The EPICOVID19-BS study: a web-based epidemiological survey in bariatric patients.

PURPOSE: To assess the occurrence and severity of SARS-CoV-2 infection/COVID-19, frequency of symptoms, clinical manifestations and behaviours in a sample of patients undergoing bariatric surgery (BS). METHODS: The EPICOVID19-BS is an observational cross-sectional study conducted in Italy during the second wave of the COVID-19 pandemic (September 2021-February 2022). Patients with severe/extreme obesity undergoing BS were asked to complete an online multiple-choice questionnaire and to provide additional clinical information and blood biochemistry. Positive COVID-19 cases were defined by the combination of positive nasopharyngeal swab test results and/or positive serological test results. Sociodemographic, clinical and behavioural characteristics were compared between positive and negative COVID-19 cases. RESULTS: A total of 745 participants were enrolled (mean age 44.5 ± 10.5 years SD, 78% female). The proportion of positive COVID-19 cases was 20.4%. They were more likely to be health care workers, to have close contacts with confirmed cases, to use anti-inflammatory drugs, to have immune system disorders, to have previous CMV infection, to have lower cholesterol levels and to have less metabolic syndrome than negative cases. Infected participants significantly increased their use of national health resources for minor health problems. The majority of participants experienced flu-like symptoms and taste and smell disturbances. Only 9.6% were hospitalised and none required intubation. CONCLUSIONS: Our results seem to support the evidence that patients undergoing BS have a low rate of severe SARS-CoV2. Further longitudinal studies in multiple obesity treatment centres are needed to more effectively monitor and control obesity in this specific population.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

T1 colon cancer in the era of screening: risk factors and treatment.

BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.

Hemorrhoid laser procedure for second- and third-degree hemorrhoids: results from a multicenter prospective study.

BACKGROUND: The aim of our study was to assess the outcome of hemorrhoidal dearterialization, achieved by a dedicated laser energy device. METHODS: From November 2012 to December 2014, 51 patients with second- or third-degree hemorrhoids were studied. The primary end point was a reduction in the bleeding rate; secondary end points were: postoperative complications, reduction in pain and prolapse, resolution of symptoms, and degree of patient's perception of improvement. The procedure was carried out as 1-day surgery. A diode laser device was employed to seal the terminal branches of the hemorrhoidal arteries, detected by a Doppler-equipped proctoscope. Follow-up was scheduled at 1 and 4 weeks, 3, 12, and 24 months. The rate and degree of symptoms was assessed with a four-point verbal rating scale. The rate of subjective symptomatic improvement was also evaluated with the Patient Global Improvement (PGI) Scale. RESULTS: Mean bleeding and pain scores at baseline were 2 and 0.57. All the patients were discharged on the day of surgery. Postoperative complications were bleeding (n = 4) and external hemorrhoidal thrombosis (n = 4). Mean bleeding and pain scores at 3, 12, and 24 months were significatively reduced. After 24 months, complete resolution of bleeding was observed in 28/29 patients (96.7 %), resolution of pain in all patients, and resolution of the mucosal prolapse in 15/18 patients (76.9 %). At 12-month follow-up, 86.3 % of patients reported improvement with the PGI Scale. CONCLUSIONS: The hemorrhoid laser procedure was effective in improving bleeding and pain symptoms in patients with grade II and III hemorrhoids.

Tailored therapy for different presentations of chronic pain after stapled hemorrhoidopexy.

