CLINICAL REPORT

Palmoplantar Keratoderma, Pseudo-Ainhum, and

Universal Atrichia: A New Patient and Review of the
Palmoplantar Keratoderma-Congenital
Alopecia Syndrome
Marco Castori,1* Michele Valiante,1 Marco Ritelli,2 Nicoletta Preziosi,1 Marina Colombi,2
Mauro Paradisi,3 and Paola Grammatico1
1

Medical Genetics, Department of Experimental Medicine, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy

Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy

VII Pediatric Dermatology Division, IDI-IRCCS, Rome, Italy

Received 17 February 2010; Accepted 19 March 2010

Palmoplantar keratoderma (PPK) may concur with congenital

alopecia (CA) in various genodermatoses. We report on a 10-yearold girl with generalized atrichia and a severe form of
PPK causing pseudo-ainhum, sclerodactyly, and contractures,
a phenotype not consistent with any well-defined condition. Nonspecific additional findings comprised mild nail dystrophy and
widespread keratosis pilaris including ulerythema ophryogenes.
Direct sequencing of the GJB2 and LOR coding regions yielded
normal results. A review identified two additional sporadic and
four familial cases with PPK and CA. Comparison between
familial cases suggested the existence of two genetically and
phenotypically distinct types of PPK-CA: (i) an autosomal
dominant form (Stevanovi
c type), a variable and benign phenotype without significant hand complications, and (ii) a more
complex autosomal recessive variant (Wallis type) with contractures, sclerodactyly, and pseudo-ainhum. Nuclear cataract may
represent an additional although not constant finding in the
Wallis type PPK-CA. Further reports are required to test this
preliminary conclusion. 2010 Wiley-Liss, Inc.

Key words: hyperkeratosis; hypotrichosis; onychodystrophy;

keratosis pilaris

INTRODUCTION
Stevanovi
c [1959] first described a four-generation family
segregating for a syndrome of hypotrichosis (alternatively named
congenital alopecia; CA) and palmoplantar keratoderma (PPK;
alopecia congenita with keratosis palmoplantaris, OMIM 104100).
Since then, this condition was described in few families with
the designation of cataractsalopeciasclerodactyly [Wallis et al.,
1989], Vohwinkel disease with CA universalis [Bhatia et al., 1989],
Alves syndrome [Stratton et al., 1993], and keratoderma
hypotrichosisleukonychia totalis [Basaran et al., 1995]. The combination of PPK and hypotrichosis can be also observed in various

2010 Wiley-Liss, Inc.

How to Cite this Article:

Castori M, Valiante M, Ritelli M, Preziosi N,
Colombi M, Paradisi M, Grammatico P. 2010.
Palmoplantar keratoderma, pseudo-ainhum,
and universal atrichia: A new patient and
review of the palmoplantar keratodermacongenital alopecia syndrome.
Am J Med Genet Part A 152A:20432047.

well-defined genodermatoses, but all of them can be differentiated

on the basis of specific additional manifestations.
Here, we report on a 10-year-old girl manifesting hypotrichosis
and PPK causing progressive contractures, pseudo-ainhum, and
sclerodactyly. She also had mild nail dystrophy and widespread
keratosis pilaris including ulerythema ophryogenes.

CLINICAL REPORT
The proposita was a 10-year-old girl, only child of a 47-year-old
Italian mother and her non-consanguineous 50-year-old Latin
American husband. Family history was unremarkable. She was
born at term after an uneventful pregnancy, labor, and delivery.
No teratogen exposure was registered. Patients birth weight was
2,470 g (<3rd centile) and length 47.5 cm (25th centile), while
*Correspondence to:
Marco Castori, MD, Medical Genetics, Department of Experimental
Medicine, Sapienza University of Rome, San Camillo-Forlanini
Hospital, Circonvallazione Gianicolense, 87, I-00152 Rome, Italy.
E-mail: mcastori@scamilloforlanini.rm.it
or marco.castori1977@gmail.com
Published online 15 July 2010 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.a.33490

