Exome sequencing identifies variants in infants with sacral agenesis.

BACKGROUND: Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non-syndromic SA. METHODS: Using buccal cell specimens from families of children with non-syndromic SA, exomes of 28 child-parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child-father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. RESULTS: Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non-erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X-linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. CONCLUSIONS: To our knowledge, this is the first study reporting a possible association between ID1 and non-syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non-syndromic SA and provide data for future studies.

The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene.

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

Factors associated with poor outcome in fetuses prenatally diagnosed with sacrococcygeal teratoma.

AIM OF THE STUDY: Outcome of fetuses, prenatally diagnosed with sacrococcygeal teratoma (SCT), is still poorly documented. This study assesses the incidence and prenatal predictors of outcome in all fetuses prenatally diagnosed with SCT. METHODS: This is a retrospective study on all fetuses prenatally diagnosed with SCT from 1998 to 2018 in the Netherlands. Poor outcome was defined as terminations of pregnancy (TOP) because of expected unfavorable outcome, intrauterine fetal death, or early neonatal death. Potential risk factors for poor outcome were analyzed. MAIN RESULTS: Eighty-four fetuses were included. Sixteen (19.0%) TOPs were excluded from statistical analysis. Eleven of the remaining 68 fetuses had poor outcome. Overall mortality was 32.1%, with a mortality excluding TOPs of 13.1%. Thirteen fetal interventions were performed in 11 (13.1%) fetuses. Potential risk factors for poor outcome were the presence of fetal hydrops (OR: 21.0, CI: 2.6-275.1, p = 0.012) and cardiomegaly (OR: 10.3, CI: 1.9-55.8, p = 0.011). CONCLUSIONS: The overall mortality of fetuses prenatally diagnosed with SCTs including tTOP was 32.1%. This high mortality rate was mainly due to termination of pregnancy. Mortality excluding TOP was 13.1%. Potential risk factors for poor outcome were fetal hydrops and cardiomegaly.

[Occurrence of rod fracture and salvage methods after primary surgery of the congenital lumbosacral deformity associated with sacral agenesis].

Objective: To analyze the occurrence of rod fracture after surgery for lumbosacral deformity associated sacral agenesis and discuss the relevant salvage methods. Methods: The clinical records of 19 patients who underwent surgical treatment for lumbosacral deformity associated sacral agenesis from January 2001 to January 2018 were retrospectively reviewed, including 11 boys and 8 girls. The average age was (9.6±5.2) years. The outcomes of surgical correction and internal fixation were evaluated by postoperative regular follow-up. We also recorded the time and position of rod fracture occurrence. The Cobb angle, coronal balance and sagittal balance were measured and compared to analyze the corresponding salvage methods and revision outcomes. Results: Three patients encountered rod fracture during follow-up, so the incidence of rod fracture after surgery for lumbosacral deformity associated sacral agenesis was 15.8%(3/19). Based on their own conditions, we formulated the individualized strategy and performed the revision surgery through the posterior-only approach. The most critical step was abundant bone-grafting and fusion in the defected sacroiliac joint. After revision, the scoliotic Cobb angle improved in two patients (91.5° vs 47.5°, 49.0° vs 28.0°) and coronal balance improved in one patient (40.3 mm vs 24.3 mm). No complication reoccurred during follow-up. Conclusion: The rod fracture after surgery for lumbosacral deformity associated sacral agenesis is quite common, which is probably correlated with its unique deformed structure and biomechanical characteristics. The individualized salvage methods and adequate bone-grafting and fusion for the defected sacroiliac joint will guarantee the reconstruction and maintenance of spine balance after revision.

Diagnóstico prenatal del síndrome de Currarino completo. Presentación de un caso / Prenatal diagnosis of complete Currarino syndrome. Case report

RESUMEN Fundamento: El síndrome de Currarino es una enfermedad poco frecuente, presenta varias malformaciones conformadas por una tríada: estenosis anal, malformación sacrococcígea y masa presacra; su diagnóstico se realiza con frecuencia en edad adulta. Objetivo: Reportar un caso que se diagnosticó con síndrome de Currarino en etapa fetal. Caso clínico: Se reportó un feto del sexo masculino de 22 semanas de gestación, con síndrome de Currarino que al realizarle la necropsia se constató la presencia de: defecto sacro coccígeo (ausencia total del sacro), masa o tumoración presacra (de aspecto quístico), ano imperforado y ausencia de pliegue interglúteo, estenosis del sigmoide y bolsa escrotal única, riñón único, pélvico y poliquístico, con salida de 2 uréteres. Conclusiones: El síndrome de Currarino se caracteriza por una tríada de presentaciones, en muchos casos se puede pasar por alto y existir subdiagnósticos, por lo que su detección precoz permite evitar complicaciones en la etapa adulta y mejorar la calidad de vida.

