47 patients in 14 families with the rare genodermatosis keratosis punctata palmoplantaris Buschke-Fischer-Brauer

ARTICLE

The palmoplantar keratodermas consist of a complex heterogeneous group of dermatoses in which there is hyperkeratosis of the skin over the palms and soles. Acquired and inherited forms exist. To date the classification of inherited palmoplantar keratodermas is mainly based on clinical appearance and histology. In some cases a molecular based classification is already possible. Generally, diffuse, focal or punctate forms are distinguished [1, 2].

Punctate palmoplantar keratoderma was first described by Buschke and Fischer in 1910 [3]. Brauer confirmed the heredity of this dermatosis in 1913 [4]. Hence, the disease is often referred to as keratosis punctata palmoplantaris Buschke-Fischer-Brauer (MIM number: 148600). Various synonyms have been used including keratoma dissipatum hereditarium palmare et plantare (Brauer), keratoma disseminatum, keratodermia maculosa disseminata symmetrica palmaris et plantaris (Buschke-Fischer), keratodermia punctata hereditaria, keratodermia palmoplantaris papulosa and others [5, 6].

Clinically, this genodermatosis presents with numerous hyperkeratotic papules that are irregularly distributed on the palms and soles. The papules may vary greatly in size and tend to coalesce over pressure points. The lesions usually start to develop in late childhood to adolescence but may also start to appear up to the fifth decade in life. The majority of cases are diagnosed incidentally since most patients do not complain about symptoms. Sometimes walking may be painful due to larger hyperkeratoses over pressure points [6-8].

Here, we describe 14 families with keratosis punctata palmoplantaris Buschke-Fischer-Brauer with a total of 47 affected individuals.

Case reports

All cases (Table I) presented the typical punctate keratoses on the palms and soles. Generally, keratoses on the soles developed earlier in life than those on the palms. They were more severe especially over pressure points. There was a marked variability in disease expression not only between families but also within some families. Mild disease presented as pinhead sized waterdrop like hyperkeratotic pearls of several millimeters in diameter (Fig. 1A and 2A). Signs of more severe disease expression included prominent hyperkeratotic papules that formed confluent plaques mostly over pressure points (Fig. 1B and 2B). 27 men and 20 women were affected. Except for three families in which affected individuals complained about palmoplantar hyperhidrosis no associated symptoms were found. One family had a late onset type of punctate palmoplantar keratoderma. Patients used mechanical measures or keratolytic ointments, if any, to reduce hyperkeratoses. One patient received systemic retinoids and was cleared nearly completely from all symptoms within two months (Fig. 3A and B). When the therapy was discontinued, the hyperkeratoses recurred.

Family A

Eight members over three generations were affected in this family (Fig. 4A). Age of onset ranged between puberty and early twenties. Clinically, a preponderance of sole involvement was noted with multiple round yellowish hyperkeratotic papules over pressure points and smaller papules at the vault. Palms were unaffected in younger family members (< 40 y). Discrete palmar hyperkeratotic papules were found in affected members of older age (> 40 y). Finger and toe nails, hair, and teeth were normal.

Histologic examination revealed the typical unspecific features hypergranulosis, acanthosis, and in parts parakeratotic hyperkeratosis [6].

Family B

There were four affected members in three generations (Fig. 4B). The youngest affected family member stated that the lesions had started to develop on the soles at 23 years of age. 16 years later (39 y) lesions also developed on the palms. There were pinhead sized hyperkeratotic papules on the palms. On the soles papules coalesced to thick and painful hyperkeratotic plaques over pressure points making walking difficult. No other skin, nail, or hair abnormalities were found.

Family C

Three members in two generations were affected (Fig. 4C). This family was only mildly affected. Tiny hyperkeratotic pearls had developed both on palms and soles shortly after puberty. The children had not realized that their father had the same lesions. No other abnormalities were present. Histologic features were consistent with keratosis punctata palmoplantaris.