2043

2044
Apgar scores were 91/105. At birth, the skin was unremarkable. The
mother recalled that the girl was born with scalp hair and eyebrows.
Both hair and eyebrows fell out at the age of 1 month and never grew
back again. During late infancy, progressive thickening of the skin at
the lateral and medial aspects of palms and soles was noted. These
changes subsequently involved the fingers and partly extended
over the extensor surfaces causing contractures and recurrent
spontaneous wounds, which healed with difficulty. Early psychomotor development and scholarship progressed normally. The
patient never complained of photophobia or photosensitivity. A
previous light microscopy study of the residual scalp hair at the
nuchal region documented trichorrhexis nodosa.
At the time of evaluation, height was 151 cm (97th centile), weight
48 kg (95th centile), and head circumference 54.5 cm (97th centile).
The patient appeared healthy, well oriented and reactive, and socialized appropriately for her chronological age. Body and scalp hair and
eyebrows were absent (Fig. 1a). Fine vellus was partly evident on the
scalp region while rare terminal hair were still visible in the nuchal
area. Eyelashes were unremarkable. On the scalp, hair follicle openings were preserved, thus suggesting a non-cicatricial cause of the hair
loss. The skin of the face was erythematous, especially on checks and
glabellar region, and showed spiny follicular plugging, particularly
evident on the checks, supraorbital ridges, and helices (ulerythema
ophryogenes; Fig. 1b). The rest of the body was covered with marked
keratosis pilaris (Fig. 1c). There was linear hyperkeratosis along the
lateral and medial aspects of the palms. This thickening extended
along the fingers and over their dorsal aspects, distally to the proximal
interphalangeal joints (Fig. 1ac). Hyperkeratosis was associated
with desquamation and mild erythema and this phenomenon was
particularly evident around nails with perionixis-like aspects. There
were skin cracks with delayed healing at the medial and lateral sides of
the palms. Nails were mildly dystrophic with light yellow discoloration, and longitudinal ridging and furrows (Fig. 2d). Annular constrictions (pseudo-ainhum) were evident at the second and fifth
fingers on both hands (Fig. 2e). Fingers appeared tapering

FIG. 1. Generalized atrichia of scalp and eyebrows (a). Note

ulerythema ophryogenes (b). Spiny keratosis follicularis on
back (c). [Color figure can be viewed in the online issue, which
is available at www.interscience.wiley.com.]

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

FIG. 2. Desquamation, hyperkeratosis, and mild erythema on the

dorsal aspect of fingers. Note pseudo-ainhum on II and V fingers
(a). Palmar vision of the band constrictions (b). Medial aspect
of the I and II fingers (c). Close-up of the nails which appear
mildly dystrophic and surrounded by perionixis (d). Particular
of the pseudo-ainhum at the II finger (e). [Color figure can be
viewed in the online issue, which is available at
www.interscience.wiley.com.]

(sclerodactyly). Interphalangeal proximal and distal joints were

limited in extension with overt contractures. A nummular hyperkeratotic and mildly erythematous area was evident on the left palm.
Feet showed hard hyperkeratosis at the heels and along the lateral
aspect of soles. Isolated callosities were also evident on pressure
regions (Fig. 3a). Skin of the periungual areas was thickened and
desquamated while nails appeared mildly dystrophic (Fig. 3b,c).
Hand films showed substantially normal distal phalanges without
evidence of osteolysis. Ophthalmological findings, audiogram, and
results of heart and kidney ultrasound studies were normal.
Due to the presence of mutilating keratoderma, the coding
regions of GJB2 and LOR, the genes known as responsible of various
forms of Vohwinkel syndrome, were sequenced as previously
described [Maestrini et al., 1999; Drera et al., 2008]. No pathogenic
change was identified in the GJB2 gene. Similarly, sequencing of

CASTORI ET AL.