BACKGROUND: As stapled hemorrhoidopexy (SH) becomes more widely used, we see more patients with chronic postoperative anal pain after this surgery. Its presentation is variable and difficult to treat. The aim of our study was to investigate the impact of chronic anal pain after SH and whether tailored therapy was likely to achieve a favorable outcome. METHODS: We retrospectively analyzed 31 consecutive patients with chronic anal pain who had undergone SH in other hospitals and were referred to our institutions. Depending on the type of pain, unrelated (at rest) or related to defecation, two groups of patients were identified. Moreover, the mean distance of the staple line from the anal verge was calculated in both groups. Treatments included: topical nifedipine, local anesthetic and steroid infiltration, removal of retained staples, anal dilation, and scar excision with mucosal suturing. A visual analog scale (VAS) was used to compare pain at baseline, postoperatively, and in the follow-up. This mean difference of the VAS score between stages was always used as the main outcome measure, depending on the type of presentation, type of pain, and type of treatment. Treatment response was defined as a 50 % decrease of VAS from baseline. RESULTS: There were 22 males and 9 females. The overall median age was 43 years (range 21-62 years). On digital examination and proctoscopy, 15 (48 %) patients had inflammatory changes, 19 (61 %) patients had staple retention, 8 (26 %) patients had anorectal stenosis, and 30 (97 %) patients had scar tissue. All patients had one or more of the following treatments listed from the least to most invasive: topical nifedipine in 12 (39 %) patients, anal dilation in 6 (19 %) patients, anesthetic and steroid infiltration in 18 (58 %) patients, removal of staples in 10 (32 %) patients, and scar excision in 18 (58 %) patients. The mean VAS score at baseline was 6.100, ± 1.953 SD, which dropped significantly after treatment to 1.733, ± 1.658 SD (p < 0.001) and remained low at follow-up (1.741 ± SD 1.251; p < 0.743). In patients with pain at rest (n = 20, 65 %), the symptoms improved in 19 (95 %) patients, while the VAS score decreased from 5.552 ± 2.115 SD to 1.457 ± 1.440 SD (95 % CI 3.217-4.964; p < 0.001). In patients with post-evacuation pain (n = 11, 35 %), the symptoms improved in 11 (100 %) patients, while the VAS score decreased from 6.429 ± 1.835 SD to 1.891 ± 1.792 SD (95 % CI 3.784-5.269; p < 0.001). Rating of response based on presentation was 90.0 % (0.9/10) after treatment of staple retention, which led to a significant decrease in the mean VAS score from 6.304 ± 1.845 SD to 1.782 ± 1.731 SD (95 % CI 3.859-5.185; p < 0.001). Anal stenosis was successfully treated in 100.0 % (n = 8/8) of cases with the mean VAS score dropping from 6.500 ± 1.309 SD to 2.125 ± 1.808 SD (95 % CI 2.831-5.919; p < 0.001). Anal inflammation improved in 60.0 % (n = 9/15) of patients and the mean VAS score dropped from 6.006 ± 2.138 SD to 1.542 ± 1.457 SD (95 % CI 3.217-4.964; p < 0.001). The response after scar tissue treatment was 94 % (n = 17/18) of patients with a mean VAS decreasing from 6.117 ± 2.006 SD to 1.712 ± 1.697 SD (95 % CI 3.812-4.974; p < 0.001). Success for topical nifedipine was between 13 and 25 % of patients depending on the clinical presentation. Anal dilation was successful in 75 % of patients, while Anesthetic and steroid infiltration in 23-54 % of patients depending on the clinical presentation. Staple removal was successful in 77 % of patients, and scar excision with mucosal suturing in 94 % of patients. CONCLUSIONS: Our retrospective study suggests that most patients with chronic anal pain after SH may be cured with treatment by applying a stepwise approach from the least to the most invasive treatment.

A nationwide audit of the use of radiotherapy for rectal cancer in Italy.

