Correspondence 213
Absorbance change at 620–720 nm
(a)
Dose (J cm–2)
Fig 2. (a) Changes of area under the differential apparent absorbance curve (620–720 nm) vs. dose of visible light and near-infrared radiation.
The mean and SD are shown for all 23 subjects for normal and vitiligo-involved sites. (b) The correlation of constitutive pigment content vs. the
degree of formation of immediate pigment darkening at the completion of irradiation. The constitutive pigment was calculated from the
difference of apparent absorbance between normal and vitiligo-involved sites at baseline measurements in the spectral range of 390–450 nm.
blood absorption. The results show that the normal skin devel-
oped a greater skin colour change at the final stage of irradia-
tion. Although the vitiligo-involved site also shows an increase
of the area under the curve, the small magnitude of change
was not significant to detect pigment formation clinically.
Figure 2(b) displays the correlation of the constitutive mela-
nin content of normal skin to the degree of formation of IPD.
The amount of constitutive melanin is quantified by an area of
differential apparent absorbance between normal and vitiligo-
involved skin at baseline in the spectral range of 390–450 nm
in which the soluble fraction of epidermal melanin predomi-
nantly contributes to the apparent absorbance.9 The result
shows that the degree of IPD response appears to be related to
the constitutive pigment expressed at short wavelengths.
In this study, we found that VIS-NIR radiation produces IPD
only in normally pigmented skin and that the presence of con-
stitutive pigment is required to induce IPD response. We con-
clude that the degree of formation of IPD from VIS-NIR
radiation is related to the content of constitutive pigment
expressed at short wavelengths (390–450 nm). This relation
has been confirmed in an ongoing study on healthy subjects
with various skin types.
Models and Methods Department,
Johnson and Johnson Consumer
Companies, Skillman, NJ 08558-9418, U.S.A.
*Department of Dermatology, Al-Sabah
Hospital, Ministry of Public Health, Kuwait
Correspondence: Nikiforos Kollias.
E-mail: NKollia@its.jnj.com
References
1 Pathak MA, Riley FJ, Fitzpatrick TB, Curwen WL. Melanin formation
in human skin induced by long-wave ultra-violet and visible light.
Nature 1962; 193:148–50.
2 Pathak MA, Stratton K. Effects of ultraviolet and visible radiation
and the production of free radicals in the skin. In: The Biologic Effects
of Ultraviolet Radiation (Urbach F, ed). New York: Pergamon Press,
1969; 207–22.
! 2010 The Authors
Journal Compilation ! 2010 British Association of Dermatologists • British Journal of Dermatology 2010 163, pp208–234
Absorbance change at 620–720 nm
(b)
Constitutive pigment at 390–450 nm
3 Kollias N, Baquer A. An experimental study of the changes in
pigmentation in human skin in vivo with visible and near infrared
light. Photochem Photobiol 1984; 39:651–9.
4 Beitner H, Wennersten G. A qualitative and quantitative transmis-
sion electron microscope study of immediate pigment darkening
reaction. Photodermatology 1985; 2:273–8.
5 Hönigsmann H, Schuler G, Aberer W et al. Immediate pigment
darkening phenomenon. A reevaluation of its mechanisms. J Invest
Dermatol 1986; 87:648–52.
6 Maeda K, Hatao M. Involvement of photooxidation of melanogenic
precursors in prolonged pigmentation induced by ultraviolet A.
J Invest Dermatol 2004; 122:503–9.
7 Nordlund JJ, Boissy RE, Hearing VJ et al. (eds). The Pigmentary System,
2nd edn. Oxford: Blackwell Publishing, 2006.
8 Arrunategui A, Arroyo C, Garcia L. Melanocyte reservoir in vitiligo.
Int J Dermatol 1994; 33:484–7.
9 Ou-Yang H, Stamatas G, Kollias N. Spectral responses of melanin to
ultraviolet A irradiation. J Invest Dermatol 2004; 122:492–6.
Key words: constitutive pigment, immediate pigment darkening, visible light and
near-infrared radiation, vitiligo
Conflicts of interest: none declared.
I. SEO Spectrum of mutations in the ANTXR2 (CMG2)
A. BAQER* gene in infantile systemic hyalinosis and juve-
N. KOLLIAS nile hyaline fibromatosis
DOI: 10.1111/j.1365-2133.2010.09769.x
MADAM, Infantile systemic hyalinosis (ISH; MIM 236490) and
juvenile hyaline fibromatosis (JHF; MIM 228600) are rare
autosomal recessive disorders that present with overlapping
clinical features such as dermal and subcutaneous fibromatosis,
gingival hypertrophy, joint contractures and bone deformities.
Both conditions arise from mutations in the gene encoding
the capillary morphogenesis protein 2 (ANTXR2, also known as
CMG2).1,2 Apart from its role as a receptor for the anthrax
toxin,3 little else is known about the precise function of the
protein. In skin and connective tissues, it may have a role in
214 Correspondence

