Ross Craigie

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease.

Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

Laparoscopic repair of late presenting congenital diaphragmatic hernia

Congenital diaphragmatic hernia usually presents in the neonatal period, with delayed presentation being uncommon. Traditionally repair was performed by laparotomy or thoracotomy. We have performed laparoscopic repair of a previously undiagnosed congenital diaphragmatic hernia that presented acutely in a 10-year-old male. Laparoscopic repair of late-presenting congenital diaphragmatic hernia is a safe and effective approach even in an emergency. The laparoscopic approach has advantages including reduced hospital stay, excellent visualisation of the defect even for obese patients, and improved cosmesis.

Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

BackgroundPatients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy.MethodsTwenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment.ResultsCHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [−0.1 (−1.2, 1.6) v −1.2 (−1.7, 0.03), p = 0.1].ConclusionsIn K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy.

Feeding Problems Are Persistent in Children with Severe Congenital Hyperinsulinism

Background Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. Aims We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. Methods FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. Results A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6–300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0–0.2), R2 = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. Conclusion FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells

Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI‐A) and the expression profile of NKX2.2, a key transcription factor expressed in &bgr;‐cells but suppressed in &dgr;‐cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI‐A following subtotal pancreatectomy. CHI‐A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI‐D). Immunohistochemistry was used to identify and quantify the proportions of insulin‐secreting &bgr;‐cells and somatostatin‐secreting &dgr;‐cells in atypical islets, and results were compared with CHI‐D (n = 3) and age‐matched control tissues (n = 3). Results: In CHI‐A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, &bgr;‐cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas &dgr;‐cell numbers were increased with 85% of islets (n = 49/57) containing >20% &dgr;‐cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI‐D islets (n = 72) were composed of >50% &bgr;‐cells, and >20% &dgr;‐cells were found only in 12% of CHI‐D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI‐A tissue contained proportions of &bgr;‐cells and &dgr;‐cells similar to those of control and CHI‐D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of &dgr;‐cells strongly imply that an immature &dgr;‐cell profile contributed to the pathobiology of CHI‐A.

A UK wide cohort study describing management and outcomes for infants with surgical Necrotising Enterocolitis.

The Royal College of Surgeons have proposed using outcomes from necrotising enterocolitis (NEC) surgery for revalidation of neonatal surgeons. The aim of this study was therefore to calculate the number of infants in the UK/Ireland with surgical NEC and describe outcomes that could be used for national benchmarking and counselling of parents. A prospective nationwide cohort study of every infant requiring surgical intervention for NEC in the UK was conducted between 01/03/13 and 28/02/14. Primary outcome was mortality at 28-days. Secondary outcomes included discharge, post-operative complication, and TPN requirement. 236 infants were included, 43(18%) of whom died, and eight(3%) of whom were discharged prior to 28-days post decision to intervene surgically. Sixty infants who underwent laparotomy (27%) experienced a complication, and 67(35%) of those who were alive at 28 days were parenteral nutrition free. Following multi-variable modelling, presence of a non-cardiac congenital anomaly (aOR 5.17, 95% CI 1.9–14.1), abdominal wall erythema or discolouration at presentation (aOR 2.51, 95% CI 1.23–5.1), diagnosis of single intestinal perforation at laparotomy (aOR 3.1 95% CI 1.05–9.3), and necessity to perform a clip and drop procedure (aOR 30, 95% CI 3.9–237) were associated with increased 28-day mortality. These results can be used for national benchmarking and counselling of parents.

Laparostomy closure in stage 4S neuroblastoma

Laparostomy in children is a rare procedure, and there is little in the literature as to the best method for closure in children with an open abdomen. We describe 2 cases with stage 4S neuroblastoma that required emergency decompressive laparostomy. Both cases highlight advantages and disadvantages with known techniques for achieving skin and fascia closure. We believe this to be the first report of a combination of extracellular matrix mesh and vacuum therapy for successful fascial and skin closure in stage 4S neuroblastoma.

A spot that can kill.

A 3-year-old girl who had recently completed treatment for acute lymphoblastic leukaemia presented with a rapidly evolving painful black lesion on her right pinna (fi gure) and associated extensive erythema and swelling. Ecthyma gangrenosum was diagnosed. Despite treatment with antibiotics and granulocyte colony-stimulating factor, the swelling and erythema continued to spread: resection of the aff ected area was undertaken. Histological examination confi rmed ecthyma gangrenosum. Successful reconstruction of the pinna was subsequently done. Ecthyma gangrenosum is a skin infection characterised by a necrotic centre surrounded by an erythematous halo. The infection is more common in children than adults, and is particularly common in immuno compromised individuals: indeed, it can be the fi rst indication of an underlying serious illness. Ecthyma gangrenosum is classically caused by Pseudomonas aeruginosa, but can be caused by a wide range of other bacteria. The lesion commonly arises in the gluteal or perineal regions but can occur at any site, as demonstrated by this case. Initial treatment consists of antimicrobials, but surgical excision may be required. Rapid recognition and treatment are essential to avert substantial tissue destruction. Isolated ecthyma gangrenosum has an estimated mortality rate of up to 25%—which is greatly increased by concomitant sepsis. Lancet 2007; 369: 1540

Granular hemostat deposits mimicking disseminated malignancy

Hemostatic matrices are a part of the surgeons armamentarium against profuse intraoperative bleeding. Granular deposits may form after the use of a liquid hemostat which can be mistaken for tumor recurrence or metastatic disease in the setting of neoplasia. We present two cases that highlight the importance of full knowledge of product usage during previous operations and the need for histological examination of these lesions.

Laparoscopic Orchidopexy in Boys with Prune Belly Syndrome—Outcome and Technical Considerations

BACKGROUND AND PURPOSE Cryptorchidism is an ubiquitous feature in prune belly syndrome (PBS). Laparoscopic orchidopexy allows dissection of the spermatic cord with minimal morbidity. We discuss the technical difficulties and outcome of three boys with PBS who underwent two-stage laparoscopic Fowler-Stephens orchidopexy (F-SO). PATIENTS AND METHODS Three boys, ages 1, 2, and 4, underwent laparoscopic F-SO. All boys had viable testes that were found within 3 cm of the deep inguinal ring. The testicular vessels were either ligated bilaterally with 4/0 polyglactin or monopolar diathermy was used and the vessels divided. Bilateral second-stage F-SO was performed within 6 months in two boys and limited to one side in the third boy. One boy awaits the contralateral second stage. RESULTS All three boys have adequately sized gonads. Based on our experience, the port incisions should be smaller than routine practice to prevent air leak in PBS. Although the intra-abdominal pressure of 12 mm Hg did not vary from our normal practice, a high flow rate is necessary after initial insufflation (6 L/min) to compensate for inevitable gas leaks because the abdominal wall is so thin. Risk of diathermy injury to the thin abdominal wall and the vessels is significant. Laparoscopy enables easy visualization of the ureter, testes, and testicular vessels and permits complete dissection of testicular vessels. It is easier to maintain integrity of spermatic vessels. CONCLUSION Use of radially expanding trocars, small incisions, and high gas flow rates permit this procedure to be performed safely with good outcome and cosmetic results in this challenging group of boys.