BACKGROUND: There is good evidence that radiotherapy is beneficial in advanced rectal cancer, but its application in Italy has not been investigated. METHODS: We conducted a nationwide survey among members of the Italian Society of Colo-Rectal Surgery (SICCR) on the use of radiation therapy for rectal cancer in the year 2005. Demographic, clinical and pathologic data were retrospectively collected with an online database. Italy was geographically divided into 3 regions: north, center and south which included the islands. Hospitals performing 30 or more surgeries per year were considered high volume. Factors related to radiotherapy delivery were identified with multivariate analysis. RESULTS: Of 108 centers, 44 (41%) responded to the audit. We collected data on 682 rectal cancer patients corresponding to 58% of rectal cancers operated by SICCR members in 2005. Radiotherapy was used in 307/682 (45.0%) patients. Preoperative radiotherapy was used in 236/682 (34.6%), postoperative radiotherapy in 71/682 (10.4%) cases and no radiotherapy in 375 (55.0%) cases. Of the 236 patients who underwent preoperative radiotherapy, only 24 (10.2%) received short-course radiotherapy, while 212 (89.8%) received long-course radiotherapy. Of the 339 stage II-III patients, 159 (47%) did not receive any radiotherapy. Radiotherapy was more frequently used in younger patients (P < 0.0001), in patients undergoing abdominoperineal resection (APR) (P < 0.01) and in the north and center of Italy (P < 0.001). Preoperative radiotherapy was more frequently used in younger patients (P < 0.001), in large volume centers (P < 0.05), in patients undergoing APR (P < 0.005) and in the north-center of Italy (P < 0.05). CONCLUSION: Our study first identified a treatment disparity among different geographic Italian regions. A more systematic audit is needed to confirm these results and plan adequate interventions.

Anastomotic leaks after anterior resection for mid and low rectal cancer: survey of the Italian Society of Colorectal Surgery.

BACKGROUND: The aim of the survey was to assess the incidence of anastomotic leaks (AL) and to identify risk factors predicting incidence and gravity of AL after low anterior resection (LAR) for rectal cancer performed by colorectal surgeons of the Italian Society of Colorectal Surgery (SICCR). METHODS: Information about patients with rectal cancers less than 12 cm from the anal verge who underwent LAR during 2005 was collected retrospectively. AL was classified as grade I to IV according to gravity. Fifteen clinical variables were examined by univariate and multivariate analyses. Further analysis was conducted on patients with AL to identify factors correlated with gravity. RESULTS: There were 520 patients representing 64% of LAR for rectal cancer performed by SICCR members. The overall rate of AL was 15.2%. Mortality was 2.7% including 0.6% from AL. The incidence of AL was correlated with higher age (p<0.05), lower (<20 per year) centre case volume (p<0.05), obesity (p<0.05), malnutrition (p<0.01) and intraoperative contamination (p<0.05), and was lower in patients with a colonic J-pouch reservoir (p<0.05). In the multivariate analysis age, malnutrition and intraoperative contamination were independent predictors. The only predictor of severe (grade III/IV) AL was alcohol/smoking habits (p<0.05) while the absence of a diverting stoma was borderline significant (p<0.07). CONCLUSION: Our retrospective survey identified several risk factors for AL. This survey was a necessary step to construct prospective interventional studies and to establish benchmark standards for outcome studies.

HESX1 expression in human normal pituitaries and pituitary adenomas.

Hesx1 is a paired-like homeobox gene first expressed during mouse embryogenesis in the anterior midline visceral endoderm. As gastrulation proceeds, Hesx1 is expressed in the ventral prosencephalon and, subsequently, at E9.0 appears in the ventral diencephalon and in the thickened layer of oral ectoderm that give rise to Rathke's pouch, the primordium of the anterior pituitary gland. Hesx1 continues to be expressed in the developing anterior pituitary until E11.5 when its transcripts disappear in a spatiotemporal sequence corresponding to progressive pituitary cell differentiation, becoming undetectable by E15.5. In the present study, we investigated whether HESX1 is expressed during adult life in human normal pituitaries and in different types of human pituitary adenomas. We analysed, using quantitative RT-PCR method, three normal pituitaries, seven GH-, two TSH-, two PRL-, one ACTH-secreting adenomas, and seven nonfunctioning pituitary tumors. HESX1 mRNA was found to be expressed in normal pituitaries and in all the pituitary tumors that we have analysed. These results suggest that in humans HESX1 is not turned-off during the adult life as it occurs in mice. Thus, HESX1 in humans might play a role in the maintenance of the anterior pituitary cell types and function, as well as in the differentiation of pituitary adenomas, whose pathogenetic mechanisms remain to be further investigated. This is the first study on HESX1 expression in humans during adult life.

