Multiple pheochromocytomas and paragangliomas in a young patient carrying a <Emphasis Type="Italic"> SDHD </Emphasis>gene mutation

We report a 13-year-old boy with an atypical manifestation of a multilocular paraganglioma. Surgical treatment was not curative despite extirpation of a left-sided abdominal paraganglioma. After surgery, the boy experienced several hypertensive crises. Further investigations including dopamine-positron emission tomography demonstrated bilateral adrenal tumours, a further right-sided paravertebral tumour as well as bilateral cervical glomus tumours. Genetic testing revealed a germline mutation in the succinate dehydrogenase subunit D (SDHD) gene. Conclusion:The final diagnosis was familial pheochromocytoma/paraganglioma type 1 (OMIM 168000). Antihypertensive treatment was succesfull and improved the patients quality of life.     

A novel non-sense mutation in the <Emphasis Type="Italic">SLC2A10</Emphasis> gene of an arterial tortuosity syndrome patient of Kurdish origin

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient’s DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.     

An ovarian tumour with a potential appendiceal origin

A 14-year-old girl underwent left oopherectomy for a multicystic ovarian mass. Histology revealed this to be an intestinal type mucinous borderline tumour (IMBT). In view of this, a semi-urgent laparoscopic appendicectomy was carried out. The appendix was histologically normal. IMBT of the ovary is a mucinous tumour with atypical proliferation of the goblet cell containing epithelium. It is known to occur simultaneously with tumours of the appendix. Paediatric surgeons need to be aware of this rare tumour and when operating on any ovarian pathology should always inspect the peritoneal cavity for mucinous deposits and examine the appendix. Presented at the VI congress of the Mediterranean association of paediatric surgeons, Barcelona, October 2006.     

Complete androgen insensitivity syndrome associated with bilateral sertoli cell adenomas and paratesticular leiomyomas: Case report and review of the literature

BackgroundComplete androgen insensitivity syndrome (CAIS) is a rare and usually unexpected cause of primary amenorrhoea that results from receptor resistance to androgens, producing a female phenotype in genetically male patients.CaseA 16-year-old girl was diagnosed with CAIS after investigations for primary amenorrhoea. Her left inguinal gonad and the right intra-abdominal gonad were resected and histopathology revealed the presence of dysgenetic multinodular testes with absence of germ cells, significant hyperplasia of Sertoli cells (Sertoli cell adenoma) and presence of paratesticular leiomyomas.ConclusionAlthough the risk of gonadal tumour development is considered to be low, a variety of tumours have been described in association with CAIS, but this is the first report of development of bilateral paratesticular leiomyomas developing concurrently with Sertoli cell adenomas.     

Mutiple DICER1‐related lesions associated with a germline deep intronic mutation

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli–Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.     

Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood

A 12-year-old boy with tuberous sclerosis complex (TSC) presented with a large retroperitoneal tumour. Exploratory surgery revealed an infiltrative tumour originating from the pancreas, with local metastases to the lymph nodes. The histologal diagnosis was a malignant islet cell tumour. Retrospectively measured pancreatic hormone levels, however, were normal. A connection between the malignancy and TSC was demonstrated by loss of heterozygosity of the TSC2 gene in the tumour. The primary mutation Q478X in this patient was identified in exon 13 of the TSC2 gene on chromosome 16. Conclusion Pancreatic islet cell tumours have been mainly associated with multiple endocrine neoplasia syndrome type 1. In our case we demonstrate a direct relationship of this tumour to tuberous sclerosis complex, in the absence of further signs of multiple endocrine neoplasia syndrome type 1. Received: 17 February 1998 / Accepted in revised form: 8 July 1998     

Noonan syndrome caused by germline <Emphasis Type="Italic">KRAS</Emphasis> mutation in Taiwan: report of two patients and a review of the literature

Noonan syndrome is a highly variable disorder that has significant phenotypic overlap with Costello syndrome and cardio-facio-cutaneous syndrome. KRAS mutation was the second reported gene for Noonan syndrome. This study screened for mutation of the KRAS gene in 57 unrelated ethnic Chinese children suffering from Noonan syndrome without PTPN11 gene mutation in Taiwan. This work only identified two patients with different missense mutations (c.40G>A, p.Val14Ile; c.108A>G, p.Ile36Met) in the exon 1 of KRAS gene. This study also analyzed the characteristics of 34 reported cases involving KRAS mutations in the literature. All these patients presented with variable phenotypes, including Noonan syndrome (n = 19), cardio-facio-cutaneous syndrome (n = 7), Costello syndrome (n = 6), and Noonan/cardio-facio-cutaneous syndrome (n = 1). The phenotype of KRAS mutations was generally severe, including short stature, mental retardation, heart defects, etc. In conclusion, this investigation demonstrates that KRAS mutations are the cause in a minority of cases of Chinese patients with Noonan syndrome in Taiwan.     

