i<} Ea Genodermatoses and Congenital Anomalies sm Fg. 27-44 Xerodeima pigmentosum. (Courtesy of Dr. Ken Kraemer) produces the appearance of premature senility. There are ‘usually selerodermatous plaques on the extremities. The int! ligence remains intact. Arteriosclerosis, anginal attacks, and hemiplegia may occur, followed by death from coronary heart disease at an early age. Mutations in LMNA and mosaicism have been identified. Treatment is symptomatic, mainly control of diabetes mellitus and treatment of leg ulecrations Coppeda F: The epidemiology of premature aging and associated comotbities. Ci Interv Aging 2013, 81023-1032. Got M sta: Weiner syndrome: a changing pattern of clinical manifestatons in Japan (1917-2008). Bios Tends 2013, 7(1): 13-22. Falimwahi A, eta: Interfacial binding and aggregation of lamin A tal domains ascociated with Hutchnson-itora progeria syndrome, Biophys Chem 2014 105:43-48, LBuper J et a Spectum and rk of neoplasia in Werner syndrome: 2 systematic review. PLAS One 2073: 6(3):<60700, XERODERMA PIGMENTOSUM Xeroderma pigmentosum is an autosomal recessive disorder characterized by defective DNA thymidine dimer excision repair, extreme sun sensitivity, freckling, and skin cancer. Sun sensitivity and lentigines are early skin findings (Fig. 27-44), with median onset before age 2 years, Skin cancers often appear before age 10, and an increase in internal cancer has been noted as well. NIH data suggest a 10,000-fold increase in skin cancer before age 20. In a study of 830 patients, 45% had basal cell carcinoma or SCC, and melanoma was noted in 5%. ‘Most of the tumors occur on the head and neck. Ocular abnor- malities were found in 40% and included ectropion, corneal ‘opacity, and neoplasms, Progressive neurologic degeneration is seen in about 20% of patients. Xeroderma pigmentosum patients in complementation group C remain free of neuro logie problems, Complementation groups are defined by cor- rection of excision repair when fibroblasts from patients in different groups are fused. A variant type with normal exci- sion repair has alse been described. Retinoids can prevent the appearance of new cancers, but side effects are significant, and 2 rebound in the number of cancers occurs when the drug is stopped, suggesting that the tumors are merely suppressed, Photoprotection remains essential for management. Individ- ual tumors may be excised or destroyed with cryotherapy. Some may be treated with topical imiquimod or 5-FU, Topical application of recombinant liposomal encapsulated T4 endonuclease V repairs UV-induced cyclobutane-pyrimidine dimers and is a promising form of therapy. Gene therapy is also being pursued, Guidelines for evaluation and manage- ‘ment from the XP Society can be found at www.apsorg. A publication from the National Institutes of Health can be found. at_www-ccnih gov/ccc/patient_education/ pepubs/ xp7_17 pat Xeroderma pigmentosum, Cockayne syndrome, and tricho- thiodystrophy are all associated with defects in nucleotide excision repair (NER). Global genome NER repairs DNA lesions throughout the genome, preventing the accumulation ‘of mutations. Transcription-coupled NER prevents cell death caused by stalled transcription by rapidly identifying and repairing defects in the transcribed strand of DNA. Skin tumors in xeroderma pigmentosum patients have sunlight induced mutations in RAS, p53, and PICH genes. Mutations in the XPG gene give rise to the complementation group G form of xeroderma pigmentosum, as well as early-onset Cock- ayne syndrome, Prenatal diagnosis is possible with cultured chorionic villus cells or amniocytes. ‘The De Sanctis-Cacchione syndrome consists of xeroderma pigmentosum with mental deficiency, dwarfism, and gonadal hypoplasia. It occurs most often in patients in complementa- tion group D. Mutations in the ERCUE gene, which also cause ‘Cockayne syndrome type 8, have been demonstrated as well COCKAYNE SYNDROME Cockayne syndrome is an autosomal recessive syndrome with sun