Hao-Fountain syndrome is an extremely rare genetic multisystem disorder characterized by different clinical aspects and a heterozygous mutation in the USP7 gene (602519) on chromosome 16p13.2. The disorder is believed to be inherited as an autosomal dominant trait due to USP7 mutations. Ubiquitin-specific protease 7, otherwise known as herpesvirus-associated ubiquitin- specific protease 7 (HAUSP), is a 135 kDa protein and a member of the Deubiquitinating enzymes (DUB) family, which functions in regulating protein stability and localization. It plays a critical role in vital intracellular processes such as epigenetic regulation, cell cycle regulation, cell growth and survival. Of note, its role in stabilizing various tumor suppressors, such as p53, Mdm2, PTEN and Myc, has been well characterized and its upregulation has been associated with many cancers.
USP7 was also observed to play an essential role in growth and development as it was associated with embryonic lethality in USP7 knockout mice [3,4,5,6,7,8,9,10].
It has been reported that USP7 may be implicated in different hormonals balance and in different genital tract disease. For example, some Authors demonstrated that USP7 activity constitutes a novel molecular pathway in modulating the epigenetic state of sex chromosomes during male meiosis and regulating human spermatogonial proliferation via the USP7-mediated p53 signaling pathway. Deubiquitination of Androgen receptor (AR) plays an equally important role in the Androgen Receptors metabolism. Several deubiquitinases have been reported as interacting with the AR and regulating its transcriptional activity; these include USP10, USP26, and USP12. In addition, a recent study demonstrated that USP7 interacts with the AR and facilitates the AR binding to chromatin in prostate cancer cells [2,3,4,5,6,7,8,9].
In males USP7 plays an important role in the expression of a subset of androgen-responsive genes.
In females it plays a role in pregnancy, specifically in the processes involving embryo implantation to the uterine wall. USP7 also regulates ovarian hormones that mediate cell proliferation and function.
It has also been reported that there is a positive correlation between USP7 levels and the estrogen receptor (ER) and the progesterone receptor (PgR) during decidualization. These results suggest that ovarian hormones have effect on USP7 expression and vice versa.
Isolated tubal torsion is a rare emergency and it has been reported to have a right-sided prevalence; this fact has been attributed to the cushioning effect of the sigmoid colon, to the slightly longer right mesosalpinx and to the more frequent exploration of patients with right lower quadrant pain for presumed appendicitis. In some reports, isolated tubal torsion appeared to be more frequent during the premenstrual phase because of the congestion of the mesosalpingeal veins at the time [11, 12].
The most common symptom is ipsilateral lower abdominal pain but a frequent association with chronic pain and eventually nausea and vomiting has been reported; laboratory analysis are usually non-specific [11,12,13,14,15].
The ultrasound evaluation includes normal ovaries with a dilated tube with thickened, echogenic walls and internal debris, representing a twisted tube; other ultrasound findings are a long tubular convoluted cystic structure that tapers toward the uterine cornua, a thin-walled cystic structure with variable septations and mixed internal echoes with visualization of a normal ipsilateral ovary. Color Doppler ultrasonography may demonstrate unilateral absence of blood flow, but the absence of this finding does not necessarily rule out tubal torsion. The value of CT scan and MRI in diagnosing this condition is still controversial [13].
The pediatric literature report, in series or case reports, less than 100 cases; most of these cases were considered secondary to underlying adnexal pathology. Menstrual history, not reported if regular or irregular, was available for 70% of the cases. The youngest patients reported was 4 years old [16].
Salpingectomy has been the standard treatment in case of a clearly necrotic tube, non-reversible ischemia or evidence of secondary tube torsion. Detorsion of the tube, without resection, was first described by Kurzbart; this is typically performed in cases of recent symptoms onset or incomplete torsion, when there is evidence of potentially viable tubal tissue. Promising results were reported following adnexal detorsion but the long term outcomes of this approach are unknown [16, 17].
Conservative treatment has been proposed also by Boukaidi et al. [14], that reported their experience with 6 cases of isolated tubal torsion; their conclusion is to preserve the tube or at least to perform a distal salpingectomy. However, literature has previously suggested that scarred or damaged tube, hydrosalpinx or tubal pathology may result in lower fertility outcomes.
The main question is whether is advisable to perform a conservative treatment or if a salpingectomy is needed.
Especially in this specific case it is essential to remember some important aspects of gynecological cancer and fertility preservation.
