Screening and surveillance recommendations for central nervous system hemangioblastomas in pediatric patients with Von Hippel-Lindau disease.

PURPOSE: Von Hippel-Lindau (VHL) disease is an autosomal-dominantly inherited tumor predisposition syndrome. One of the most common tumors are central nervous system (CNS) hemangioblastomas. Recommendations on the initiation and continuation of the screening and surveillance program for CNS tumors in pediatric VHL patients are based on small case series and thus low evidence level. To derive more robust screening recommendations, we report on the largest monocentric pediatric cohort of VHL patients. METHODS: We performed a retrospective analysis on a pediatric cohort of 99 VHL patients consulted at our VHL center from 1992 to 2023. Clinical, surgical, genetic, and imaging data were collected and statistically analyzed. RESULTS: 42 patients (50% male) developed CNS hemangioblastomas, of whom 18 patients (56% male) underwent hemangioblastoma surgery (mean age at first surgery: 14.9 ± 1.9 years; range 10.2-17). The first asymptomatic patient was operated on at the age of 13.2 years due to tumor progress. Truncating VHL mutation carriers had a significantly higher manifestation rate (HR = 3.7, 95% CI: 1.9-7.4, p < 0.0001) and surgery rate (HR = 3.3, 95% CI: 1.2-8.9, p = 0.02) compared with missense mutation carriers. CONCLUSION: We recommend starting MRI imaging at the age of 12 years with examination intervals every (1-) 2 years depending on CNS involvement. Special attention should be paid to patients with truncating variants. Affected families should be educated regularly on potential tumor-associated symptoms to enable timely MRI imaging and eventually intervention, as CNS hemangioblastoma may develop before screening begins. GERMAN CLINICAL TRIALS REGISTER REGISTRATION NUMBER: DRKS00029553, date of registration 08/16/2022, retrospectively registered.

Simple and rapid characterization of novel large germline deletions in SDHB, SDHC and SDHD-related paraganglioma.

Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with hereditary paraganglioma and pheochromocytoma. Although most mutations in SDHB, SDHC and SDHD are intraexonic variants, large germline deletions may represent up to 10% of all variants but are rarely characterized at the DNA sequence level. Additional phenotypic effects resulting from deletions that affect neighboring genes are also not understood. We performed multiplex ligation-dependent probe amplification, followed by a simple long-range PCR 'chromosome walking' protocol to characterize breakpoints in 20 SDHx-linked paraganglioma-pheochromocytoma patients. Breakpoints were confirmed by conventional PCR and Sanger sequencing. Heterozygous germline deletions of up to 104 kb in size were identified in SDHB, SDHC, SDHD and flanking genes in 20 paraganglioma-pheochromocytoma patients. The exact breakpoint could be determined in 16 paraganglioma-pheochromocytoma patients of which 15 were novel deletions. In six patients proximal genes were also deleted, including PADI2, MFAP2, ATP13A2 (PARK9), CFAP126, TIMM8B and C11orf57. These genes were either partially or completely deleted, but did not modify the phenotype. This study increases the number of known SDHx deletions by over 50% and demonstrates that a significant proportion of large gene deletions can be resolved at the nucleotide level using a simple and rapid method.

Is there any role for minimally invasive surgery in NET?

Neuroendocrine tumors (NET) represent the variability of almost benign lesions either secreting hormones occurring as a single lesion up to malignant lesions with metastatic potential. Treatment of NET is usually performed by surgical resection. Due to the rarity of NET, surgical treatment is mainly based on the experience and recommendations of experts and less on the basis of prospective randomized studies. In addition, the development and establishment of new surgical procedures is made more difficult by their rarity. The development of laparoscopic-assisted surgery has significantly improved the treatment of many diseases. Due to the well-known advantages of laparoscopic surgery, this method has also been increasingly used to treat NET. However, due to limited comparative data, the assumed superiority of laparoscopic surgery in the area NET remains often unclear or not yet proven. This review focuses on the present usage of laparoscopic techniques in the area of NET. Relating to the current literature, this review presents the evidence of various laparoscopic procedures for treatment of adrenal, pancreatic and intestine NET as well as extraadrenal pheochromocytoma and neuroendocrine liver metastases. Further, this review focuses on recent new developments of minimally invasive surgery in the area of NET. Here, robotic-assisted surgery and single-port surgery are promising approaches.

[A 47-year-old patient with paroxysmal arterial hypertension and gastric tumors]. / 47-jährige Patientin mit paroxysmaler arterieller Hypertonie und gastralen Raumforderungen.