Family D

There were five affected members in three generations (Fig. 4D). Symptoms started to develop in the early twenties on the soles and several years later on the palms. Disease expression was quite variable within this family. The grandfather of the two youngest affected brothers had severe symptoms and could hardly bend his fingers due to hyperkeratotic papules. The two brothers themselves had pinhead sized papules and yellowish hyperkeratotic papules 1-2 cm in size over pressure points. Their father suffered from even milder symptoms. All affected members also suffered from palmoplantar hyperhidrosis.

Family E

Three members in three generations were affected (Fig. 4E). Age of onset ranged from puberty to mid-twenties. The symptoms started to develop on the soles. Later, smaller hyperkeratotic papules also developed on the palms. The youngest affected male suffered from thick and painful plantar hyperkeratoses. A retinoid therapy (acitretin (Tigason®), Roche, Basel, Switzerland) with 75 mg/d was initiated. After 11 weeks of continuous therapy the symptoms had nearly cleared (Fig. 3). Subsequently, acitretin was reduced to 50 mg/d as maintenance therapy. Unfortunately, this dose was insufficient to prevent relapse. Because the patient could not tolerate 75 mg/d the therapy was discontinued and symptoms fully recurred.

Family F

Three members in two generations were affected (Fig. 5F). Patients presented typical symptoms with more pronounced disease on the soles.

Family G

Typical symptoms were present in the patient and his brother (Fig. 5G). Their father died during world war II and no further information is available about the father’s family.

Family H

Three members in two generations were affected (Fig. 5H). There was intrafamilial variability of disease expression as the youngest affected male had milder symptoms than his mother and uncle. In addition, all affected patients suffered from plantar hyperhidrosis.

Family I

This family has already been reported in detail elsewhere. Three affected family members had typical lesions (Fig. 5I). Histology was consistent with keratosis punctata palmoplantaris.

Families J to L

Only one affected member was found in each of these three families (2 men, 1 woman). Age of disease onset in
all three affected individuals was during adolescence. Parents and siblings of these patients were normal. One patient had no children. The children of the other two patients were not affected but too young to finally exclude the diagnosis. Thus, it is possible that these were the first patients in their families who developed the disease due to spontaneous mutation.

Family M

A mother and one daughter were affected in this family (Fig. 5M). Interestingly, this family seems to represent a late onset type of keratosis punctata palmoplantaris. The mother noticed first symptoms in her fifties. The 40 year old daughter was unaware that she was affected. She had single pinhead sized hyperkeratotic papules on the palms and several of these papules on the soles that were hardly noticeable. Careful examination of the mother revealed no signs of malignancy or other internal disease.

Family N

Eight members in three generations were affected (Fig. 5N). Symptoms developed after puberty and could be aggravated by mechanical irritation. Palmoplantar hyperhidrosis was present in all affected members.

Discussion

Keratosis punctata Buschke-Fischer-Brauer is a rare genodermatosis. Its incidence is reported as 1.17 per 100,000 in Croatia [9]. So far, only a few extended families have been reported. These studies indicate an autosomal dominant mode of inheritance of the disease. However, the causative gene has not been mapped or identified yet [10].

The clinical symptoms of the affected members of our families matched the typical features of keratosis punctata. There was interfamilial but also intrafamilial variation in the severity of disease expression (Fig. 1 and 2). Generally, disease expression was more severe on the soles than on the palms, probably due to higher pressure to the soles. Lesions seemed to develop on the soles earlier in life than on the palms. The distribution between affected men and women did not differ significantly (27 men, 20 women, p = 0.6, Student’s t-test). However, it is noticeable that in families D, G, and I only males were affected. Some authors argue that a lack of affected females in family pedigrees may be due to a less severe disease expression in females [11]. All of our family pedigrees are consistent with autosomal dominant inheritance (Fig. 4 and 5). We calculated that 45.4 % of all children from known affected individuals were also clinically affected (expected percentage: 50 %; sib method of Weinberg). Using the proband method of Weinberg [12] (the index patient is substracted and the frequency of the trait is analysed among his sibs) we calculated a frequency of affected individuals of 43.4 %. Only children older than the age of disease onset in the index patient of the corresponding family were included in the calculation. In addition, most of our families also show male to male transmission which excludes X-linked inheritance.