ABSTRACT Background: Currarino syndrome is a non-frequently disease, presenting several malformations consisting of a triad: anal stenosis, sacrococcygeal malformation and presacral mass; its diagnosis is habitually performed in adulthood. Objective: To report a case diagnosed with Currarino syndrome in the fetal stage. Case report: A 22-week gestation male fetus with Currarino syndrome, at necropsy he was found to have: sacrococcygeal defect (total absence of the sacrum), presacral mass or tumors (cystic appearance), non-perforated anus and absence of intergluteal fold, sigmoid stenosis and single scrotal pouch, single, pelvic and polycystic kidney, with exit of 2 ureters. Conclusions: Currarino syndrome is characterized by a triad of appearances, in many cases it can be overlooked and underdiagnosed, so early detection can prevent complications in adulthood and improve life quality.

Presacral neuroendocrine tumors associated with the Currarino syndrome.

Currarino syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis, and presacral masses. The presacral masses are typically benign; however, malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in six cases. We report three individuals from two families affected by CS in which multiple individuals developed presacral NETs. The first family, 491, had six members with features of CS, including two siblings who presented with presacral, Grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing. A second somatic variant/deletion in MNX1 was not detected in either patient's tumor. In the second family, 342, the proband presented with an incidentally discovered presacral NET. The proband's father had previously undergone resection of a presacral NET, and so genetic testing was performed, which did not reveal an MNX1 mutation or copy number variants. The lack of a second, somatic mutation in the tumors from family 491 argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs. These cases highlight the variable presentation of CS, and the potential for malignancy in these patients.

Experience with human tail and its outcome.

There are some common genetic heritages between human and mammals. Human tail, though rare is one of the most noticeable. Till the date, around 60 cases reported in the literature. A true human tail is a benign vestigial caudal cutaneous structure composed of adipose, connective tissue, muscle, vessels and nerves. A true human tail can be distinguished from a pseudotail as the latter is commonly associated with underlying spinal dysraphism, which requires specialised management. We report a case series of four caudal appendages. Two clients were infants, while others two were toddler and presented with cutaneous appendage arising from the lumbosacral region. Out of four, only one had associated spinal dysraphism and neurological manifestation while others did not have spinal dysraphism and neurological manifestation. The appendage was removed by the surgical excision. Clinicians should emphasise the use of 'true tail' and 'pseudo-tail' as the specific disparate terms as the clinical, radiological and histological findings of these conditions differs significantly, along with the management strategies and outcomes.

Role of urodynamics in male patients of high-anorectal malformations: a prospective study.

PURPOSE: Association of spinal or vertebral anomalies and the iatrogenic denervation during surgical correction of anorectal malformation patients especially in boys can lead to neurogenic bladder inthese subset of patients. The paucity of literature with regard to urodynamic studies focusing exclusively in male children with high-anorectal malformations (HARM) lead us to analyze the urodynamic changes. The objective was to study urodynamic profile in male patients who have undergone surgery for anorectal malformation. METHODS: Male high-anorectal malformation patients who had completed all the stages of repair were prospective studied. Following the basic work up, all patients based on the urodynamics were categorized into 2 groups as safe or unsafe bladders. Unsafe bladder was defined as detrusor pressure > 40 cm (high detrusor pressure) or pressure variability of 15 cm of water (detrusor overactivity) or significant post-void residue. MRI was limited to patients with only abnormal urodynamics to rule out spinal causes of neurogenic bladder and due to financial constraints, it could not be offered to all patients. RESULTS: 41 HARM meet the exclusion criteria. All patients were asymptomatic with none having history of urinary tract infections. Ultrasound showed bladder wall thickening in 31.7% patients. UDS revealed reduction in bladder capacity and compliance was noted in 31.7% and 30% patients, respectively. Elevated detrusor pressures (> 40 cm of water) were noted in 10% (4/41), detrusor overactivity with concomitant elevated detrusor pressures in 19.5% (8/41) and normal UDS in 70% (29/41). 13 patients (31.7%) had abnormal cystometric parameters with 12(30%) having unsafe bladders. MRI confirmed sacral agenesis in 1 patient with unsafe bladder. CONCLUSION: Urodynamics can demonstrate occult neurovesical dysfunction in patients with HARM. This would help in early renal protective therapy and prevent the burden of long-term sequelae of neurovesical dysfunction in HARM patients.

