A case of gestational gigantomastia in a 37-years-old woman associated with elevated ANA: a casual linkage?

Hypertrophy of the breast (macromastia and gigantomastia) is a rare medical condition of the breast connective tissues. The etiology of this condition is still not clear; rarely, gigantomastia has been reported to develop in the setting of an autoimmune illness. We reported a case of a 37-years-old woman with undifferentiated connective tissue disease of 2-years duration presented with enlargement of breasts. The breast enlargment started at 5 months of gestation. She successfully underwent reduction mammoplasty with free nipple graft. In the succeeding months the level of antinuclear ANA remained stable. It is uncertain whether a positive antinuclear antibodies in gigantomastia is a casuative agent or an effect.


Introduction
The increase of breast size in puberty and pregnancy is a physiological event. Breast hypertrophy is a benign progressive enlargement, which can occur in both breasts or only in one breast.
Gigantomastia is a rare breast condition characterised by rapid, diffuse and excessive breast hypertrophy (> 1,5 kg). The extremely rapid growth of the breasts can result in intense heat; the enlargement can cause muscular discomfort and over-stretching of the skin envelope, which can lead in some cases to ulceration. The swelling can suppress the milk supply, pinching off the milk ducts, and leading to mastitis. It may be associated with puberty, pregnancy, induced by drugs, in a context of immune-mediated diseases or without an associated cause (idiopathic).

Patient and observation
A 37-years-old woman presented at29 weeks gestation with marked bilateral breast swelling;this enlargement started at 23 weeks' gestation and continued to increase rapidly as the pregnancy progressed, complicated by infection skin atrophy, marked venous engorgement, ulcerations, necrosis and subsequent hemorrhage.
She reported that this was the first time she had experienced excessive breast enlargement; this had not occurred in her previous pregnancy (4 years ago). During her hospitalization, breasts continued to increase in size (bra size passed from fifth to tenth measure),with skin atrophy, necrosis and multiple ulcers measuring 2-5 cm in diameter ( Figure 1). The patient was complaining on mastalgia, severe back pain, breathing difficulties, moving difficulties and pain near ulcerations.
Past surgical history included only a cesarean and appendicectomy (when she was 14 yo). She had no familial history of breast disease.
Her medical history is notable for mild Raynaud´s phenomenon and recurrent arthralgias (most commonly of the hands and feet), but she had never been treated for arthralgias. She had been diagnosed withundifferentiated connective tissue disease three years before.
Laboratory assays detected the presence of antinuclear ANA (1:2560, homogenous and nucleolar) and elevated anti-dsDNA.
Tests for antibodies to anti-ENA and for antiphospholipid (lupus anticoagulant and anticardiolipin), anticentromere, anti-Scl-70, and antiplatelet antibodies were negative, as was a Coombs test.

Discussion
The pathophysiology of gigantomastia is still unknow; although no precise mechanism is known for this rare clinical entity, theories such as end-organ hyper-sensitivity, autoimmune stimulation antibodies, high IGF-1 and hyperprolactinemia have been proposed.
Several cases of gigantomastia have been described in association with autoimmune disorders, such as systemic lupus erythematosus, myasthenia gravis, Grave's disease, chronic arthitis, psoriasis and Hashimoto's thyroiditis [1][2][3][4]. Our patient showed a homogeneous pattern of ANA; this type of pattern of ANA was previously observed in 70% of patients with morphea. A homogeneous pattern might be associated with antibodies to native DNA or antibodies to histone and increased manifestation of autoimmunity [9]. Despite the clinical association of ANAs, the relationship of these antibodies to specific disease manifestations is often unknown because the target antigens are intracellular molecules that are highly conserved and ubiquitously expressed.
The persistence of this type of autoreactivity in the human population suggests that antinuclear antibodies may be an important component of the normal immune response.
Immunological changes are known to occur within the immune system during pregnancy; ANA (mild titer) in normal pregnancy has been variously reported to range from 1-53% [7]. As suggested by Gronkowski et al about the correlation between ANA and infertility ("Antinuclear antibodies cause an inflammation in the uterus that does not allow it to be a suitable host for implantation of the embryo") [10], the mechanism by which ANAs cause gigantomastia based on a hypothesis antinuclear antibodies cause an inflammation Page number not for citation purposes 4 in the breast that lead to anabnormal proliferation of glandular tissue.
It is possible that gigantomastia is a manifestation of a UCTD flare during pregnancy? It is a casual linkage? It is possible that antinuclear antibodies cause an abnormal proliferation of breast?
What´s the mechanism? We don't think it's a coincidence that this patient showed the extremely rapid growth of the breasts after a diagnosis of UCTD, because she didn't present this type of complication in her first pregnancy. About surgical management, reduction mammaplasty asorgan-conserving therapy is a method of choice in a situation when no next pregnancy is expected or when the operation is performed in line with the delivery, so there is no opportunity for recidivating.

Conclusion
This report describes the first known case of gestional gigantomastia associated with undifferentiated connective tissue disease; if there is a role of ANA in the genesis of this disease it is uncertain wheter is a casuative agent or an effect of the gigantomastia.