Arterial hypertension caused by a paraganglioma is rare and approximately one third of all cases of paraganglioma occur as part of a hereditary syndrome. Among these the Carney-Stratakis syndrome is characterized by the occurrence of paraganglioma/pheochromocytoma and gastrointestinal stromal tumors caused by germline mutations of the succinate dehydrogenase subunit genes (B-D). We report the case of a 47-year-old female patient suffering from Carney-Stratakis syndrome with an endocrine active thoracic paraganglioma which was successfully resected with the assistance of a heart-lung machine and the gastric stromal tumors were removed in a second surgical intervention.

Increased expression of secreted frizzled-related protein 4 in polycystic kidneys.

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disease associated with progressive renal failure. Although cyst growth and compression of surrounding tissue may account for some loss of renal tissue, the other factors contributing to the progressive renal failure in patients with ADPKD are incompletely understood. Here, we report that secreted frizzled-related protein 4 (sFRP4) is upregulated in human ADPKD and in four different animal models of PKD, suggesting that sFRP4 expression is triggered by a common mechanism that underlies cyst formation. Cyst fluid from ADPKD kidneys activated the sFRP4 promoter and induced production of sFRP4 protein in renal tubular epithelial cell lines. Antagonism of the vasopressin 2 receptor blocked both promoter activity and tubular sFRP4 expression. In addition, sFRP4 selectively influenced members of the canonical Wnt signaling cascade and promoted cystogenesis of the zebrafish pronephros. sFRP4 was detected in the urine of both patients and animals with PKD, suggesting that sFRP4 may be a potential biomarker for monitoring the progression of ADPKD. Taken together, these observations suggest a potential role for SFRP4 in the pathogenesis of ADPKD.

Neurofibromatosis type 1: should we screen for other genetic syndromes? A case report of co-existence with multiple endocrine neoplasia 2A.

BACKGROUND: NF 1 is a genetic disorder with an autosomal dominant pattern of inheritence. It is associated with neoplastic disorders mainly derived from the neural seath. However, the co-existence of NF1 with the full spectrum of MEN 2A has rarely been reported. The aim of the study was to investigate the presence of secondary neoplasias in a patient with diagnosed NF1, and in particular the presence of hyperparathyroidism and the possible co-existence with another pheochromocytoma-related syndrome. METHODS: We report a case of a 70 years old female patient who had NF1. The patient was referred to our center and was diagnosed with an isolated pheochromocytoma of the right adrenal gland for which she underwent right adrenalectomy. We further investigated for the presence of another pheochromocytoma-related syndrome and in particular for the presence of hyperparathyroidism and medullary thyroid cancer. Molecular screening for germline mutations of the genes NF1, RET and VHL has also been performed. RESULTS: The patient was further diagnosed with hyperparathyroidism and medullary thyroid cancer, having the full spectrum of the clinical picture of the MEN2A syndrome. The genetic testing revealed the germline mutation for NF1 but not for the RET proto-oncogene which is generally found in MEN2A cases. CONCLUSION: To our knowledge this is a rare case of co-existence of two pheochromocytoma-related genetic syndromes, and generates the question of whether all patients with these syndromes should undergo a thorough clinical and laboratory investigation for the possibility of another co-existing pheochromocytoma-related genetic syndrome.

Molecular characterisation of a common SDHB deletion in paraganglioma patients.

BACKGROUND: Hereditary susceptibility to familial paraganglioma syndromes is mainly due to mutations in one of six genes, including three of the four genes encoding the subunits of the mitochondrial succinate dehydrogenase complex II. Although prevalence, penetrance and clinical characteristics of patients carrying point mutations affecting the genes encoding succinate dehydrogenase have been well studied, little is known regarding these clinical features in patients with gross deletions. Recently, we found two unrelated Spanish families carrying the previously reported SDHB exon 1 deletion, and suggested that this chromosomal region could be a hotspot deletion area. METHODS: We present the molecular characterisation of this apparently prevalent mutation in three new families, and discuss whether this recurrent mutation is due either to the presence of a founder effect or to a hotspot. RESULTS: The breakpoint analysis showed that all Iberian Peninsular families described harbour the same exon 1 deletion, and that a different breakpoint junction segregates in an affected French pedigree. CONCLUSIONS: After haplotyping the SDHB region, we concluded that the deletion detected in Iberian Peninsular people is probably due to a founder effect. Regarding the clinical characteristics of patients with this alteration, it seems that the presence of gross deletions rather than point mutations is more likely related to abdominal presentations and younger age at onset. Moreover, we found for the first time a patient with neuroblastoma and a germline SDHB deletion, but it seems that this paediatric neoplasia in a pheochromocytoma family is not a key component of this disease.

[Pheochromocytoma - still a challenge]. / Das Phäochromozytom - noch immer eine Herausforderung.

