Are the complications after laparo-assisted endo-rectal pull-through for Hirschsprung disease related to the change of the anal tone?

The main advantage of the laparo-assisted transanal endorectal pull-through technique (LA - TERPT) for Hirschsprung Disease (HD) is the respect to the rectal-anal anatomy. Postoperative complications have been observed recently. The present study aims to determine how often these postoperative complications occur in these patients. From January 2009 to December 2018, a retrospective analysis was conducted on 36 children (25 males) with HD who underwent LA-TERPT. Data were collected on the age of diagnosis and surgery, sex, the presence of other pathologies, and cases of enterocolitis. In all cases, anorectal manometry (ARM) was performed to evaluate the anal tone. The median age at diagnosis was 2 months and the mean age at surgery was 5 months. Nine related pathologies were identified: five cases of Down syndrome, one case of hypertrophic stenosis of the pylorus, atresia of the esophagus, polydactyly, and anorectal malformation. A patient with total colonic aganglionosis was identified through laparoscopic serummuscular biopsies. Enterocolitis was diagnosed in 7 cases before and 6 after surgery. At follow-up, the complications recorded were: 5 cases of constipation (treated with fecal softeners), one case of anal stenosis (patient with anorectal malformation), 16 cases of soiling (treated with enemas) and 1 child with fecal incontinence (treated with a transanal irrigation system). The ARM was performed in all 36 cases and showed normal anal tone, except for one case with anal hypotonia. LA-TERPT is an important surgical technique for HD. According to the literature, soiling is the most main complication after HD surgery, probably due to "pseudo-incontinence" with normal anal sphincter tone.

Primary non-refluxing megaureter: Natural history, follow-up and treatment.

Primary non-refluxing megaureter (PMU) is a congenital dilation of the ureter which is not related to vesicoureteral reflux, duplicated collecting systems, ureterocele, ectopic ureter, or posterior urethral valves and accounts for 5 to 10% of all prenatal hydronephrosis (HN) cases. The etiology is a dysfunction or stenosis of the distal ureter. Most often PMU remains asymptomatic with spontaneous resolution allowing for non-operative management. Nevertheless, in selective cases such as the development of febrile urinary tract infections, worsening of the ureteral dilatation, or reduction in relative renal function, surgery should be considered. CONCLUSION: Ureteral replantation with excision of the dysfunctional ureteral segment and often ureteral tapering is the gold-standard procedure for PMU, although endoscopic treatment has been shown to have a fair success rate in many studies. In this review, we discuss the natural history, follow-up, and treatment of PMU. WHAT IS KNOWN: • PMU is the result of an atonic or stenotic segment of the distal ureter, resulting in congenital dilation of the ureter, and is frequently diagnosed on routine antenatal ultrasound. WHAT IS NEW: • Most often, PMU remains asymptomatic and clinically stable, allowing for non-operative management. • Nevertheless, since symptoms can appear even after years of observation, long-term ultrasound follow-up is recommended, even up to young adulthood, if hydroureteronephrosis persists. • Ureteral replantation is the gold standard in case surgery is needed. In selected cases, however, HPBD could be a reasonable alternative.

Unusual position of pilonidal sinus in children may explain its malformative etiology: Case report and review of the literature.

INTRODUCTION: Pilonidal sinus is a condition that causes inflammation and abscesses in the sacral region and affects adolescents and young adults. The etiology of this condition remains controversial. CASE PRESENTATION: A six year old boy was observed to have an orifice in the frontonasal region which contained hair. He had two previous infections which were treated with antibiotics. Magnetic Resonance Imaging showed no cranial malformations. Surgery was performed under general anesthesia and the pilonidal sinus was completely excised. At follow-up the child was in good health. CLINICAL DISCUSSION: This case in a child with a frontonasal skin anomaly highlights that skin anomalies may be a cause of pilonidal sinus. CONCLUSION: Skin malformations can be the underlying cause of pilonidal sinus in some cases.

Analysis of microsatellite instability (MSI) in pediatric gonadal and extra-gonadal germ cell tumors.

