Chromosomal Abnormalities Chromosome Mutations/Anomalies / Diseases Number 1 1. CMM 1 (Cutaneous Malignant Melanoma) is on the chromosome 1 = Autosomal Dominant, for dysplastic Nevi (BK moles = BK derived from the initials of two of their patient for cutaneous pigmented lesion which had particular clinical representation). (Page 318). 1) Dysplastic nevus = a nevus exceeding 5 mm in diameter, with irregular, indistinct, or notched borders and mixed tan-to-black and pink-to-red color. Microscopically these are basally nested and scattered intraepidermal melanocytes with hyperchromatic nuclei larger than those of basal keratinocytes. If multiple and associated with a family history of melanoma, these nevi have a high risk of malignant change, but isolated dysplastic nevi in the absence of a family history of melanoma are less frequently premalignant. See: dysplastic nevus syndrome. 2) Malignant mole syndrome = irregularly shaped, variously colored, distinctively melanocytic, 5–10-mm nevi occurring in large numbers (to over 100) primarily on the trunk and extremities, with a high risk of malignancy; probably autosomal dominant inheritance. 2. Variegate porphyria (VP)= porphyria characterized by abdominal pain and neuropsychiatric abnormalities, by dermal sensitivity to light and mechanical trauma, by increased fecal excretion of proto- and coproporphyrin, and by increased urinary excretion of ,-aminolevulinic acid, porphobilinogen, and porphyrins; due to a deficiency of protoporphyrinogen oxidase; autosomal dominant inheritance, caused by mutation in the gene for protoporphyrinogen oxidase (PPOX) on chromosome 1q. Syn: South African type porphyria, protocoproporphyria hereditaria. 3. Owren disease= Factor 5 deficiency = Factor V Leiden deficiency = Factor 5 Leiden deficiency = due to mutation of chromosome 1q23= a congenital deficiency of factor V, resulting in prolongation of prothrombin time; bleeding and clotting times are consistently prolonged; autosomal recessive inheritance caused by mutation in the F5 gene on chromosome 1q. Factor 5 Leiden deficiency is the most common inherited disorder that causes hypercoagulable state and predisposed to thromboses especially DVT (deep venous thrombosis) of 1 lower extremities. Prevalence of factor V deficiency may be as high as 5-6% in the population. (Note: Factor V Leiden is not the same as factor V deficiency. Factor 5 Leiden causes a hypercoagulable state (=thrombophilia = increase risk of clotting and DVT) whereas factor 5 deficiency causes an increase risk of bleeding). 4. Uridyl Diphosphate-galactose-4-epimerase deficiency = UDP-galactose-4-epimerase deficiency = Cytogenetic Location: 1p36-p35 . GALE gene is “UDP-galactose-4-epimerase. The GALE gene is located on the short (p) arm of chromosome 1 between positions 36 and 35. The GALE gene provides instructions for making an enzyme called UDP-galactose-4-epimerase. This enzyme enables the body to process a simple sugar called galactose, which is present in small amounts in many foods. Galactose is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas. UDP- galactose-4-epimerase converts a modified form of galactose (UDP-galactose) to another modified sugar (UDP-glucose). Glucose is a simple sugar that is the main energy source for most cells. This enzyme also promotes the reverse chemical reaction, the conversion of UDP-glucose to UDP-galactose. UDP-galactose is used to build galactose-containing proteins and fats, which play critical roles in chemical signaling, building cellular structures, transporting molecules, and producing energy. Galactosemia is caused by mutations in the GALE gene. More than 20 mutations in the GALE gene have been identified in people with a form of galactosemia known as type III or galactose epimerase deficiency. Most of these genetic changes alter a single protein building block (amino acid) in UDP-galactose-4-epimerase, which makes the enzyme unstable or disrupts its usual function. Some GALE mutations severely reduce or eliminate the activity of UDP- galactose-4-epimerase in all of the body's tissues. These genetic changes lead to a severe form of galactosemia type III described as the generalized form. A loss of enzyme activity prevents cells from processing galactose obtained from the diet. As a result, compounds associated with galactose processing can build up to toxic levels in the body. The accumulation of these substances damages tissues and organs, leading to serious complications such as clouding of the lens of the eye (cataract), intellectual disability, and damage to the liver, kidneys, and brain. Other mutations in the GALE gene reduce the activity of UDP-galactose-4-epimerase in red blood cells only. These genetic changes underlie a much milder form of galactosemia type III described as the 2 peripheral form. Affected individuals may not have any of the complications typically associated with galactosemia and often do not require treatment. Researchers are unclear why the effects of some GALE mutations are restricted to blood cells, while other mutations affect all of the body's tissues and cause severe medical problems. In uridyl diphosphate galactose – 4- epimerase deficiency gets hypotonia and nerve deafness (Peds, p 6). 