Biomedical subjects
Publications and source records attributed to N Scott Adzick.
We present a case of intestinal obstruction owing to a gallstone ileus in a patient 20 years after a Kasai procedure for biliary atresia in which a stapled antireflux valve was constructed to treat recurrent cholangitis. The etiology of this rare presentation is discussed.
Congenital hyperinsulinism (HI) exists in 2 histologic forms, focal and diffuse, and rarely has been attributed to lesions in ectopic pancreatic tissue. The ability to distinguish focal from diffuse HI and locate focal lesions has been difficult, thus limiting the optimal management of HI. We present a case of HI resulting from focal pancreatic and ectopic pancreatic lesions. After a near-total pancreatectomy failed to improve the patient's condition, a positron emission tomography (PET) scan performed with 18F-fluoro-L-dihydroxyphenylalanine demonstrated a focal lesion remaining in the head of the pancreas as well as 4 hot spots inferior to the remaining pancreas. Surgical exploration found pancreatic rests in the jejunum responsible for the hot spots seen on PET. Resection of the remainder of the pancreas as well as the small intestinal lesions resulted in correction of the patient's HI. Pathology confirmed the presence of focal HI lesions in the pancreatic head and small intestinal specimens. This case supports the ability of ectopic pancreatic tissue to contribute to the pathology of HI. It highlights the ability of PET to successfully identify focal lesions, including ectopic tissue, responsible for hyperinsulinemic hypoglycemia.
OBJECTIVE: To examine the impact of fetal myelomeningocele (MMC) repair on fetal head biometry and cerebrospinal fluid (CSF) spaces assessed by magnetic resonance imaging (MR) studies. STUDY DESIGN: Axial measurements of intracranial structures were taken at defined anatomical landmarks. Pre- and postnatal head biometry data and CSF spaces obtained from in utero repaired MMC fetuses (n = 22) were compared to the pre- and postnatal measurements of MMC patients that underwent standard neurosurgical MMC repair after birth (n = 16) and a cohort of age-matched control patients (prenatal, n = 52; postnatal, n = 9). RESULTS: In fetuses with MMC, initial MR scans showed an almost complete absence of supratentorial and posterior fossa CSF spaces. No differences in postnatal CSF spaces were found between controls and prenatally repaired MMC newborns. In fetuses with postnatal MMC repair, CSF spaces remained significantly reduced (p < 0.0001). The mean ventricular diameter (VD) increase in the postnatal repaired MMC group was significantly higher compared to the mean percentage of VD increase in the fetal repaired MMC group (6.4 vs. 4.2 mm; p = 0.02). Pre- and postnatal brain thickness measurements were significantly reduced in both MMC populations compared to age-matched normal values (p < 0.0001). In contrast to postnatally repaired patients, in utero repair fetuses showed significant reversal of hindbrain herniation and normalization of the posterior fossa CSF spaces. CONCLUSION: Mid-gestational repair of MMC promotes normalization of extra-axial CSF spaces. Due to progressive ventriculomegaly, brain thickness remains decreased in both prenatal repaired and age-matched non-repaired MMC patients when compared to age-matched normal values. Restoration of CSF volume in the posterior fossa after in utero repair is indicative of reversal of hindbrain herniation.
We present the first case of the prenatal diagnosis of congenital hyperinsulinism based on the genetic analysis of known family mutations in the SUR1 gene. An amniocentesis was performed at 16 weeks gestation at which time two mutations in the SUR1 gene were identified consistent with the diagnosis of diffuse hyperinsulinism. The mother was transported to our facility and underwent an elective caesarian section at 38 weeks gestation. The diagnosis was confirmed and treatment was initiated within the first minutes of life. After a short course of failed medical management, the patient underwent a 98% pancreatectomy with subsequent good glycemic control. This case highlights the benefits of the timely in utero diagnosis of hyperinsulinism by mutational analysis.