sensitivity and neurologic degeneration related to muta: tions in five genes (CSA, C88, XPB, XPD, and XPG) encoding for proteins involved in the transcription-coupled subpathway ‘of nucleotide excision DNA repair. It differs from xeroderma pigmentosum in the lack of freckling and skin cancer and in the presence of dwarfism, beaked nose, loss of subcutaneous tissue, deafness, basal ganglia calcification, failure of brain ‘growth, and retinopathy ‘Cockayne described the syndrome as dwarfism with retinal atrophy and deafness. Dermatologic features include photo dermatitis with telangiectasia, atrophy, and scarring. The hhands and feet are large and cyanotic. Microcephaly, sunken eyes, severe flexion contractures, dorsal kyphosis, cryptorchi- ism, cataracts, growth retardation, mental retardation, hypo- thalamic and cerebellar dysfunction, and retinitis pigmentosa ‘with optic atrophy may be seen, There is progressive neuto- logic disturbance with a shortened life span, Dermal fibro blasts and lymphoblastoid cell lines, as well as cultured amniotic fluid cells from an affected fetus, demonstrate impaired colony-forming ability and decreased DNA and RNA synthesis after UV light exposure (254 nm), The DNA helicases unwind DNA and are important in DNA replication, DNA repair, and RNA transcription. Mutations in XPB or XPD DNA helicase can result in xeroderma pigmen- tosum, Cockayne syndrome, or trichothiodystrophy. The ‘Cockayne syndrome complementation group A (CSA) and (CSB genes responsible for the syndrome are associated with RNA polymerase. CSB protein plays a role in transcription as well as global NER. Cockayne syndrome has also been associ- ated with mutations in XPC, XERODERMA PIGMENTOSUMICOCKAYNE SYNDROME COMPLEX ‘Some patients have skin features of xeroderma pigmentosum land neurologic features of Cockayne syndrome. Patients in complementation groups B, D, and G have presented with the complex. Mutations in the associated genes may give rise to Clinical manifestations of xeroderma pigmentosum, Cockayne syndrome, or the xeraderma pigmentosum/Cockayne syn- drome complex.TRICHOTHIODYSTROPHY Trichothiodystrophy is an autosomal recessive disorder char- acterized by photosensitivity, ichthyosis, brittle hair, intellec- impairment, decreased fertility, and short stature (PTBIDS), A review of 112 patients noted a wide spectrum of clinical features that varied from patients with only hair involvement those with profound developmental defects. Common fea- es included intellectual impairment (86%), short stature (73%, ichthyosis (65%), ocular abnormalities (1%), infections (46%), and photosensitivity (42%). More than half the patients hhad abnormal characteristics at birth, and 19 patients died before age 10, Tay syndrome is similar to trichothiodystrophy but lacks photosensitivity, Abnormalities in NER of |UV-damaged DNA are present in about 50% of Tay patients. The UV sensi- tivity and defective NER are similar to those of xeroderma pigmentosum patients, but these patients do not experience fan increased incidence of skin cancer. Two of the three deseribed complementation groups match xeroderma pig- ‘mentosum groups B and D, with the XPD gene accounting for most photosensitive trichothiodystrophy. A combined xero- derma pigmentosum/trichothiodystrophy complex has been described. Patients with trichothfodystrophy without xero- derma pigmentosum do not have an increase in skin cancer formation. The hait, with sulfur reduced to 50% of the normal value, has distinctive features under polarizing and light microscopy and scanning EM. With light microscopy, keratin orientation alternates in a pattern. With polarizing microscopy, the hair shows alternating bright and dark regions that give a striking, striped, of tiger tail, appearance, but the pattern may not be evident at birt, and a similar pattern of bright and dark bands has been described in the keratitis ichthyosis deafness syn- drome, Hairs demonstrate heterogeneous deficiency in sulfur, ‘with the