Gonadal and extragonadal pediatric germ cell tumors (GCTs) are rare neoplasms with different clinical behavior. Although surgery and cisplatin-based chemotherapy are resolutive in most cases, some patients do not respond to chemotherapy and have a worse outcome. Microsatellite instability (MSI) was correlated to resistance to chemotherapy and sensitivity to immunotherapy in different neoplasms. A series of 21 pediatric GCTs were tested by immuno-histochemistry and PCR to evaluate MSI status. Next generation sequencing was applied to further evaluate cases with discordant results between immunohistochemistry and PCR. Twenty-one cases of pediatric GCT were included in the series. The mean age ranged between 1 and 10 years. Nine cases were gonadal GCTs and the remaining 12 were extra-gonadal GCTs. By immunohistochemistry, one case showed a deficit of Mismatch repair (MMR) proteins. This case was a 1-year-old children affected by gonadal yolk sac tumor. However, all cases resulted microsatellite stable (MSS) by PCR and NGS. MSI was not detected in our series of pediatric GCTs, as well as the data present in literature about adult patients with GCTs. Molecular techniques could have a role to confirm the MSI status in case of dMMR by immunohistochemistry.

Unusual location of apocrine hidrocystoma in children: Case series.

INTRODUCTION AND IMPORTANCE: Apocrine Hidrocystoma is a relatively rare benign tumour that begins from the apocrine sweat glands of the head and neck. The Authors present a case series of children with urogenital localization. CASES PRESENTATION: Two boys (15 years and 9 years) presented with a small mass on the glans. Another 15-year-old boy presented with a cystic lesion in the right side of the scrotum where he had a previous surgery. The last case, a 17-year-old boy, presented because of a penile cyst of 8 mm. All four had surgical operations because of aesthetic discomfort or problems during micturition. Histological examination showed a diagnosis of apocrine hidrocystoma in all cases. CLINICAL DISCUSSION: This benign tumour rarely affects the urogenital system in children, but when it happens the child can have discomfort and proper treatment is mandatory. CONCLUSION: Surgery is the preferred treatment with a low risk of recurrence.

Pediatric endoscopic pilonidal sinus treatment (PEPSiT): report of a multicentric national study on 294 patients.

This study aimed to report a multicentric national experience about the outcomes of pediatric endoscopic pilonidal sinus treatment (PEPSiT). The medical records of all pediatric patients, aged up to 18 years, who underwent PEPSiT in the period 2019-2021, were retrospectively reviewed. Patients' demographics, operative details, and post-operative outcomes were assessed. A total of 294 patients (182 boys), with median age of 14 years (range 10-18), receiving PEPSiT in the study period, were enrolled. Pilonidal sinus disease (PSD) was primary in 258 (87.8%) and recurrent in 36 (12.2%). The median operative time was 36 min (range 11-120). The median VAS pain score was 0.86 (range 0-3) and the median duration of analgesic use was 27 h (range 12-60). The overall success rate was 95.2% (280/294) and the median time to full healing was 23.4 days (range 19-50). Six/294 (2.0%) patients developed Clavien 2 post-operative complications. The recurrence rate was 4.8% (14/294) and all recurrences were re-operated using PEPSiT. Redo-surgery for wound debridement was performed in one (0.3%) patient with late healing. On multivariate analysis, hirsutism and typology of sinus (pits ≥ 2, paramedian and more proximal to the anus) were predictors of PSD recurrence (p = 0.001). To date, this is the largest series of PEPSiT published in the pediatric population. The outcomes reported after a 3 years experience confirm that PEPSiT is a safe, effective, and real minimally invasive procedure to treat adolescents with PSD. It provides patients quick and painless recovery, satisfactory success, and high quality of life.

In Which Patients and Why Is Laparoscopy Helpful for the Impalpable Testis?

Since laparoscopy has been proposed in the management of the nonpalpable testis (NPT), this technique has been widely diffused among pediatric surgeons and urologists, but its application is still debated. We conducted a retrospective review to highlight how diagnostic and surgical indications for laparoscopy are selective and should be targeted to individual patients. From 2015 to 2019, 135 patients with NPT were admitted to our surgical division. Of these, 35 were palpable on clinical examination under anesthesia and 95 underwent laparoscopy. The main laparoscopic findings considered were: intra-abdominal testis (IAT), cord structures that are blind-ending, completely absent, or entering the abdominal ring. The patients' mean age was 22 months. In 48 cases, an IAT was found, and 42 of these underwent primary orchidopexy while 6 had the Fowler-Stephens (FS) laparoscopic procedure. Of the first group one patient experienced a testicular atrophy while two a reascent of the testis. In the FS orchidopexy group, one patient had testicular atrophy. Cord structures entering the internal inguinal ring were observed in 35 children, and all were surgically open explored. In 3 cases of these, a hypotrophic testis was revealed and an open orchidopexy was executed. In the remaining the histological examination revealed viable testicular cells in four patients and fibrosis, calcifications, and hemosiderin deposits in the others. Eleven patients presented with intrabdominal blind-ending vessels and one a testicular agenesia. A careful clinical examination is important to select patients to submit to laparoscopy. Diagnostic laparoscopy, and therefore, the anatomical observation of the testis and cord structures are strictly related to develop a treatment plan. In IAT, many surgical strategies can be applied with good results. Laparoscopy offers a concrete benefit to the patient.