basement membrane integrity through its binding to type IV

collagen and laminins.4 Moreover, recent studies have shown
that the fibromas in JHF contain accumulations of type VI col-
lagen with reduced type I collagen.5 The type VI collagen is
more resistant to proteolytic disruption by pepsin, which may
account for the accumulation in various tissues.5 It is likely
that the ANTXR2 mutations affect the biosynthesis and degrad-
ation of collagens, leading to abnormal collagen deposition.
Here, we investigated the molecular basis of ISH and JHF in
two unrelated Egyptian families and reviewed the spectrum of (a)
published ANTXR2 mutations to assess the implications for
genotype–phenotype correlation and genetic counselling.
Family 1 was a consanguineous Egyptian pedigree with
three children, all affected with ISH. The first child died at the
age of 3 days from respiratory distress. The second child had
multiple cutaneous swellings, painful joint contractures, gingi-
val hypertrophy, repeated chest infections and intractable diar-
rhoea. He died at 4 years of age from cardiac arrest. A third
child died before the age of 2 years from repeated attacks of
diarrhoea. She also had painful flexural contractures of the
(b) (c)
elbows, wrists and knees, which progressed from the age of
4 months. The clinical features of the second child at the age
of 4 years are shown in Figure 1(a). Comprehensive clinical
and skin pathology details on this family have recently been
published.6
Family 2 was also consanguineous and had three children
affected with JHF. All these individuals are alive and are now
aged 12, 10 and 6 years. Each started to manifest the disease
around the age of 2 years with progressive generalized spread-
ing of firm, fairly mobile swellings all over the body. Gingival (d) (e)
hypertrophy and bony swellings, particularly affecting the
knees, were also present. The clinical features are illustrated in Fig 1. Clinical appearances of infantile systemic hyalinosis
Figure 1(b–e). (ISH) ⁄ juvenile hyaline fibromatosis (JHF). (a) An affected 4-year-old
Blood sampling and ANTXR2 gene sequencing analysis were individual with ISH in family 1 shows marked fibromas affecting the
performed after obtaining informed consent, in accordance face, particularly the lower lip, as well as limb contractures and bony
with the Declaration of Helsinki Principles. Polymerase chain deformities. (b) The affected 12-year-old boy with JHF from family 2
reaction (PCR) amplification of genomic DNA was carried out shows prominent fibrous nodules on his scalp and right ear. (c) The
with 17 primer pairs spanning the coding exons and flanking affected 10-year-old sibling in family 2 also shows marked fibrous
introns of the ANTXR2 gene. The PCR products were purified nodules on his scalp and ears; many of the nodules are ulcerated.
(d) This same individual has very prominent fibromatosis affecting his
using a QIAquick PCR purification kit (Qiagen, Crawley, U.K.)
forehead and scalp as well as his ears and nose. (e) This boy also has
and sequenced in an ABI 3730 Genetic Analyzer (Applied Bio-
bony swellings and deformities affecting both knees.
systems, Warrington, U.K.). Genomic DNA sequencing from
the second affected sibling in family 1 identified a homozy-
gous deletion in exon 13, c.1074delT (NC_000004Æ11). This zygote with ISH (other mutation c.304insA)7 and a compound
deletion causes a frameshift and a premature termination heterozygote with JHF (other mutation c.1181T>C).8 Thus,
codon 50 amino acids downstream, designated the mutation c.1074delT represents the most frequently
p.Pro358fsX50. In family 2, sequencing of genomic DNA observed mutation in ANTXR2, and the clinical data demon-
from all three affected individuals identified a homozygous strate the variable phenotypic appearances, reflecting the con-
deletion mutation in exon 15, c.1340delC. This mutation sequences of the different mutated second alleles in these
leads to a frameshift and a premature termination codon 12 patients. Of the published ANTXR2 mutations, there are 10
amino acids downstream, designated p.Pro447fsX12 (Fig. 2). missense mutations, nine frameshift or nonsense mutations,
When added to previously published ANTXR2 mutations, 25 five splice site mutations and one in-frame insertion (3-bp).
different mutations have now been reported. Full details of The missense mutations occur within both the von Willebrand
these mutations are listed in Table S1 (see Supporting Infor- A domain and the cytoplasmic domain.1 The von Willebrand
mation). The mutation in family 1 has been identified in three A domain appears to be the critical part of the protein for
other patients: a homozygote with ISH,1 a compound hetero- interactions with other basement membrane proteins,

