Supernumerary nipples in association with Hailey-Hailey disease in a Tunisian family
Published Web Locationhttps://doi.org/10.5070/D30sx5m5cg
Supernumerary nipples in association with Hailey-Hailey disease in a Tunisian family1. Dermatology Department, Habib Thameur Hospital-Tunis, Tunisia. firstname.lastname@example.org
R Benmously Mlika1, S Deghais1, M Bchetnia2,3, C Charfeddine2, M Mokni3,4, S Kassar5, S Haouet6, S Boubaker5, I Mokhtar1, S Abdelhak2, A Ben Osman Dhahri4
Dermatology Online Journal 14 (6): 15
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
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.
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 .
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 . Supernumerary nipples have been described in association with many anomalies such as peptic ulcer, cardiovascular disease , kidney and urinary malformations , and Becker Nevus . 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 . It usually presents in the third or fourth decade. This genodermatosis has been described in association with psoriasis , bullous pemphigoid  and the dysplastic nevus syndrome . We report here the occurrence of supernumerary nipples in 2 members of a Tunisian family affected by HHD.
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.
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 . No additional physical abnormalities were noted in the above-mentioned patients.
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 . 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 . 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 .
Hailey-Hailey disease is an autosomal dominant Ca2+ ATPase disorder with an incidence of 1/50000 . 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 . 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 . 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 .
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) . 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).
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