ORIGINAL ARTICLE

A Gene Locus Responsible for Reticulate Pigmented

Anomaly of the Flexures Maps to Chromosome
17p13.3
Cheng-Rang Li1,2,4, Qing-He Xing2,4, Ming Li3, Wei Qin2, Xue-Zhuang Yue1, Xiao-Ju Zhang2, Hui-Jun Ma1,
Da-Guang Wang1, Guo-Yin Feng2, Wen-Yuan Zhu1 and Lin He2

Reticulate pigmented anomaly of the flexures (RPAF), also called Dowling–Degos disease, is a rare autosomal-
dominant cutaneous disorder characterized by spotted and reticulate pigmentation of the flexures. The gene, or
even the chromosomal location, for RPAF has not yet been identified. In this study, one Chinese family with
RPAF was identified and subjected to a genomewide screen for linkage analysis. We identified a locus at
chromosome 17p13.3 with a maximum two-point limit of detection score of 3.61 at markers D17S831and
D17S1866 (at recombination fraction y ¼ 0.00). Haplotype analyses indicated that the disease gene is located
within the 6.8 cM region distal to D17S1798. It is the first locus identified for RPAF. This study provides a map
location for isolation of a disease gene causing RPAF.
Journal of Investigative Dermatology (2006) 126, 1297–1301. doi:10.1038/sj.jid.5700271; published online 30 March 2006

INTRODUCTION 1982; Kikuchi et al., 1988), pilonidal sinus (Brown, 1982),

Reticulate pigmented anomaly of the flexures (RPAF, MIM
number: 179850), also called Dowling–Degos disease, was
first described as a benign form of acanthosis nigricans and
illustrated eoithelial proliferations of deeper parts of the sweat
ducts by Dowling (Dowling and Freudenthal, 1938), first
recognized as a distinct clinical entity by Degos (Degos and
Ossipowski, 1954), and first named by Jones (Jones and
Grice, 1974). As a new rare genodermatosis, RPAF generally
shows an autosomal-dominant pattern of inheritance (Crova-
to et al., 1983b), with variable penetrance (Kikuchi, 2000).
It is characterized by spotted and reticulate pigmentation
of the flexures (Jones and Grice, 1978; Crovato et al., 1983b).
Other features include dark comedone-like lesions on the
neck (Crovato et al., 1983b), comedones and pitted scars
near the angle of the mouth (Crovato et al., 1983b; Kim et al.,
1999), follicular lesions such as epidermoid cysts (Brown,
1 quantitative increase of the melanosomes, which were
Department of Dermatology, The First Affiliated Hospital of Nanjing Medical
University, Nanjing, Jiangsu, China; 2Bio-X Life Science Research Center,
Shanghai Jiao Tong University, Shanghai, China and 3Department of
Dermatology, Wuxi Second People’s Hospital affiliated to Nanjing Medical
University, Wuxi, China
4
These two authors contributed equally to this work.
Correspondence: Professor Wen-Yuan Zhu, Department of Dermatology, The
First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road,
Nanjing, Jiangsu 210029, China. E-mail: zhuwenyuan@yahoo.com or
Professor Lin He, Bio-X Life Science Research Center, Shanghai Jiao Tong
University, PO Box 501, Hao Ran Building, 1954 Hua Shan Road, Shanghai
200030, China. E-mail: helin@sjtu.edu.cn or helinanna@hotmail.com
Abbreviations: DSH, dyschromatosis symmetrica hereditaria; RAK, reticulate
acropigmentation of Kitamura; RPAF, reticulate pigmented anomaly of the
flexures
Received 27 September 2005; revised 2 January 2006; accepted 4 January
2006; published online 30 March 2006
association with hidradenitis suppurativa (Weber et al., 1990;
Bedlow and Mortimer, 1996), multiple seborrhoeic warts
(Boyle and Burton, 1985; Cliff et al., 1997), and squamous
cell carcinomas (Ujihara et al., 2002). Occasional reports of
overlap/association of RPAF and reticulate acropigmentation
of Kitamura (RAK) (Erel et al., 1993; Thami et al., 1998) have
also been illustrated. The skin lesions affect the axillae and
groins in young patients and can spread to wide areas in later
life (Jones and Grice, 1974). Most RPAF patients had onset
after 11 years old (all references in this article), in which the
oldest is 57 years old (Howell and Freeman, 1978). Sandhu
et al. (2004) reported that a female patient had onset in early
childhood without definite onset age.
Histopathology revealed typical thin branching-like pat-
tern of epidermal downgrowths (Jones and Grice, 1978;
Crovato et al., 1983b). Electron microscopic study of
pigmented lesions showed a strong melanocytic activity with
distributed in the keratinocytes according to a dispersed
pattern as in black skin (Grosshans et al., 1980).
RESULTS
Clinical findings
The subjects are from a four-generation RPAF family
consisting of more than 60 individuals, which includes at
least 21 patients. The mode of inheritance is clearly
autosomal-dominant with complete penetrance. In total, 15
family members participated in this study. The affected
individuals had spotted and reticulate pigmentation of the
flexures (Figure 1). The immunohistochemistry and electron
microscopy of lesions from patients with RPAF can be seen in
our study (Zhang and Zhu, 2005).

