Neural Crest Tumors Research Articles

The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare syndrome presenting in early childhood associated with a high risk of mortality between 50 and 60%. It is characterised by rapid, early onset of obesity between 1.5–7 years, along with central hypoventilation and hypothalamic dysfunction, such as central hypothyroidism, hyperprolactinemia, disorders of sodium and water balance, growth hormone deficiency, adrenocortical insufficiency, or disorders of puberty and features of autonomic dysregulation. Up to half of cases have neural crest tumours, most commonly ganglioneuromas or ganglioneuroblastomas. The incidence of ROHHAD syndrome in any population is unknown. Currently, there is no specific diagnostic or genetic biomarker for ROHHAD, and diagnosis is based on clinical signs and symptoms, which is often challenging, and consequently may be delayed or unrecognised. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality. Aetiology remains unclear; an autoimmune origin has been postulated, with immunosuppressive agents being used with variable benefit. With no cure, multidisciplinary management is largely supportive. Therefore, there are many unanswered questions in ROHHAD syndrome. In this review article, we outline the challenges posed by ROHHAD syndrome, including aetiology, genetics, diagnosis, screening, management, and prognosis. We present research priorities to tackle these issues to improve outcomes.

Inaugural Patient-Reported Registry of Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome: Presentation, Diagnosis, and Treatment of 194 Patients

BackgroundOpsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neuroimmune disease with peak onset at 18 months, associated with neural crest tumors in 50% of patients. In part due to its rarity, misdiagnosis at onset is common, can delay treatment, and may contribute to adverse outcomes. Patient-reported registries may overcome some of these challenges in rare disease research. In this context, the OMSLife Foundation collaborated with the National Organization of Rare Diseases to create a patient-reported registry in OMAS. MethodsRetrospective analysis was performed of data entered by parents of patients with OMAS into nine online surveys assessing demographics, symptoms at onset, triggers, time of diagnosis, treatment, and additional therapies. ResultsA total of 194 patients were enrolled. There was a female predominance (54%) and high rate of parental autoimmunity (31%). Age at onset peaked between 12 and 18 months overall. The age of onset was older in female patients (median [interquartile range]: females 22 [15 to 31] vs males 18 [14 to 23], P = 0.0223, P = 0.0223). Symptoms at onset most commonly included ataxia (84%) and were typically severe. Initial misdiagnosis occurred in nearly 50% and tumor discovery was delayed in 18 patients, but overall median time to correct diagnosis was 25 days. Most patients (56%) received combination immunomodulatory therapies, and nearly all underwent supportive therapies. ConclusionsPatient- and parent-powered research is feasible in OMAS and created the second largest published cohort of pediatric patients with OMAS. Results were similar to other large cohorts and also validated findings from prior case reports and smaller case series.

METB-02. GENETIC COUNSELLING IN SOTOS AND NS1-RELATED OVERGROWTH SYNDROMES PREDISPOSING TO BRAIN TUMORS

Abstract BACKGROUND Sotos and many other overgrowth syndromes are among the rare tumor predisposition syndromes that might be under-recognized in pediatric neuro-oncology practice. NSD1 gene (5q35), belonging to the histone lysine methyltransferases family, is involved in the majority of Sotos patients who exhibited haploinsufficiency and loss-of-function variants of the gene, but also in other overgrowth entities such as Beckwith-Wiedemann syndrome. Somatic mutations in this gene are likewise responsible of numerous cancers, particularly brain tumors. Here, we aim to assess the neurologic cancer risks and provide genetic counseling for appropriate clinical follow-up in Sotos syndrome. METHODS From our genetic counseling database at the medical University of Sfax (Tunisia), we selected among patients presented for genetic management of overgrowth syndromes, those with Sotos syndrome. RESULTS Only two Tunisian consanguineous pedigrees were enrolled in this study. Two boys were diagnosed with typical Sotos syndrome based on the three major clinical manifestations: specific facial dysmorphism, mental retardation and excessive growth including advanced bone age and macrocephaly. Chromosomes 5 in both pedigrees did not show structural abnormalities. During genetic counselling, parents were informed about the molecular testing options and the advantage of the exome sequencing. Furthermore, they were informed about the rate of cancer predisposition (3%) and the gains of neurologic and neuro-oncologic management, particularly regarding the intellectual disability and the increased risk of developing neural crest tumors, astrocytoma, glioma/glioblastoma and neuroblastoma cancer, during childhood. CONCLUSIONS Neurological pediatric malignancies are described in patients with Sotos syndrome, but the genotype-phenotype correlation is still unclear. It is suggested that NDS1 disruptions in Sotos patients trigger specific patterns of DNA methylation alterations leading to the development of cancer. Accurate molecular exploration is needed in the heterogeneous Sotos condition in order to improve the management according to the implicated gene and to benefit in the future from targeted therapies.