Classification of the "human tail": Correlation between position, associated anomalies, and causes.

INTRODUCTION: Numerous case reports have indicated that the "human tail" is not always a harmless protrusion but can be associated with anomalies such as occult dysraphic malformations. However, the definition and classification of this anomaly have not been discussed. A prevailing hypothesis is that the "human tail" is a residual embryonic tail. Herein, we attempted to classify and define the human tail and investigate the frequency of this anomaly. MATERIALS AND METHODS: We first defined the human tail as a protrusion on the dorsal side of the lumbar, sacrococcygeal, and para-anal regions identified after birth. We collected case reports written in English, Japanese, French, German, and Italian that were published from the 1880s to the present. RESULTS: We discovered two important findings: (a) the cause of this anomaly may differ even though the "tails" resemble each other closely in appearance and (b) its position tends to be correlated with the type of anomaly and its associated cause. We propose a new classification of the human tail based on these findings. CONCLUSION: Our classification may facilitate more accurate treatment and precise case descriptions of the human tail.

Pregnancy in a woman with sacral agenesis from prenatal counseling to delivery: A case report.

Sacral agenesis or CRS (caudal regression syndrome) is a rare congenital condition involving approximately 1 in 25 000 live births (Sharma et al., 2015) and leading to the absence of lower sacral vertebral bodies and severe malformations of the pelvis. This condition is associated with an extreme reduction of the xipho-pubic distance and of the pelvic dimensions. It is reasonable to think that this might lead to an increased difficulty in obtaining a spontaneous pregnancy and to a consistently increased risk of maternal and perinatal complications. In literature, very little is known about pregnancy in patients with sacral agenesis and therefore on the appropriate way to counsel a patient with this condition who is trying to get pregnant (Greenwell et al., 2013). Although a case of pregnancy in a woman with sacral agenesis is mentioned in a book (J. Rogers, 2006) no cases of women with CRS carrying a pregnancy until a viable age for the fetus are reported in medical literature: as far as we know this is the first case reported in literature of a woman with this condition followed before and throughout the pregnancy with reported pre- and perinatal management, leading to a near-term pregnancy. This case could be useful for clinicians who are requested to counsel female patients with the same condition on the possibility of a pregnancy and possible outcomes.

Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997-2011.

BACKGROUND: Diabetes is associated with an increased risk for many birth defects and is likely to have an increasing impact on birth defect prevalence because of the rise in diabetes in the United States in recent decades. One of the first analyses in which specific birth defects were assessed for their relationship with both pregestational and gestational diabetes used data from the initial 6 years of the National Birth Defects Prevention Study. That analysis reported strong associations for pregestational diabetes with several birth defects, but few exposures among some of the less common birth defects led to unstable estimates with wide confidence intervals. Since that analysis, the study continued to collect data for another 8 years, including information on approximately 19,000 additional cases and 6900 additional controls. OBJECTIVE: Our objective was to use data from the National Birth Defects Prevention Study, the largest population-based birth defects case-control study in the United States, to provide updated and more precise estimates of the association between diabetes and birth defects, including some defects not previously assessed. STUDY DESIGN: We analyzed data on deliveries from October 1997 through December 2011. Mothers of case and control infants were interviewed about their health conditions and exposures during pregnancy, including diagnosis of pregestational (type 1 or type 2) diabetes before the index pregnancy or gestational diabetes during the index pregnancy. Using logistic regression, we separately assessed the association between pregestational and gestational diabetes with specific categories of structural birth defects for which there were at least 3 exposed case infants. For birth defect categories for which there were at least 5 exposed case infants, we calculated odds ratios adjusted for maternal body mass index, age, education, race/ethnicity, and study site; for defect categories with 3 or 4 exposed cases, we calculated crude odds ratios. RESULTS: Pregestational diabetes was reported by 0.6% of mothers of control infants (71 of 11,447) and 2.5% of mothers of case infants (775 of 31,007). Gestational diabetes during the index pregnancy was reported by 4.7% of mothers of control infants (536 of 11,447) and 5.3% of mothers of case infants (1,653 of 31,007). Pregestational diabetes was associated with strong, statistically significant odds ratios (range, 2.5-80.2) for 46 of 50 birth defects considered. The largest odds ratio was observed for sacral agenesis (adjusted odds ratio, 80.2; 95% confidence interval, 46.1-139.3). A greater than 10-fold increased risk was also observed for holoprosencephaly (adjusted odds ratio, 13.1; 95% confidence interval, 7.0-24.5), longitudinal limb deficiency (adjusted odds ratio, 10.1; 95% confidence interval, 6.2-16.5), heterotaxy (adjusted odds ratio, 12.3; 95% confidence interval, 7.3-20.5), truncus arteriosus (adjusted odds ratio, 14.9; 95% confidence interval, 7.6-29.3), atrioventricular septal defect (adjusted odds ratio, 10.5; 95% confidence interval, 6.2-17.9), and single ventricle complex (adjusted odds ratio, 14.7; 95% confidence interval, 8.9-24.3). For gestational diabetes, statistically significant odds ratios were fewer (12 of 56) and of smaller magnitude (range, 1.3- 2.1; 0.5 for gastroschisis). CONCLUSION: Pregestational diabetes is associated with a markedly increased risk for many specific births defects. Because glycemic control before pregnancy is associated with a reduced risk for birth defects, ongoing quality care for persons with diabetes is an important opportunity for prevention.