MKRN3 role in regulating pubertal onset: the state of art of functional studies.

Puberty is a critical process characterized by several physical and psychological changes that culminate in the achievement of sexual maturation and fertility. The onset of puberty depends on several incompletely understood mechanisms that certainly involve gonadotropin-releasing hormone (GnRH) and its effects on the pituitary gland. The role of makorin ring finger protein 3 (MKRN3) in the regulation of pubertal timing was revealed when loss-of-function mutations were identified in patients with central precocious puberty (CPP), which to date, represent the most commonly known genetic cause of this condition. The MKRN3 gene showed ubiquitous expression in tissues from a broad spectrum of species, suggesting an important cellular role. Its involvement in the initiation of puberty and endocrine functions has just begun to be studied. This review discusses some of the recent approaches developed to predict MKRN3 functions and its involvement in pubertal development.

Can Infant Dyschezia Be a Suspect of Rectosigmoid Redundancy?

Infant dyschezia is a functional gastrointestinal disorder that occurs in children less than nine months of age. This disorder causes much anxiety among parents who consult different physicians when suspecting major intestinal problems. The aim of this study is to verify whether infant dyschezia involves an anatomic abnormality (redundancy) of the colon. In this retrospective study (48 months) we analyzed all the children younger than 9 months who came to our attention through the suspicion of gastrointestinal abnormality (Hirschsprung's disease, anorectal malformations, colonic disorders or constipation). They all had a complete medical history, clinical examination and diagnostic tests, such as blood samples, suction rectal biopsy, a study of stool characteristics and, finally, a contrast enema. In cases with infant dyschezia, different colonic sizes and rectosigmoid length were measured, which created a ratio with the diameter of the second lumbar vertebra. These values were compared with those reported in the literature as normal for the age of one year. Of the 24 patients evaluated (mean age 4 months), 9 were excluded for different diagnoses (aganglionic megacolon, hypothyroidism, constipation). The comparison of the ratios obtained in the remaining 15 cases showed a significantly higher rectosigmoid length (redundancy) in children with dyschezia, 18.47 vs. 9.75 (p < 0.001). The rectosigmoid redundancy, a congenital anomaly already reported as a cause of refractory constipation, may be present in children with infant dyschezia.

The Challenge of Melanocytic Lesions in Pediatric Patients: Clinical-Pathological Findings and the Diagnostic Value of PRAME.

Pediatric melanoma is a rare disease especially in children aged younger than 10 years old. Recent estimates report a rise of disease incidence in both adults and children. Diagnostic work-up is challenging in pediatric melanoma, as it displays a wide range of clinical presentations. Immunohistochemical biomarkers have been reported as predictors of malignancy in melanoma, however data specific to pediatric melanoma are poor. Our study aims to contribute to provide evidence of pediatric melanoma clinical features and differential diagnosis in this patient population. We describe our experience with a retrospective case series of pigmented skin lesions including malignant melanoma, atypical spitzoid tumor, and benign nevi in children and adolescents aged less than 16 years. We described the clinical and demographic characteristics of the cohort and evaluated the immunohistochemical expression of the PReferentially expressed Antigen in MElanoma (PRAME) for differential diagnosis of melanoma in children. The series displayed a similar distribution of melanoma between males and females, and the most common site of melanoma onset were the upper and lower limbs. In our cohort, PRAME was negative in most cases. Focal and slight positivity (from 1 to 5% of the neoplastic cells) was observed in four cases (two Spitz nevi and two atypical Spitz tumors). A moderate positivity in 25% of the neoplastic cells was observed in one case of atypical Spitz tumor. Immunohistochemical expression of PRAME might be useful in the differential diagnosis of malignant melanoma.

The "Dark Side" of Pneumoperitoneum and Laparoscopy.