FIG. 3. Callosities at the feet (a). Involvement of the toes and

mild dystrophic changes of the toenails (b,c). [Color figure
can be viewed in the online issue, which is available at
www.interscience.wiley.com.]

LOR did not disclose a causal mutation but showed the presence of
the known polymorphism c.567_568ins12 (CTCTGGCGGCGG)
[p.Y189YSGGG] in the patient and in her unaffected mother.

DISCUSSION
Our patient shows the unusual combination of generalized
hypotrichosis, widespread keratosis pilaris including ulerythema

2045
ophryogenes, and PPK with consequent sclerodactyly, interphalangeal joint contractures, and pseudo-ainhum. Considering the
relatively high frequency of keratosis pilaris and ulerythema
ophryogenes in the young population, the combination of PPK
and hypotrichosis is the most consistent manifestation in the
present case.
The combination of PPK and CA/hypotrichosis/atrichia may be
observed in various ectodermal dysplasias and keratinization disorders, including Clouston syndrome, HOPP syndrome, keratosis
follicularis spinulosa decalvans (KFSD), KID syndrome, odontoonycho-dermal dysplasia, Lelis syndrome, Olmsted syndrome, and
Sch
opfSchulzPassarge syndrome [Patel et al., 1991; Steiner et al.,
2002; Van Steensel et al., 2002; M
egarban
e et al., 2004; Mevorah
et al., 2005; Mazereeuw-Hautier et al., 2007; Castori et al., 2008,
2009]. Differential diagnosis is based on specific additional findings, as illustrated in Table I. Our patient clearly does not meet the
diagnostic criteria for any of the above-mentioned well-defined
conditions. In the present case, the co-existence of keratosis pilaris
with ulerythema ophryogenes points out a possible overlap with
KFSD. At least eight articles have described the combination of PPK
and KFSD [Kuokkanen, 1971; Stevanovi
c, 1988; Herd and Benton,
1996; Kunte et al., 1998; Alfadley et al., 2002; Gimelli et al., 2002;
Garman et al., 2005; Janjua et al., 2008] and the authors are aware of
an additional not jet published family [Castori, personal
communication]. In contrast to the present patient, in KFSD hair
loss is always secondary to an inflammatory process which leads to
scarring alopecia. However, in two of these patients this phenomenon could not be confirmed because of scanty clinical details
[Alfadley et al., 2002; Gimelli et al., 2002].

TABLE I. Differential Diagnosis of Conditions Presenting With Palmoplantar Keratoderma and Congenital Alopecia/Atrichia/Hypotrichosis
Clouston
HOPP
KID
Lelis
Olmsted
Features
syndrome
syndrome
KFSD
syndrome OODD syndrome syndrome SSPS
Palmoplantar keratoderma

Atrichia/hypotrichosis

(cicatricial)

Keratotic plaques not on









palmoplantar surfaces
Pseudo-ainhum








Contractures








Dystrophic nails
(thickened) (thickened)

(thickened)

Acro-osteolysis







Hypo/anhidrosis






Hyperpigmentation/acanthosis nigricans






Keratosis pilaris








Folliculitis








Telangiectasias/facial erythema






Keratitis/photophobia






Eyelid cysts








Periodontitis








Oligodontia/enamel defects





Smooth tongue








Leukokeratosis








Deafness








, common feature; , occasional feature; , never reported feature; KFSD, keratosis follicularis spinulosa decalvans; OODD, odonto-onycho-dermal dysplasia; SSPS, SchopfSchulzPassarge
syndrome.




D

n.a






n.a.















C, cataract; D, (monolateral) deafness; F, female; M, male; MC, meningocoele; n.a., not available; PPK, palmoplantar keratoderma.
Tabulated details are on basis of the available clinical description and published pictures.

n.a.













Pt 3
F
<1
Pt 2
F
8

Characteristic
Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 1 Pt 2 Pt 3 Pt 4
Sex
F
M
F
M
M
F
F
M
M
Age at diagnosis (years) n.a. 35 7 3.5 2 n.a. n.a. n.a. n.a.
Hypotrichosis
Eyebrows/lashes


Scalp
 

Body
 n.a. n.a. n.a.

