D
CP
CED
CPD • A memorable patient
Clinical and Experimental Dermatology
Limited ectrodactyly, ectodermal dysplasia and cleft lip–palate syndrome with a p63 mutation, associated with linear and whorled naevoid hypermelanosis P. Pratsou,1 C. L. Defty,1 L. Ozoemena,2 J. A. McGrath,3 C. Moss4 and J. E. Gach1 1 Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; 2GSTS Pathology, St Thomas’ Hospital, London, UK; 3King’s College London (Guy’s Campus), London, UK; and 4Department of Dermatology, Birmingham Children’s Hospital, Birmingham, UK
doi: 10.1111/ced.12259
An 18-year old Malaysian student presented with pigmented marks on his trunk and limbs, which had been present since birth. He also had uncorrected congenital deformities of his hands and feet, and a history of surgically treated congenital cataracts and glaucoma. He was the third of four children born to nonconsanguineous parents, with no family history of similar problems or of orofacial clefting. On physical examination, the patient was found to have widespread macular hyperpigmentation in streaks and whorls along the lines of Blaschko (Fig. 1). He also had hypodontia, microdontia and ectrodactyly with median clefts of both hands and feet (Fig. 2), consistent with split-hand split-foot malformation (SHFM). The hair and nails appeared normal, and systemic examination was unremarkable. Blood samples were collected, and DNA extracted from lymphocytes. Mutation analysis identified a heterozygous cytosine to thymine transition at nucleotide 982 (c.982C>T) in the p63 gene, resulting in the missense mutation, p.Arg280Cys, within the DNA-binding domain. The proband’s parents were not available for genetic testing. p63-associated disorders encompass a spectrum of phenotypes with varying combinations of ectodermal dysplasia, orofacial clefting, and limb, ocular and other malformations. Heterozygous missense mutations affecting several amino acid residues of p63 have been reported. Interestingly, our patient’s missense muta-
Correspondence: Dr Penelope Pratsou, Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, UK E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 13 October 2013
266
Clinical and Experimental Dermatology (2014) 39, pp266–268
tion has been previously found in patients with both ectrodactyly, ectodermal dysplasia and cleft lip–palate (EEC) syndrome and non-syndromic SHFM.1 EEC syndrome, which is often incomplete, best describes our patient’s clinical phenotype of ectrodactyly and ectodermal dysplasia without orofacial clefting. No other p63-associated features were clinically identified in our patient (Table 1). The balance between the ΔNp63/ TAp63 isoforms may contribute to phenotypic variability in EEC syndrome, with TAp63 serving as genetic modifier.2 In addition, our patient had linear and whorled naevoid hypermelanosis (LWNH), a pigmentary pattern often associated with chromosomal mosaicism, and probably reflecting mosaicism for a mutation affecting a pigmentary gene.3 Of note, the only other reported patient with LWNH associated with SHFM had a son with EEC syndrome resulting from the p63 mutation R204W. Mosaicism for this mutation was found in the father, and was considered to be the likely cause of his pigmentary pattern and milder clinical phenotype.4 Although the identified mosaicism was for a mutation in p63 rather than in a pigmentary gene, the mutation might have disrupted expression of a pigmentary gene, as p63, a transcription factor, is known to regulate the expression of genes involved in epidermal differentiation.5 Thus, we did consider the possibility that somatic mosaicism for p63 may have caused the pigmentary mosaicism (PM) in our patient; however, we did not detect any mosaicism for the p63 mutation. DNA extracted from punch biopsies of both affected and unaffected skin contained the mutation p.Arg280Cys. Neither was there any evidence of chromosomal mosaicism to account for LWNH; cytogenetic analysis of adequate numbers of blood lymphocytes and skin fibroblasts was normal. Chromosomal mosaicism could not be excluded
ª 2014 British Association of Dermatologists
D CP A memorable patient
(a)
(b)
(c)
Figure 1 Striking macular hyperpigmented streaks and whorls in a blaschkoid distribution affecting (a) anterior trunk, (b) back and (c)
thighs.