Laparoscopic surgery has been one of the most common procedures for abdominal surgery at pediatric age during the last few decades as it has several advantages compared to laparotomy, such as shorter hospital stays, less pain, and better cosmetic results. However, it is associated with both local and systemic modifications. Recent evidence demonstrated that carbon dioxide pneumoperitoneum might be modulated in terms of pressure, duration, temperature, and humidity to mitigate and modulate these changes. The aim of this study is to review the current knowledge about animal and human models investigating pneumoperitoneum-related biological and histological impairment. In particular, pneumoperitoneum is associated with local and systemic inflammation, acidosis, oxidative stress, mesothelium lining abnormalities, and adhesion development. Animal studies reported that an increase in pressure and time and a decrease in humidity and temperature might enhance the rate of comorbidities. However, to date, few studies were conducted on humans; therefore, this research field should be further investigated to confirm in experimental models and humans how to improve laparoscopic procedures in the spirit of minimally invasive surgeries.

Laparoscopic Fowler-Stephens orchidopexy for intra-abdominal cryptorchid testis: a single institution experience.

Fowler-Stephens Laparoscopic Orchiopexy (FSLO) permits the mobilization of Intra-Abdominal Testis (IAT) to the scrotal position after spermatic vessel ligation. We reported our experience of FSLO for IAT. The charts of all boys who underwent a FSLO were retrospectively reviewed. Data were analysed for demographic data, procedure, complications and follow-up results. From January 2008 to June 2016, 160 laparoscopies for Non Palpable Testis (NPT) were performed at a mean age of 3,2 years. 61% of patients had a right NPT, while 6% were bilateral. In 64 cases, an IAT was found: 20 were managed by FSLO with a two-stage procedure in 11 patients. There were no differences in hospitalisations; one patient had a prolonged ileus. Follow-up ranged from 1 to 8 years. Of the 20 patients who underwent FSLO, testicular atrophy developed in three; the remaining testes were in the scrotal position, with normal consistency. FSLO was applied in 31% of IAT. The overall success rate of the technique was 85 %. The percentage of atrophy associated after spermatic vessels interruption appears to provide a good chance of testicular survival.

Nuck cyst: a rare cause of inguinal swelling in infancy.

BACKGROUND: Inguinal and/or inguino-scrotal swellings, such as hernia and hydrocele, are among the commonest anomalies in childhood. Hydrocele of the canal of Nuck is an uncommon diagnosis and a rare cause of swelling in women that occurs due to a patent vaginal process. METHODS: From January 2001 to January 2016, 353 female patients 1-14 years of age were admitted to our university hospital division for inguinal swelling. We have performed 403 inguinal approaches, and of these, 399 (99%) had inguinal hernias, 3 (0.74%) had a cyst of the canal of Nuck, and 1 (0.24%) had a lipoma. All of the patients with Nuck cysts underwent surgical exploration of the swelling through a right inguinal skin crease incision. RESULTS: The patients were between the ages of 1 and 8 years. The cyst sizes varied between 25 and 40 mm. All the patients exhibited right, tender, painless, non-reducible masses. In all patients, ultrasound confirmed the suspected diagnosis. The histological findings revealed fibrous-walled cystic formations with mild chronic inflammatory infiltrate that were covered by mesothelial epithelium. The patients' postoperative follow-ups at 1, 6 and 12 months revealed normally healed incisions with no recurrences. CONCLUSIONS: The surgical findings and the histological demonstrations of serous epithelium seemed to validate the hypothesis that the patency of the inguinal canal combined with fluid secretion of the peritoneal serosa participated in the formation of the cysts. Surgery with high ligature of the vaginal process is considered the therapy of choice for this pathology.

Bedside surgery in the newborn infants: survey of the Italian society of pediatric surgery.

INTRODUCTION: This is the report of the first official survey from the Italian Society of Pediatric Surgery (ISPS) to appraise the distribution and organization of bedside surgery in the neonatal intensive care units (NICU) in Italy. METHODS: A questionnaire requesting general data, staff data and workload data of the centers was developed and sent by means of an online cloud-based software instrument to all Italian pediatric surgery Units. RESULTS: The survey was answered by 34 (65%) out of 52 centers. NICU bedside surgery is reported in 81.8% of the pediatric surgery centers. A lower prevalence of bedside surgical practice in the NICU was reported for Southern Italy and the islands than for Northern Italy and Central Italy (Southern

Pneumoperitoneum Modifies Serum and Tissue CCL2-CCL5 Expression in Mice.