Evaluation and Long-term Management of Neurogenic Bladder in Spinal Dysraphism.

Spinal dysraphism, which includes conditions such as myelomeningocele and sacral agenesis, is one of the most common causes of congenital lower urinary tract dysfunction. Early evaluation of the neurogenic bladder serves to minimize renal damage, and the main goals of management include preserving renal function, achieving acceptable continence, and optimizing quality of life. The survival of patients with such conditions has improved to greater than 80% reaching adulthood, owing to advances in diagnostic and therapeutic modalities. The result is a real, and unfortunately often unmet, need for successful transitional care in this complex patient population. Clinicians must be able to identify the unique challenges encountered by patients with neurogenic bladder as they shift through different stages of their life.

Sacral Skin Temperature and Pressure Ulcer Development: A Descriptive Study.

Existing evidence is inadequate to assume increased skin temperature is a risk factor for the development of pressure ulcers (PUs). PURPOSE: The purpose of this prospective, descriptive study was to examine the relationship between sacral skin temperature and PU development. METHODS: Using convenience sampling methods, patients who were hospitalized in the tertiary intensive care unit (ICU) of the internal medicine department of a university hospital in Izmir, Turkey, between April and December 2015 were eligible to participate if they were ⟩18 years of age, had an expected hospital stay of at least 5 days, a Braden score ≤12, and were admitted without a PU. Demographic and clinical data collected included age, gender, body mass index, diagnosis, mattress type, length of follow-up (days), systolic and diastolic blood pressure, body temperature, hemoglobin level, sacral skin temperatures in the supine and lateral positions, room temperature, PU stage and duration, and Braden score. Temperature was measured the day of hospitalization as a baseline measurement (day 1) and once every day thereafter up to 22 days, until the patient did or did not develop a PU, died, was no longer undergoing position change, or was discharged. Sacral skin temperature was taken immediately after the patient was moved to a lateral position following 120 minutes of supine position (referred to as supine position sacral skin temperature measurement) and after 30 minutes in lateral position (referred to as lateral position sacral skin temperature measurement). Data were collected using paper-and-pencil questionnaires and entered into a software program for analysis. Descriptive statistics, Student's t test, one-way analysis of variance test, Pearson product-moment correlation analysis, and Spearman's rank-order correlation analysis were used for data analysis. RESULTS: Of the 37 patients who met the inclusion criteria and were monitored for at least 5 days, 21 (56.8%) developed PUs. No statistically significant difference in supine position sacral skin temperature on day 1 or day 5 was found between patients who did and did not develop a PU (36.90° C ± 0.29° C and 37.15° C ± 0.53° C, respectively, on day 1; t = -1.656, P = .112; and 37.37° C ± 0.53° C and 37.30° C ± 0.79° C, respectively, on day 5; t = 0.259, P = .798). Day 5 lateral position skin temperatures also did not differ significantly between the 2 groups (37.44° C ± 0.44° C and 37.31° C ± 0.75° C, respectively; t = 1.306, P = .621). A statistically significant difference was noted between mean sacral skin temperature in the supine position among patients ages 75 to 90 years compared with patients 38 to 64 years and 65 to 74 years (36.93° C ± 0.39° C; F = 13.221, P = .000) and with use of a viscoelastic mattress compared with an alternating pressure air mattress and continuous lateral rotation alternating pressure air mattress (37.85° C ± 0.54° C; F = 14.039, P = .000). No statistically significant differences in sacral skin temperatures were found for any of the of the other variables assessed. CONCLUSION: Sacral skin temperatures were not statistically different between ICU patients who did and did not develop a PU. Additional research may help increase understanding of the relationship between skin temperature and PU development.

