Generalized Dowling-Degos disease
Yu-Hung Wu, MD,a,band Yang-Chih Lin, MDa,b,c
Background: Dowling-Degos disease (DDD)isa rareinheriteddisease characterizedbyreticular hyperpig-
mentation on flexor surfaces.
Objective: We sought to describe several cases of generalized DDD, a presentation that resemble
dyschromatosis universalis hereditaria.
Methods: The clinical manifestations, histopathologic, and genetic studies of a family with autosomal
dominant inheritance were analyzed.
Results: The father and his sister had reticular hyperpigmentation on flexor surfaces, whereas the daughter
and son had generalized hyperpigmentation with numerous hypopigmented or erythematous macules and
papules on the trunk and limbs. Skin biopsy specimens from both types of lesions all had typical features
of DDD. Biopsy specimens from axillary skin had features of Galli-Galli disease, an acantholytic form.
There were no mutations of the double-stranded RNA-specific adenosine deaminase or keratin 5 genes.
Limitation: Generalizations cannot be drawn from genetic study of only one family.
Conclusion: DDD can present with generalized hyperpigmentation and hypopigmented papules.
( J Am Acad Dermatol 2007;57:327-34.)
such as the neck, axilla, anticubital fossa, submam-
mary area, and groin.1-3Pigmentation on the back
of hands is occasionally found having overlap fea-
tures with reticulate acropigmentation of Kitamura
(RAPK).4-9Rarely, hypopigmented macules or pap-
ules resembling dyschromatosis symmetrica hered-
(DUH) have been reported.8,10-12DDD, DSH, DUH,
and RAPK share clinical features with each other but
have different pathology findings. The genetic basis
for each is still being worked out. An association has
been found between DSH and the double-stranded
whereas loss-of-function in the keratin 5 (KRT5)
owling-Degos disease (DDD) is a rare pig-
mented skin disorder characterized by re-
ticular hyperpigmentation on flexor areas,
gene and a gene locus mapping to chromosome
17p13.3 have been described recently in cases of
DDD.21,22We reported a family with autosomal
dominant inheritance (Fig 1) of a skin disorder with
The proband was a 30-year-old woman who
presented with progressively generalized skin le-
her mother’s and had numerous symmetrically dis-
tributed hypopigmented or erythematous macules
and papules on the chest, abdomen (Figs 2, A and
C), back (Fig 2, B), axilla (Fig 2, D), back aspects of
the limbs, and perioral areas. There was no atrophy
in the lesions. Some comedone-like lesions were
present on the face with pits in the perioral area. No
DSRAD: double-stranded RNA-specific adenosine
DUH:dyschromatosis universalis hereditaria
RAPK:reticulate acropigmentation of Kitamura
dyschromatosis symmetrica hereditaria
From the Department of Dermatology, Mackay Memorial Hospi-
tala; Mackay Medicine, Nursing, and Management Collegeb;
and Lee-Ming Institute of Technology.c
Supported by the Mackay Memorial Hospital grant MMH-E-95004.
Conflicts of interest: None declared.
Reprint requests: Yu-Hung Wu, MD, Department of Dermatology,
Mackay Memorial Hospital, 92, Sec 2, Chung-Shan N Rd, Taipei,
Taiwan, 10449. E-mail: firstname.lastname@example.org.
ª 2007 by the American Academy of Dermatology, Inc.
breaks in the epidermal ridge pattern on the palms
and soles were seen. The mucosa, nails, teeth, and
hair were normal. Two cafe ´-au-lait spots were pre-
sent on her flank and back. Skin biopsy specimens
from a hypopigmented papule (Fig 4, A), an ery-
thematous papule (Fig 4, B), and pigmented skin
showed similar features. There were downward
elongations of the rete ridges in a reticulated or
fenestrated pattern and occasional horn cysts. The
overlying epidermis was thin and atrophic. The
hyperpigmented skin had the least degree of epi-
dermal elongation. A moderate superficial lympho-
cytic perivascular infiltrate was present in the
erythematous papule. Fontana-Masson stain demon-
strated prominent, diffuse basal melanin deposition
in the pigmented skin. The pigmentation was lost in
the hypopigmented and erythematous lesions ex-
cept for a small amount only at the tips of rete pegs
(Fig 4, D). Five tender papules in the axilla were
excised later because of causing discomfort. They
were all similar histologically to the biopsy speci-
mens from the abdomen except that all 5 axillary
lesions had lacunae or clefts in the suprabasal areas
(Fig 5).Somealsohad obvious intracellular edemain
the upper epidermis.