BACKGROUND AND OBJECTIVES: Laparoscopy is the preferred method when operating in the abdomen. In this study, we evaluated systemic and morphological peritoneal cytokine modifications (RANTES/CCL5 and MCP-1/CCL2) due to CO2 pneumoperitoneum in rats. METHODS: Twenty-five prepubertal Sprague-Dawley rats were randomized into three groups. Pneumoperitoneum lasting 30 minutes, was induced with a flow of 0.5 L/min, in two groups (S1 and S2, n = 20), at a P/CO2 of 6 and 10 mm Hg, respectively. In the control group (C, n = 5), only anesthesia was carried out. All animals were sacrificed after 24 hours. The serum of the rats was collected for ELISA, and the levels of the cytokines RANTES and MCP-1 were investigated. An immunohistochemical analysis of RANTES and MCP-1 was performed on samples of the peritoneum, and the morphological evaluation was conducted with a blinded evaluation by two independent, experienced pathologists by using a grading system (0, 1+, 2+, 3+: no, faint, moderate, and strong reactivity, respectively). RESULTS: RANTES mean levels were significantly different in the S1, S2, and C groups (70.3 ± 2.26, 58.23 ± 4.32, 29.66 ± 4.03, respectively, P = .0001). The levels of MCP-1 were 32.1 ± 1.63 in the S1 group, 27.0 ± 9.26 in the S2 group, and 16.4 ± 9.55 in the C group (P = .159). Normal control peritoneum showed little reactivity, whereas a moderate to strong cytoplasmic reaction to anti-CCL5/CCL2 antibodies was observed in mesothelial and inflammatory cells in the S1 and S2 groups. CONCLUSION: CO2 pneumoperitoneum evokes an inflammatory response by modifying plasma RANTES levels and peritoneal CCL5/CCL2 expression.

Functional constipation or redundancy of the colon?

OBJECTIVES: Constipation is a common problem in children, and most of the time, the cause is defined as functional. Our hypothesis is that children with functional refractory constipation had anatomic alterations of the colon. METHODS: All children with chronic refractory constipation who visited our centre underwent accurate clinical examination, contrast enema (CE), anorectal manometry (ARM) and rectal suction biopsies (RSB). In case of functional constipation, three operators measured the size of the colon using radiograms and calculated the ratio based on the width of the second lumbar vertebra. The measurements carried out were compared with those reported in the literature on patients of the same age without constipation. RESULTS: Over a period of 24 months, 69 patients with chronic refractory constipation, aged between 1 and 14 years, visited our department. A CE was performed on 67, and 2 were excluded because of anal stenosis. Sixty-five underwent anorectal manometry. Rectal suction biopsies were needed in 14 children, and 2 of them were found to have colonic aganglionosis. After a complete evaluation, 57 (82.61%) patients were diagnosed having functional constipation. By comparing the data of the patients with those of normal children reported by the other authors, we found that none of the measurements was statistically significant except for the rectosigmoid length: the mean value in one-year-old patients was 19.03 vs. 9.75, and in older children, it was 19.46 vs. 9.59. CONCLUSIONS: Recognizing an anatomic anomaly in patients suffering from functional constipation is important for specific treatment, especially when the ratio (rectosigmoid length/L2) is higher than 15.

The isolated tubal torsion: an insidious pediatric and adolescent pelvic urgency.

Isolated tubal torsion (ITT) is a rare cause of acute abdominal pain. Preoperative diagnosis is difficult because of a lack of specific signs. Surgery is recommended to preserve the integrity of the tube. Seven patients of median age of 13 years (range 9 to 15) came to our observation for worsening abdominal pain, nausea and vomiting. On admission, all girls had blood tests and ultrasound. Laparoscopy was performed for diagnosis in all cases. The girls had one-month and one-year ultrasound and clinic follow up. In all cases diagnosis was delayed, median 66 hours after the onset of symptoms and laparoscopy showed necrosis of the Fallopian tube. In five girls a laparoscopic salpingectomy was performed. In the other two, an open salpingectomy was necessary because of pelvic adhesions. Histology showed a hemorrhagic infarction of the Fallopian tubes. At follow up all patients were asymptomatic with normal ovaries, but one ovarian cyst. In the differential diagnosis of acute abdominal pain in children or female adolescents the possibility of ITT should be considered for a conservative treatment. Laparoscopy allows for definitive diagnosis and treatment.

Transscrotal orchidopexy for palpable cryptorchid testis: follow-up and outcomes.

