Sporadic phaeochromocytoma in childhood: clinical and molecular variability

Sporadic phaeochromocytoma is an infrequent tumour during paediatric age and may or may not be associated with specific autosomal dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (VHL) type 2 or neurofibromatosis (NF) type 1. We report two cases of benign, adrenal, and unilateral phaeochromocytoma that clearly demonstrate the clinical and molecular heterogeneity of this disease during the paediatric period. The first patient presented a characteristic symptomatic form of sporadic phaeochromocytoma. The second patient, an incidental finding, was practically asymptomatic and had a de novo germline point mutation in the VHL gene (Arg167Trp). The frequency of de novo mutations in susceptible genes (especially the VHL gene) in paediatric patients with sporadic phaeochromocytoma and the elevated mortality of these cancer syndromes suggest that screening for mutations should be performed even in cases of non-familial sporadic phaeochromocytoma.     

Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations

BACKGROUND: Paraganglioma (PGL) and phaeochromocytoma (PCC) are chemotherapy and radiation-resistant neuroendocrine tumors that arise from sympathetic tissue, and rarely occur in children. PCC may be associated with predisposing (germline) conditions like the multiple endocrine neoplasia type 2 (MEN2; OMIM 164761), von Hippel-Lindau syndrome (VHL; OMIM 193300), and rarely neurofibromatosis type 1 syndrome (NF1; OMIM 162200) and multiple endocrine neoplasia type 1 (MEN1; OMIM 131100). PGL, on the other hand, may be related to predisposing germline conditions like the familial PGL syndrome and the NF1 syndrome. In adult studies, one of the highest predisposing factors for germline mutation among patients presenting apparently sporadic PCC/PGL was their age at presentation. The aim of this study was to determine the rate of germline mutations among the rare patients presenting with sporadic PGL during childhood. PROCEDURE: In this study, we report the genetic analysis for predisposing conditions for the only three PGL cases retrospectively identified at our pediatric institution in the last 20 years. RESULTS: None had NF1 clinical associated lesions. Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene. We report a novel mutation, c.778 del C. Importantly, several non-symptomatic relatives were found to be carriers, thus ensuring them a clinical follow-up. CONCLUSION: According to our findings, PGL presenting during childhood represents an early manifestation of an adult disease caused by predisposing germline mutations. These results underline the importance of genetic studies in pediatric PGLs.     

Metachronous Occurrence of Multifocal Phaeochromocytoma

The authors report an 8-yr-old boy who presented with hypertension, psychosis, and visual disturbances due to a left adrenal phaeochromocytoma which was excised. After 4 years, the child developed multifocal phaeochromocytomas in the left suprarenal area, right adrenal gland, and left para-aortic region. The tumors were excised along with re-implantation of normal adrenal tissue from the right adrenal into the omentum. The course of the disease and the family history were suggestive of von Hippel-Lindau (VHL) disease.     

Phaeochromocytoma in children

Phaeochromocytoma is a rare clinical entity in children. Contrary to traditional teaching, which suggested that 10% of phaeochromocytomas are "familial", a germline mutation has been identified in up to 59% (27/48) of apparently sporadic phaeochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline mutation in the Von Hippel-Lindau gene, the genes encoding the subunits B and D of succinate dehydrogenase, the RET proto-oncogene predisposing to multiple endocrine neoplasia type 2, or the neurofibromatosis type 1 gene. Of these, the Von Hippel-Lindau gene is the most commonly mutated gene in children presenting with a phaeochromocytoma. Genetic counselling is recommended before gene testing and investigation of the wider family. This review provides guidance on the aetiology, investigation, management, histopathology, genetics and follow-up of children with a phaeochromocytoma.     