A 28-year-old man, younger brother of the pro-
band, had progressively generalized skin lesions
since early childhood. His skin was very similar to
his sister’s, with generalized hyperpigmentation and
or erythematous papules on the chest, abdomen,
back, back aspects of the limbs, axilla, and perioral
areas. Histologically, skin biopsy specimens were
similar in appearance to his sister’s, with reticulated
elongations of the rete ridges, occasional horn
cysts, a thin and atrophic overlying epidermis, and a
mild superficial lymphocytic perivascular infiltrate.
and a paucity of pigmentation in the hypopigmented
and erythematous papules. No lacunae or acantho-
lytic clefts were seen.
skin lesions since early childhood. There were retic-
ulated hyperpigmented macules and papules on his
forehead, perioral area, chest (Fig 3, A), neck (Fig 3,
B), elbow, and the back aspects of his forearm (Fig 3,
C), axilla (Fig 3, D), hands, and feet. There were,
however, no hypopigmented lesions. The perioral
lesions were similar to those of the proband. A skin
biopsy was not performed. The father’s younger
had skin findings similar to this man’s.
Genetic studies were performed after obtaining
informed consent from 6 available family members
(Fig 1). Blood samples were collected and genomic
DNA was extracted from peripheral blood leuko-
cytes using a commercial kit (GFX Genomic Blood
DNA Purification Kit, Amersham Biosciences, Piscat-
away, NJ). Twelve primers were designed for the
DSRAD gene15,18,19and forward and reverse primers
(59TGGGTAACAGAGCCACCTTC 39 and 59AAGCCA
AAACATCTTCCTTCT 39) for the hot-spot sites of
mutations found in exon 1 of the KRT5 gene.21All
the primers were amplified by polymerase chain
948C, then continued for 33 cycles (30 seconds at
948C, 30 seconds at 558C, and 60 seconds at 728C)
using 50 ng of genomic DNA, 1U Taq polymerase
(ABgene), 0.25 mmol/L dNTPs, 1.5 mmol/L MgCl2,
and 0.52 ?mol/L of each primer per 25 mL mix. The
polymerase chain reaction product was purified and
then directly sequenced on an automated DNA se-
quencer (ABI Prism 3730, Applied Biosystems, Fos-
ter City, Calif). No mutation was found either in the
affected individuals or unaffected family members.
DDD, also described as ‘‘reticulate pigmented
anomaly of the flexures,’’23is transmitted as an
autosomal dominant disorder with variable pene-
trance.1,10The proband’s father, sister, and niece had
typical DDD. The pigmentation was reticular and
limited in the flexural areas. However, the proband
and her brother had generalized pigmentation along
with hypopigmented macules and papules. In terms
of histology, the hypopigmented macules and
Fig 1. Pedigree of family with Dowling-Degos disease.
Proband (P) and her brother had generalized disease.
Her father (F), F’s sister, and her daughter had typical pig-
mented lesion on flexural surfaces.
J AM ACAD DERMATOL
328 Wu and Lin
Fig 2. Skin lesions of proband, 30-year-old woman. A, Generalized hyperpigmentation with
numerous symmetrically distributed hypopigmented or erythematous macules and papules on
chest, abdomen, and back (B). C, Close-up of papules on abdomen. D, Reddish papules rather
than reticulated pigmentation in axilla.
Fig 3. Father of proband, 55-year-old man. A, Reticulated pigmented macules and papules on
neck. B, Close-up of lesions on neck. C, Reticulated pigmented maculopapules on flexor
surface of elbow and axilla (D).