(a)
(b)
(c)
Figure 2 (a,b) Split-hand split-foot malformation; (c) retention of deciduous lower central incisors, indicating hypodontia and conical
upper lateral incisors, consistent with microdontia.
entirely, because standard cytogenetic techniques can detect chromosomal mosaicism in only 20–30% of cases. Furthermore, abnormal cells may grow preferentially to normal cells in vitro, masking mosaicism. In addition, the lines of Blaschko reflect embryonic migration paths of ectodermally derived tissues, thus cytogenetic analysis of fibroblasts may fail to detect mosaicism for a pigmentary gene.3 Nonetheless, the absence of demonstrable chromosomal mosaicism lends support to the unifying hypothesis of undetected mosaicism for the p.Arg280Cys mutation disrupting
ª 2014 British Association of Dermatologists
expression of a pigmentary gene in our patient, resulting in LWNH. Another possible explanation is functional autosomal mosaicism mediated by epigenetic mechanisms (methylation/demethylation), which can cause PM due to partial activation or silencing of pigmentary genes.6 This might have caused PM either directly or as a ‘second hit’. This is the second reported case of EEC syndrome due to a p63 mutation and LWNH. In the absence of demonstrable chromosomal mosaicism, we suggest
Clinical and Experimental Dermatology (2014) 39, pp266–268
267
D
CP
A memorable patient
Table 1 Features seen in p63-associated disorders compared with our patient, and with the father and son previously reported by Kosa-
ki et al.4 Previous cases4 Our patient
Father
Son
EEC
SHFM
+
+
+
++
+++
+ +
+ + + + + + +/ +++
Ectrodactyly Ectodermal dysplasia Hair Skin Nails Teeth Lacrimal glands Sweat glands Breast/nipple Cleft lip/palate Eyes Fused eyelid Cataract Glaucoma
+
+
+
AEC
RHS
+/ +++ +++ ++ ++ + ++
+++ + ++ ++ ++ ++
+
++
LMS
ADULT
++
++
+/ +/ + + +++
NSCL
+ ++ + ++ + + +++
+++ + +
+/
ADULT, acro–dermato–ungual–lacrimal–tooth syndrome; AEC, ankyloblepharon–ectodermal dysplasia–clefting syndrome; EEC, ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome; LMS, limb–mammary syndrome; NSCL, non-syndromic cleft lip; RHS, Rapp–Hodgkin syndrome; SHFM, split-hand split-foot malformation. +++, Consistent feature; ++, frequently seen; +, occasionally seen; +/ , rarely seen; , not seen. Table adapted from van Bokhoven and Brunner.7
that undetected mosaicism for the p63 mutation might be responsible for PM by disrupting expression of a pigmentary gene.
Learning points
•
p63 mutations cause a variety of overlapping clinical phenotypes, which can include ectodermal dysplasia and ectrodactyly. • Mosaicism for a p63 mutation may cause a milder phenotype. • Genetic mosaicism cannot always be detected by cytogenetic analysis of blood cells and fibroblasts. • Several different mechanisms, including epigenetic silencing, may disrupt pigmentary gene expression, resulting in PM.
Acknowledgements We are grateful to the staff in the West Midlands Regional Genetics Laboratory at Birmingham Women’s Hospital for their technical assistance.
268
Clinical and Experimental Dermatology (2014) 39, pp266–268
References 1 van Bokhoven H, Hamel BC, Bamshad M et al. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 2001; 69: 481–92. 2 Vernersson Lindahl E, Garcia EL, Mills AA. An allelic series of Trp63 mutations defines TAp63 as a modifier of EEC syndrome. Am J Med Genet A 2013; 161A: 1961–71. 3 Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol 2004; 151: 269–82. 4 Kosaki R, Naito Y, Torii C et al. Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation. Am J Hum Genet 2008; 146A: 2574–7. 5 Fessing MY, Mardaryev AN, Gdula MR et al. p63 regulates Satb1 to control tissue-specific chromatin remodelling during development of the epidermis. J Cell Biol 2011; 194: 825–39. 6 Happle R. Transposable elements and the lines of Blaschko: a new perspective. Dermatology 2002; 204: 4–7. 7 van Bokhoven H, Brunner HG. Splitting p63. Am J Hum Genet 2002; 71: 1–13.
