Dermatology Online Journal

Supernumerary nipples in association with Hailey-Hailey disease in a Tunisian family
R Benmously Mlika¹, S Deghais¹, M Bchetnia^2,3, C Charfeddine², M Mokni^3,4, S Kassar⁵, S Haouet⁶, S Boubaker⁵, I Mokhtar¹, S Abdelhak², A Ben Osman Dhahri⁴
Dermatology Online Journal 14 (6): 15

1. Dermatology Department, Habib Thameur Hospital-Tunis, Tunisia. rym.benmously@rns.tn
2. Molecular Investigation of Genetic Orphan Diseases Research Unit (MIGOD), Institut Pasteur de Tunis, Tunisia
3. Study of Hereditary Keratinization Disorders Research Unit, la Rabta Hospital, Tunis, Tunisia
4. Dermatology Department - La Rabta Hospital Tunis, Tunisia
5. Anatomo-pathology Department - Institut Pasteur de Tunis, Tunis, Tunisia
6. Anatomo-pathology Department - La Rabta Hospital Tunis, Tunisia

---

Abstract

Supernumerary nipples (SNs) or polythelia are developmental abnormalities of breast tissue. They are located along the embryonic mammary lines. Polythelia usually occurs as a sporadic abnormality, although familial aggregation has been occasionally reported. Hailey-Hailey disease is a rare autosomal genodermatosis characterized by disturbed keratinocyte adhesion. These cutaneous disorders have been described in correlation with many other abnormalities. We report here the association of Hailey-Hailey disease and supernumerary nipples in a Northern Tunisian family. To our knowledge, this is the first report of such a clinical association.

---

Introduction

Supernumerary nipples (SNs), also known as polythelia are the most common forms of accessory breast tissue malformations. Extra nipples usually occur as a sporadic abnormality, although familial aggregation has been occasionally reported [1].

The mode of inheritance of polythelia seems to be heterogeneous because four modes have been suggested: autosomal dominant, X-linked dominant, autosomal recessive and paradominance transmission [2]. Supernumerary nipples have been described in association with many anomalies such as peptic ulcer, cardiovascular disease [3], kidney and urinary malformations [4], and Becker Nevus [2]. Hailey-Hailey disease (HHD, MIM 16960), also known as benign chronic pemphigus, is an inherited blistering dermatosis that is characterized by vesicles, crusted erosions and warty papules [5]. It usually presents in the third or fourth decade. This genodermatosis has been described in association with psoriasis [6], bullous pemphigoid [7] and the dysplastic nevus syndrome [8]. We report here the occurrence of supernumerary nipples in 2 members of a Tunisian family affected by HHD.

Case report

A 44-year-old woman (HH1) presented to the dermatology department for evaluation of recurrent painful cutaneous erosions for 32 years, developing at sites of friction.

Figure 1	Figure 2
Pedigree of family HH. Each generation is designated by Roman numerals (I-IV). Squares and circles indicate male and female members, respectively. Arabic numerals within symbols correspond to the number of individuals. Slashes indicate that an individual is deceased. Shaded symbols indicate HH disease-affected individuals. Hatched symbols indicate HH with SN-affected individuals. Double lines indicate consanguineous relationships. Figure 2. Erythematous and scaly erosions of the submammary fold in a patient with Hailey-Hailey disease

A detailed family history revealed that other members of her family presented the same phenotype and showed an autosomal dominant mode of inheritance (Fig. 1).

On examination, cutaneous lesions showed erythematous and scaly erosions of the neck, the axillae, the submammary folds, the groin, and the perineum (Fig. 2). In addition, a supernumerary nipple located on the left side within the milk line, extending from the axilla to the groin, was found (Fig. 3). On examination the accessory breast gland had a diameter of 1.5 cm and was located in the lower medial quadrant of the main breast.

Figure 3	Figure 4
Figure 3. Supernumerary nipple of 1.5 cm diameter of the left breast. Figure 4. The "dilapidated brick wall" during Hailey-Hailey disease (HE x 40)

Histological examination showed defects in cell-to-cell adhesion in the suprabasal layers of the epidermis (Fig. 4). Direct immunofluorescence was negative, confirming the non-autoimmune nature of the acantholysis. According to these data, the diagnosis of Hailey-Hailey disease was established.

All available members underwent dermatological examination and clinical data were documented. This revealed that her 46-year-old sister (HH 2) was affected by HHD since the age of 9. She presented with a small-sized supernumerary nipple of the right areola according to Schmidt's criteria [9]. No additional physical abnormalities were noted in the above-mentioned patients.