Myelomeningocele (MMC) is the most common cause of neurogenic bladder dysfunction (NBD). We recently developed a novel retinoic acid (RA)-induced MMC model in fetal rats. The objective of this study was to use this model to assess functional and structural characteristics of the detrusor muscle in MMC-associated NBD. Time-dated pregnant Sprague-Dawley rats were gavage fed 60 mg/kg RA dissolved in olive oil or olive oil alone [embryonic day 10 (E10)]. Bladder specimens from olive oil-exposed fetuses (OIL; n = 71), MMC (n = 79), and RA-exposed-no MMC (RA, n = 62) were randomly assigned for functional and histopathological evaluation and protein analysis. Contractility responses to field and agonist-mediated stimulation (KCl and bethanecol) were analyzed. The expression patterns of alpha-smooth muscle actin, myosin, desmin, vimentin, and collagen III and I were analyzed by immunohistochemistry and Western blotting. Spatial and temporal distribution of nerve fibers within the detrusor muscle was monitored by neurotubulin-beta-III throughout gestation. Neither OIL, MMC, nor RA detrusor responded to field stimulation. MMC bladder strips showed a significant decrease in contractility after KCl and bethanechol stimulation compared with OIL and RA bladders. Bladder detrusor morphology and expression patterns of smooth muscle markers were similar between groups. Detrusor muscles in OIL and RA fetuses were densely innervated, possessing abundant intramural ganglia and nerve trunks that branch to supply smooth muscle bundles. In MMC bladders, neurotubulin-beta-III-positive nerve fibers were markedly decreased with advancing gestational age and were almost completely absent at term (E22). We conclude that the biomechanical properties of fetal rat MMC bladders are analogous to that seen in humans with MMC-associated NBD. Decreased nerve density indicates loss of peripheral neural innervation throughout gestation. The early observation of decreased innervation and decreased contractility in the absence of morphologic abnormalities in muscle structure or extracellular matrix supports a pathophysiological hypothesis that denervation is the primary insult preceding the observed alterations in bladder muscle structure and function.
BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of severe hypoglycemia in the neonatal and infancy period. Histologically, there are two subtypes with diffuse and focal disease. The preoperative differentiation of these two forms is very important because the surgical management is radically different. The focal form of the disease can be cured if the focal lesion can be localized accurately and completely resected with surgery. AIM: We report the case of a child who underwent three pancreatectomies with a choledochoduodenostomy and a cholecystectomy but continued to have severe hyperinsulinemic hypoglycemia. METHODS/RESULTS: Radiological investigations including imaging with (18)fluoro-L-Dopa positron emission tomography scan showed a clear focus of increased (18)F-fluoro-L-Dopa uptake in the vicinity of the former head of the pancreas. On the magnetic resonance imaging scan, this focal uptake appeared to localize adjacent or next to duodenum (in the wall or cavity of the duodenum). CONCLUSIONS: This unique case highlights the importance of correctly localizing and completely resecting the focal lesion in patients with CHI. (18)Fluoro-L-Dopa positron emission tomography scan can identify ectopic focal lesions in patients with CHI.
Prenatal identification of lung abnormalities has increased with prenatal surveillance. Treatment usually requires serial ultrasound observation but in rare situations in utero therapy may be required for fetal survival. We review the genetics, prenatal evaluation, and treatment of lung abnormalities with congenital cystic adenomatoid malformation (CCAM). Other lung lesions, bronchopulmonary sequestration (BPS), hybrid lesions involving both malformations, congenital lobar emphysema (CLE), are briefly included as differential diagnosis options. Outcome of fetuses identified to have CCAM lung abnormalities resulting in fetal hydrops and having in utero therapy (thoracoamniotic shunting, fetal thoracotomy, EXIT delivery) are discussed. In the appropriate situation, this maternal fetal surgery approach for CCAM is life-saving for the affected fetus with acceptable maternal morbidity risks in the present and future pregnancies.