Pheochromocytomas are rare, mostly benign catecholamine-producing tumors arising from the chromaffin cells of the adrenal medulla or in the paraganglia. Clinical presentation is highly variable but typically with hypertension, severe headaches, palpitations and sweating. Biochemical testing by 24 h urinary fractioned metanephrines or catecholamines and plasma free metanephrines as the most sensitive screening approach, confirms the catecholamine excess. Computed tomography scan and magnetic resonance imaging of the adrenal glands and abdomen as well as functional imaging with (123)Iod-MIBG scintigraphy and (18)F-dopa positron emission tomography are used for tumor localization. Because approximately a quarter of tumors develop secondary to germ-line mutations, screening for genetic alterations is important. The therapy of choice is the endoscopic adrenal sparing surgery following preoperative alpha-blockade. Regular follow-up remains essential due to possible recurrence and malignancy.

[Genetics of pheochromocytoma and the relevance in surgery]. / Genetik von Phäochromozytomen und ihre Bedeutung in der Chirurgie.

Chromaffin tumors, e.g. pheochromocytomas and paragangliomas are caused by germline mutations of several susceptibility genes in 30-40% of the patients. The corresponding syndromes are multiple endocrine neoplasia type 2 (MEN2, RET gene), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), paraganglioma syndrome types 1-5 (PGL1-5, SDHx gene) and familial pheochromocytoma due to mutations in the MAX and TMEM127 genes. Clinically, screening for such diseases should be carried out by clinical symptoms and mutation analyses. Important indications can be found in the history of patients and their families, young age of manifestation (<30 years), extra-adrenal localization and the presence of metastatic pheochromocytomas. Organ-preserving endoscopic adrenal operations are nowadays standard for hereditary pheochromocytomas. Previous studies have shown that the reoccurrence of tumors in residual tissue is rare and can occur many years later and that metastatic tumors arising from such recurrences are very rare. When a mutation is detected in a susceptibility gene, a multidisciplinary follow-up care tailored to each individual syndrome is essential.

[Juxtapapillary capillary retinal angioma with epiretinal membrane of the macula in familial Von-Hippel-Lindau-Syndrome]. / Juxtapapilläres kapilläres retinales Angiom mit epiretinaler Membran der Makula bei familiärem Von-Hippel-Lindau-Syndrom.

A case of juxtapapillary capillary retinal angioma associated with a vascularized epiretinal membrane of the macula in a 6-year-old girl is presented. Von-Hippel-Lindau-Syndrome was revealed by molecular genetic methods, and further family members were identified as gene carriers. The retinal angioma embedded in an epiretinal membrane was removed completely with the membrane by pars plana vitrectomy with a good functional result. Histopathology confirmed the diagnosis of capillary angioma.

[Von Hippel-Lindau disease. Interdisciplinary patient care]. / Von-Hippel-Lindau-Erkrankung. Interdisziplinäre Patientenversorgung.

Von Hippel-Lindau disease is an important hereditary tumor syndrome with a clear option for effective treatment if diagnosed in time. Interdisciplinary cooperation is the key to successful management. Major components of the disease are retinal capillary hemangioblastomas, hemangioblastomas of cerebellum, brain stem and spine, renal clear cell carcinomas, pheochromocytomas, multiple pancreatic cysts and islet cell carcinomas, tumors of the endolymphatic sac of the inner ear, and cystadenomas of the epididymis and broad ligament. A well structured screening program should be performed at yearly intervals.

MANAGEMENT OF ENDOCRINE DISEASE: Outcome of adrenal sparing surgery in heritable pheochromocytoma.

The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in MEN2 or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits <5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of the cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and the results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN2.

Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas.

Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHB and SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novo promoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (P<0.001). This suggests that 11p15.5-imprinted genes may be implicated in the pathogenesis of both familial (germline VHL and SDHD mutations) and sporadic phaeochromocytomas.

Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.

BACKGROUND: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown. METHODS: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups. RESULTS: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups. CONCLUSION: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

Spontaneous regression of retinal angiomatous lesions in v. Hippel-Lindau disease (VHL).

BACKGROUND: Very little documentation of spontaneous regression of an angiomatous retinal lesion in v. Hippel-Lindau disease (VHL) exists. It is commonly believed that a spontaneous change of hemangiomas into fibrotic lesions occurred. PATIENTS/METHODS: Follow-up examinations of four patients with VHL in the Freiburg VHL study were carried out. RESULTS: A 16-year-old girl revealed a vascular lesion at the border of the optic disc. Control examination nine years later revealed complete spontaneous regression of the retinal vascular changes. A slight retinal vascular change at the superior border in her right eye was found in a 36-year-old woman. A control examination 20 years later revealed regression of the lesion. A 41-year-old woman showed in the retinal periphery a small fibrotic white hemangioma with a pigmented feeder vessel as sign of spontaneous tumor regression. A 12-year-old boy had a retinal microaneurysm inferior to the optic disc that disappeared several years later. CONCLUSION: Documentations of spontaneous regression of minor angiomatous retinal lesions in VHL exist. Such vascular changes are rare. Every retinal lesion should be controlled by follow-up examination and documentation. In case of retinal lesion growth, treatment is necessary.