Discussion

Supernumerary nipples may appear in women and men and are signs of the development of an atavistic structure, which is the reappearance of ancestral characteristics in individual members of a species [10]. The frequency of this condition ranges from 0.22 to 5.6 percent depending on various factors such as the ethnic group and geographical area [9]. An extensive range of congenital and hereditary anomalies has been reported in association with polythelia, including the association with Becker Nevus, cardiovascular anomalies, and gastro-intestinal alterations. The association with renal malformations has been repeatedly investigated but the results are still controversial [10].

Hailey-Hailey disease is an autosomal dominant Ca²⁺ ATPase disorder with an incidence of 1/50000 [5]. It is related to mutations in the ATP2C1 gene that maps to chromosome 3q21. This gene encodes a secretory pathway Ca²⁺/Mn²⁺ ATPase (SPCA1) localized in the Golgi apparatus [11]. This pump supplies the Golgi with both Ca²⁺ and Mn²⁺. Hailey-Hailey disease has been reported in association with a number of dermatological diseases such as psoriasis and bullous pemphigoid.

In the Tunisian family studied herein, we report the association of two dermatological abnormalities, supernumerary nipples and HHD. Supernumerary nipples are exhibited by 2 members of this family and their HHD showed autosomal dominant transmission. Supernumerary nipples are more likely inherited as autosomal recessive although a paradominance transmission could not be ruled out. Paradominance means that the defect is caused by a somatic mutation occurring early in embryogenesis, giving rise to a clone of mosaic cells that are homozygous or hemizygous for the mutation [11]. The hypothesis seems to be unlikely because two members of this family had supernumerary nipples. Hailey-Hailey disease, shown by 4 members in this family is caused by a defect in a Ca²⁺ ATPase leading to a widespread separation of the suprabasal keratinocytes of the epidermis and to abnormal keratinization [12].

Therefore, it is difficult to explain the coexistence of these two dermatoses. It is most likely that HHD and supernumerary nipples resulted from two single synchronous or asynchronous mutations inside their specific embryonic developmental fields (skin and mammary anlagen) [2]. This clinical association is still far from clear and needs additional investigations at the molecular genetic level.

Acknowledgments: We wish to thank the patients and family members. This work was supported by the Tunisian Ministry of high education and Scientific Research (Research Unit on Molecular Investigation of Genetic Orphan Disorders UR 26/04 and Research Unit on Study of Hereditary Keratinisation Disorders UR 24/04).

References

1. Leung AK. Familial supernumerary nipples. Am J Med Genet 1988; 31: 631-5. PubMed

2. Urbani CE, Betti R. Supernumerary nipples occurring together with Becker's naevus: an association involving one common paradominant trait? Hum Genet 1997; 100: 388-90. PubMed

3. Brightmore T. Bilateral double nipples. Br J Surg. 1972; 59: 55-7. 4 Mehes K. Association of supernumerary nipples with other anomalies. J Pediatr 1983; 102:161. PubMed

4. Mehes K. Association of supernumerary nipples with other anomalies. J Pediatr 1983; 102:161.

5. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992; 27: 40-50. PubMed

6. Hayakawa K, Shiohara T. Coexistence of psoriasis and familial chronic pemphigus: efficacy of ultraviolet B treatment. Br J Dermatol 1999;140: 374-5. PubMed

7. Mehregan DA, Umbert IJ, Peters MS. Histologic findings of Hailey-Hailey disease in a patient with bullous pemphigoid. J Am Acad Dermatol 1989; 21: 1107-12. PubMed

8. Mallen JK. Psoriasis, chronic benign familial pemphigus, and dysplastic naevus syndrome in a family. Australas J Dermatol 1992; 33: 55. PubMed

9. Schmidt H. Supernumerary nipples: prevalence, size, sex and side predilection - a prospective clinical study. Eur J Pediatr 1998; 157: 821-3. PubMed

10. Galli-Tsinopoulou A, Krohn C, Schmidt H. Familial polythelia over three generations with polymastia in the youngest girl. Eur J Pediatr 2001; 160: 375-7. PubMed

11. Dhitavat J, Fairclough RJ, Hovnanian A, Burge SM. Calcium pumps and keratinocytes: lessons from Darier's disease and Hailey-Hailey disease. Br J Dermatol 2004; 150: 821-8. PubMed

12. Richard G, Korge BP, Wright AR, Mazzanti C, Harth W, Annicchiarico-Petruzzelli M, Compton JG, Bale SJ. Hailey-Hailey disease maps to a 5 cM interval on chromosome 3q21-q24. J Invest Dermatol 1995; 105: 357-60. PubMed

© 2008 Dermatology Online Journal