Role of genomic imprinting in Wilms' tumour and overgrowth disorders

Activation of the silent maternal IGF2 allele has recently been found in approximately half of Wilms' tumour (WTs) examined. This process of imprint relaxation leads to biallelic expression of IGF2 and it has been suggested that this is a key event in the onset of some WTs. Although it has previously been proposed that the 11p15 chromosome region contains a growth-promoting gene and a tumour suppressor gene, the simplest explanation is that increased expression of the IGF2 gene is responsible for somatic overgrowth in the BWS and predisposition to tumours. This model explains overgrowth in BWS cases with unbalanced translocations with paternal dup(11p), and cases with balanced maternal translocations which are physically close to the IGF2 gene. Maternal translocations are envisaged to disrupt the maternal IGF2 imprint by a mechanism similar to the position-effect variegation mechanism in Drosophila. Relaxation of IGF2 imprinting has also been detected in several patients with the BWS syndrome and a patient with gigantism and Wilms' tumour. Recent gene disruption experiments have shown that inactivation of the mouse h19 gene leads to biallelic Igf2 expression and extensive proportional overgrowth. This mouse model has parallels with the BWS and WT where it has been found that biallelic IGF2 expression is accompanied by an epigenetic modification of the H19 gene. From these data it is possible to speculate that an epigenetic modification of the H19 gene may be the primary event leading to the relaxation of IGF2 imprinting. © 1996 Wiley-Liss, Inc.     

Sertoli Leydig cell ovarian tumour and gastric polyps as presenting features of Peutz–Jeghers syndrome

We report a case of Peutz–Jeghers syndrome (PJS) in a 2‐year old with precocious puberty secondary to a Sertoli–Leydig cell tumour. Family history of PJS and other neoplasms were discovered. The tumour was excised and the STK11 gene deletion identified in both patient and father. Screening revealed hamartomatous gastric polyps, which were removed. Current recommendations for screening of children with PJS begin at age 8 years, based on reported occurrence of complications 1 . This report illustrates the importance of considering early screening, along with close clinical review and patient/parent education, for detection of life threatening neoplasms and complications. Pediatr Blood Cancer 2010;55:206–207. © 2010 Wiley‐Liss, Inc.     

Carcinoid and mucoepidermoid bronchial tumours in children

The aim of the study was to determine the characteristic features and outcome of carcinoid or mucoepidermoid tumours in children. A retrospective analysis of all patients treated for a carcinoid or mucoepidermoid tumour in France between 1984 and 2001 was performed. There were 11 cases of carcinoid tumour and 6 cases of mucoepidermoid tumour. The mean age of the patients was 10.5±3.0 years, with a range of 5 to 15 years. Twelve and 6 patients presented with evidence of bronchial obstruction and haemoptysis, respectively. Fibre optic bronchoscopy confirmed the presence of a bronchial tumour in all cases and endobronchial biopsies were diagnostic in 11 of 12 cases. A chest CT scan revealed the presence of a hypervascular tumour in 8 of 12 patients. The distribution of the location of the tumours was equal between the right and the left lung, and, in 9 cases, the airways were totally occluded by the tumour. Complete surgical resection (lobectomy in 15 patients and pneumonectomy in 2 patients) was performed in all cases without pre-operative chemotherapy or radiotherapy. The mean duration of follow-up was 4.0±3.0 years. In 2 patients, auscultation assymetry and an episode of haemoptysis revealed the recurrence of a mucoepidermoid tumour, successfully cured by removal of the tumour and chemotherapy and radiotherapy in one child. No death was observed. Conclusion:Pulmonary carcinoid and mucoepidermoid tumours are rare in children. Bronchoscopic removal should not be performed. With aggressive surgical therapy, the prognosis is excellent. Fibre optic bronchoscopy confirms the presence of an endobronchial mass. A biopsy is needed for diagnosis and complete surgical removal is the treatment of choice. Long-term results are excellent but a clinical follow-up is recommended.No financial support was received for this study.     