[Rectal cancer: locoregional recurrence in relation to surgical and complementary treatment]. / Il cancro del retto: le recidive locoregionali in rapporto alle terapie chirurgiche e complementari adottate.

Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectal cancer and the impact of adjuvant therapy. On the other hand, improvements in surgical techniques, as the total mesorectal excision, have apparently reduced the risk of LR. Furthermore, in selected cases, neoadjuvant therapy seems to reduce much more the incidence of LR. A list of prognostic factors which affect the onset of LR, other than the different procedures, was considered. To investigate such evidences a retrospective analysis was undertaken in our series, focusing on examination of the employed techniques as potential predictors of local recurrence. Thus, in a 18-yr-period (1986-2003), two hundred and ninety-five patients who had undergone elective curative surgical resection of rectal cancer were included in the study. The demographic, operative and follow-up data were collected retrospectively. All patients underwent total mesorectal excision, whereas neoadjuvant therapy was performed in a selected series of patients, according to defined entry criteria patterns. Results evidenced LR in 7.1% of patients and occurred between 6 months to 8 year following surgery. Comparisons were made between patients who had different surgical procedures; indeed sphyncter saving procedures correlated with a higher incidence of LR rather than abdomino-perineal resection. Pelvic recurrences were observed more frequently compared to the anastomotic ones. A limited number of patients with LR underwent surgery due to the associated condition of metastatic lesions; the follow-up related to such series evidenced a mortality rate of 57% within 3 year from reoperation. A low local recurrence rate can be achieved after total mesorectal excision (TME) without preoperative radiotherapy. Our results suggest that preoperative radiotherapy may be employed only for those patients who are at a higher risk for local recurrence.

MEN1 gene mutations are a rare event in patients with sporadic neuroendocrine tumors.

BACKGROUND: Neuroendocrine tumors of the gastroenteropancreatic (GEP) tract are encountered either as a sporadic type or as part of multiple endocrine neoplasia type 1 (MEN-1) syndrome. Inactivating MEN1 gene mutations have been found to be responsible for this syndrome and have also been described in sporadic cases. The aim of the present study was to evaluate the presence of mutations in the MEN1 gene in a series of 10 well-differentiated neuroendocrine tumors: five of the foregut and five of the midgut tract. METHODS: Retrospective screening for MEN1 gene mutations was carried out in 10 archived, paraffin-embedded neuroendocrine tumors. Polymerase chain reaction amplification and automated sequence analysis of the DNA extracted from the tumors were performed. RESULTS: One mutation (359 del 4) in exon 2 of the MEN1 gene was identified in a neuroendocrine tumor of the foregut (VIPoma of the pancreas). No mutation was identified in midgut neuroendocrine tumors. CONCLUSIONS: Our data confirm that retrospective genetic analysis can be used to identify mutations in the MEN1 gene and indicate that somatic MEN1 gene mutations are a rare event in sporadic neuroendocrine GEP tumors. The frequency of these mutations was 10% in our series, which may differ from that in other studies, due to the small number of cases analyzed.

Two familial giant pituitary adenomas associated with overweight: clinical, morphological and genetic features.