In fetal sheep with surgically created diaphragmatic hernia (DH), tracheal occlusion (TO) can restore lung growth but does not ameliorate the increase in inter-alveolar wall thickness (T(W)). We determined whether prenatal exposure to glucocorticoids (GC) could reduce T(w) in fetuses with DH undergoing TO. At 65 days of gestation, DH was created in 12 fetal sheep, and TO subsequently performed at 110 days (DH/TO). Six of these fetuses were exposed to betamethasone (DH/TO + GC; 0.5 mg/kg; maternal, IM) 48 hr before delivery; Sham operated fetuses (n = 7) served as controls. At 139 days, we measured alveolar surface density (S(V)), parenchymal tissue fraction, T(W), alveolar type 2 (AE2) cell density and lung surfactant protein (SP) mRNA expression. Prenatal GC decreased T(W) and S(V) by 33% and 27% respectively, and increased fixed lung volume (by 55%), AE2 cell density and partially restored SPmRNA expression. Our data indicate that prenatal exposure to GC can reverse some of the negative effects of prolonged fetal TO. We hypothesize that a GC-induced reduction in lung liquid volume during TO contributes, in part, to the observed increase in AE2 cell density and SPmRNA expression.
OBJECTIVE: This study was undertaken to examine short-term neurodevelopmental outcomes in children with myelomeningocele (MMC) who underwent in utero neurosurgical closure. STUDY DESIGN: Between 1998 and 2002, 51 fetuses underwent in utero MMC closure at our Center. Thirty (63%) of these children have returned for neurodevelopmental testing at 2 years of age using the Bayley Scales of Infant Development and Preschool Language Scales. RESULTS: Overall shunt rate was 43% in this group. Neurodevelopmental testing found 67% with cognitive language and personal-social skills in the normal range, 20% with mild delays, and 13% with significant delays. Children with shunted hydrocephalus scored lower than those with unshunted ventriculomegaly. CONCLUSION: Children who have undergone fetal MMC closure have characteristic neurodevelopmental deficits that do not appear worsened by fetal surgery, and developmental outcomes may be improved by decreasing the need for ventriculoperitoneal shunting.
BACKGROUND: The use of the ex utero intrapartum treatment (EXIT) procedure has salvaged many fetuses with giant neck masses. Despite an adequate airway, a subset of these patients die from an inability to achieve adequate gas exchange. METHODS: We reviewed our experience with the EXIT procedure from 1996 to 2004. The EXIT was used to deliver 23 fetuses with giant neck masses. RESULTS: Three fetuses with giant cervical teratomas died of severe pulmonary hypoplasia. On postmortem, these patients had severe airway distortion by the mass. The carina was retracted superiorly to the first or second rib resulting in compression of the lungs in the apices of the chest and pulmonary hypoplasia. Hypoplasia was reflected in the lung weights of 24 vs 38 g and 17 vs 34 g for age-matched normal lung. CONCLUSIONS: Unsuspected obstructive fetal neck masses can be fatal because of an inability to secure an airway. Prenatal ultrasonography can identify fetuses at risk, allowing the fetus to be salvaged using the EXIT procedure. Despite obtaining airway control, a subset of these patients will die because of pulmonary hypoplasia. When counseling patients with large cervical masses it is important to discuss potential pulmonary hypoplasia in these patients.