Neurofibromatosis type 2 diagnosed in the absence of vestibular schwannomas. A case report and guidelines for a screening protocol for children at risk

 A 5-year-old girl presented with multiple tumours of the central nervous system. As on the first MRI scan bilateral vestibular schwannomas were not detected due to their small size, she initially did not meet the criteria for neurofibromatosis type 2 (NF2), although her clinical symptoms were highly suggestive for the diagnosis. Using molecular studies, a mutation in the NF2 gene was found confirming the clinical suspicion at an early age and indicating the value of molecular analysis. Follow-up MRI 3 years later demonstrated bilateral vestibular schwannomas more clearly, since they had increased in size. Conclusion In children, magnetic resonance imaging can be inconclusive for the diagnosis of neurofibromatosis type 2, since very small vestibular schwannomas may be missed. In these cases molecular studies may provide additional evidence for the diagnosis. We propose guidelines for a screening protocol for children at risk for having neurofibromatosis type 2. Received: 11 October 2000 / Accepted: 27 February 2001     

Recurrent polytopic chromaffin paragangliomas in a 9-year-old boy resulting from a novel germline mutation in the von Hippel-Lindau gene

Pheochromocytomas are frequently associated with inherited cancer syndromes such as von Hippel-Lindau disease (VHL). Retinal angioma and hemangioblastomas of the central nervous system are hallmarks of VHL, but its clinical variety is remarkably broad. Pheochromocytomas as the sole or first manifestation of VHL are rare but have been observed. In this case report, the authors describe an unusual case of initial collapse, seizures, and hypertensive crisis in a child who later was found to have multiple extraadrenal pheochromocytomas. Molecular diagnostics revealed a novel point mutation in the VHL gene (VHL nt. 406 T-->G). Only 7 months after the first lesions had been removed, a new paraganglioma developed in the contralateral periadrenal region. When encountering pheochromocytomas in children, the clinician should be aware that an associated tumor syndrome might be present, and appropriate molecular screening should be initiated. Molecular genetics aid in the clinical decision-making and clinical management of individual patients with pheochromocytoma.     

Pediatric pheochromocytoma in association with Von Hippel–Lindau disease: Focus on screening strategies

IntroductionVon Hippel–Lindau disease (VHL) is a syndrome of familial predisposition to the development of malignant and benign tumours, due to mutations in the VHL tumour suppressor gene. Pheochromocytoma is a tumour that develops in the adrenal gland, rare in pediatric age, and may be associated with genetic abnormalities including mutations in the VHL gene. Systematic screening of pheochromocytoma in children carrying a VHL mutation has been proposed. However, some VHL patients who have been screened may develop symptoms associated with pheochromocytoma despite screening. Here, we report on such a case.Clinical caseA 13-year-old boy, known to be a carrier of a mutation of the VHL gene, undergoing annual screening, was admitted to our hospital for clinical symptoms related to a right adrenal pheochromocytoma discovered on abdominal imaging. After hemodynamic stabilisation, the pheochromocytoma was surgically resected. Histology confirmed the diagnosis of pheochromocytoma. The postoperative care was simple. The event-free period is currently 2 years.DiscussionThe present case has led us to reflect on the French and international screening strategies for pheochromocytoma in children carrying a mutation of the VHL gene. Between 2013 and 2018, six different recommendations were proposed for pheochromocytoma screening in secondary prevention for children with a VHL mutation, with variability regarding the age of onset and complementary examinations to be carried out. Despite the existence of these recommendations, our case demonstrates that a pheochromocytoma can develop by escaping well-performed screening. The role of early abdominal imaging should be redefined to improve the efficiency of screening.ConclusionThe discovery of a pheochromocytoma in a child must be systematically investigated for an underlying genetic cause. In the particular case of children carrying a mutation of the VHL gene, annual abdominal imaging should be included in the pheochromocytoma screening protocol from the age of 5 years.     

A concise genetic and clinical guide to multiple endocrine neoplasias and related syndromes

