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SHORT COMMUNICATION Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Fibroblast Growth Factor Receptor 3 Epidermal Naevus Syndrome with Urothelial Mosaicism for the Activating p. Ser249Cys FGFR3 Mutation
Didier BESSIS 1, 2, Julie PLAISANCIÉ 3, Véronique GASTON 3 and Eric BIETH 3
1
Department of Dermatology, Saint-Eloi Hospital, University Hospital of Montpellier, 80 avenue A. Fliche, FR-34295 Montpellier cedex 5,
2
INSERM U1058, Montpellier, and 3 Department of Medical Genetics, Purpan Hospital, University Hospital of Toulouse, Toulouse, France. E mail: d-bessis @ chu-montpellier. fr Accepted Oct 26, 2016; Epub ahead of print Oct 27, 2016
Fibroblast growth factor receptor 3 epidermal naevus syndrome( FGFR3-ENS), also known as Garcia-Hafner- Happle syndrome, is a rare and distinctive epidermal naevus( EN) syndrome, clinically characterized by a systematized keratinocytic EN of soft and velvety type, with inconstant cerebral and skeletal involvement( 1). We report here a new case of FGFR3-ENS with the postzygotic FGFR3 p. Ser249Cys mutation detected in both affected skin and urothelial cells.
CASE REPORT
A 30-month-old girl was referred for assessment of systematized EN. She was born at term and was otherwise healthy, with normal skeletal and neurocognitive development and no remarkable family history. Skin changes were first noted on the neck at 4 months, with spreading to trunk, limbs and face over the first year of life. Physical examination disclosed a systematized and widespread linear brown EN of a soft and velvety type, following Blaschko’ s lines, associated with confluent thick and papillomatous plaques over the neck, axillary and groin regions( Fig. 1). Histological examination of the EN revealed hyperkeratosis, acanthosis and papillomatosis. Urine sediment failed to reveal haematuria. Ophthalmologic examination, electroencephalogram, total-body skeletal radiographs, and pelvic ultrasonography were normal. Cerebral magnetic resonance imaging( MRI)
Fig. 1. Systematized and widespread epidermal naevus distributed along Blaschko’ s lines.( a) Trunk involvement.( b) Confluent papillomatosis acanthosis nigricans-like lesions of the axillary area.
Fig. 2. Detection of the c. 746C > G( p. Ser249Cys) FGFR3 mutation in the proband by( A) allele-specific PCR and( B) Sanger sequencing.( A) Genomic DNA was isolated from different types of tissue and subjected to duplex PCR amplification generating 2 amplicons: a first amplicon of 397 bp used as an internal control( to check the efficiency of the amplification), and a second smaller amplicon whose reverse primer is located on the c. 746C > G mutation( expected size 237 bp). This allele-specific primer allows efficient discrimination of the mutation in cases of mosaicism. The PCR products were then separated by electrophoresis in 2 % agarose gel. Note the single 397 bp amplicon in the healthy control( gDNA isolated from blood) in Lane 1 vs. 2 amplicons with similar intensity in the heterozygous control for the c. 746C > G mutation( trophoblast cells) in Lane 2. Lane 3: presence of the 2 expected amplicons with lower intensity for the smaller amplicon in the proband skin lesion specimen. In this tissue, the c. 746C > G mosaicism was estimated at approximately 30 %. Lane 4: absence of the mutation in the proband healthy skin specimen. Lane 5: presence of the 2 expected amplicons in the proband urine sample with mosaicism estimated at 10 %. Lane 6: absence of the mutation in the proband blood sample. Lane 7: presence of the 2 expected amplicons in the proband saliva sample: mosaicism was estimated at approximately 5 %. Lane 8: although very faint, the 2 expected amplicons can be noted in the proband hair sample with mosaicism estimated at approximately 5 %. Lane 9: negative control. Lane 10: pBR322 DNA / BsuRI( HaeIII) DNA ladder( Thermo Fisher Scientific, Waltham, MA, USA).( B) Electropherograms generated by Minor Variant Finder( MVF) software to detect the c. 746C > G mosaicism in the FGFR3 gene sequencing of, respectively:( a) the proband skin lesion specimen,( b) the proband urine sample, and( c) a negative control. After removing the background noise signal due to sequencing, the c. 746C > G mosaicism was estimated by the MVF software at:( a) 34.2 %,( b) 8.6 %, and( c) 0 %( no detection of the mutation) on the respective forward sequences. Note, this mosaicism rate was also calculated on the reverse FGFR3 sequence and the mean of the 2 ratios( forward and reverse) was calculated. The position of the c. 746C > G mutation detected by the software is indicated by a vertical blue line. doi: 10.2340 / 00015555-2554 Acta Derm Venereol 2017; 97: 402 – 403
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica.