A Novel Missense Mutation in the CYLD Gene in a Spanish Family

CORRESPONDENCE

ase chain reaction; and further sequencing analysis was RESEARCH LETTERS performed. We identified 1 mutation not previously reported. The mutation was found in all patients but not in the healthy members of this family. The change was a point mutation in exon 20 (G2687C) that resulted in sub- A Novel Missense Mutation stitution of glycine at 896 by alanine (Figure 2). The in the CYLD Gene in a Spanish Family mutation was not detected in 110 unrelated controls. With Multiple Familial Trichoepithelioma Comment. Herein, we report a novel CYLD gene rooke-Spiegler syndrome (BSS) includes the com- mutation at nucleotide 2687 that carries out 1 amino bination of spiradenomas, cylindromas, and acid change at glycine 896 in the 4 affected members trichoepitheliomas. It has been postulated that of this family but not in the proband. The fact that we B have not detected this change in 110 unaffected controls BSS results from defects in the regulation of putative stem cells of the folliculosebaceous-apocrine unit.1 This fol- makes a contribution to the genotype-phenotype corre- licular dysregulation may give rise to 3 different geno- lation in MFT. dermatoses: familial cylindromatosis (FC), multiple fa- The CYLD gene is considered a negative regulator of ␬ 5 milial trichoepithelioma (MFT), or the classic triad of BSS. nuclear factor kappa B(NF- B). Thereby, inhibition or

See also pages 1125, 1153, A B and 1194 I. The gene for FC was mapped to chromosome 1 16q12-q13.2 At present, 32 different germline muta- G/A 3 tions in the CYLD gene have been described, 20 in II. families with FC, 8 in families with MFT, and 4 in fami- 1 2 3 lies with BSS. Taken together, these observations sug- G/A G/A G/A gest that these inherited syndromes associated with skin III. 1 appendage tumors not only share a common genetic ba- G/G sis but also may represent phenotypic variation of the same disease.4

Report of a Case. An 8-year-old girl came to our department with her parents. Her mother, grandmother, and 2 aunts were diagnosed as having trichoepithelioma since Figure 1. Clinical picture (A) and family pedigree (B) for the present case. A, childhood (Figure 1). The parents of our patient wanted Multiple trichoepitheliomas are present on the upper eyelids, nose, nasolabial to know if their daughter might harbor any genetic sus- folds, and the upper lip in the mother of the proband. B, Pedigree of the ceptibility for these cutaneous lesions. family: for individuals whose DNA samples have been analyzed, the allele sequences at codon 896 have been indicated as G (glycine) or A (alanine). Blood samples were obtained from available family The proband (arrow) encodes foraGonboth alleles (G/G), whereas the members and 110 unrelated controls. Genomic DNA was affected family members are heterozygous for the mutation (black circles) extracted; all coding exons were amplified by polymer- encode an A on the mutant allele.

A Wild-type sequence B Mutant sequence Intron 19 Exon 20 G896A

C T C T G T G C C A T A G G T G G T C A G A A T G C T C T G T G C C A T A G S T G G T C A G A A T G

Figure 2. Genetic analysis of the family with multiple familial trichoepithelioma. Shown are wild-type DNA (A) and mutant sequences (B) of exon 20 of CYLD from control and affected members, respectively.