& 2006 The Society for Investigative Dermatology www.jidonline.org 1297

 C-R Li et al.
Gene Locus Responsible for Reticulate Pigmented Anomaly

Two-point linkage analysis
We first undertook a genomewide scan of this family. A
supportive limit of detection score was obtained with marker
D17S831 (Zmax ¼ 3.61, y ¼ 0.00). For fine mapping of the
gene, 15 additional polymorphic microsatellite marks at
17p13.3 were further tested. The markers D17S831 and
D17S1866 showed strong evidence for linkage to chromo-
some 17p with a maximal limit of detection score of 3.61
(y ¼ 0.00). Limit of detection scores 43 were also obtained
with D17S1529 (Zmax ¼ 3.01, y ¼ 0.00). The pairwise limit of
detection scores between the relevant markers and the locus
for RPAF are given in Table 1. Conversely, no significant
linkage with markers on other chromosomal regions was
found.
Haplotype analysis
To determine the confine interval of the linked region
containing the RPAF locus, recombination events among
the family members were analyzed by haplotype reconstruc-
tion (Figure 2). The recombination events between the RPAF
phenotype and the markers that span the region of interest
3 cm
Figure 1. Clinical feature of one patient: The flat-pigmented lesions involve
the groin and the area of perinea.
defined the smallest cosegregating region that included
critical meiotic recombinants in this pedigree. Careful
examination of the haplotype confirmed that disease-asso-
ciated alleles cosegregated with the phenotype of RPAF in
this pedigree. The recombinant haplotype carried by indivi-
dual III:8 places the RPAF gene distal to D17S938. The
recombinant haplotype carried by individual III:1 furthermore
places the RPAF gene distal to D17S1810. The recombination
events, presenting in individuals IV:2 and IV:3, furthermore
define the proximal border of RPAF gene to D17S1798. These
results suggest that one gene responsible for RPAF lies in the
6.8 cM region distal to D17S1798.
DISCUSSION
Clinical manifestations of RPAF are dominated by spotted
and reticulate pigmentation of the flexures (Jones and Grice,
1978; Crovato et al., 1983b). The pigmentation is progres-
sive, symmetrical, often extensive and completely asympto-
matic (Sandhu et al., 2004), and can spread to wide areas in
later life (Jones and Grice, 1974). Although RPAF is a disorder
of pigmentation, no evidence has been found that RPAF
confers an increased risk of forming melanoma. However,
RPAF was reported to be associated with squamous cell
carcinomas on the dappled pigmentation localized to the
patient’s left buttock (Ujihara et al., 2002). In few cases, skin
lesions were reported to become more pronounced after sun
exposure (Lee et al., 2000; Sandhu et al., 2004).
Several human genetic pigmental diseases, such as RAK
(Crovato et al., 1983a; Crovato and Rebora, 1986; Berth-
Jones and Graham-Brown, 1989; Cox and Long (1991);
Ostlere and Holden, 1994; Lestringant et al., 1997; Thami
et al., 1998), dyschromatosis symmetrica hereditaria (DSH,
MIM number: 127400) (Thami et al., 1998; Sandhu et al.,
2004), and dyschromatosis universalis hereditaria (MIM
number: 127500) (Sandhu et al., 2004), show some overlap