BACKGROUND/PURPOSE: Mesenchymal nuclear transcription factors (MNTF) are involved in lung development and maturation and regulate surfactant protein (SP) expression. Prolonged (>2 weeks) fetal tracheal occlusion (TO) has been shown to accelerate lung growth and inhibit pulmonary surfactant synthesis. The effects of TO on SP expression and MNTF, however, have not been formally assessed. The objectives of this study were to evaluate the effects of short-term (3 days) TO on normal lung growth and protein expression of pulmonary MNTF involved in SP synthesis. METHODS: At E19 (term, 22 days), 2 fetuses per time-dated Sprague-Dawley rats underwent either TO (n = 23) or a sham (n = 22) operation. Lungs were harvested 72 hours post surgery. Pulmonary SP-A; SP-B; SP-C messenger RNA (mRNA) expression; and SP-A and SP-B, Hoxb5, thyroid transcription factor 1, and retinoic X receptor-alpha protein expression were analyzed. RESULTS: Lung weight was significantly increased by TO (TO 0.32 +/- 0.02g vs SHAM 0.14 +/- 0.01 g; P < .001), resulting in 123% increase of the lung-to-body-weight ratio. No difference of SP-A-mRNA (177 +/- 4.3 TO vs 169 +/- 4.4 SHAM; P = .25), SP-B-mRNA (87.7 +/- 0.2 TO vs 87.4 +/- 0.02 SHAM; P = .33), and SP-C-mRNA (186.5 +/- 3.2 TO vs 183.2 +/- 2.7 SHAM; P = .45) expression was found. Surfactant protein A (175.6 +/- 25.3 TO vs 192.5 +/- 19.8 SHAM; P = .59) and SP-B (163.4 +/- 5.2 TO vs 166.8 +/- 9.3 SHAM; P = .75) protein expression were similar in both groups; however, Hoxb5 (70.3 +/- 18.9 TO vs 130.6 +/- 5.1 SHAM; P = .02) and thyroid transcription factor 1 (102.6 +/- 19 TO vs 181.1 +/- 6.3 SHAM; P = .007) expression were significantly decreased. Retinoic X receptor-alpha expression tended to be increased by TO (171.9 +/- 6.0 TO vs 155.4 +/- 6.7 SHAM; P = .06). CONCLUSIONS: Short-term TO late in gestation induces rapid lung growth. Surfactant protein-mRNA and protein expression are not significantly altered. Thyroid transcription factor 1 and Hoxb5 are down-regulated by TO, suggesting that duration and timing of occlusion are important in balancing the effects of TO on lung growth vs lung maturation.
Congenital hyperinsulinism is a rare pancreatic endocrine cell disorder that has been categorized histologically into diffuse and focal forms. In focal hyperinsulinism, the pancreas contains a focus of endocrine cell adenomatous hyperplasia, and the patients have been reported to possess paternally inherited mutations of the ABCC8 and KCNJ11 genes, which encode subunits of an ATP-sensitive potassium channel (K(ATP)). In addition, the hyperplastic endocrine cells show loss of maternal 11p15, where imprinted genes such as p57(kip2) reside. In order to evaluate whether all cases of focal hyperinsulinism are caused by this mechanism, 56 pancreatectomy specimens with focal hyperinsulinism were tested for the loss of maternal allele by two methods: immunohistochemistry for p57(kip2) (n=56) and microsatellite marker analysis (n=27). Additionally, 49 patients were analyzed for K(ATP) mutations. Out of 56 focal lesions, 48 demonstrated clear loss of p57(kip2) expression by immunohistochemistry. The other eight lesions similarly showed no nuclear labeling, but the available tissue was not ideal for definitive interpretation. Five of these eight patients had paternal K(ATP) mutations, of which four demonstrated loss of maternal 11p15 within the lesion by microsatellite marker analysis. All of the other three without a paternal K(ATP) mutation showed loss of maternal 11p15. K(ATP) mutation analysis identified 32/49 cases with paternal mutations. There were seven patients with nonmaternal mutations whose paternal DNA material was not available, and one patient with a mutation that was not present in either parent's DNA. These eight patients showed either loss of p57(kip2) expression or loss of maternal 11p15 region by microsatellite marker analysis, as did the remaining nine patients with no identifiable K(ATP) coding region mutations. The combined results from the immunohistochemical and molecular methods indicate that maternal 11p15 loss together with paternal K(ATP) mutation is the predominant causative mechanism of focal hyperinsulinism.
