Palmoplantar keratoderma, pseudo-ainhum, and universal atrichia: A new patient and review of the palmoplantar keratoderma-congenital alopecia syndrome^†

INTRODUCTION

Stevanović 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 cataracts–alopecia–sclerodactyly [Wallis et al., 1989], Vohwinkel disease with CA universalis [Bhatia et al., 1989], Alves syndrome [Stratton et al., 1993], and keratoderma–hypotrichosis–leukonychia totalis [Başaran et al., 1995]. The combination 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. Patient's birth weight was 2,470 g (<3rd centile) and length 47.5 cm (25th centile), while 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. 1a–c). 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 (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 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, 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, odonto-onycho-dermal dysplasia, Lelis syndrome, Olmsted syndrome, and Schöpf–Schulz–Passarge syndrome [Patel et al., 1991; Steiner et al., 2002; Van Steensel et al., 2002; Mégarbané 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; Stevanović, 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].

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 [Stevanović, 1959; Bhatia et al., 1989; Wallis et al., 1989; Başaran 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 [Stevanović, 1959; Wallis et al., 1989], wide, flat, and thin nails with peeling [Stratton et al., 1993], leukonychia [Başaran 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 [Stevanović, 1959; Başaran 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 (Stevanović 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 constant differential. According to this hypothesis, the sporadic cases by Rai and Shenoi 2005 and Stratton et al. 1993 may be examples of the Stevanović 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.