Table 1. Two-point linkage analysis between RPAF locus and the chromosome 17p markers
LOD score at h=
Markers Location (cM) 0.00 0.10 0.20 0.30 0.40 Zmax hmax

D17S1866 0.00 3.61 2.97 2.25 1.45 0.59 3.61 0.00

D17S926 0.60 0.45 0.40 0.33 0.23 0.12 0.45 0.00
D17S849 0.60 0.74 0.58 0.44 0.30 0.15 0.74 0.00
D17S1840 1.30 1.43 1.14 0.83 0.51 0.21 1.43 0.00
D17S1529 3.40 3.01 2.47 1.84 1.16 0.43 3.01 0.00
D17S831 6.70 3.61 2.97 2.25 1.45 0.58 3.61 0.00
D17S1798 6.80 3.98 1.78 0.14 0.15 0.03 0.15 0.30
D17S1845 7.20 0.83 0.99 0.91 0.59 0.17 0.99 0.10
D17S1828 10.00 2.22 0.34 0.16 0.08 0.02 0.02 0.40
D17S1810 11.60 2.69 0.81 0.85 0.57 0.19 0.85 0.20
D17S938 14.40 5.69 0.14 0.25 0.22 0.06 0.25 0.20
D17S1812 17.00 2.77 0.69 0.33 0.14 0.03 0.03 0.40
Genetic coordinates in centiMorgans according to 1996 Genethon Map (http://www.genlink.wustl.edu/cgi-bin/dcop.cgi?f=1&s=1&mt=gen-
emap&m1=D17S1866&m2=D17S1812&vg=v&chr=17) are in the column ‘‘Location’’.

1298 Journal of Investigative Dermatology (2006), Volume 126

 C-R Li et al.
Gene Locus Responsible for Reticulate Pigmented Anomaly

I:1 I:2

II:1 II:2 II:3 II:4 II:5 II:6 II:7

D17S1866 7 2 7 2 4 5 6 1 7 2 1 2
D17S849 2 2 2 2 2 1 2 1 2 2 1 2
D17S926 2 2 2 2 2 1 2 2 2 2 2 2
D17S1840 2 2 2 2 2 1 3 2 2 2 2 2
D17S1529 4 1 4 1 3 1 2 3 4 1 3 1
D17S831 3 7 3 7 1 2 6 5 5 7 5 7
D17S1798 3 4 3 4 1 3 4 2 2 4 2 4
D17S1845 1 3 1 3 5 2 2 3 3 3 3 3
D17S1828 2 2 2 2 2 1 2 3 3 2 3 2
D17S1810 2 4 2 4 4 5 3 2 2 4 2 4
D17S938 4 1 4 1 1 5 5 4 6 1 6 1
D17S1812 3 3 3 3 3 2 3 3 4 3 3 3

III:1 III:2 III:3 III:4 III:5 III:6 III:7 III:8 III:9

D17S1866 2 5 4 2 2 4 2 5 2 5 7 1
D17S849 2 1 2 2 2 2 2 1 2 1 3 1
D17S926 2 1 2 2 2 2 2 1 2 1 2 2
D17S1840 2 1 2 2 2 2 2 1 2 1 2 2
D17S1529 1 1 3 1 1 3 1 1 1 1 4 3
D17S831 7 2 1 7 7 1 7 2 7 2 2 5
D17S1798 4 3 1 4 4 1 4 3 4 3 4 2
D17S1845 3 2 5 3 3 5 3 2 3 2 5 3
D17S1828 2 1 2 2 2 2 2 1 2 1 1 3
D17S1810 2 5 4 4 4 4 4 5 4 5 1 2
D17S938 4 5 1 1 1 1 1 5 1 5 5 1
D17S1812 3 2 3 3 3 3 3 2 3 2 3 3

