not explicitly preclude anti-EGFR therapy. Combination therapies targeting both BRAF and EGFR have shown to improve survival for individuals with wild-type RAS and mutant BRAF. The 2018 FDA-approved drug label for cetuximab states that for mCRC, cetuximab is indicated for K- and N-RAS wild-type (no mutation), EGFR-expressing tumors. The label states that an FDA-approved test must be used to confirm the absence of a RAS mutation (in either KRAS or NRAS) prior to starting cetuximab. While the FDA label also states that EGFR expression should also be confirmed by an approved test prior to starting therapy for mCRC, this is largely not implemented in practice, nor is it recommended by professional oncology society guidelines. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have mutations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to cetuximab (and panitumumab) highly unlikely unless given a BRAF inhibitor. [from Medical Genetics Summaries]

'Familial pseudohyperkalemia' (PSHK) is a term that was coined to describe conditions in which a patient presents with pseudohyperkalemia as a result of a temperature-based abnormality in the transport of potassium (K) and sodium (Na) across the red cell membrane, in association with essentially normal hematology. PSHK can be considered to be the clinically benign, nonhemolytic cousin of hereditary stomatocytic leaky-cell, congenital hemolytic anemias (see 194380) (summary by Gore et al., 2002). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380. [from OMIM]

Chylomicron retention disease (CMRD), characterized by the inability to secrete chylomicrons from the enterocytes following the ingestion of fat, typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat. This leads to steatorrhea – the severity of which relates to the fat content of the diet – and in some cases, hepatomegaly. Organ systems outside of the gastrointestinal tract may also be affected (often due to malnutrition and deficiencies of fat-soluble vitamins), including neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency, poor bone mineralization and delayed bone maturation due to vitamin D deficiency, prolonged international normalized ratio (INR) due to vitamin K deficiency, mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms), and (in a small proportion of adults) cardiomyopathy with decreased ejection fraction. Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels, and low serum concentrations of fat-soluble vitamins (A, D, E, and K). Endoscopy typically demonstrates a gelée blanche ("white hoar frosting") appearance of the duodenal mucosa. [from GeneReviews]

Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (155600). [from OMIM]

Familial atypical multiple mole melanoma (FAMMM) syndrome is an inherited genodermatosis characterized by the presence of multiple melanocytic nevi (often >50) and a family history of melanoma as well as, in a subset of patients, an increased risk of developing pancreatic cancer (see this term) and other malignancies. [from ORDO]

An autosomal dominant disorder defined by the presence of multiple dysplastic nevi and a history of melanoma in two family members. Patients are at an increased risk for the development of melanoma. [from NCI]