An autopsy case of an adult woman with Rapid-Onset Obesity with Hypoventilation, Hypothalamic, Autonomic Dysregulation, and Neuroendocrine Tumors (ROHHAD(NET)) syndrome developing nonalcoholic steatohepatitis and hepatocellular carcinoma: A case report.

Nonalcoholic steatohepatitis (NASH) is an important etiology of hepatocellular carcinoma (HCC), and there is no established therapy for this syndrome. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD(NET)) is an extremely rare syndrome considered to be life-threatening, with death occurring around 10 years of age. We present the oldest known autopsy case of this syndrome that developed HCC. This case provided important information on not only improving the course of this syndrome, but also understanding the natural history and therapeutic modalities of NASH and HCC. The patient was diagnosed with ROHHAD(NET) syndrome in childhood, and liver cirrhosis due to NASH was diagnosed at age 17. HCC was detected at age 20, and embolization and irradiation were performed. At age 21, she died from accidental acute pancreatitis and subsequent liver failure and pulmonary hemorrhage. Rapid onset of obesity, hypoventilation, and hypothalamic disturbance appeared in childhood and was diagnosed as this syndrome. At age 17, liver cirrhosis due to NASH was diagnosed by liver biopsy, and at age 20, HCC was diagnosed by imaging. Transarterial chemoembolization and irradiation were performed, and the HCC was well controlled for a year. At age 21, she died from accidental acute pancreatitis, subsequent liver failure and pulmonary hemorrhage. Autopsy revealed that the HCC was mostly necrotized. This case was valuable not only for other ROHHAD(NET) syndrome cases, but also in improving our understanding of the natural history of NASH and HCC.

Biodistribution and radiation dosimetry of 124I-mIBG in adult patients with neural crest tumours and extrapolation to paediatric models

AimPositron emission tomography (PET) using 124I-mIBG has been established for imaging and pretherapeutic dosimetry. Here, we report the first systematic analysis of the biodistribution and radiation dosimetry of 124I-mIBG in patients with neural crest tumours and project the results to paediatric patient models.MethodsAdult patients with neural crest tumours who underwent sequential 124I-mIBG PET were included in this retrospective single-center analysis. PET data were acquired 4, 24, 48, and/or 120 h after administration of a mean of 43 MBq 124I-mIBG. Whole-body counting and blood sampling were performed at 2, 4, 24, 48 and 120 h after administration. Absorbed organ dose and effective dose coefficients were estimated in OLINDA/EXM 2.2 according to the MIRD formalism. Extrapolation to paediatric models was performed based on mass-fraction scaling of the organ-specific residence times. Biodistribution data for adults were also projected to 123I-mIBG and 131I-mIBG.ResultsTwenty-one patients (11 females, 10 males) were evaluated. For adults, the organs exposed to the highest dose per unit administered activity were urinary bladder (1.54 ± 0.40 mGy/MBq), salivary glands (0.77 ± 0.28 mGy/MBq) and liver (0.65 ± 0.22 mGy/MBq). Mean effective dose coefficient for adults was 0.25 ± 0.04 mSv/MBq (male: 0.24 ± 0.03 mSv/MBq, female: 0.26 ± 0.06 mSv/MBq), and increased gradually to 0.29, 0.44, 0.69, 1.21, and 2.94 mSv/MBq for the 15-, 10-, 5-, 1-years-old, and newborn paediatric reference patients. Projected mean effective dose coefficients for 123I-mIBG and 131I-mIBG for adults were 0.014 ± 0.002 mSv/MBq and 0.18 ± 0.04 mSv/MBq, respectively.ConclusionPET-based derived radiation dosimetry data for 124I-mIBG from this study agreed well with historical projected data from ICRP 53. The effective dose coefficients presented here may aid in guidance for establishing weight-based activity administration protocols.

Blood Lymphocyte Subsets and Proinflammatory Cytokine Profile in ROHHAD(NET) and non-ROHHAD(NET) Obese Individuals.