PPK


Keratosis pilaris/dry skin     





Ulerythema ophryogenes     




Nail changes

n.a. n.a. n.a.
Contractures
    

Sclerodactyly
    

Pseudo-ainhum
    

Additional findings
    
C
C
C
C

Pt 1
M
16

n.a.

n.a.

n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
MC

Rai and Shenoi Present

[2005]
case
M
F
23
10
Pt 3
F
3
Pt 2
F
8
Pt 1
F
32

Basaran et al. [1995]

Stratton et al.
[1993]
F
10
Bhatia et al. [1989]
Wallis et al. [1989]
Stevanovi
c [1959]

The combination of PPK and CA was also reported in a handful

of additional patients with apparently unique phenotypes. In
particular, Pinheiro et al. [1981] described a 12-year-old Brazilian
boy with a novel ectodermal dysplasia which combined PPK and
CA with poikiloderma-like lesions, aplasia cutis congenita, absent
right nipple, minor facial anomalies, and corneal leukoma. The
tricho-oculo-dermo-vertebral syndrome was originally described
in a 20-year-old woman with PPK, hypotrichosis, dystrophic
nails, generalized ichthyotic skin changes, facial anomalies,
cataract, and kyphoscoliosis [Alves et al., 1981]. Of note, a second
patient was claimed to be affected with the same condition,
alternatively named Alves syndrome [Stratton et al., 1993]. However, based on clinical details and available pictures, the sole
relevant clinical findings in this second individual were hypotrichosis, PPK, nail changes, and dry skin. Although clinical variability
of the same gene cannot be definitively excluded, it is very likely that
these two patients have different conditions. In particular, the
patient of Stratton et al. [1993] is undoubtedly more similar
to our case and, consequently, was included in the following
discussion as a further example of PPK-CA. Steijlen et al. [1994]
described a family with PPK, hypotrichosis, mental retardation,
and parodontopathy, segregating as an autosomal recessive
trait. Finally, two unrelated patients were described with a provisionally distinct forms of ectodermal dyplasia comprising PPK,
hypotrichosis, and other features [Akhyani and Kiavash, 2007;
Nakamura and Ishikawa, 2007].
A review identified 4 additional familial [Stevanovi
c, 1959;
Bhatia et al., 1989; Wallis et al., 1989; Basaran et al., 1995] and 2
sporadic [Stratton et al., 1993; Rai and Shenoi, 2005] cases with
PPK-CA, for a total of 18 individuals including the present
patient(Table II). Twelve of the 14 patients also manifested
nail changes, comprising brittle nails [Stevanovi
c, 1959; Wallis
et al., 1989], wide, flat, and thin nails with peeling [Stratton
et al., 1993], leukonychia [Basaran et al., 1995], dystrophy
of all 20 nails [Rai and Shenoi, 2005], and nail dystrophy
with longitudinal ridging (present case). No patient showed
thickened nails. Therefore, nail changes are a consistent, although
mild and probably secondary to the transgrediens PPK finding in
PPK-CA.
Among the familial cases, two constitute a dominant pattern of
inheritance and one shows lack of penetrance and male-to-male
transmission [Stevanovi
c, 1959; Basaran et al., 1995]. In the remaining, the disorder is transmitted in a horizontal fashion and
parents are consanguineous in one instance [Bhatia et al., 1989;
Wallis et al., 1989]. In both genetic forms there is a slight excess of
affected females. Phenotype comparison suggests a possible
clinical dichotomy. In fact, in the recessive form, PPK causes joint
contractures and is often complicated by annular constrictions
and tapering of fingers (Table II). This progression usually represents the patients major complaint, as well documented by the
present case. Accordingly, two types of PPK-CA can be delineated:
(i) an autosomal dominant form (Stevanovi
c type), a variable but
benign phenotype without significant hand complications, and (ii)
a more severe autosomal recessive variant (Wallis type) with
contractures, sclerodactyly, and pseudo-ainhum. Nuclear
cataract, observed in all affected members in the family published
by Wallis et al. [1989], may represent an additional although not