greatest loss in areas of trichoschisis (clean fractures). Trichorthexis nodosa-like fractures may also be seen. In addi- tion, the hair is extremely flattened and folds ov like a thick ribbon. The hair shaft outline is irregular and slightly undulating, and the melanin granules are distributed in a wavy pattern, With scanning EM, the surface shows marked ridging and fluting, and the cuticle scales may be absent or greatly reduced. ‘Aarann MO, etal: Cockayne Syndiome group B protein stimulates NEILZ DNA glycesyase act, Mech Ageing Dev 2014; 136:1-14 Diiovanra a et a: Shining 2 ight on weradetma pigmentosum. J Invest Dermatol 2012; 152(3 Pt2) 785-708, Ferrando J tal: Further insights in wichothioistophy: a clinical, rmcteseopic, and utrastuctural study of 20 cases and iterature review Int J Tichology 2012: 43): 158163 Grossboig AL: Update on pediatie photosensitty disordets. Cu Opin Pediat 2015; 2545474470, areata M, at a: From laboratory tests to functional chatacterisaton of Cockayne syndtome. Mech Ageing Dev 2013, 13460) 171-178, Lehmann AR, etal: Xeroderma pigmentesum. Orphanet J Rare D5 2011; 670, Nodeinbofor Li otal: Xerodetma pigmentosum and other diseases of human prematute aging and DNA repair molecules to patents. Mech ‘Ageing Dev 2011; 132(6-7)340-947. BLOOM SYNDROME (BLOOM-TORRE-MACHACEK SYNDROME) Bloom syndrome is transmitted as an autosomal recessive trait, chiefly among Jewish persons of Fastern Furopean origin, Itis characterized by photosensitive telangiectatic erythema in the butterfly area of the face and dwarfism. Telangiectatic Fg. Z745 Bloom syndrome. erythematous patches resembling Iupus erythematosus develop in the first 2 years of life (Pig. 7-45). Bullous, crusted. lesions may be present on the lips. Exacerbation of skin lesions occurs during the summer. Other changes that may be noted are café au lait spots, ichthyosis, acanthosis nigricans, syndactyly, irregular dentition, lens opacities, prominent ears, hypospadias, and cryptorchidism. The stunted growth is char~ acterized by normal body proportions, no endocrine abnor ‘malities (except diabetes mellitus), and low birth weight at full term, Dolichocephaly and narrow, delicate facies are present, Immune functions are abnormal, and Gl and respiratory infec tions often occur. Cancer of all cell types and sites is increased in frequency. Leukemia, Iymphoma, adenocarcinoma of the sigmoid colon, and oral and esophageal SCC, as well as other ‘malignancies, have been associated with Bloom syndrome, ‘About one quarter of patients under age 20 develop a n plasm, Regular use of a broad-spectrum sunscreen, as well as photoprotection, is recommended. Testing for Bloom syn- drome should be performed in childzen with consanguineous parents and dysmorphie features, because growth hormone {treatment is contraindicated in these patients, The gene mutated in Bloom syndrome, BLM, codes for a RecQ DNA helicase, BLM is localized to the nuclear bodies and the nucleolus and is critical for genomic stability. BLM interacts with WRN, the DNA helicase mutated in Werner syndrome, and is part of a large BRCA-1-containing complex containing DNA repair factors, BLM expression is highest during the S and G2 phases of the cell cycle, BLM associates ‘with telomeres and ribosomal DNA. BLM interacts directly with ATM, the protein product of the gene mutated in ataxia- telangiectasia, and together they recognize abnormal DNA structures. Pk Cl, et a: Soliton stucture ofthe ReeO C-terminal domain of human Bloom syndrome protein. J Biomol NMR 2014, 56(2) 141147 Range JS ot a: Bloom synctomein short chlden born small for gestational age: a challenging diagnosis. J Cin Endocenol Metab 203; €9(10) 3000-2038, ‘Thomas ER, at al Surveilance and testment of malignancy in Bloom syndtome. Clin Oncol (R Cal Radial) 2008; 20(6)375-378 ROTHMUND-THOMSON SYNDROME (POIKILODERMA CONGENITALE) Rothmund-Thomson syndrome is a rare autosomal recessive disorder. Poikiloderma begins at 3-6 months of age, with 3 2 Es : é i & sr