More than half of the ovarian cancers occur in the reproductive age group, compromising the reproductive potential; the main factor behind the poor survival rates of ovarian cancer is the stage at presentation and diagnosis.
The origin and the pathogenesis of epithelial ovarian cancer have perplexed investigators for decades. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. Ovarian cancer is, in fact, the most lethal gynecologic malignancy. Among ovarian cancers it has been reported that, despite well-known and profound differences among the various histologic types, the vast majority of ovarian carcinomas are high-grade serous carcinomas. Ovarian cancer may originate from the ovarian surface epithelium (mesothelium), which invaginates into the underlying stroma resulting in inclusion cysts that eventually undergo malignant transformation. Again, ovarian cancer spreads from the ovary to the pelvis, abdomen and distant sites [18,19,20,21,22,23].
Recently a new theory has been proposed: the most persuasive data support the view that serous tumors develop from the fimbriated portion of the fallopian tube, endometrioid and clear cell tumors from the endometrial tissue passing through the fallopian tube, resulting in endometriosis, and mucinous and Brenner tumors from transitional-type epithelium located at the tubal-mesothelial junction where the fimbria makes contact with the peritoneum.
Embriologically, the cervix, the endometrium and the fallopian tubes derive from the müllerian ducts, whereas the ovaries develop from the mesodermal epithelium on the urogenital ridge, separate from the müllerian ducts. Therefore, an alternate theory proposes that tumors with a müllerian phenotype (serous, endometrioid and clear cell) are derived from müllerian-type tissue and not mesothelium.
This müllerian-type tissue (columnar epithelium, often ciliated) lines cysts located in paratubal and paraovarian locations that have been referred collectively as the “secondary müllerian system”. According to this theory, ovarian tumors develop from these cysts. As the tumor enlarges, it compresses and eventually obliterates ovarian tissue resulting in an adnexal tumor that appears to have arisen from the ovary. Distal fimbriae end of the fallopian tubes, closer to the ovary, has been considered as primary precursor of high-grade serous carcinoma.
Subsequent studies, in which fallopian tubes were more carefully examined, confirmed that in situ and small, early invasive tubal carcinomas occurred in women with a genetic predisposition for the development of ovarian cancer.
Generally, before a carcinoma acquires the ability to metastasize it must first invade and gain access to blood vessels or lymphatics. Some Authors observed that the fimbria contain a rich angiolymphatic vasculature. Moreover, they are in almost direct contact with the basement membrane of the tubal epithelium and therefore a tubal carcinoma may not need to attain a very large size in order to invade this highly accessible angiolymphatic network.
If it can be unequivocally shown that the serous carcinomas in these women develop almost exclusively in the fimbria, then salpingectomy alone would be sufficient to reduce the risk of ovarian cancer. Accordingly, for women undergoing a hysterectomy for benign uterine disease, removal of only the fallopian tubes with the sparing of the ovaries would improve quality of life and overall survival while still reducing the risk of ovarian carcinoma. Such an approach has important public health implications. This field is important also for the association between impaired fertility potential, Fallopian tube disease and assisted medical procreation [14, 17,18,19].
Hao-Fountain syndrome comes with different clinical aspects but less is known about the genital and fertility “area”; literature data show the possibility of endocrine complications (pubertal delay, autoimmune diseases), immunological deficit and predisposition to autoimmune diseases and a wide variety of cancers. Moreover, in this case, as suggested by Capra et al. [24], the correct diagnosis allowed us to plan neuropsychiatric, endocrinological, immunological, cardiological, and potential oncological risk follow-up.
The association between USP7 defect and cancer, hypogonadism, infertility and gynecological disorders may add new symptoms to this syndrome. Tubal torsion and ovarian problems in these patients should be excluded in case of abdominal pain. Even if it is well known that menarcheal age is inversely associated with the risk of ovarian cancer, those having adnexal or tubal -ovarian torsion should be followed annually, especially in those case with conervative treatment, in order to avoid future fertility and oncological problems. Miniinvasive surgery seems to be the best option for these young patients as for older female; it is clear that a well oncological expertise help to avoid incomplete resections. This specific mutation may favor and could be associated with some gynecological disorders; our case and this genetic condition offer new inside in the management of tubal torsion [25, 26]; from a clinical perspective the implications of this new paradigm might bring to even more far-reaching consequences.