! 2010 The Authors

Journal Compilation ! 2010 British Association of Dermatologists • British Journal of Dermatology 2010 163, pp208–234

(a) (b)
Fig 2. Molecular pathology of infantile systemic hyalinosis and
juvenile hyaline fibromatosis in these two families. (a) Genomic DNA
sequencing in an affected individual in family 1 shows a homozygous
single nucleotide deletion, designated c.1074delT. (b) Genomic DNA
sequencing of an affected individual in family 2 reveals a homozygous
single nucleotide deletion, c.1340delC.
although pathogenic mutations therein may affect either
ligand binding or protein folding and thus have variable
consequences for protein function.9 Nonsense ⁄frameshift
mutations may disrupt protein function through synthesis
of truncated proteins lacking critical domains.
Nevertheless, the patients in our study, and other published
cases, highlight the potential limitations of accurately predict-
ing the clinical outcome from the nature of the mutation(s)
detected in genomic DNA alone. Indeed, a fuller understand-
ing of the consequences of the mutations on mRNA stability
and protein synthesis is necessary to define genotype–pheno-
type correlation more accurately. ISH and JHF may show clini-
10 Nofal A, Sanad M, Assaf M et al. Juvenile hyaline fibromatosis and
cal and molecular overlap, observations that provide further
support for an alternative term, such as ‘hyaline fibromatosis
syndrome’ that unifies these conditions.10
Acknowledgments
The authors acknowledge financial support from the Depart-
ment of Health via the National Institute for Health Research
Comprehensive Biomedical Research Centre award to Guy’s &
St Thomas’ NHS Foundation Trust in partnership with King’s
College London and King’s College Hospital NHS Foundation
Trust. Travel funding sponsorship from the British Association
of Dermatologists (to K.F.) is also gratefully acknowledged.
Clinical Genetics, !Molecular Genetics Department, G.Y. EL-KAMAH
Division of Human Genetics and K. FONG*
Genome Research National Research M. EL-RUBY
Centre, Cairo, Egypt H.H. AFIFI
*St John’s Institute of Dermatology, S.E. CLEMENTS*
King’s College London (Guy’s Campus), J.E. LAI-CHEONG*
London SE1 9RT, U.K. K. AMR!
"Department of Dermatology, Kasr El-Eini Faculty M . E L - D A R O U T I "
of Medicine, Cairo University, Cairo, Egypt J.A. MCGRATH*
Correspondence: John McGrath.
E-mail: john.mcgrath@kcl.ac.uk
[Correction to author name Affifi (sic) made after online pub-
lication 19 July 2010]
! 2010 The Authors
Journal Compilation ! 2010 British Association of Dermatologists • British Journal of Dermatology 2010 163, pp208–234
Correspondence 215
References
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capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis
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3 Scobie HM, Rainey GJ, Bradley KA et al. Human capillary morpho-
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in infantile systemic hyalinosis with severe labio-gingival enlarge-
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case report and mutation analysis in a Chinese infant. Br J Dermatol
2007; 156:602–4.
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in the gene encoding capillary morphogenesis protein 2 in a Japa-
nese patient with juvenile hyaline fibromatosis. Br J Dermatol 2007;
157:1037–9.
9 Deuquet J, Abrami L, Difeo A et al. Systemic hyalinosis mutations in
the CMG2 ectodomain leading to loss of function through retention
in the endoplasmic reticulum. Hum Mutat 2009; 30:583–9.
infantile systemic hyalinosis: a unifying term and a proposed grad-
ing system. J Am Acad Dermatol 2009; 61:695–700.
Key words: collagen, dermis, genodermatosis, hyaline
Conflicts of interest: none declared.
Supporting Information
Additional Supporting Information may be found in the online
version of the article:
Table S1. Published mutations in ANTXR2 (CMG2) and their
clinical consequences.
Please note: Wiley-Blackwell are not responsible for the con-
tent or functionality of any supporting materials supplied by
the authors. Any queries (other than missing material) should
be directed to the corresponding author for the article.
Cartilaginous matrix-producing apocrine
carcinoma of the skin
DOI: 10.1111/j.1365-2133.2010.09771.x
MADAM, Matrix-producing carcinoma of the breast (MPCB) is
an extremely rare subtype of metaplastic carcinoma defined as