Rapid-onset obesity with central hypoventilation, hypothalamic dysfunction, and autonomic dysregulation with neural crest tumors (ROHHAD-NET) syndrome pathophysiology remains elusive. Acquired neuroimmunological dysfunction has been proposed as a possible pathogenetic pathway. The aim of our study was to characterize lymphocyte subpopulations subsets in peripheral blood (PB) and to evaluate a panel of proinflammatory cytokines/chemokines in ROHHAD(NET) patients vs controls. We included 11 ROHHAD(NET) patients, 7 ROHHAD and 4 ROHHAD-NET, selected by clinical criteria. Controls were 11 simple obese children, matched for age and sex. Flow cytometric analysis and enzyme-linked immunosorbent assay were performed on PB and serum samples of the 2 groups. Analysis revealed that T lymphocytes are significantly increased in ROHHAD(NET) patients (P = .04) with a prevalence of CD4-T cells (P = .03) and a lower number of activated CD8-T cells (P = .02). With regard to regulatory subset, patients displayed increased regulatory B cells (P = .05) and type-1 regulatory T cells (P = .03). With regard to CD8-T cells, a lower number of T effector memory was observed (P = .02). In contrast, among CD4-T cells, we found a higher number of T naive (P = .04) and T effector (P = .0008). Interleukin-8 (IL-8) levels and monocyte chemotactic protein-1 were increased in patients vs controls (P = .008 and P = .01, respectively). Furthermore, IL-8 levels were higher in the subgroup with neural tumor (P = .0058) (ROHHAD-NET) than in patients without neural tumor (ROHHAD). Soluble HLA-G was significantly lower in patients vs controls (P = .03). Our findings contribute to support the hypothesis of immune dysregulation, which may underlie this complex, often fatal disease. Because ROHHAD(NET) syndrome is an ultra-rare disease, multicentric studies are needed to improve the effect of our data in the management of this condition.

1034 A Rare Case of ROHHAD Syndrome

Abstract Introduction Early diagnosis of pediatric syndromes that are rare and involve multiple systems can be challenging. Rapid onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation characterizes ROHHAD syndrome which, if undiagnosed, can lead to potentially harmful outcomes including deferring radiological workup for a neural crest tumor (which has an over 50% association) and cardiopulmonary arrest. Report of case(s) A 10-year-old female with a history of obesity, precocious puberty, recurrent hypothermia, recurrent sodium derangements, bilateral ptosis, seizure disorder, and GERD initially presented to sleep clinic as a 4-year-old in 2017 when she recently began snoring with excessive daytime sleepiness as a result of rapid onset of weight gain. BMI at that time was 99th percentile and Epworth was 11. An in-lab polysomnography revealed severe OSA with AHI 26.4 events/hour; nocturnal hypoxemia with TS90 27% and O2 nadir 70%; and sleep related hypoventilation based on elevated pCO2 on end-tidal capnometry. Patient underwent adenotonsillectomy, revision adenoidectomy, and was started on CPAP before transitioning to BiPAP over the span of the next several years with serial polysomnographies ultimately showing significant improvement of sleep apnea with AHI 5.4 events/hour. Sleep-related hypoventilation, however, remained persistent with blood gases showing pCO2 as high as 89. PHOX2B gene testing was negative and secondary causes of hypoventilation were ruled out. During this time, she was also followed by Endocrinology for suspected hypothalamic dysfunction resulting in precocious puberty, deceleration of growth rate, sodium derangements. Autonomic dysfunction was also suspected due to recurrent hypothermia including a recent admission for Temperature < 95F and ophthalmologic abnormalities including bilateral ptosis. At a multidisciplinary care conference, a working diagnosis of ROHHAD syndrome was made based on the rapid onset of obesity, hypoventilation on sleep studies and CBGs, hypothalamic dysfunction, and autonomic degeneration. Workup for neural crest tumor with MRI chest and abdomen unremarkable. Outside academic consultation was sought for management which recommended shared decision-making regarding steroids, immunosuppressive therapy (eg rituximab, cyclophosphamide), and IVIG. Conclusion For ROHHAD syndrome, there are very few documented cases in the United States and there is no known laboratory marker; diagnosis remains clinical and takes multidisciplinary collaboration, education, and a high degree of suspicion. Support (if any)

Síndrome opsoclonus mioclonus paraneoplásico en pediatría: reporte de caso y revisión de la literatura