Differential diagnoses of keratosis punctata palmoplantaris include calluses due to pressure and viral warts [6]. Porokeratosis punctata palmaris et plantaris (punctate porokeratosis) (MIM number: 175860) may present very similar to punctate keratosis and is also transmitted in an autosomal dominant fashion [13]. However, cornoid lamellae are the characteristic histologic feature in this entity. In acrokeratoelastoidosis (MIM number: 101850) disorganized elastic fibres are the histopathological hallmark [14]. These were not present in our patients. The history in our families gave no evidence for a toxic origin of keratoses, e.g. arsenic which can lead to pinhead like yellowish keratotic papules [6], nor for a paraneoplastic origin of palmoplantar keratoses [6].

The majority of our patients applied mechanical measures to reduce prominent hyperkeratotic plugs mostly located over pressure points on the soles. They felt that this procedure is superior to the use of keratolytic ointments which often leads to skin maceration. This is in accordance with literature data indicating no major beneficial effects of keratolytic ointments as well as topical retinoids or topical calcipotriol on the keratoses [6]. Systemic treatment with oral retinoids may yield better results, however, at the cost of more severe side effects. Baran et al. [15] and Hesse et al. [16] reported good results with etretinate or acitretin, respectively. In contrast, Christiansen [17] found mixed responses to etretinate in 9 patients. Happle et al. [18] observed only slight benefit in one patient using this retinoid. In general, maintenance therapy was required to prevent relapse [16]. We treated one patient (family E) with acitretin. After 11 weeks the hyperkeratoses were nearly cleared (Fig. 3). Maintenance therapy with a reduced retinoid dosage led to disease relapse and symptoms fully recurred after discontinuance of treatment.

DNA from affected and unaffected family members is collected at a national registry (Max Delbrueck Center for molecular medicine, Berlin-Buch, Germany) for genetic studies. Identification of the disease gene(s) might lead to a better classification of the heterogeneous group of punctate palmoplantar keratodermas [14]. There are reports that punctate palmoplantar keratoderma may present as cutaneous horns [19]. Other abnormalities have been infrequently reported in association with keratosis punctata including a variety of nail dystrophies [6, 16], neurologic abnormalities like spastic paralysis [20], anodontia [21], HLAB27 associated arthropathy [22], or combinations of color blindness, ulcus ventriculi or duodeni, syndactylia and others [23]. In contrast to the well recognized association of diffuse or focal palmoplantar keratoderma and malignancies [1], it is highly questionable whether one can associate punctate palmoplantar keratoderma with malignancies. So far, there have been only three reports of hereditary punctate keratoses in association with malignancy. Ena et al. [24] described a family with 8 affected individuals, one developed adenocarcinoma of the colon at the age of 53. Bennion et al. [5] reported on 8 affected individuals, two developed adenocarcinoma of the colon (44y, 65y) and one adenocarcinoma of the pancreas (65y). Stevens et al. [1] investigated a large kindred in which 10 of 43 individuals with punctate palmoplantar keratoderma developed malignancies (Hodgkin’s disease, renal, breast, pancreatic, and colonic adenocarcinomas). These authors discuss a number of factors which might suggest an association of punctate palmoplantar keratoderma with malignancy including alterations in keratin gene expression. However, the same authors excluded linkage of Buschke-Fischer-Brauer
punctate keratoderma to keratin gene clusters on 12q and 17q [25].

CONCLUSION

In conclusion, knowledge of the gene(s) which cause punctate palmoplantar keratoderma and its function might provide insights into possible cancer risks. This knowledge could lead to strategies for cancer prevention. For example, in a family with Howel-Evans syndrome (tylosis and squamous cell carcinoma of the esophagus) most patients were smokers, highlighting the possibly important role of environmental factors in the development of malignancies in palmoplantar keratodermas [14]. Genetic studies could reveal if one entity of punctate palmoplantar keratoderma exists with a broad phenotypic spectrum, or, if subtypes exist like hereditary painful callosities [26] or a subtype possibly being associated with increased cancer susceptibility.

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