IV:1 IV:2 IV:3

D17S1866 2 3 5 3 2 3
D17S849 2 1 1 1 2 1
D17S926 2 2 1 2 2 2
D17S1840 2 1 1 1 2 2
D17S1529 1 4 1 4 1 2
D17S831 7 5 2 5 7 4
D17S1798 4 4 4 4 1 3
D17S1845 3 2 3 2 5 4
D17S1828 2 3 2 3 2 3
D17S1810 2 3 2 3 4 5
D17S938 4 2 4 2 1 3
D17S1812 3 1 3 1 3 3

Figure 2. Haplotype analysis of family. Affected and unaffected individuals are represented by black and open symbols. ’, the chromosome region shared by
affected members of the pedigree.

with RPAF. Several reported that Dowling–Degos disease and Dyschromatosis universalis hereditaria is characterized by
RAK may be different clinical expressions of the same pigmented flecks and spots over much of the body other than
disease. Kim et al. reported a Dowling–Degos disease patient that limited to the flexures of body (Miyamura et al., 2003).
with pigmentation of the dorsum of hands and proximal In addition, the gene for dyschromatosis universalis heredi-
nailfolds. However, in this patient the ‘‘pitting’’ of the palms, taria has previously been mapped to chromosome
which is the character of RAK, was not observed. Three 6q24.2–q25.2 (MIM number: 127500) (Miyamura et al.,
patients in our pedigree had dotted hyperpigmented brown- 2003; Xing et al., 2003). Thus, RPAF has a wider clinical
ish black macules on dorsal aspects of the hands and feet, spectrum including RAK-, DSH-, and dyschromatosis uni-
which were something like RAK. However, we did not find versalis hereditaria-like pigmentation, and the genetic basis
typical characteristic pits on the palms. DSH is an autosomal- of RPAF is likely to differ from that of DSH and dyschroma-
dominant inheritance characterized by pinpoint, pea-sized, tosis universalis hereditaria. It remains to be seen if RPAF and
hyperpigmented, and hypopigmented macules limited largely RAK is one single entity.
to the dorsal aspects of the hands and feet (Zhang et al., RPAF is also likely to be genetically heterogeneous, as
2004). However, RPAF are dominated by spotted and most examples are autosomal-dominant (Crovato et al.,
reticulate pigmentation of the flexures. In addition, the gene 1983a, b; Kikuchi, 2000; Lee et al., 2000), but some patients
for DSH has previously been mapped to chromosome with sporadic RPAF have been reported (Howell and Free-
1q11–1q21 (Zhang et al., 2003), in which the RNA-specific man, 1978; Bedlow and Mortimer, 1996; Kim et al., 1999).
adenosine deaminase gene (DSRAD, MIM number: 601059) Crovato et al. reported one of the biggest pedigrees and
was identified as the disease gene for DSH (Miyamura et al., revised previous literature. They thought RPAF inherited in
2003; Liu et al., 2004; Zhang et al., 2004; Li et al., 2005). the autosomal-dominant transmission and is commoner in