El síndrome opsoclonus mioclonus (SOM) es una entidad poco frecuente en pediatría que por consenso de expertos se define como aquel que cumple tres de cuatro criterios: opsoclonus, ataxia, mioclonus, alteraciones de la conducta o del sueño y diagnóstico de neuroblastoma. Frecuentemente el SOM en niños se presenta asociado a tumores de la cresta neural, siendo el neuroblastoma el más prevalente, seguido por ganglioneuroblastoma, ganglioneuroma y hepatoblastoma. La asociación SOM y neuroblastoma tiene su pico de incidencia entre los 6 y 36 meses de edad y la posibilidad de que un niño con SOM tenga un neuroblastoma es de cerca del 50%. Si bien el SOM no es una patología frecuente en pediatría, su asociación con enfermedades neoplásicas sí lo es y desconocer su existencia y la presentación clínica puede llevar a demoras o subdiagnóstico del tumor con impacto negativo en el pronóstico tanto de la entidad de base como del futuro neurológico del paciente. Se presenta el caso de una niña de 15 meses con SOM asociado a ganglioneuroblastoma retroperitoneal que mejoró luego de la resección del tumor y el tratamiento con corticoides e inmunoglobulina.

Retrospective analysis of mediastinal tumors in childhood

Background: The aim of this study was to determine etiologic distribution, epidemiologic properties, treatment, clinical course and late effects of the treatment of the patients diagnosed with mediastinal tumor. Methods: Patients under 18 years old diagnosed with mediastinal tumors between January 1990 and June 2011 at the 19 Mayis university department of child oncology were examined retrospectively. Results: There were 50 (61%) males, 32 (39%) females with mediastinal tumor. Median age at diagnosis was 9.28 years (30 days-17.4 years). Most common symptoms were respiratory distress (29.2%) and cough (23.1%). Sixty eight cases (82.9%) were malignant. Two cases died before diagnosis. Thirty seven cases (45.1%) were located in anterior followed by 16 (19.5%) in middle and 23 (28%) in posterior mediastinum. Most common malignant tumors were lymphomas (n=46, 67.6%), followed by sarcomas (n=12, 17.6%), neural crest tumors (n=8, 11.8%) and germ cell tumors (n=2, 2.9%). Thirteen cases had vena cava superior syndrome and 4 cases had signs of spinal cord compression at the time of diagnosis. Forty eight cases (58.5%) were alive and symptom free on follow-up (mean 39.5 months, 3-139 months), and 22 (26.8%) were died. Sixteen cases (23.5%) had late effects. Overall survival for all malignant tumors were 60.5±7.8%. Conclusions: Mediastinal tumors should be considered in children with acute progressive respiratory distress and cough. Early diagnosis is still most important factor for prognosis.

Presentation of A Cutaneous Granular Cell Tumor in A 52-Year-Old Man in Remote Australia

Granular cell tumors are rare neural crest tumors which predominantly occur in the skin. While most of these tumors are benign, malignant potential exists. Malignant granular cell tumors behave aggressively and are associated with poor outcomes. However, the distinction can be difficult at initial diagnosis. This case describes the presentation of a benign cutaneous granular cell tumor to a remote health service in Northwest Queensland, Australia.

0994 Neuroblastoma as the Initial Manifestation of Familial PHOX2B NPARM Positive Congenital Central Hypoventilation Syndrome

Abstract Introduction Congenital Central Hypoventilation Syndrome (CCHS) is a genetic disorder of the autonomic nervous system caused by mutations in the PHOX2B gene. Children with CCHS often present as neonates in hypoxemic, hypercarbic respiratory failure. Most causative mutations are de novo Polyalanine Repeat Mutations (PARMs). Non-Polyalanine Repeat Mutations (NPARMs) have been associated with more severe disease, specifically the need for 24-hour ventilatory support, Hirschsprung disease, and neural crest tumors; however, NPARMs may have variable expressivity and incomplete penetrance, resulting in delayed or atypical presentations. We report a toddler with maxillary sinus neuroblastoma, which led to the diagnosis of familial PHOX2B NPARM positive CCHS. Report of case(s) A two-year-old boy presented with right-sided facial swelling. A facial CT uncovered a right maxillary sinus lytic lesion, and biopsy confirmed neuroblastoma. After full recovery from the procedure, he had persistent nocturnal hypoxemia and hypercapnia requiring bilevel positive airway pressure (PAP) during sleep, raising concern for CCHS. Genetic testing revealed a novel PHOX2B NPARM, c.428dup, which likely causes a frameshift and premature protein termination (p.Val144Glyfs*34). His maternal grandfather, mother and brothers tested positive for the same mutation. Family history revealed that his maternal grandfather and maternal great-uncles had frequent childhood apneic spells associated with syncope, his maternal grandfather is currently on nocturnal bilevel PAP, and his mother almost drowned as a younger child while having a breath-holding contest under water. His six-year-old brother underwent polysomnography which showed hypoventilation, now managed with bilevel PAP. His five-year-old brother also underwent polysomnography and does not require nocturnal ventilatory support at this time. Conclusion We report a rare case of familial PHOX2B NPARM positive CCHS which initially presented as maxillary sinus neuroblastoma. Additionally, the child and his family display varying disease severity despite having the same NPARM, highlighting the variable expressivity in this novel NPARM. Support (if any) None