ª 2014 British Association of Dermatologists
CP
CED
CPD • A memorable patient
Clinical and Experimental Dermatology
Limited ectrodactyly, ectodermal dysplasia and cleft lip–palate syndrome with a p63 mutation, associated with linear and whorled naevoid hypermelanosis P. Pratsou,1 C. L. Defty,1 L. Ozoemena,2 J. A. McGrath,3 C. Moss4 and J. E. Gach1 1 Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK; 2GSTS Pathology, St Thomas’ Hospital, London, UK; 3King’s College London (Guy’s Campus), London, UK; and 4Department of Dermatology, Birmingham Children’s Hospital, Birmingham, UK
doi: 10.1111/ced.12259
An 18-year old Malaysian student presented with pigmented marks on his trunk and limbs, which had been present since birth. He also had uncorrected congenital deformities of his hands and feet, and a history of surgically treated congenital cataracts and glaucoma. He was the third of four children born to nonconsanguineous parents, with no family history of similar problems or of orofacial clefting. On physical examination, the patient was found to have widespread macular hyperpigmentation in streaks and whorls along the lines of Blaschko (Fig. 1). He also had hypodontia, microdontia and ectrodactyly with median clefts of both hands and feet (Fig. 2), consistent with split-hand split-foot malformation (SHFM). The hair and nails appeared normal, and systemic examination was unremarkable. Blood samples were collected, and DNA extracted from lymphocytes. Mutation analysis identified a heterozygous cytosine to thymine transition at nucleotide 982 (c.982C>T) in the p63 gene, resulting in the missense mutation, p.Arg280Cys, within the DNA-binding domain. The proband’s parents were not available for genetic testing. p63-associated disorders encompass a spectrum of phenotypes with varying combinations of ectodermal dysplasia, orofacial clefting, and limb, ocular and other malformations. Heterozygous missense mutations affecting several amino acid residues of p63 have been reported. Interestingly, our patient’s missense muta-
Correspondence: Dr Penelope Pratsou, Department of Dermatology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, UK E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 13 October 2013
266
Clinical and Experimental Dermatology (2014) 39, pp266–268
tion has been previously found in patients with both ectrodactyly, ectodermal dysplasia and cleft lip–palate (EEC) syndrome and non-syndromic SHFM.1 EEC syndrome, which is often incomplete, best describes our patient’s clinical phenotype of ectrodactyly and ectodermal dysplasia without orofacial clefting. No other p63-associated features were clinically identified in our patient (Table 1). The balance between the ΔNp63/ TAp63 isoforms may contribute to phenotypic variability in EEC syndrome, with TAp63 serving as genetic modifier.2 In addition, our patient had linear and whorled naevoid hypermelanosis (LWNH), a pigmentary pattern often associated with chromosomal mosaicism, and probably reflecting mosaicism for a mutation affecting a pigmentary gene.3 Of note, the only other reported patient with LWNH associated with SHFM had a son with EEC syndrome resulting from the p63 mutation R204W. Mosaicism for this mutation was found in the father, and was considered to be the likely cause of his pigmentary pattern and milder clinical phenotype.4 Although the identified mosaicism was for a mutation in p63 rather than in a pigmentary gene, the mutation might have disrupted expression of a pigmentary gene, as p63, a transcription factor, is known to regulate the expression of genes involved in epidermal differentiation.5 Thus, we did consider the possibility that somatic mosaicism for p63 may have caused the pigmentary mosaicism (PM) in our patient; however, we did not detect any mosaicism for the p63 mutation. DNA extracted from punch biopsies of both affected and unaffected skin contained the mutation p.Arg280Cys. Neither was there any evidence of chromosomal mosaicism to account for LWNH; cytogenetic analysis of adequate numbers of blood lymphocytes and skin fibroblasts was normal. Chromosomal mosaicism could not be excluded
ª 2014 British Association of Dermatologists
D CP A memorable patient
(a)
(b)
(c)
Figure 1 Striking macular hyperpigmented streaks and whorls in a blaschkoid distribution affecting (a) anterior trunk, (b) back and (c)
thighs.