Genetic testing for pheochromocytoma-associated syndromes.

Pheochromocytoma and paraganglioma are tumors of the autonomic nervous system. Various syndromes have been found to be associated with the development of pheochromocytomas and paragangliomas: multiple endocrine neoplasia type 2 (MEN 2, susceptibility gene: RET), von Hippel-Lindau disease (VHL, susceptibility gene: VHL), neurofibromatosis 1 (NF 1), and paraganglioma syndromes type 1, 3, and 4 (susceptibility genes: succinate dehydrogenase gene, SDH, subunits D, C and B, respectively). Prevalence and clinical features of pheochromocytomas and paragangliomas are different for each of these syndromes. Mutational analysis of the susceptibility genes of these syndromes in patients presenting with pheochromocytoma or paraganglioma may help to judge the risks of multifocality of the tumor as well as development of malignant pheochromocytoma or of other malignant tumors. Here we review the recent progress in clinical characterization and genetic testing for these syndromes. Based on tumor characteristics and prevalence data we give recommendations for an efficient genetic testing procedure in patients presenting with pheochromocytomas and paragangliomas.

[Genetics of pheochromocytoma]. / Genetik der Phäochromozytome.

About one third of all patients with a pheochromocytoma are carriers of germ line mutations of 1 of the 10 susceptibility genes. Thus, these patients can be diagnosed and classified with specific tumor syndromes. This group is composed of the entities of multiple endocrine neoplasia type 2 (MEN2) due to mutations in the RET gene, von Hippel-Lindau disease (VHL, VHL gene), the paraganglioma syndromes types 1-4 (PGL1-4) due to mutations of the genes SDHD, SDHAF2, SDHC, SDHB, neurofibromatosis type 1 (NF1) due to mutations of the NF1 gene and familial pheochromocytoma syndromes due to mutations of the SDHA, TMEM127 and MAX genes. Patients with hereditary pheochromocytomas run a lifelong risk of relapse of pheochromocytoma. In addition extraparaganglial tumors are frequent and include medullary thyroid carcinoma in MEN2 or renal cancer or neuroendocrine pancreatic cancer as well as hemangioblastomas of the retina and the central nervous system in VHL. Furthermore, renal cancer may be associated with PGL4 and PGL3. In conclusion, molecular genetic screening is essential for the diagnosis of pheochromocytoma-associated cancer syndromes and is thus the cornerstone for successful lifelong preventive medicine of such patients and their relatives.

Essentials and pitfalls in the treatment of CNS hemangioblastomas and von Hippel-Lindau disease.

Hemangioblastomas are rare CNS tumors, which are mostly located in the posterior fossa or spinal cord and occasionally in spinal nerves. They can occur sporadically or as a component tumor of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor syndrome. The limited awareness of several pitfalls in the therapy of these rare lesions results in delayed or suboptimal treatment for many of these patients, especially those with VHL disease. The University of Freiburg serves as a reference center for patients with VHL disease and hemangioblastomas. The current therapeutic strategies for hemangioblastoma patients and typical pitfalls are presented here.

[Fabry disease. An interdisciplinary challenge]. / Morbus Fabry. Eine interdisziplinäre Herausforderung.

Fabry disease is an inherited X-linked lysosomal storage disease due to a genetic defect of the GLA gene which encodes the protein of the enzyme alpha-galaktosidase A. Under normal concentrations this lysosomal enzyme is involved in degradation and catabolism processes of membrane glycosphingolipids in almost all cells of the human organism. The enzyme deficiency leads to a progressive accumulation of globotriaosylceramide (Gb3) in various tissues and organ systems and is responsible for the large variability of the clinical signs and symptoms of the disease. First signs and symptoms such as painful neuropathy (acroparethesia), hypo- or unhidrosis and gastrointestinal disturbances can be found already in childhood and mainly affect quality of life. In the following decades of life, renal cardiac, and cerebrovascular complications occur in hemizygous males and with some delay in a part of heterozygous females as well. If not treated, these complications result in increased morbidity and premature mortality. With the introduction of the enzyme replacement therapy (ERT) in 2001 a causal treatment is available. Published data from clinical trials and observational studies demonstrated that ERT mitigates signs and symptoms of the disease as well as quality of life, and has the potential to reduce mortality. The efficacy of ERT seems to be less pronounced in severe cases of the disease, which makes an early diagnosis and treatment more important in order to prevent or improve the progression of the disease.