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Wu and Lin 329
papules had features typical of DDD, with narrow,
elongated rete pegs and a thin and atrophic over-
lying epidermis. A reticular pattern with horn cysts
was present. The generalized hyperpigmentation
seen in other areas was caused by basal deposition
of melanin. In the hypopigmented papules, the
melanin was confined to the tips of rete ridges. The
erythematous papules were histologically similar
except for papillary dermal perivascular inflamma-
tion. What set the findings in the proband and her
brother apart was the hypopigmented lesions com-
bined withgeneralized hyperpigmentation.Thisisin
contrast to the usual flexural distribution in classic
DDD. The generalized form has been reported only
rarely8,10,11and clinically resembles DUH.11
Because of the overlap of clinical features, there
is debate as to whether DDD, DUH, and RAPK are
separate entities or represent a spectrum of a single
pigmentary disorder. A more common pigmented
disorder associated with DDD is RAPK, which is
characterized by atrophic pigmented spots on the
back of the hands and feet, palmar pits, and
breakage of epidermal ridges. These lesions may or
may not be observed in patients with DDD.4-7,9,12
They were not present in our patients, and the
hypopigmented lesions we did observe are not a
feature of RAPK. Rather, diffuse symmetrically dis-
tributed hypopigmented macules or papules mixed
with hyperpigmentation are characteristic findings
in DUH (a generalized disorder) and DSH (a local-
ized disorder). In DSH, the pigmentary changes are
confined to the back aspects of the hands and feet.
and DUH macules are of normal skin structure aside
from the hypopigmentation24and are, therefore,
histologically different from the features of general-
ized DDD. Because hypopigmented lesions can be
present in DDD, we believe a number of previously
reported cases of DDD-RAPK syndrome or DDD-
DUH overlap may actually have been cases of gen-
eralized DDD (Table I).
The genetic defect of DDD has not yet been well
defined. A recently reported series described loss-
of-function mutations in the KRT5 gene in two
Fig 4. Skin biopsy specimens from proband of hypopigmented (A) and erythematous (B)
papules have similar findings characterized by downward elongations of rete ridges with
reticulated or fenestrated pattern and occasional horn cysts. Overlying epidermis is thin and
atrophic. Moderate superficial lymphocytic perivascular infiltrate is present in erythematous
papule. C, Skin biopsy specimen from hyperpigmented skin on abdomen showing basal
hyperpigmentation with slight epidermal elongations. D, Loss of basal pigment in hypopig-
J AM ACAD DERMATOL
330 Wu and Lin
German pedigrees.21Among 8 patients, 5 had
p.Ile140fs mutation and one a p.Ser5X nonsense
mutation, all located in exon 1 of the KRT5 gene.
These mutations were not found in our patients.
KRT5 genemutationshave previously been
recognized as involved in the pathogenesis of epi-
dermolysis bullosa simplex.25-27However, no asso-
ciation between DDD and epidermolysis bullosa has
been reported. Although the authors of the German
report hypothesize that K5 haploinsufficiency may
Table I. Features of 11 reported patients with generalized Dowling-Degos disease
SexAge, y Age of onset, yFamily history Biopsy Site of lesions DiagnosisYear
Lower trunk, thighs Leukoderma with features
of DDD- RAPK (case 1-5)
Overlap of RAPK, DSH, and DDD
DDD with DUH
DDD with DUH
DDD, Dowling-Degos disease; DSH, dyschromatosis symmetrica hereditaria; DUH, dyschromatosis universalis hereditaria; F, female; M, male;
RAPK, reticulated acropigmentation of Kitamura.
Fig 5. Apparent acantholytic form of Dowling-Degos disease (DDD) (Galli-Galli disease) in
skin biopsy specimens from proband’s axilla. A, Typical histologic features of DDD charac-
terized by downward elongations of rete ridges with reticulated or fenestrated pattern and
occasional horn cysts. Suprabasal acantholysis is present at margin. B, Higher power view of
suprabasal acantholysis. C, Lacunae or clefts in suprabasal areas. D, Intracellular edema
(spongiosis) of upper epidermis. (A to D, Hematoxylin-eosin stain; original magnifications:
A, 340; B and C, 3100; D, 3200.)