(a)
(b)
(c)
Figure 2 (a,b) Split-hand split-foot malformation; (c) retention of deciduous lower central incisors, indicating hypodontia and conical
upper lateral incisors, consistent with microdontia.
entirely, because standard cytogenetic techniques can detect chromosomal mosaicism in only 20–30% of cases. Furthermore, abnormal cells may grow preferentially to normal cells in vitro, masking mosaicism. In addition, the lines of Blaschko reflect embryonic migration paths of ectodermally derived tissues, thus cytogenetic analysis of fibroblasts may fail to detect mosaicism for a pigmentary gene.3 Nonetheless, the absence of demonstrable chromosomal mosaicism lends support to the unifying hypothesis of undetected mosaicism for the p.Arg280Cys mutation disrupting
ª 2014 British Association of Dermatologists
expression of a pigmentary gene in our patient, resulting in LWNH. Another possible explanation is functional autosomal mosaicism mediated by epigenetic mechanisms (methylation/demethylation), which can cause PM due to partial activation or silencing of pigmentary genes.6 This might have caused PM either directly or as a ‘second hit’. This is the second reported case of EEC syndrome due to a p63 mutation and LWNH. In the absence of demonstrable chromosomal mosaicism, we suggest
Clinical and Experimental Dermatology (2014) 39, pp266–268
267
D
CP
A memorable patient
Table 1 Features seen in p63-associated disorders compared with our patient, and with the father and son previously reported by Kosa-
ki et al.4 Previous cases4 Our patient
Father
Son
EEC
SHFM
+
+
+
++
+++
+ +
+ + + + + + +/ +++
Ectrodactyly Ectodermal dysplasia Hair Skin Nails Teeth Lacrimal glands Sweat glands Breast/nipple Cleft lip/palate Eyes Fused eyelid Cataract Glaucoma
+
+
+
AEC
RHS
+/ +++ +++ ++ ++ + ++
+++ + ++ ++ ++ ++
+
++
LMS
ADULT
++
++
+/ +/ + + +++
NSCL
+ ++ + ++ + + +++
+++ + +
+/
ADULT, acro–dermato–ungual–lacrimal–tooth syndrome; AEC, ankyloblepharon–ectodermal dysplasia–clefting syndrome; EEC, ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome; LMS, limb–mammary syndrome; NSCL, non-syndromic cleft lip; RHS, Rapp–Hodgkin syndrome; SHFM, split-hand split-foot malformation. +++, Consistent feature; ++, frequently seen; +, occasionally seen; +/ , rarely seen; , not seen. Table adapted from van Bokhoven and Brunner.7
that undetected mosaicism for the p63 mutation might be responsible for PM by disrupting expression of a pigmentary gene.
Learning points
•
p63 mutations cause a variety of overlapping clinical phenotypes, which can include ectodermal dysplasia and ectrodactyly. • Mosaicism for a p63 mutation may cause a milder phenotype. • Genetic mosaicism cannot always be detected by cytogenetic analysis of blood cells and fibroblasts. • Several different mechanisms, including epigenetic silencing, may disrupt pigmentary gene expression, resulting in PM.
Acknowledgements We are grateful to the staff in the West Midlands Regional Genetics Laboratory at Birmingham Women’s Hospital for their technical assistance.
268
Clinical and Experimental Dermatology (2014) 39, pp266–268
References 1 van Bokhoven H, Hamel BC, Bamshad M et al. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet 2001; 69: 481–92. 2 Vernersson Lindahl E, Garcia EL, Mills AA. An allelic series of Trp63 mutations defines TAp63 as a modifier of EEC syndrome. Am J Med Genet A 2013; 161A: 1961–71. 3 Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol 2004; 151: 269–82. 4 Kosaki R, Naito Y, Torii C et al. Split hand foot malformation with whorl-like pigmentary pattern: phenotypic expression of somatic mosaicism for the p63 mutation. Am J Hum Genet 2008; 146A: 2574–7. 5 Fessing MY, Mardaryev AN, Gdula MR et al. p63 regulates Satb1 to control tissue-specific chromatin remodelling during development of the epidermis. J Cell Biol 2011; 194: 825–39. 6 Happle R. Transposable elements and the lines of Blaschko: a new perspective. Dermatology 2002; 204: 4–7. 7 van Bokhoven H, Brunner HG. Splitting p63. Am J Hum Genet 2002; 71: 1–13.
ª 2014 British Association of Dermatologists