OBJECTIVE: Pituitary adenomas are usually sporadic, although rare familial cases have been described. Here we report two first degree female cousins with giant pituitary adenoma and overweight. Both presented with secondary amenorrhoea, occasional headache and weight gain. MATERIALS AND METHODS: In both patients clinical, morphological and genetic studies were performed. Both patients underwent surgery and post-operative medical therapy with somatostatin analogues and dopamine agonist, followed by a conventional radiotherapy course. RESULTS: Clinical examination at presentation revealed an acromegaloid habitus only in the second patient. Basal and dynamic hormonal evaluation showed high serum GH and serum IGF-I values, higher in the second than in the first patient, and a mild hyperprolactinaemia only in the first patient. On optical and electron microscopy, both tumours were oncocytic adenomas, immunopositive for GH in the first patient and GH/prolactin in the second. The genetic analysis for germ-line mutations of the multiple endocrine neoplasia type 1 gene was negative. Two years after radiotherapy a remarkable shrinkage of both tumours was observed, whereas the overweight worsened in both patients, accompanied by high plasma leptin values. CONCLUSION: To our knowledge, this is the first report of familial pituitary adenomas including one case of a clinically silent GH-secreting adenoma. In addition, it provides further evidence that familial pituitary tumours can occur as a multiple endocrine neoplasia type 1 unrelated disease.

Central hypothyroidism: consequences in adult life.

Central hypothyroidism (CH) is a rare cause of hypothyroidism, generally due to either pituitary or hypothalamic defects. On the basis of its etiology, it is possible to distinguish acquired and hereditary forms. Hereditary CH can be isolated or associated with combined pituitary hormone deficiency (CPHD). In the former case, alterations of only two genes, TSHbeta and the TRH receptor, have so far been described as responsible for the disorder. In hereditary CH associated with CPHD, inactivating mutations of different pituitary transcription factors (HESX1, PROP-1, POU1F1) have been found involved in the pathogenesis of the disease. Finally, an association between CH and severe obesity has been described in patients with leptin receptor (Leptin-R) mutations. The clinical consequences of CH in adult life vary greatly depending on the etiology, the severity of the thyroid impairment, the extent of the associated hormone deficiencies, and the age of the patient at the time of the onset of the disease. In general, acquired CH is less severe than the congenital form because of the constitutive activity of the wild-type TSH-receptor. Symptoms and signs of thyroid insufficiency are usually milder than those of primary hypothyroidism, and goiter is always absent. In CPHD, most patients have other endocrine manifestations of the disease (growth failure, delayed puberty, adrenal insufficiency, diabetes insipidus) that lead them to seek medical attention before the hypothyroidism becomes severe. Early diagnosis of the congenital form by neonatal screening for hypothyroidism is strongly recommended in order to avoid cretinism. Replacement therapy with L-thyroxine administration has to be established as soon as possible.

Loss of heterozygosity of the MEN1 gene in a large series of TSH-secreting pituitary adenomas.

Thyrotropin-secreting pituitary adenomas (TSH-omas) are rare tumors (0.5% of all pituitary adenomas) showing an invasive behavior and usually sporadic, although a few cases are associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant inherited syndrome. This disorder is linked to loss of heterozygosity (LOH) on 11q13 and inactivating mutations of MEN1 gene, which is located in the same chromosomal region. As other types of anterior pituitary adenomas, TSH-omas are the result of a monoclonal outgrowth where the intrinsic genetic defects involving oncogenes or tumor suppressor genes occur in a progenitor cell. However, so far no activating mutations of particular oncogenes or inactivating mutations of tumor suppressor genes have been identified. Starting from the observation that 3-30% of sporadic pituitary adenomas show LOH on 11q13, and that allelic losses on the long arms of chromosome 11, beside 10 and 13, are significantly associated with the transition from the non-invasive to the invasive phenotype, we decided to investigate LOH on 11q13 and mutations of menin in a large series of TSH-omas. Thirteen tumors were evaluated. DNA was extracted from tumors by standard methods and genomic DNA from peripheral blood leukocytes was used as control. LOH was screened by using 3 polymorphic markers on 11q13: D11S956, PYGM, INT-2. In 3 out of 15 cases we could demonstrate LOH on 11q13, but none of the tumors showed menin mutation after sequence analysis. These data strongly suggest that menin does not play a causative role in the development of TSH-omas, and are in agreement with other studies demonstrating a limited role of menin in pituitary sporadic tumorigenesis.

Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene.

BACKGROUND: One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. OBJECTIVE: To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. PATIENTS: Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. METHODS: GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. RESULTS: Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. CONCLUSION: In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.