Although classification schemes have sought to categorize congenital cystic lung malformations, studies including the pathology of pulmonary malformations occurring specifically during the fetal period are limited. To better characterize such histopathology, we reviewed a total of 23 fetal lung malformations seen at the Children's Hospital of Philadelphia from 1996 to 2004. Twenty-one of the 23 fetal pulmonary malformations could be categorized into 1 of 3 groups based upon the predominant histologic features present within each lesion. Group 1 (9/21) demonstrated tubular airspaces lined by columnar epithelium. Group 2 (6/21) contained airspaces lined by cuboidal epithelium and surrounded by smooth muscle with abundant interstitial mesenchyme. Group 3 (6/21) showed a mixture of relatively mature-appearing airspaces lined by flattened epithelium and scattered dilated bronchiole-like structures. Cysts were of variable size but in all cases showed a respiratory-type lining. Gestational ages ranged from 21 5/7 to 38 2/7 weeks. Patients in groups 1 and 2 were generally younger than those in group 3; however, morphology did not seem to correlate entirely with normal stages of fetal lung development, and group 2 lesions in particular were the least akin to normal fetal lung. In 4 cases a systemic vascular supply to a lobe of lung was identified, providing evidence that such vasculature is embryonic in origin. The histopathology of fetal lung malformations highlights the variability seen in such lesions at all ages, and it is hoped that continued investigations will provide further insight into these enigmatic lesions.
Fetal tracheal occlusion (TO) accelerates lung growth and can reverse severe lung hypoplasia associated with diaphragmatic hernia (DH), however, lung compliance (Cl) and respiratory gas exchange remain abnormal. We determined the individual and combined effects of prenatal glucocorticoids (GC) and exogenous surfactant therapy (S) on postnatal pulmonary function in lambs with DH that underwent prolonged TO. DH was created in 22 fetal sheep at 65 d of gestation and TO performed at 110 d. Eleven DH/TO animals received prenatal GC (betamethasone, 0.5 mg/kg) 48 h before delivery; six GC-treated and five non-GC lambs were administered surfactant (Infasurf, 3 mg/kg) at birth. Six sham-operated lambs served as controls. Lambs were delivered at 139 d gestation and ventilated for 2 h. GC or surfactant therapy alone significantly improved respiratory gas exchange, Cl, and ventilatory efficiency index. Total lung capacity was normalized only in DH/TO lambs that received both GC and S.
OBJECTIVE: The purpose of this study was to determine whether prenatal MRI provides additional information about fetal sacrococcygeal teratoma compared with prenatal sonography. MATERIALS AND METHODS: Twenty-two pregnant women with fetal sacrococcygeal teratoma underwent prenatal MRI (mean gestational age, 23 weeks). The size, location, mass characteristics, and compressive effects of the tumors were determined and correlated with sonography and postnatal findings. RESULTS: Based on the MRI findings, the following American Academy of Pediatrics, Surgical Section classifications were assigned: type I in six patients, type II in 12, and type III in four. No type IV tumors were found. The sacrococcygeal teratoma appeared entirely cystic in five fetuses, microcystic in one, mixed cystic and solid in 12, and solid in four. The diagnosis of sacrococcygeal teratoma was accurate in all cases assessed at our center using both MRI and sonography. Two additional patients initially referred with the diagnosis of sacrococcygeal teratoma had a different diagnosis at reevaluation at our institution (healthy, n = 1; myelomeningocele, n = 1). MRI was superior to sonography for detecting displacement of the colon (n = 11), urinary tract dilatation (n = 9), hip dislocation (n = 4), intraspinal extension (n = 2), and vaginal dilation (n = 1). In fetuses with sacrococcygeal teratoma types II and III, MRI better showed the cephalic extent of the tumor compared with sonography. MRI findings were confirmed at surgery or autopsy in all patients. Three fetuses with high output cardiac physiology underwent open fetal resection of the tumor at 21-, 24-, and 26-weeks' gestational age with two surviving. CONCLUSION: Our results show that ultrafast fetal MRI is a useful adjunct to the prenatal evaluation of fetal sacrococcygeal teratoma. Compared with sonography, MRI more accurately characterized the intrapelvic and abdominal extent of the tumors and provided more information on compression of adjacent organs. The additional anatomic resolution provided by MRI resulted in more accurate prenatal counseling and improved preoperative planning for surgical resection.