5. Stargardt Disease= fundus flavimaculatus initiated with atrophic macular lesions, caused by mutation in the ATP- binding cassette transporter, retina-specific gene (ABCR) on 1p. 6. Fucosidosis = A metabolic storage disease characterized by accumulation of fucose-containing glycolipids and deficiency of the enzyme )-fucosidase; progressive neurologic deterioration begins after the first year of life, accompanied by spasticity, tremor, and mild skeletal changes; autosomal recessive inheritance, caused by mutation in the )-1-fucosidase gene on chromosome 1. 7. Mutilating keratoderma= diffuse keratoderma of the extremities, with the development during childhood of constricting fibrous bands around the middle phalanx of the fingers or toes that may lead to spontaneous amputation; there may be congenital deafness; autosomal dominant inheritance, caused by mutation in the gene for loricrin (LOR), a component of the epidermal differentiation complex on 1q. Syn: keratoma hereditarium mutilans, Vohwinkel syndrome. 8. Hyperprolinemia= A metabolic disorder characterized by enhanced plasma proline concentrations and urinary excretion of proline, hydroxyproline, and glycine; autosomal recessive inheritance. Type I hyperprolinemia is associated with a deficiency of proline oxidase and renal disease; Type II hyperprolinemia is associated with a deficiency of !- pyrroline-5-carboxylate dehydrogenase, mental retardation, and convulsions and is caused by mutation in the !-pyrroline 5 carboxylate gene (P5CD) on 1p. 9. t (2, 13) = alveolar Rhabdomyosarcoma. (Kaplan peds, p218). The most common types of rhabdomyosarcoma (RMS) are alveolar RMS (ARMS), which are characterized by the specific translocation t (2; 13)(q35; q14) or its rarer variant, t (1; 13)(p36; q14), producing the fusion genes PAX3-FKHR and PAX7-FKHR, respectively, and embryonal RMS (ERMS), which is characterized by multiple numeric chromosome changes. 10. Multiple epiphyseal dysplasia (EDM)= a disorder 3 of epiphyses characterized by difficulty in walking, pain and stiffness of joints, stubby fingers, and often short stature; on X-ray examination, the epiphyses are irregular and mottled, the ossification centers are late in appearance and may be multiple, but the vertebrae are normal. There are at least 3 forms of autosomal dominant inheritance: EDM1 due to mutation in the cartilage oligomeric matrix protein gene (COMP) on chromosome 19p; EDM2, due to mutation in the type IX collagen gene (COL9A2) on 1p; and EDM3, which is linked to an unknown locus. There is also an autosomal recessive form. Syn: dysplasia epiphysealis multiplex 11. Erythrokeratodermia variabilis= a dermatosis characterized by hyperkeratotic plaques of bizarre, geographic configuration, associated with erythrodermic areas that may vary remarkably in size, shape, and position from day to day; hair, nares, and teeth are not affected; onset is usually in the first year of life. Autosomal dominant or recessive inheritance, caused by mutation in the connexin gene encoding gap junction protein beta-3 (GJB3) on 1p. 12. 1p19q codeletion in anaplastic oligodendrogliomas= Neuronal differentiation in oligodendrogliomas with 1p19q codeletion and support the hypothesis that the cell of origin for gliomas with 1p19q codeletion could be a bi-potential progenitor cell, able to give rise to both neurons and oligodendrocytes. Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. A recent study analyzed survival based on chromosomal deletions and the effects of radiation or chemotherapy as treatment, with the following results (both low-grade and anaplastic oligodendrogliomas): 1p/19q deletion with radiation = 121 months (mean), 1p/19q deletion with chemotherapy = over 160 months (mean not yet reached), no 1p/19q deletion with radiation = 58 months (mean), and no 1p/19q deletion with chemotherapy = 75 months (mean). Another study divided anaplastic oligodendrogliomas into the following four clinically relevant groups of histology with the following results: combined 1p/19q loss = median survival was >123 months (not yet reached), 1p loss only = median survival was 71 months, 1p intact with TP53 mutation = median survival 71 months, and 1p intact with no TP53 mutation =