Adult-onset Focal Nesidioblastosis with Nodular Formation Mimicking Insulinoma

Nesidioblastosis is defined as the neoformation of the islets of Langerhans from the pancreatic ductal epithelium and is recognized as the most common cause of hyperinsulinemic hypoglycemia in infants. We herein report an extremely rare case of adult-onset focal nesidioblastosis with the unusual feature of hyperplastic nodular formation. A 55-year-old woman was admitted to our hospital for a tumor detected in the body of the pancreas by magnetic resonance imaging screening. Laboratory examinations showed a high insulin level in the blood. Contrast-enhanced computed tomography and the selective arterial calcium injection test suggested the presence of multiple insulinomas in the body and tail of the pancreas, and, thus, the patient underwent distal pancreatectomy. A histopathological examination of the tumor in the body of the pancreas showed the nodular hyperplasia of islet-like cell clusters. In addition, many small intralobular ductules and islet cells appeared to be budding from the proliferating ductal epithelium, forming “ductuloinsular complexes”. No other abnormal lesion was detected in the remainder of the pancreas. The histopathological diagnosis was focal nesidioblastosis. The patient has remained free of the recurrence of hypoglycemic episodes for more than 31 months. The present case of rare adult-onset focal nesidioblastosis with hyperplastic nodular formation was preoperatively identified as an apparent pancreatic tumor mimicking insulinoma. Nesidioblastosis and insulinoma need to be considered in cases of hyperinsulinemic hypoglycemia, even in adult patients.

Hyperinsulinemic hypoglycemia in growth restricted convalescent preterm neonates: clinical characteristics and impediments to early diagnosis

Objectives Describe clinical characteristics, course, and risk factors for hyper-insulinemic hypoglycemia (HIH) in preterm infants and identify impediments to early diagnosis. Methods Electronic records of infant–mother dyads were used to describe clinical characteristics, lab parameters, and course of HIH. Results All eight patients (gestational ages 26w0d–29w3d) had intrauterine growth restriction (IUGR) due to placental insufficiency, (4/8) were small for gestational age. All maintained normal glucose levels with glucose infusion during the first 48 h six of eight patients had cholestasis despite being on parenteral nutrition for short time (average 17 days). Four of eight patients were treated with diazoxide (average 22 days). Four of eight patients who recovered spontaneously (average 49 days after diagnosis) responded to continuous feeds and hydrocortisone for other clinical indications. Conclusions In IUGR preterms, HIH is asymptomatic, may be prolonged, requiring diazoxide treatment. Transient cholestasis is seen in majority of patients. Euglycemia should be demonstrated on bolus gavage feeds, off glucocorticoids before discontinuing blood glucose monitoring.

Case Report: A Difficult-to-Diagnose Case of Hyperinsulinemic Hypoglycemia Surgically Treated After Developing Acute Pancreatitis

The patient is a 28-year-old Japanese man diagnosed with severe congenital hyperinsulinemic-hypoglycemia six months after birth. Clinical records revealed no imaging evidence of pancreatic tumor at the time of diagnosis. Subsequently, he had developmental disorders and epilepsy caused by recurrent hypoglycemic attacks. The patient’s hypoglycemia improved with oral diazoxide. However, he developed necrotizing acute pancreatitis at 28 years of age, thought to be due to diazoxide. Discontinuation of diazoxide caused persistent hypoglycemia, requiring continuous glucose supplementation by tube feeding and total parenteral nutrition. A selective arterial secretagogue injection test revealed diffuse pancreatic hypersecretion of insulin. He underwent subtotal distal (72%) pancreatectomy and splenectomy. There was no intraoperative visible pancreatic tumor. His hypoglycemia improved after the surgical procedure. The histopathological study revealed a high density of islets of Langerhans in the pancreatic body and tail. There were large islets of Langerhans and multiple neuroendocrine cell nests in the whole pancreas. Nests of neuroendocrine cells were also detected in lymph nodes. The pathological diagnosis was grade 1 neuroendocrine tumor (microinsulinomas) with lymph node metastases. This patient is a difficult-to-diagnose case of hyperinsulinemic hypoglycemia surgically treated after developing acute pancreatitis. We believe this is a unique case of microinsulinomas with lymph metastases diagnosed and treated as congenital hyperinsulinemic hypoglycemia for almost 28 years.

Maternal mosaicism for a missense variant in the SMS gene that causes Snyder-Robinson syndrome

There is increasing recognition for the contribution of genetic mosaicism to human disease, particularly as high-throughput sequencing has enabled detection of sequence variants at very low allele frequencies. Here, we describe an infant male who presented at 9 months of age with hypotonia, dysmorphic features, congenital heart disease, hyperinsulinemic hypoglycemia, hypothyroidism, and bilateral sensorineural hearing loss. Whole-genome sequencing of the proband and the parents uncovered an apparent de novo mutation in the X-linked SMS gene. SMS encodes spermine synthase, which catalyzes the production of spermine from spermidine. Inactivation of the SMS gene disrupts the spermidine/spermine ratio, resulting in Snyder-Robinson syndrome. The variant in our patient is absent from the gnomAD and ExAC databases and causes a missense change (p.Arg130Cys) predicted to be damaging by most in silico tools. While Sanger sequencing confirmed the de novo status in our proband, PCR and deep targeted resequencing to ~84,000-175,000x depth revealed that the variant is present in blood from the unaffected mother at ~3% variant allele frequency. Our findings thus provided a long-sought diagnosis for the family while highlighting the role of parental mosaicism in severe genetic disorders.

Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations

Background Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively. Results All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3. Conclusions We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Hepatic Artery Embolization for Palliation of Symptomatic Hypoglycemia in Patients with Hepatic Insulinoma Metastases

Purpose To determine the safety and effectiveness of bland hepatic artery embolization (HAE) for palliation of symptomatic hypoglycemia in patients with hepatic insulinoma metastases refractory to medical management. Materials and Methods An IRB-approved retrospective review was undertaken of all patients with a tissue (n=18) or imaging (n=2) diagnosis of hepatic insulinoma metastases and symptomatic hyperinsulinemic hypoglycemia refractory to medical management who underwent bland hepatic artery embolization (HAE) at a single center between 1/1/1998 and 11/1/2020. Twenty patients (10 women, 10 men; mean age, 56 y; range, 18–84 y) were identified who individually underwent 1 (n = 7), 2 (n = 5), 3 (n = 5), 4 (n = 2), or 5 (n = 1) HAEs, for an overall total of 45 HAEs. Post-HAE hypoglycemia recurrence was defined as onset of adrenergic symptoms (e.g. sweating, weakness, tremor), neuroglycopenic symptoms (e.g. confusion, loss of consciousness), and/or documented serum glucose <50 mg/dL, in the absence of an alternative explanation. Median time to first hypoglycemia recurrence, hypoglycemia-free survival (HFS), and overall survival (OS) were calculated using Kaplan-Meier method. Results Prior to HAE, all patients experienced adrenergic or neuroglycopenic symptoms alleviated by glucose intake, and 60% (n = 12) of patients had documented serum glucose <50 mg/dL within 1 week of the first treatment. Median post-HAE follow-up was 9.4 months (mean, 26 m; range, 0.1–190 m). Post-procedural hypoglycemic symptom relief after the first HAE was reported in 100% (n = 20) of patients prior to discharge or at follow-up. Post-HAE hypoglycemia recurrence occurred in 60% (n = 12) of patients with a median time to first hypoglycemia recurrence of 2 months (mean, 14 m; range, 0.2–60 m). After the first HAE, median HFS was 14.5 months, and median OS was 16 months. One patient experienced labile post-procedure blood glucose levels requiring ICU admission for IV dextrose. Otherwise, no major procedure-related complications occurred. Conclusion Bland HAE is a safe, effective, and repeatable procedure for palliation of symptomatic hypoglycemia in patients with hepatic insulinoma metastases refractory to medical management.

Hyperinsulinemic Hypoglycemia in Three Generations of a Family with Glucokinase Activating Mutation, c.295T>C (p.Trp99Arg)

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease with heterogeneous clinical manifestations. There are only a few reports of heterozygous activating mutations of glucokinase (GCK) attributable to FHH, with no reports describing effects in the course in pregnancy with affected mother/affected child. A large kindred with FHH and GCK:c.295T>C (p.Trp99Arg) pathogenic variant was identified in which four family members from three generations were affected. The clinical follow up in one clinical center lasted up to 30 years, with different times of diagnosis ranging from neonate period to adulthood. The severity of hypoglycemia was mild/severe and fasting was the trigger for hypoglycemia. Response to diazoxide varied from good, in the neonate, to moderate/poor, in childhood/adulthood; however, this was biased by poor compliance. Treatment with somatostatin analogues was discontinued due to side effects. Over time, patients developed clinical adaptation to very low glucose levels. During pregnancy, episodes of severe hypoglycemia in the first trimester were observed, which responded very well to steroids. The clinical course of the GCK:c.295T>C (p.Trp99Arg) mutation varied in the same family, with the development of clinical adaptation to very low glucose levels over time. Treatment with steroids might prevent hypoglycemia during pregnancy in an affected mother.

Hyperinsulinemic Hypoglycemia in an Adolescent: Case Report and Systematic Review

Background: Hyperinsulinemic hypoglycemia is the most common cause of severe and persistent hypoglycemia in neonates and children. It is a heterogeneous condition with dysregulated insulin secretion, which persists in the presence of low blood glucose levels.Objectives: Describe a clinical case of hyperinsulinemic hypoglycemia, secondary to nesidioblastosis in an adolescent; and to report the results of a systematic review performed using PubMed and Lilacs to assess existing cases available under the following terms: “Nesidioblastosis”, “adults”, “adolescents” and “children”.Patient and Methods: We report a case of a 15-year-old male with hyperinsulinemic hypoglycemia, who underwent a subtotal pancreatectomy after inadequate response to medical therapy. Pathological examination was positive for nesidioblastosis (diffuse β-cell hyperplasia by H-E and immunohistochemical techniques). The patient’s blood glucose levels normalized after surgery and he remains asymptomatic after 1 year of follow-up. The systematic review allowed us to identify 41 adolescents from a total of 205 cases reported in 22 manuscripts, from a total of 454 found in the original search done in PubMed and Lilacs.Conclusions: Although very well reported in children, hyperinsulinemic hypoglycemia can occur in adolescents or young adults, as it happens in our reported case. These patients can be seen, treated and reported by pediatricians or adult teams either way due to the wide age range used to define adolescence. Most of them do not respond to medical treatment, and subtotal distal pancreatectomy has become the elected procedure with excellent long-term response in the vast majority.