Descriptive and risk factor analysis of nonsyndromic sacral agenesis: National Birth Defects Prevention Study, 1997-2011.

Sacral agenesis is a rare birth defect characterized by partial or complete absence of the sacrum. We sought to (a) describe case characteristics, (b) estimate birth prevalence, and (c) identify risk factors for nonsyndromic sacral agenesis using data from the National Birth Defects Prevention Study (NBDPS). The NBDPS was a population-based, case-control study involving pregnancies with estimated dates of delivery from October 1997 through December 2011. We estimated birth prevalence using all NBDPS eligible cases. Using self-reported maternal exposure information, we conducted multivariable logistic regression analysis to identify potential risk factors overall and among women without diabetes. The birth prevalence of sacral agenesis was 2.6/100,000 live births. In the multivariable analysis, multifetal pregnancy, pre-existing Type 1 diabetes, and pre-existing Type 2 diabetes were positively and significantly associated with sacral agenesis, albeit estimates were imprecise. Preexisting Type 1 diabetes was the strongest risk factor (adjusted odds ratio = 96.6, 95% confidence interval = 43.5-214.7). Among women without diabetes, periconceptional smoking was positively and significantly associated with sacral agenesis. Our findings underscore the importance of smoking cessation programs among women planning pregnancy and the importance of better understanding the role of glycemic control before and during pregnancy when designing interventions for primary prevention of sacral agenesis.

Differentiating Deep Tissue Pressure Injury (DTPI) From Other Causes of Purpura in the Sacrococcygeal Area: A Multiple Case Series.

BACKGROUND: Recent revisions to the pressure injury staging system include guidance on differential diagnoses for deep tissue pressure injury (DTPI). Accurately identifying DTPI is critical; however, purpura in the setting of vascular disorders and systemic infectious processes can share similar features confounding diagnosis. CASES: In this three-case series, we describe suspected DTPI with an uncharacteristic shape or occurring in the presence of additional lesions distributed outside of typical pressure areas prompted further evaluation. CONCLUSIONS: The interdisciplinary approach we adapted was useful in determining the cause of purpura when the DTPI was ruled out by the certified wound care nurse.

Prenatal diagnosis of caudal regression with heterotaxy syndrome: "A mermaid with a broken heart".

Caudal regression syndrome (CRS) is a rare congenital malformation with varying degrees of early gestational developmental failure. It is characterized by agenesis of the sacrum and lumbar spine, with lower limb neurological deficit and accompanying deformities of the pelvis, lower extremities, genitourinary, and gastrointestinal systems. We report a case of CRS associated with rare complex congenital heart defect, that is, heterotaxy syndrome, diagnosed prenatally.

Expansion Thoracoplasty as a Life-Saving Procedure in an Adolescent With Severe Spinal Deformity and Sacral Agenesis.

STUDY DESIGN: Case report. OBJECTIVES: To describe use of expansion thoracoplasty (ET) for severe thoracic insufficiency syndrome (TIS) in an adolescent with severe spinal deformity. BACKGROUND: ET is typically performed in young patients with TIS to increase chest cavity volume, improve alveolar expansion, and potentially improve alveolar proliferation. ET has not been well-described in adolescent patients with TIS. METHOD: A mature adolescent with previously treated myelokyphosis and sacral agenesis developed severe TIS with dependence on supplemental oxygen and noninvasive ventilation. She was treated with two-stage bilateral ET and vertical expandable prosthetic titanium rib (VEPTR) placement. Yearly pulmonary function testing (PFT) was performed over 7 years of follow-up. RESULTS: Significant clinical pulmonary improvement was achieved and maintained at final follow-up, as the patient no longer required supplemental oxygen. Percentage predicted forced vital capacity (FVC) improved from 29% to 36%; percentage predicted forced expiratory volume-1 second (FEV1) improved from 30% to 36%. CONCLUSIONS: This case demonstrates that improvement and stabilization of respiratory function can be achieved with instrumented ET in a skeletally mature adolescent with severe TIS and spinal deformity.

[Caudal regression syndrome: about a case]. / Syndrome de régression caudale: à propos d'un cas.

Caudal regression syndrome is a rare malformative syndrome associated, to varying degrees, with agenesis of sacral and coccygeal vertebrae, lower limb shortening and gastrointestinal, genitourinary and cardiovascular abnormalities. Its relationship with gestational diabetes is well established, but its exact cause is poorly established. We here report a rare case of caudal regression syndrome in a 8-month old infant of diabetic mother with polymalformative syndrome and chronic constipation.