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 C-R Li et al.
Gene Locus Responsible for Reticulate Pigmented Anomaly
women. However, in our family, the distribution between the
affected men and women did not differ significantly.
In this work, we have mapped dominant RPAF to the region
within the 6.8 cM region distal to D17S1798 of chromosome
17p13.3, where there are 21 known genes and 16 predicted
genes within this 2-Mb critical region (http://www.ncbi.nlm.
nih.gov/mapview/). It is unfortunate that no gene or sequence in
the region has been found to be homologous to any of 4100
known loci that affect pigmentation in the mouse, according to
the search of all currently available databases (Coat Color
Genes). However, pigment epithelium-derived factor (MIM
number: 172860), a member of the serpin gene family, can be
considered as candidate genes for RPAF. Pigment epithelium-
derived factor is synthesized by retinal pigment epithelial cells
and may influence development/differentiation of the neural
retina (Steele et al., 1993). Pigment epithelium-derived factor-
deficient mice by targeted disruption had retinas with malposi-
tioned vessels, irregular pigmentation, a reduced number of
ganglion cells, and increased microvessel density (Doll et al.,
2003). MYO1C (myosin 1C, MIM number: 606538) and MNT
(MAK-binding protein, MIM number: 603039), which play
roles in signal pathways, can be thought as candidate genes for
RPAF. ABR (active BCR-related gene, MIM number: 600365)
and CRKII (Oncogene CRK, MIM number: 164762), which are
or associate with oncogene, can also be regarded as candidate
genes for RPAF, because of a case of RPAF associated with
squamous cell carcinomas in the pigmented area of RPAF
(Ujihara et al., 2002). Whether these genes are related to RPAF
will be determined in our further study.
In summary, we clearly show that a gene responsible for
RPAF in the human genome has been first localized in the
region of chromosome 17p13.3. Our results may help us to
search and clone the disease gene of RPAF. The characteriza-
tion of the RPAF gene will provide important clues to
understand the molecular mechanism of pigmentation and
increase ultimate hope for effectively interventional strategies.
MATERIALS AND METHODS
Subjects
One family from the Jiangsu province of China with typical features
of RPAF was recruited for this work. It showed an autosomal-
dominant inheritance pattern and was ascertained by the First
Affiliated Hospital of Nanjing Medical University. Clinical, histo-
logical, and electron microscopic characteristics supported the
diagnosis of RPAF (Zhang and Zhu, 2005). The study was conducted
according to The Declaration of Helsinki Principles. The medical
ethical committee of the Nanjing Medical University approved all
described studies. After having given written informed consent,
samples of peripheral blood were taken from some available family
members, and genomic DNA was extracted from peripheral blood
by use of the the QIAamp DNA blood minikit (QIAgen, Germany).
Genotyping
We performed a genomewide scan in this Chinese family to
determine the chromosomal regions linked to RPAF, using 382
polymorphic microsatellite markers covering 22 autosomes, with an
average marker density of 10 cM (ABI Prism Linkage Mapping Set
Version 2.0). For fine mapping, 15 additional microsatellite markers
1300 Journal of Investigative Dermatology (2006), Volume 126
were selected from the Généthon Human Linkage Map (Dib et al.,
1996). Marker order and intermarker distances were obtained from
linkage map of the Cooperative Human Linkage Center (CHLC). All
the markers were amplified by PCR. The reactions were performed in
a 5 ml volume containing 10 ng genomic DNA, 3.0 mM MgCl2,
0.2 mM of each dNTP, 0.04 mM of each primer, and 0.3 U
HotstarsTaq DNA polymerase (QIAgen, Germany) with a touch-
down program by means of our standard procedure (Li et al., 2005).
PCR products were electrophoresed on a MegaBACE-1000 DNA
sequencer (Amersham Bioscience, Piscataway City, NJ). The size of
the allele was determined on the basis of MegaBACE ET400-R Size
Standard. Following the electrophoresis, data were collected and
analyzed with Image Control manager and Genetic Profiler software
(Amersham Bioscience, Piscataway City, NJ). All genotyping data
were verified by PedCheck (O’Connell and Weeks, 1998). Geno-
types of each locus were further reviewed and scored independently
by two observers in case of discrepancy.
Linkage and haplotype analyses
A two-point limit of detection score was calculated, by use of
Linkage Programs Version 5.10 (Lathrop and Lalouel, 1984), under
an assumed genetic model: autosomal dominant, a disease-allele
frequency of 0.0001, evenly shared allele frequency, zero pheno-
copy rate, no sex difference, and full penetrance. Subsequent
haplotypes were performed with Cyrillic version 2.1.3 (Cherwell
Scientific) to confine interval of the linked region.
CONFLICT OF INTEREST
The authors state no conflict of interest.
ACKNOWLEDGMENTS
We are most grateful to the family with RPAF who have so willingly
participated and encouraged us in this study. We express our thanks to Dr Yun
Liu, Feng-Ping Yang, and Jing Zhang for their help.
ELECTRONIC DATABASE INFORMATION
URLs for data presented herein are as follows:
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/
Omim/
Cooperative Human Linkage Center, http://gai.nci.nih.gov/CHLC/
The GDB Human Genome Database, http://www.gdb.org/
Généthon, http://www.genethon.fr/php/index.php
Center for medical Genetics, http://research.marshfieldclinic.org/genetics/
Default.htm
Coat Color Genes, http://ifpcs.med.umn.edu/micemut.htm
(Please visit the website at www.cherwell.com and www.cytillicsoftware.
com to get more information.)
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