Oophorectomy in children. Who and why: 13-year experience in a single centre

Aim: Oophorectomy performed in children is extremely uncommon. We aimed to investigate the disease pattern and the association between the underlying pathology and the clinical presentation among those patients who had their ovaries removed in their childhood. Methods: A retrospective study was performed on 41 consecutive children who underwent oophorectomy in a tertiary referral centre in the period between June 1995 and May 2008. Results: The median age was 11 years, ranged from 11 weeks to 15 years at the time of surgery. The primary presentations were acute lower abdominal pain (n= 20), progressive abdominal distension or abdominal mass (n= 13), chronic abdominal pain (n= 3), irregular menses (n= 1), antenatal diagnosis (n= 3) and incidental finding (n= 1). Ultrasound examination was performed in 31 patients and positive findings of ovarian pathology were found in all but one examination. Twenty cases of ovarian torsion were confirmed intra‐operatively. Patients presenting with acute abdominal pain were more likely to have torsion than other presentations (P < 0.01). Non‐neoplastic conditions and ovarian neoplasms were found in 11 and 30 patients, respectively. The most common neoplasm was mature teratoma (52%). Malignant neoplasms included immature teratoma (n= 3), dysgerminoma (n= 1), mixed dysgerminoma + yolk sac tumour (n= 2), yolk sac tumour (n= 2) and juvenile granulose cell tumour (n= 1). Malignant neoplasms were found to have more chronic presentation and less torsion than benign pathologies (P < 0.05). Conclusion: Although ovarian pathology is uncommon in children, a girl presenting with acute lower abdominal pain or progressive abdominal distension should raise the suspicion and prompt immediate investigation to rule out ovarian torsion or ovarian neoplasms.     

A case of Sertoli-Leydig cell tumour of the ovary with a multilocular cystic appearance on CT and MR imaging

We present a case of Sertoli-Leydig cell tumour of the ovary in a 14-year-old girl who presented with abdominal distension. Ultrasonography showed a multilocular cystic lesion filled with finely echogenic fluid. Contrast-enhanced CT demonstrated a huge multilocular cystic mass with thickened septa. At MR imaging, the capsule of the cyst was focally thickened, showing intermediate signal intensity on T2-W images. Although extensive cyst formation of Sertoli-Leydig cell tumour is rare, this tumour should be considered in the differential diagnosis of a multilocular cystic ovarian tumour in a young female.     

Does diagnostic delay result in decreased survival in paediatric brain tumours?

To study the hypothesis that a delay in the diagnosis of paediatric brain tumours results in decreased survival outcome probability, we compared the prediagnostic period of 315 brain tumour patients (median age 6.7 years, range, 0 to 16 years) with progression-free and overall survival. The median prediagnostic symptomatic interval was 60 days (range, 0 to 3,480 days), with a median parental delay of 14 days (range, 0 to 1,835 days) and a median doctor’s delay of 14 days (range, 0 to 3,480 days). The prediagnostic symptomatic interval correlated significantly with the patient age, tumour histology, tumour location and year of diagnosis, but not with gender. We then grouped the patients according to histology (low-grade glioma [n=77], medulloblastoma [n=57], high-grade glioma [n=40], craniopharyngioma [n=27], ependymoma [n=20] and germ cell tumours [n=18]). Contrary to common belief, long prediagnostic symptomatic interval or long doctor’s delay did not result in decreased survival outcome probability in any of these groups. The effect of tumour biology on survival seems to be dominant and overwhelms any possible opposing effect on survival of a delay in diagnosis.     

Late onset subgaleal hemorrhage infection with <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis>?

We report a case of an infected subgaleal hematoma caused by an unusual micro-organism in a previously healthy 11-month-old girl. Our patient presented at the emergency department with an increasing scalp swelling for 2 weeks, and culture of the evacuated fluid yielded Streptococcus pneumoniae. Although she was born after vacuum delivery and a scalp swelling was noticed from the third day of life, this swelling disappeared completely at the age of 3 months. Parents were thoroughly questioned but we could not find out a new traumatic head event. We postulate that in our patient, a subgaleal hemorrhage developed after vacuum delivery and possibly infected 11 months later, presumably from hematogenous seeding of an acute otitis media. The patient recovered well after surgical drainage and antimicrobial therapy.     

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol

Background

Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more.

Procedure

Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine–bleomycin–cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide–cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups.

Results

One hundred fifteen patients were included: median age of 12.8 years (0.4–18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80–92) and 95% (89–98), respectively (median follow-up: 3.5 years, range: 0.2–5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84–93), 5-year OS 93% (89–95), p = .561). The 5-year EFS were 93% (95% CI: 80–98), 88% (71–95) and 79% (62–90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66–97), 64% (30–85), 95% (72–99) and 87% (74–94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003–1.007).

Conclusion

Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.     