(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 WWW.ARCHDERMATOL.COM 1209

©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 inactivation of CYLD enhances the action of NF-kB and leads phatase, nonreceptor type 11), a gene encoding a tyrosine- to increased resistance to apoptosis and carcinogenesis.6 phosphatase protein named SHP-2, with 2 particular “hot To our knowledge, this mutation has not been previ- spots” in exons 7 and 12.2-5 Despite overlapping clinical ously described. The known mutations of the CYLD gene manifestations, LS is distinct from Noonan syndrome, an- are mostly located in the C-terminal portion. other PTPN11 gene mutation–related disorder but with Germline mutations display tissue-specific function a different mutation spectrum. Herein we report the first loss. Another possibility would be that the germline mu- case to our knowledge of typical LS featuring a new tation determines the tissues where the preferred sec- PTPN11 gene mutation. ond hit occurs. When the second hit occurs in eccrine- apocrine cells, the patients become susceptible to multiple Report of a Case. A 39-year-old woman with a medical cylindromas; in hair follicle cells, the patients exhibit sus- history of deafness and a familial background of Down ceptibility to multiple cylindromas or MFT.6 syndrome in a sister was referred for evaluation of pig- Our study shows the importance of mutation screen- mentary changes that first appeared during infancy as- ing of the CYLD gene in patients affected with FC and MFT sociated with mild facial dysmorphism. Clinical exami- as well as their relatives to identify early clinical manifes- nation disclosed multiple light or dark brown macules tations. Analysis of control volunteers in this report con- of varied sizes scattered throughout her whole body sur- firms the role of this missense mutation as the cause of this face including her face, palmoplantar areas, lips, and con- syndrome. Further studies evaluating the effect of this mu- junctiva (Figure 1). There were no lentigines on the other tation in animal models must be considered. mucous membranes. Facial examination revealed hyper- telorism. Electrocardiography showed a first-degree atri- Agustıń Espanã,MD oventricular block, whereas heart ultrasound evalua- Fermin Garcıá-Amigot, PhD tion did not find any valve abnormality. Hearing Leyre Aguado, MD investigations confirmed sensorineural deafness. There Jesu´s Garcıá-Foncillas, MD were no urogenital abnormalities, endocrinopathy, or Correspondence: Dr Espan˜ a, Department of Dermatol- growth retardation. A diagnosis of LS was established ogy, University Clinic of Navarra, University of Na- based on the presence of 4 criteria. varra, PO Box 31080, Pamplona, Navarra, Spain (aespana After obtaining the patient’s consent, we undertook @unav.es). direct sequencing of the PTPN11 coding region and dis- Financial Disclosure: None reported. covered a previously undescribed (to our knowledge) het- Funding/Support: This study was supported in part by erozygous missense mutation in exon 13, namely a the Spanish Academy of Dermatology. G1493T transversion leading to an R498L change in amino Role of the Sponsor: The sponsor had no role in the de- acid sequence (Figure 2). No genetic analysis of her rela- sign and conduct of the study, in the collection, analysis tives could be carried out to establish a diagnosis of de and interpretation of data, or in the preparation review, novo or inherited mutation. or approval of the manuscript. Comment. The SHP-2 phosphatase plays several impor- 1. Clarke J, Ioffreda M, Helm KF. Multiple trichoepithelioma: a folliculosebaceous- tant roles in cellular physiologic function, mainly in cell apocrine genodermatosis. Am J Dermatopathol. 2002;24(5):402-405. proliferation, differentiation, migration, and adhe- 2. Fenske C, Banerjee P, Holden C, Carter N. Brooke-Spiegler syndrome locus 6-8 assigned to 16q12-q13. J Invest Dermatol. 2000;114(5):1057-1058. sion. This protein contains 2 main domains: a C- 3. The Human Gene Mutation Database at the Institute of Medical Genetics in terminal protein-tyrosine phosphatase (PTP) domain in- Cardiff [registration required]. http://www.hgmd.cf.ac.uk/ac/all/php ?gene=CYLD. Accessed February 9, 2007. volved in catalytic activity and 2 N-terminal Src homology 4. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in Brooke- 2 (SH2) domains interacting with the PTP domain, keep- Spiegler syndrome, familial cylindromatosis, and multiple trichoepithe- ing it folded and inactive (Figure 2).3 To our knowl- lioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005;124 (5):919-920. edge, only 7 PTPN11 mutations have been reported in 5. Regamey A, Hohl D, Liu JW, et al. The tumor suppressor CYLD interacts with patients with LS, all of them in the PTP domain in exons TRIP and regulates negatively nuclear factor kB activation by tumor necrosis 7 (Y279C and Y279S), 12 (T468M and A461T), and 13 factor. J Exp Med. 2003;198(12):1959-1964. 6. Liang YH, Gao M, Sun LD, et al. Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005;153(6):1213-1215.

A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome

n 1969, Gorlin et al1 described an autosomal domi- nant syndrome encompassing multiple lentigines, I electrocardiographic abnormalities, ocular hyper- telorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, currently known as LEOPARD syndrome (LS). Recently, it has been reported that most cases of LS are probably related to heterozygous mutations of PTPN11 (protein-tyrosine phos- Figure 1. Numerous lentiginous elements scattered throughout the trunk.

(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007 WWW.ARCHDERMATOL.COM 1210