Something old has become new: PET imaging of neural-crest tumors with [18F]-meta-fluorobenzylguanidine

Something old has become new: PET imaging of neural-crest tumors with [18F]-meta-fluorobenzylguanidine

Rapid-Onset Obesity, Hypothalamic Dysregulation, Hypoventilation, Autonomic Dysregulation, and Neuroendocrine Tumour: Rare Syndrome with Myriad Anaesthesia Implications.

Anaesthesia management of a child with rapid-onset obesity, hyperphagia, and hypothalamic dysfunction syndrome is complex due to the multisystem involvement, the most important features being morbid obesity, autonomic dysfunction, and dyselectrolytemia due to hypothalamic dysfunction. The acronym of the disease was amended in 2008 to rapid-onset obesity, hyperphagia, hypothalamic dysfunction neural crest tumour to include the risk of ganglioneuroma or ganglioneuroblastoma. Patients usually require removal of tumour in the prone position. Obstructive sleep apnea, difficult airway and intravenous access, and haemodynamic lability all add to the trials faced by the paediatric anaesthesiologist. Invasive haemodynamic monitoring, ultrasonography, bispectral index monitoring, and meticulous calculation of drug dosages help in smoothening the course of anaesthesia in the presence of constant vigilance.

18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

RF14 | P984 Early Onset of Insulin Resistance In a Patient with ROHHAD(NET) Syndrome

Abstract Background ROHHAD(NET) is a rare syndrome with a constellation of rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumors. The endocrine disruptions can include obesity, growth hormone dysregulation, hyperprolactinemia, sodium/water imbalances, central hypothyroidism, adrenal insufficiency and puberty disorders. There have been just over 100 cases described thus far and only one adult patient described with severe insulin resistance. We present a pediatric patient diagnosed with ROHHAD(NET) with overgrowth and extremely elevated insulin concentrations Case Our patient initially presented with severe obesity, rapid linear growth, abnormal lipids, and elevated fasting insulin at the age of 2.5 years. He progressively developed breathing abnormalities, hypothalamic dysfunction, autonomic dysregulation, and a neural crest tumor. With this group of symptoms, criteria for ROHHAD (NET) was met. He progressed to develop insulin resistance, hyperprolactinemia, diabetes insipidus, central hypothyroidism and central adrenal insufficiency. He also required right adrenalectomy for a poorly differentiated neuroblastoma and ganglioneuroblastoma. Results Evaluation of his obesity included a negative monogenic obesity genetic panel (>30 genes tested), normal leptin levels (11.6 ng/ml) and borderline elevated IGF-1 levels 166 ng/ml (z-score 2.5). Glucose levels were usually in the normal range but increased into the diabetes range when he was stressed or sick. HbA1c ranged from 5.6-6.2% (Ref. range <6%) between age 2.5 and 4.5 years. A standard oral glucose tolerance test with blood draws performed at 0, 30, 60 and 120 minutes showed glucose levels of 78,118,123 and 122 mg/dl, insulin of 36,302, 338 and 449 mIU/L and c-peptide levels of 2.9,13.2,14.5 and 16.3 ng/ml respectively. Age at this time was 3.0 years and height, weight and BMI were on the 100% (Z-score 4.28,6.95 and 4.28 respectively) and HbA1c was 5.7% Management: Although glucose tolerance was normal, insulin and C-peptide concentrations were extremely elevated for age and prepubertal status, suggestive of marked insulin resistance. Subsequently, he was started on liquid Metformin 250 mg BID as an adjunct to a calorie-restricted diet. He tolerated this well. His response to therapy has been hard to assess given frequent illnesses and hospitalizations for his various comorbidities; however, he has shown no progression to hyperglycemia, except during acute sickness. Conclusion To the best of our knowledge, this is the youngest patient with ROHADD(NET) reported to have very elevated insulin levels. In addition to rapidly progressing obesity, he had impressive linear overgrowth. Hyperglycemia and insulin resistance could be secondary to severe associated obesity and/or speculatively related to his underlying condition. This case expands the reported morbidities associated with this often-fatal disease Presentation: Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions

SummaryThe RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.