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE II. Comparison Between Previously Published Patients With the Association of Palmoplantar Keratoderma and Hypotrichosis, and Present Case

2046

CASTORI ET AL.
constant differential. According to this hypothesis, the sporadic
cases by Rai and Shenoi [2005] and Stratton et al. [1993] may be
examples of the Stevanovi
c type PPK-CA possibly arising as de novo
mutations, while our patient is most probably affected by the Wallis
type PAN syndrome. Further reports are required to test this
hypothesis.

ACKNOWLEDGMENTS

2047
Kunte C, Loeser C, Wolff H. 1998. Folliculitis spinulosa decalvans:
Successful therapy with dapsone. J Am Acad Dermatol 39:891893.
Kuokkanen K. 1971. Keratosis follicularis spinulosa decalvans in a family
from northern Finland. Acta Derm Venereol 51:146150.
Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder
PM, Hovnanian A, Monaco AP, Munro CS. 1999. A missense mutation in
connexion 26, D66H, causes mutilating keratoderma with sensorineural
deafness (Vohwinkels syndrome) in three unrelated families. Hum Mol
Genet 8:12371243.

The authors thank Prof. John M. Opitz for his editorial support
and having revised the text, and Mrs. Paola Menichetti
(Scientific Library, IDI-IRCCS, Rome, Italy) for her kind assistance
in bibliographic search.

Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, Man SY, Bodemer C,

Prins C, Antille C, Saurat JH, Atherton D, Harper JI, Kelsell DP,
Hovnanian A. 2007. Keratitis-ichthyosis-deafness syndrome: Disease
expression and spectrum of connexin 26 (GJB2) mutations in 14 patients.
Br J Dermatol 156:10151019.

REFERENCES

M
egarban
e H, Haddad M, Delague V, Renoux J, Boehm N, M
egarban
e A.

2004. Further delineation of the odonto-onycho-dermal dysplasia syndrome. Am J Med Genet Part A 129A:193197.

Akhyani M, Kiavash K. 2007. Ectodermal dysplasia with alopecia, onychodysplasia, hypohidrosis, keratoderma, abnormal teeth and deafness.
Indian J Dermatol Venereol Leprol 73:409411.

Mevorah B, Goldberg I, Sprecher E, Bergman R, Metzker A, Luria R, Gat A,

Brenner S. 2005. Olmsted syndrome: Mutilating palmoplantar keratoderma with periorificial keratotic plaques. J Am Acad Dermatol 53:
S266S272.

Alfadley A, Al Hawsawi K, Hainau B, Al Aboud K. 2002. Two brothers with

keratosis follicularis spinulosa decalvans. J Am Acad Dermatol 47:
S275S278.
Alves AF, dos Santos PA, Castelo-Branco-Neto E, Freire-Maia N. 1981. An
autosomal recessive ectodermal dysplasia syndrome of hypotrichosis,
onychodysplasia, hyperkeratosis, kyphoscoliosis, cataract, and other
manifestations. Am J Med Genet 10:213218.
Basaran E, Yilmaz E, Alpsoy E, Yilmaz GG. 1995. Keratoderma, hypotrichosis and leukonychia totalis: A new syndrome? Br J Dermatol 133:
636638.
Bhatia KK, Chaudhary S, Pahwa US, Mehrotra GC. 1989. Keratoma
hereditaria mutilans (Vohwinkels disease) with congenital alopecia
universalis (atrichia congenita). J Dermatol 16:231236.
Castori M, Ruggieri S, Giannetti L, Annessi G, Zambruno G. 2008.
Sch
opf-Schulz-Passarge syndrome: Further delineation of the phenotype
and genetic considerations. Acta Derm Venereol 88:607612.
Castori M, Covaciu C, Paradisi M, Zambruno G. 2009. Clinical and genetic
heterogeneity in keratosis follicularis spinulosa decalvans. Eur J Med
Genet 52:5358.
Drera B, Tadini G, Balbo F, Marchese L, Barlati S, Colombi M. 2008. De
novo occurrence of the 730insG recurrent mutation in an Italian
family with the ichthyotic variant of Vohwinkel syndrome, loricrin
keratoderma. Clin Genet 73:8588.
Garman ME, Nu~
nez-Gussman J, Metry D. 2005. What syndrome is this?
Pediatr Dermatol 22:170174.
Gimelli G, Giglio S, Zuffardi O, Alhonen L, Suppola S, Cusano R, Lo Nigro
C, Gatti R, Ravazzolo R, Seri M. 2002. Gene dosage of the spermidine/
spermine N(1)-acetyltransferase (SSAT) gene with putrescine
accumulation in a patient with a Xp21.1p22.12 duplication and keratosis
follicularis spinulosa decalvans (KFSD). Hum Genet 111:235241.

