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1.
Fam Cancer ; 17(4): 601-606, 2018 10.
Article in English | MEDLINE | ID: mdl-29356994

ABSTRACT

Many cancer predisposition syndromes are preceded or accompanied by a range of typical skin signs. Gorlin syndrome is a rare multisystem inherited disorder which can predispose to basal cell carcinomas (BCCs), childhood medulloblastomas in addition to various developmental abnormalities; the majority of cases are due to mutations in the PTCH1 gene. Approximately 5% of cases have been attributed to a mutation in the SUFU gene. Certain phenotypic features have been identified as being more prevalent in individuals with a SUFU mutation such as childhood medulloblastoma, infundibulocystic BCCs and trichoepitheliomas. Recently hamartomatous skin lesions have also been noted in families with childhood medulloblastoma, a "Gorlin like" phenotype and a SUFU mutation. Here we describe a family previously diagnosed with Gorlin syndrome with a novel SUFU splice site deleterious genetic variant, who have several dermatological features including palmar sclerotic fibromas which has not been described in relation to a SUFU mutation before. We highlight the features more prominent in individuals with a SUFU mutation. It is important to note that emerging therapies for treatment of BCCs in patients with a PTCH1 mutation may not be effective in those with a SUFU mutation.


Subject(s)
Carcinoma, Basal Cell/genetics , Mutation , Patched-1 Receptor/genetics , Repressor Proteins/genetics , Basal Cell Nevus Syndrome/genetics , Carcinoma, Basal Cell/pathology , Female , Fibroma/genetics , Fibroma/pathology , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Pedigree , RNA Splice Sites , Skin Neoplasms/genetics , Skin Neoplasms/pathology
2.
Heart Lung Circ ; 26(6): 612-618, 2017 Jun.
Article in English | MEDLINE | ID: mdl-27916589

ABSTRACT

BACKGROUND: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins. METHODS AND RESULTS: Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners. CONCLUSIONS: Thus, our data conclude that, similar to previously described ANK2 loss-of-function "point mutations", large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed.


Subject(s)
Ankyrins/genetics , Arrhythmias, Cardiac/genetics , Chromosomes, Human, Pair 4/genetics , Chromosomes, Human, Pair 9/genetics , Haploinsufficiency , Translocation, Genetic , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Adult , Arrhythmias, Cardiac/physiopathology , Family , Female , Fetal Diseases/genetics , Fetal Diseases/physiopathology , Humans , Male , Pregnancy
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