Congenital diaphragmatic hernia (CDH) impairs fetal lung growth and increases the density of alveolar epithelial type 2 (AE2) cells. There is controversy whether surfactant protein (SP) expression is altered in CDH. The primary aim of this study was to assess SP expression (mRNA and protein) in the left and right lungs of fetal sheep with and without a diaphragmatic hernia (DH). Left-sided DH was created in four fetal sheep at 65 days of gestational age (g.a.). Sham-operated animals were used as controls. At 138 days g.a., lungs were harvested and the following parameters were measured: SP-A, -B, and -C mRNA expression (Northern blot), SP-A and -B expression (Western blot), and AE2 cell density (immunohistochemistry). The lung weight-to-body weight ratio was reduced by 42% in DH animals. The left-to-right lung weight ratio was lower in DH animals (0.47 +/- 0.03 vs. 0.69 +/- 0.03), indicative of asymmetric lung growth. SP-A, -B, and -C mRNA expression were increased by 61.7%, 32.9%, and 75.5%, respectively, in the left lungs of DH animals. SP-A and SP-B were also increased in DH. In the right lung, SP expression (mRNA and protein) was not different between groups. AE2 cell density was higher (by 67%) in the left but not right lungs of DH animals. Although DH in fetal sheep results in significant lung hypoplasia, SP expression is not reduced. On the contrary, SP expression was increased in the ipsilateral lung of fetuses with left-sided DH. Furthermore, AE2 cell density is increased in DH, suggesting that the increase in SP mRNA and protein levels is due to increases AE2 cell number. Our data further support the premise that fetal lung hypoplasia favors an AE2 phenotype.
BACKGROUND/PURPOSE: Mediastinal teratomas are rare congenital germ cell tumors that prenatally can compress mediastinal structures and cause hydrops. Two possible presentations of massive fetal mediastinal teratoma include hydrops leading to fetal demise, or fetal esophageal and airway compression causing late-gestation polyhydramnios and preterm labor. The authors present 2 cases of fetal mediastinal teratoma that illustrate successful strategies for either of these presentations. METHODS: A 37-year-old woman carrying a fetus with a mediastinal mass and secondary hydrops at 23 weeks of gestation underwent in utero resection of the mass. Delivery was by cesarean delivery at 25 weeks because of preterm labor. A 24-year-old mother carrying a fetus with a mediastinal mass and severe polyhydramnios at 36 weeks of gestation underwent an ex utero intrapartum therapy procedure for establishment of an airway and tumor resection on uteroplacental support. RESULTS: These strategies resulted in physiologic improvement in the first case and controlled resection and resuscitation in the second. The first patient had significant sequelae of prematurity including bronchopulmonary dysplasia but is currently well at 9 months of age. The second patient is well at 1 year of age. CONCLUSIONS: Massive fetal mediastinal teratoma can result in fetal or neonatal mortality by a variety of mechanisms. Optimal prenatal and perinatal management is required to salvage fetuses compromised by this lesion.
BACKGROUND: Indications for the ex utero intrapartum therapy (EXIT) procedure have expanded to include any fetal anomaly in which resuscitation of the neonate may be compromised. METHODS: We reviewed the medical records of 9 patients after resection of lung lesions during the EXIT procedure. RESULTS: The mean gestational age at EXIT procedure was 35.4 weeks. All lung masses maintained large sizes late into gestation with mean mass volume/head circumference ratio of 2.5 at presentation and 2.2 at EXIT. Seven of 9 fetuses demonstrated hydropic changes (n = 6) and/or polyhydramnios (n = 5), and underwent prenatal intervention including thoracentesis, thoracoamniotic shunt placement, amnioreduction, and/or betamethasone administration. Overall survival after EXIT for lung mass resection was 89%. The average time on placental bypass was 65 minutes. Postnatal complications included reoperation for air leak (n = 1), reoperation for bleeding (n = 1), and death from sepsis and prematurity (n = 1). Venoarterial extracorporeal membrane oxygenation was used in 4 neonates for persistent pulmonary hypertension. Maternal prenatal complications included polyhydramnios (n = 5), preterm labor (n = 4), and chorioamnionitis (n = 1). One mother required perioperative blood transfusion. CONCLUSION: The EXIT procedure allows for controlled resection of large fetal lung lesions at delivery, avoiding acute respiratory decompensation related to mediastinal shift, air trapping, and compression of normal lung.