Several familial neoplastic syndromes are associated with endocrine gland oncogenesis. The main ones are: multiple endocrine neoplasia type 1 (MEN 1), which affects primarily the pituitary, pancreas, and parathyroid glands; MEN 2A and MEN 2B, which involve mainly the thyroid and parathyroid glands and the adrenal medulla; familial medullary thyroid carcinoma (FMTC), which affects only the thyroid gland; and, finally, Carney complex, which affects the adrenal cortex, pituitary, thyroid gland, and the gonads. Carney complex is also associated with pigmentation abnormalities and myxoid and other neoplasms of mesenchymal origin. Thus, this syndrome also belongs to another group of genetic disorders, those associated with pigmentation defects and multiple tumors, including tumors of the endocrine glands. Peutz-Jeghers syndrome and Cowden disease are just two of these disorders that have recently been elucidated at the molecular level. von Hippel-Lindau disease is another condition that affects the pancreas and adrenal medulla and its gene is also known. The inheritance of the MENs, Carney complex, and related syndromes is autosomal dominant. Clinical recognition of these syndromes at a young age improves clinical outcome and prognosis of the various tumors and decreases associated morbidity and mortality. This review considers a wider, more inclusive view of the MEN syndromes, summarizes their clinical features and presents the newest information on their molecular elucidation.     

Interventional stent implantation in a child with patent ductus venosus and pulmonary hypertension

 We report on the rare case of a 4-year-old boy with patent ductus venosus and pulmonary hypertension presenting with progressive fatigue, tachypnoea at rest and tachycardia. Cardiac catheterisation revealed suprasystemic pressure in the pulmonary arteries with severely elevated pulmonary vascular resistance. In order to reduce the diameter of the ductus venosus, a stent was implanted interventionally, which closed, as expected, spontaneously 2 years later. Pulmonary arterial pressure and pulmonary vascular resistance decreased significantly and the general condition of the boy improved dramatically. Conclusion To the best of our knowledge, this represents the first report of successful interventional stent occlusion of a patent ductus venosus associated with severe pulmonary hypertension. The future will tell whether this intervention is curative or represents a bridging procedure for subsequent liver transplantation. Received: 21 September 2000 / Accepted: 14 March 2001     

Orolabial signs are important clues for diagnosis of the rare endocrine syndrome MEN 2B. Presentation of two unrelated cases

Multiple endocrine neoplasia syndromes (MEN) are genetic disorders with glandular hyperplasia and consecutive malignant neoplasia. MEN type 2B is the least common form of these tumor syndromes. It presents with typical dysmorphic features, mucosal neuromas, ganglioneuromatosis, medullary thyroid carcinoma (MTC) and phaeochromocytoma. The prognosis depends on the presence of MTC. We have surprisingly found two unrelated patients with this syndrome at our department within two weeks. In the medical history of a 17-year-old boy, Crohn’s disease had been considered because of abdominal pain and distention. He had marfanoid appearance and previously undergone minor surgeries for a large tongue with neuromas and hypertrophic gums. Two weeks later, a 10-year-old girl presented with a hard palpable mass on her neck. She had thickened lips, neuromas on the tongue and a solitary thyroid nodule. Genetic analysis was carried out in both patients and a heterozygous M918T mutation of the RET proto-oncogene was found. Laboratory tests and imaging studies were consistent with MTC. Phaeochromocytoma was not present. Both patients underwent total thyroidectomy and lymph node dissection. Histological examination confirmed the diagnosis of MTC. In conclusion, the initial diagnosis of MEN 2B should be suspected on the presence of typical facial/oral signs and gastrointestinal symptoms. Hormonal tests and imaging techniques of the thyroid and the adrenals can confirm the clinical diagnosis of MEN 2B and genetic analysis can prove its germline origin.     

Respiratory tract infections by Mycoplasma pneumoniae in children: a review of diagnostic and therapeutic measures

 This review discusses the current knowledge on laboratory tests and treatment of respiratory tract infections caused by Mycoplasma pneumoniae (MP) in children. MP infection is endemic in most areas of the world. The highest incidence is seen in children aged between 3 and 14 years. Most infections are mild and non-pneumonic. Parapneumonic complications of MP pneumonia are rare. Complications are described affecting the skin, central nervous system, kidneys, heart, muscles and the eyes. To diagnose an acute MP infection in children, a combination of PCR and IgM serology is sensitive and convenient. In both tests it is possible to obtain a result in 1 to 2 days. As a consequence, adequate antibiotic treatment can be prescribed to the child. Macrolides are the first choice in treatment of MP infection in children. Conclusion  The most sensitive and rapid test to diagnose a Mycoplasma pneumoniae infection in children is a combination of nasopharyngeal polymerase chain reaction and IgM enzyme immunoassay. The treatment of choice in children is a macrolide. Received: 25 October 2000 and in revised form: 28 February and 30 March 2001 / Accepted: 30 March 2001     

Is peptic ulcer a common cause of upper gastrointestinal symptoms?