Metalloprotease ADAM9 cleaves ephrin-B ligands and differentially regulates Wnt and mTOR signaling downstream of Akt kinase in colorectal cancer cells

Ephrin-B signaling has been implicated in many normal and pathological processes, including neural crest development and tumor metastasis. We showed previously that proteolysis of ephrin-B ligands by the disintegrin metalloprotease ADAM13 is necessary for canonical Wnt signal activation and neural crest induction in Xenopus, but it was unclear if these mechanisms are conserved in mammals. Here, we report that mammalian ADAM9 cleaves ephrin-B1 and ephrin-B2 and can substitute for Xenopus ADAM13 to induce the neural crest. We found that ADAM9 expression is elevated in human colorectal cancer (CRC) tissues and that knockdown (KD) of ADAM9 inhibits the migration and invasion of SW620 and HCT116 CRC cells by reducing the activity of Akt kinase, which is antagonized by ephrin-Bs. Akt is a signaling node that activates multiple downstream pathways, including the Wnt and mTOR pathways, both of which can promote CRC cell migration/invasion. Surprisingly, we also found that KD of ADAM9 downregulates Wnt signaling but has negligible effects on mTOR signaling in SW620 cells; in contrast, mTOR activity is suppressed while Wnt signaling remains unaffected by ADAM9 KD in HCT116 cells. These results suggest that mammalian ADAM9 cleaves ephrin-Bs to derepress Akt and promote CRC migration and invasion; however, the signaling pathways downstream of Akt are differentially regulated by ADAM9 in different CRC cell lines, reflecting the heterogeneity of CRC cells in responding to manipulations of upstream Akt regulators.

Congenital Central Hypoventilation Syndrome: Optimizing Care with a Multidisciplinary Approach.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung’s disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.

Theragnostics before we found its name.

Theragnostics embraces "gnosis" and "prognosis" and concerns a treatment strategy which combines diagnostics with therapeutics. The birth of what we call today theragnostics can be traced in 1936, with the proposal of radioiodine, the first radiopharmaceutical approved in 1951 by FDA, in USA, as 131I sodium iodide. In 1957, 89Sr was also approved as first therapeutic radiotracer for skeletal metastases, followed in the subsequent years by 186Rh, 153Sm and, more recently, 223Ra, the first alpha emitter clinically utilized, allowing curative results and not only a palliative effect. Proposed in first eighties as [131I] Metaiodobenzylguanidine (MIBG), the theragnostic couple 123I/131I MIBG is still used in neural crest tumors, while, starting from partially unsatisfactory results in 70's, models based on antibodies for radioimmunoscintigraphy/radioimmunotherapy have been subsequently upgraded thanks to the introduction of monoclonal antibodies and other significant biological and technical improvements. The "Theragnostics called with this name" can be dated to early 90's with the first proposal of the somatostatin model, actually widely operating in neuroendocrine tumors with radio-chelates usable for diagnosis and therapy. Since then, many investigators are working on new theragnostics agents, also outside of the nuclear medicine, based on peptides, antibodies and other tools to find new models applicable in the clinical practice. The fast growth is stimulated by the interest of big pharma. Theragnostic concepts are the roots of nuclear medicine and new great goals are soon to be achieved in the direction of an increasing precision and tailored medicine.

Quantitation of Neuroblastoma Markers Homovanillic Acid (HVA) and Vanillylmandelic Acid (VMA) in Urine by Gas Chromatography-Mass Spectrometry (GC/MS).

Neuroblastoma and other neural crest tumors can be characterized by the increased production and excretion of catecholamines and their metabolites. Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are important catecholamine metabolites that can be measured to provide relatively rapid laboratory diagnosis and clinical follow-up of neuroblastoma. We present a procedure to quantify HVA and VMA in urine samples which have been diluted to a creatinine concentration of 2mg/dL. Diluted samples are spiked with deuterated internal standards, acidified, and extracted with an organic solvent. A bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) and pyridine mixture is added to the dried extract to create trimethylsilyl derivatives of HVA and VMA. The derivatized compounds are measured using gas chromatography-mass spectrometry (GC/MS).