Metastatic primitive neuroectodermal tumour of the ovary

Primitive neuroectodermal tumours (PNET) of the ovary are rare, aggressive tumours which are associated with high morbidity and mortality. Previously reported cases have shown limited response to therapy in patients presenting with metastatic disease and survival rates have been discouragingly low. We report the case of a 13-year-old girl who presented with a primary ovarian PNET and extensive metastatic disease. Pathologic studies confirmed the neural origin of the tumour and its morphologic appearance of neuroblastoma. Incomplete surgical resection was followed by treatment with aggressive multi-agent chemotherapy including cis-platinum, etoposide, cyclophosphamide, anddoxorubicin as per a neuroblastoma treatment protocol. Complete clinical remission ensued and she received consolidative therapy with myeloablative doses of thiotepa, melphalan, and carboplatin followed by autologous peripheral blood progenitor cell rescue. All therapy was well tolerated and the patient remains in complete remission with no evidence of disease 18 months from presentation. Mega-dose chemotherapy followed by progenitor cell rescue may provide optimal therapy for patients presenting with metastatic ovarian PNET. Med. Pediatr. Oncol. 29:308–312, 1997. © 1997 Wiley-Liss, Inc.     

Association of rib anomalies and malignancy in childhood

A relationship exists between tumours and malformations both generally and in particular combinations. This is also valid for minor errors of morphogenesis suggesting that embryonic tumours are an expression of aberrant intra-uterine morphogenesis. We speculated that these minor aberrations might also manifest in other morphological defects, especially in minor anomalies and malformations of the ribs. We reviewed chest roentgenographs of 1000 children with malignancies for rib anomalies and compared them to 200 patients with mainly infectious diseases. We found 242 rib anomalies in 218 children with tumours (21.8%) and 11 (5.5%) in children without malignancy. This difference was statistically highly significant (P<0.001). A high incidence of cervical ribs was found in neuroblastoma (33%), brain tumour (27.4%), leukaemia (26.8%), soft tissue sarcoma (24.5%), Wilms tumour (23.5%) and Ewing sarcoma (17.1%). Only neuroblastoma showed a high incidence of rib bifurcation (4.5%). The increased incidence of these mesenchymal defects in children with malignancies may be another clue for an altered morphogenesis in tumour origin. In neuroblastoma the rib anomaly may be another expression of neurocristopathy as proposed for the association of congenital heart disease and neuroblastoma.     

Long-term follow-up of a patient with primary hypomagnesaemia and secondary hypocalcaemia due to a novel <Emphasis Type="Italic">TRPM6</Emphasis> mutation

Hypomagnesaemia with secondary hypocalcaemia (HSH) is a rare condition usually presenting in the newborn period as refractory seizures, other symptoms of increased neuromuscular excitability and growth disturbances. A case with a novel TRPM6 mutation with an excellent long-term outcome is reported to highlight the observation that clinical suspicion is essential for an early diagnosis and treatment of HSH. The compliance of a long-term treatment with oral magnesium supplements is critical to avoid abnormalities of neurological and physical development. The finding of novel mutations supports the notion that the molecular study of the whole TRPM6 gene is required for diagnostic accuracy. Furthermore, the molecular study of the different types of hereditary hypomagnesaemia is critical to further improve our knowledge of magnesium homeostasis.     

A missense mutation (G604S) in the S5/pore region of <Emphasis Type="Italic">HERG</Emphasis> causes long QT syndrome in a Chinese family with a high incidence of sudden unexpected death

Long QT syndrome (LQTS) is characterized by abnormalities in cardiac repolarization that lead to prolongation of the electrocardiographic (ECG) QT interval. Mutations in the human ether-a-go-go-related gene (HERG, KCNH2) cause the chromosome 7-linked LQT2 form of congenital LQTS, which is characterized by a prolonged QT interval and a bifid T-wave with an increased susceptibility to life-threatening cardiac arrhythmias, especially in children. We describe the genotypic and phenotypic pedigree of a large Chinese family (n = 36) in which 11 members were diagnosed with LQTS on the basis of typical ECG patterns for LQT2. Symptomatic syncopal episodes appeared in seven members of this family at a young age; an additional four members had died suddenly at ages of 18, 19, 24 and 70 years, respectively. Screening for SCN5A and HERG candidate genes identified a heterozygous missense mutation 1810G→A in exon 7 of HERG that leads to the substitution of the amino acid glycine by serine (G604S); this mutation was located in the S5/pore region of the HERG protein and was associated with a malignant phenotype. Ten of the family members carrying the mutation showed a prolongation of the corrected QT interval (QTc), and seven of these had experienced multiple syncopal episodes. The retrospective examination of documented ECG records revealed that one family member who had died suddenly also had a prolonged QT interval. This study is the first to demonstrate a close correlation between clinical phenotype and genotype with a 100% penetrance based on the pedigree of a Chinese family with LQT2. Yanmin Zhang and Nan Zhou contributed equally to this investigation.