CLINICAL REPORT

Palmoplantar Keratoderma, Pseudo-Ainhum, andUniversal Atrichia: A New Patient and Review of thePalmoplantar Keratoderma-CongenitalAlopecia SyndromeMarco Castori,1* Michele Valiante,1 Marco Ritelli,2 Nicoletta Preziosi,1 Marina Colombi,2

Mauro Paradisi,3 and Paola Grammatico1

1Medical Genetics, Department of Experimental Medicine, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy2Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy3VII 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-year-

old 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. Non-

specific 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 (Stevanovic type), a variable and benign pheno-type without significant hand complications, and (ii) a more

complex autosomal recessive variant (Wallis type) with contrac-

tures, 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

Stevanovic [1959] first described a four-generation familysegregating 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 keratodermahypotrichosisleukonychia totalis [Basaran et al., 1995]. The com-bination of PPK and hypotrichosis can be also observed in various

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 (

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 psycho-

motor 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 social-

ized 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 open-

ings 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 associatedwith 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 discolora-

tion, and longitudinal ridging and furrows (Fig. 2d). Annular con-

strictions (pseudo-ainhum) were evident at the second and fifth

fingers on both hands (Fig. 2e). Fingers appeared tapering

(sclerodactyly). Interphalangeal proximal and distal joints were

limited in extension with overt contractures. A nummular hyper-

keratotic 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

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.]

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.]

2044 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

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

ophryogenes, and PPK with consequent sclerodactyly, interpha-

langeal 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 dis-

orders, including Clouston syndrome, HOPP syndrome, keratosis

follicularis spinulosa decalvans (KFSD), KID syndrome, odonto-

onycho-dermal dysplasia, Lelis syndrome, Olmsted syndrome, and

SchopfSchulzPassarge syndrome [Patel et al., 1991; Steiner et al.,2002; Van Steensel et al., 2002; Megarbane et al., 2004; Mevorahet al., 2005; Mazereeuw-Hautier et al., 2007; Castori et al., 2008,

2009]. Differential diagnosis is based on specific additional find-

ings, 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; Stevanovic, 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 phenome-

non could not be confirmed because of scanty clinical details

[Alfadley et al., 2002; Gimelli et al., 2002].

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.]

TABLE I. Differential Diagnosis of Conditions Presenting With Palmoplantar Keratoderma and Congenital Alopecia/Atrichia/Hypotrichosis

FeaturesClouston

syndromeHOPP

syndrome KFSDKID

syndrome OODDLelis

syndromeOlmsted

syndrome SSPSPalmoplantar 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, SchopfSchulzPassargesyndrome.

CASTORI ET AL. 2045

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]. How-

ever, based on clinical details and available pictures, the sole

relevant clinical findings in this second individual were hypotri-

chosis, 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 provi-

sionally 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 [Stevanovic, 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 [Stevanovic, 1959; Walliset 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 [Stevanovic, 1959; Basaran et al., 1995]. In the re-maining, 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 repre-

sents 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 (Stevanovic type), a variable butbenign 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

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