We retrospectively reviewed the results of transscrotal orchidopexy in the surgical management of palpable testis. From January 2014 to June 2017, 130 male children with a total of 140 palpable undescended testes (UDT) underwent transscrotal orchidopexy. The charts were retrospectively reviewed for demographic data, preoperative position and mobility of the testis, patency of the peritoneal vaginal duct (PVD), and post-operative complications. The resting position of the testis and its traction towards the scrotum were assessed before surgery and under anaesthesia. The mean age of the patients was 4.6 years. The position of the testis assessed at surgery was in most cases at the external inguinal ring (62.8%), at the neck of the scrotum (15.7%), in the inguinal canal (12.8%), or in an ectopic position (8,5%). A PVD was found in 66 testes (47.1%). Two surgical cases required an inguinal incision. In each patient, the postoperative course was unremarkable. The testicle at 1-year follow-up was in a scrotal position in 134 cases, but 6 patients required a second surgical intervention for re-ascent of the testis. No testicular atrophy or inguinal hernias were observed. Transscrotal orchidopexy is a simple and effective procedure for the treatment of palpable UDT. The incidence of complications is low and manageable, with rapid postoperative recovery and early resumption of normal activities.

Risk Factors of Cholelithiasis Unrelated to Hematological Disorders in Pediatric Patients Undergoing Cholecystectomy.

BACKGROUND: Pediatric cholelithiasis unrelated to hematological disorders is an increasing disease. We analyzed our experience in the surgical treatment of these cases to evaluate risk factors, clinical presentation, intervention and follow-up. METHODS: From January 2010 to December 2016, we retrospectively recorded all data (hematological study, familiarity, use of lithogenic drugs and parenteral nutrition) of cholecystectomies for cholelithiasis not related to hematological diseases. The body mass index (BMI) was calculated (obesity if > 25), medical treatment, surgery and follow-up were evaluated. All patients underwent ultrasound for diagnosis and major biliary tract assessment prior to surgery. All patients had a 1-year follow-up. RESULTS: There were twenty-four cases (eight males), with a median age of 11.2 years. Predisposing factors were familiarity in 19, use of lithogenic drugs in 5 and total parental nutrition (TPN) in 3. Median BMI was 19.8 kg/m2, with BMI > 25 kg/m2 in eight cases. Regarding the clinical presentation, 14 had acute pain in the right upper quadrant, 5 had cholecystitis and 5 had non-specific abdominal pain. The medical treatment lasted 6 months in all, except for five (three operated after 2 months and two after 12 months). Preoperative ultrasound did not show stones in the biliary tract. MRI was performed in three cases for suspected malformation of the biliary tract (negative). Laparoscopic cholecystectomy was performed in all cases: mean intervention time was 95 min. A case of postcolecystectomy syndrome was found. At follow-up, all were asymptomatic, except two (recurrent abdominal pain). CONCLUSION: Main predisposing factors are familiarity and obesity. Preoperative ultrasound in our series replaced the intraoperative study of the biliary tract. Laparoscopic cholecystectomy is the gold standard.

The DMT1 IVS4+44C>A polymorphism and the risk of iron deficiency anemia in children with celiac disease.

BACKGROUND: Iron deficiency anemia in celiac disease is related to impaired duodenal mucosal uptake, due to villous atrophy. Iron enters the enterocytes through an apical divalent metal transporter, DMT1. Different DMT1 transcripts have been identified, depending on the presence of an iron-responsive element that allows DMT1 up-regulation during iron starvation. An intronic DMT1 polymorphism, IVS4+44C>A, has been associated with metal toxicity, and the CC-carriers show high iron levels. AIMS: This study investigates the association between DMT1 IVS4+44C>A and anemia in a cohort of 387 Italian celiac children, and the functional role of the polymorphism. METHODS AND RESULTS: By association analysis, we found that DMT1 IVS4+44-AA genotype confers a four-fold risk of developing anemia, despite of atrophy degree. By analysis of mRNA from gastroesophageal biopsies, we found that total DMT1 is significantly upregulated in presence of mild, but not severe, atrophy, independently from IVS4+44C>A variant, and in normal but not in atrophic CC-biopsies. Moreover, we found that A-allele is associated to preferential expression of the DMT1 transcripts lacking the iron-responsive element, thus limiting the DMT1 overexpression that normally occurs to respond to iron starvation. DISCUSSION: Possibly, the IVS4+44-AA-related dysregulation of the iron-induced changes in DMT1 expression is not able to impair iron absorption in physiological condition. However, if exacerbated by the concomitant massive loss of functional absorbing tissue paralleling worsened stages of villus atrophy, it might be ineffective in counteracting iron deficiency, despite of DMT1 overexpression. CONCLUSION: We suggest, for the first time, that celiac disease may unmask the contribution of the DMT1 IVS4+44C>A polymorphism to the risk of anemia.