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Wu and Lin 331
Table II. Similarities and differences among Dowling-Degos disease, Galli-Galli disease, reticulated acropigmentation of Kitamura, dyschromatosis
universalis hereditaria, and dyschromatosis symmetrica hereditaria
Generalized DDD Classic DDD Galli-GalliRAPK DUHDSH
Possible CK5 or
AD, occasionally AR
Possibly chromosome 6
AD, occasionally AR
Back of hands
and feet, face
Scattered macules, papules Reticulated
fossae), back of
fossae), back of
LocationGeneralized, flexural areas,
Back of hands, neck
Facial pits, comedo-like
pits, broken epidermal
ridges, cafe ´-au-lait spots
Palmar pits, broken
Hyperpigmentation Tips of rete ridges
Yes Yes YesYesNoNo
Diffuse basal cell layer Basal hyperpigmentation
HypopigmentationElongation of rete
with pigment in the
tip of rete ridges
Acantholysis Usually noYes No NoNo
Only a few cases of Galli-Galli disease have been reported.
AD, Autosomal dominant; AR, autosomal recessive; DDD, Dowling-Degos disease; DSH, dyschromatosis symmetrica hereditaria (also known as reticulate acropigmentation of Dohi); DSRAD,
double-stranded RNA-specific adenosine deaminase; DUH, dyschromatosis universalis hereditaria; RAPK, reticulated acropigmentation of Kitamura.
J AM ACAD DERMATOL
332 Wu and Lin
cause an excess of unpaired, soluble K14 that is then
responsible for DDD, this requires further confirma-
tion. Another larger linkage analysis from a 4-gener-
gene locus mapping to chromosome 17p13.3.22
Several genes are located in this region, however,
and no particular candidate gene or sequence affect-
ing pigmentation was recognized. Looking at the
recently been mapped to chromosome 1q21,14with
gene.13,14,28Interestingly, no DSRAD mutation has
been found in patients with DUH.29A previous
linkage analysis of patients with DUH described as
DSH showed a possible gene locus on chromosome
6.28The information is still sketchy, but it appears
that DDD, DSH, and DUH may well be genetically
distinct disorders. Because we were unable to iden-
tify anomalies of eitherthe KRT5 gene orDSRAD, we
suggest that other genes must be responsible for this
disorder, at least in the family we studied.
Five axillary skin biopsy specimens from one
of our patients had histopathologic features of
acantholysis, a phenomenon previously described
as Galli-Galli disease.30,31In fact, this entity has been
regarded as an acantholytic variant of DDD, with
essentially the same gross clinical features. On close
inspection of the histology, the acantholysis is seen
to occur on top of the epidermis, forming lacunae
with subtle suprabasal acantholysis of the rete pegs.
By contrast, 5 other specimens from the abdomen or
chest of the same two patients had no acantholysis.
Therefore, it is most likely that the apparent acan-
tholysis was in fact either an artifact produced during
fixation or else was separation caused by a very thin
epidermis or spongiosis.
To summarize these different disorders with over-
lapping clinical or histopathologic features, it seems
that there are two major groups (Fig 6). The first is
DDD. Most patients in this group have the charac-
teristic histologic findings of elongated rete ridges,
horn cyst formation, and hyperpigmented tips. The
distribution may be reticulate in flexural areas (clas-
sic DDD) or generalized with hypopigmented pap-
ules (generalized DDD), and it may be distinguished
by the presence of acantholysis histologically (Galli-
Galli disease).30,31Patients may or may not have
atrophic brown macules on the back of hands and
feet, palmar pits, and broken epidermal ridges, the
entity known as RAPK.4-7,9,12The second major
group is dyschromatosis, including DUH and DSH.
Clinically, both have hyperpigmented and hypo-
pigmented lesions and histopathologic findings that
are similar to each other but that differ from the
DDD group (Table II). The genotypes underlying
DUH and differ, however, so they may either be two
separate entities with a similar phenotype or one
disorder with different genotypes.29
In conclusion, DDD can be present in a general-
ized form with hypopigmented lesions instead of
reticulate hyperpigmentation confined to the flexor
areas. This form can be differentiated from DUH by
histopathology. The genetic basis, however, remains
elusive. Care should be taken not to confuse similar
entities on the basis of clinical appearance alone.
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