Nakamura M, Ishikawa O. 2007. A patient with alopecia, nail dystrophy,

palmoplantar hyperkeratosis, keratitis, hearing difficulty and micrognathia without GJB2 or GJB6 mutations: A new type of hydrotic
ectodermal dysplasia? Br J Dermatol 156:777779.
Patel RR, Bixler D, Norins AL. 1991. Clouston syndrome: A rare autosomal
dominant trait with palmoplantar hyperkeratosis and alopecia.
J Craniofac Genet Dev Biol 11:176179.
Pinheiro M, Pereira LC, Freire-Maia N. 1981. A previously undescribed
condition: Tricho-odonto-onycho-dermal syndrome. A review of the
tricho-odonto-onychial subgroup of ectodermal dysplasias. Br J Dermatol 105:371382.
Rai VM, Shenoi SD. 2005. Ichthyosis follicularis with congenital atrichia,
nail dystrophy and palmoplantar keratoderma. Variant of IFAP syndrome or a new entity? Dermatol Online J 11:36.
Steijlen PM, Neumann HA, der Kinderen DJ, Smeets DF, van der Kerkhof
PC, Happle R. 1994. Congenital atrichia, palmoplantar hyperkeratosis,
mental retardation, and early loss of teeth in four siblings: A new
syndrome? J Am Acad Dermatol 30:893898.
Steiner CE, Cintra ML, Marques-de-Faria AP. 2002. Ectodermal dysplasia
with acanthosis nigricans (Lelis syndrome). Am J Med Genet 113:
381384.
Stevanovi
c DV. 1959. Alopecia congenita: The incomplete dominant form
of inheritance with varying expressivity. Acta Genet Stat Med 9:127132.
Stevanovi
c DV. 1988. Keratosis follicularis spinulosa decalvans with birefringent hairs. An association with variable keratoderma. Dermatol
Monatsschr 174:736740.
Stratton RF, Jorgenson RJ, Krause IC. 1993. Possible second case of trichooculo-dermo-vertebral (Alves) syndrome. Am J Med Genet 46:313315.

Herd RM, Benton EC. 1996. Keratosis follicularis spinulosa decalvans:

Report of a new pedigree. Br J Dermatol 134:138142.

Van Steensel MA, Van Geel M, Steijlen PM. 2002. New syndrome of
hypotrichosis, striate palmoplantar keratoderma, acro-osteolysis and
periodontitis not due to mutations in cathepsin C. Br J Dermatol
147:575581.

Janjua SA, Iftikhar N, Pastar Z, Hosler GA. 2008. Keratosis follicularis

spinulosa decalvans associated with acne keloidalis nuchae and tufted
hair folliculitis. Am J Clin Dermatol 9:137140.

Wallis C, Ip FS, Beighton P. 1989. Cataracts, alopecia, and sclerodactyly: A

previously apparently undescribed ectodermal dysplasia syndrome on
the island of Rodrigues. Am J Med Genet 32:500503.