 The aim of the study was to investigate retrospectively a cohort of children with peptic ulcer disease during a period that covers the recent changes in diagnosis and management of the disease. Over a period of 9 years, 2550 children underwent upper gastrointestinal endoscopy for various reasons. All children, in whom a diagnosis of primary peptic ulcer was established, were included in the study. Previous and current medical history, family history, endoscopic and histological outcome were evaluated and the children were regularly followed-up on an out-patient basis. Primary peptic ulcer was diagnosed in 52 (10 gastric and 42 duodenal, 2%) out of 2550 children. The median age of children with gastric ulcer was 6.5 years, whereas of those with duodenal ulcer was 10.5 years (P=0.04). With regard to clinical symptoms no significant difference was found between children with and without ulcer. The prevalence of Helicobacter pylori infection was significantly higher in children with duodenal ulcer (62%) compared to those with gastric ulcer (20%; P<0.001). At first follow-up visit, 1 month after the end of treatment, 19 symptomatic children underwent a repeat endoscopy, which showed ulcer healing in 95% and failure in H. pylori eradication in 27%. During the long-term follow-up (median 3.5 years), six children became symptomatic. Two of them had duodenal ulcer associated with positive H. pylori. Conclusion Peptic ulcer disease is an uncommon disorder in childhood with non specific clinical features; it seems that efficient treatment and successful Helicobacter pylori eradication result in clinical improvement and cure as well as in long-term healing of ulcers. Received: 25 September 2000 and in revised form: 22 February and 28 March 2001 / Accepted: 29 March 2001     

Jugular venous malformation in an 8-year-old boy: treatment with endovascular sclerotherapy

 An 8-year-old male presented with a mass in the left supraclavicular region first noted 3 months earlier and which gradually became more prominent. Ultrasound showed a lobular, well-delineated hypoechoic lesion which increased in size on Valsalva manoeuvre. Doppler waveform analysis suggested a slow flow vascular lesion. Venography showed a saccular, multilobular venous malformation which connected with the external jugular and subclavian veins. With an angiographic catheter, the venous malformation was treated by endovascular sclerotherapy. Four weeks later, ultrasonography showed a resolution of the lesion. Conclusion Endovascular sclerotherapy appears to be an effective and safe treatment for jugular venous malformation. Received: 23 November 2000 / Accepted: 5 February 2001     

Long-term follow-up of portacaval shunt in glycogen storage disease type 1B

 In two girls with glycogen storage disease (GSD) type 1b, terminolateral portacaval shunt (PCS) with partial circular resection of the lobus quadratus of the liver was performed at the age of 12 and 10 years, respectively. At that time, the patients had a height of −3.1 and −1.7 SDS, respectively. PCS resulted in a spectacular growth spurt of 35 cm within the first 5 years after surgery in both of them. As first sign of puberty, breast enlargement started 2.5 years after PCS in both patients. Improved glucose tolerance was evidenced by increased levels of blood glucose and insulin after PCS. Diet with raw cornstarch (CS), 2g/kg body weight four times daily, was started 8 years after PCS in patient 1, but initiated with nightly gastric feeding at the age of 2 years in patient 2, 8 years before PCS. Treatment with recombinant granulocyte colony-stimulating factor (rhGCSF), 6 μg/kg body weight every 36–48 h, was started 20 years after PCS in patient 1, but only 1 month before PCS in patient 2. Progressive development of up to 7–8 liver adenomas was observed after PCS, but without conclusive signs of malignancy on Ferrit MRI. The PCS is still open 23 and 7 years after PCS, respectively. Terminolateral PCS with partial circular resection of the lobus quadratus of the liver associated with dietary control and rhGCSF might still have a place in the treatment of GSD type 1b because it improves the tolerance to fasting and the quality of life and moreover yields excellent metabolic control. Conclusion Treatment of glycogen storage disease type 1b by portacaval shunt might be considered in patients with height-for-age below the 3rd percentile occurring in spite of dietary control, or before considering liver transplantation which, if necessary, can still be performed after shunt surgery. Received: 12 October 1998 and in revised form: 17 June 1999 and 12 October 1999/Accepted: 13 October 1999     

Chronic constipation due to Hirschsprung's disease and desmosis coli in a family

 Five members of a family are described, all of whom suffered from chronic constipation and megacolon. Detailed clinical and histologic evaluation of each member revealed that two individuals have histologic evidence of desmosis coli and three have Hirschsprung's disease, one of whom also has desmosis coli. The latter combination has never been described before, either in a family or in a single patient. Genetic studies of the family did not reveal an increase in the number of shared markers for the RET proto-oncogene, suggesting that this previously undescribed familial association is likely not caused by a mutation in the RET gene, but by other genetic abnormalities. Accepted: 18 April 2001     

Prepubertal diagnosis of X-linked congenital adrenal hypoplasia presenting after infancy

X-linked congenital adrenal hypoplasia (CAH) presents classically with adrenal insufficiency within the first 6 months of life, as the fetal adrenal cortex progressively involutes. However, there is increasing recognition of delayed presentation after infancy with the need for accurate molecular diagnosis to avoid an erroneous diagnosis of other more common causes of adrenal insufficiency in childhood. We report our genetic studies of a pedigree with two affected boys presenting with late onset X-linked CAH, diagnosed by the presence of a known W171X mutation of the DAX-1 gene, in whom the mother was an obligate heterozygote. Unlike other causes of adrenal insufficiency, the significance of this diagnosis lies in the important association of hypogonadotropic hypogonadism, and the provision of accurate genetic counselling. Conclusion This study demonstrates that genetic analysis for X-linked congenital adrenal hypoplasia is essential to confirm the diagnosis in prepubertal patients presenting with adrenal insufficiency after infancy. Received: 22 November 1999 / Accepted: 9 March 2000     

Congenital neuroblastoma mimicking early onset sepsis

 A newborn girl presented with symptoms of severe early onset sepsis but also with systemic hypertension (SH) at age 3 h. Plasma catecholamine (CAT) levels were extremely elevated, reflecting increased release of CAT from a congenital neuroblastoma (NB). Clinical symptoms at time of admission were: prolonged capillary refill (5 s), tachycardia, tachydyspnoea, metabolic acidosis (pH 7.17, lactate 11.8 mmol/l), fever (38.4 °C) and SH: 90/50/65 mmHg (systolic/diastolic/mean). The infant experienced organ failure (lung, heart, liver). A retroperitoneal dumbbell tumour was detected. Plasma CAT levels at age 15 h were: noradrenaline 219 nmol/l; adrenaline 13 nmol/l; and dopamine 65.3 nmol/l. SH responded to intermittent α-adrenergic blockage. CAT-related symptoms ceased within 1 week. The intraspinal NB was surgically removed when cord compression became symptomatic. The neurological and developmental state is normal at age 17 months. The abdominal NB regressed spontaneously. Conclusion A neuroblastoma should be considered in newborn infants presenting with a shock-like condition together with systemic hypertension. Received: 1 January 2001 and in revised form: 19 March 2001 / Accepted: 19 March 2001     

Two pediatric patients with Von Hippel-Lindau disease type 2b: from patient to screening, from screening to patient

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor susceptibility disease characterized by the development of hemangioblastomas of the brain, spinal cord and retina; pheochromocytomas and renal cell carcinoma. The disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3p26-p25. In this paper, we present two patients with VHL disease type 2B confirmed by genetic analysis. Diagnosis in the first patient was based on demonstration of retinal hemangioblastoma in association with bilateral pheochromocytoma. Family screening revealed renal cell carcinoma in her father and uncle. The second patient was discovered during family screening of another index case in adult age. VHL disease should be clinically suspected in any individual with a pheochromocytoma especially when there is bilateral and/or multifocal disease or family history. Screening of patients and at-risk family members for VHL-associated tumors should be essential in management of VHL.