Search PubMed⌕ Search

Biomedical subjects

C J Lips

Publications and source records attributed to C J Lips.

At least 19 recordsLinked to original sources

Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines.

Counselling of patients and closely related family members has to take a central place in management of hereditary diseases, like multiple endocrine neoplasia (MEN) syndromes including von Hippel-Lindau (VHL) disease. In the strategy of health care, preventive medicine such as periodic clinical examination of families at-risk needs a high priority, because in general it is assumed that continuity in attendance is cost-effective. Counselling has to be based on individual medical experience of the doctor, adjusted to common guidelines and the findings in the family. Information leaflets, appropriate outpatient departments and an extensive network of specialists will facilitate continuity in care. Flow diagrams involving practical guidelines for diagnosis, treatment and follow up need to be applicable and after adjustment, should be accepted generally. Specially trained paramedics for counselling are required as a network that will guarantee periodic clinical examination and secure optimal prevention. Such paramedics will coordinate nationwide multidisciplinary guidance, and organize preventive and emergency cure for these patients. They will be supervised by expert clinicians in the field, and collaborate with specialists for social and psychological issues, patient organizations and clinical genetic centres. All of these professionals are responsible together for providing patients with up to date clinical information (via newsletters, Internet, etc.). Recently, in the Netherlands, a project was initiated to guarantee continuity in care and study the delivery of care. In order to realize this plan, funding has to be provided in the current research programme. In a future system support has to be obtained on a continuous base, preferably by the government and health care insurers and supervised by the national institute for health care.

Family↗

[From gene to disease; from the RET gene to multiple endocrine neoplasia types 2A and 2B, sporadic and familial medullary thyroid carcinoma, Hirschsprung disease and papillary thyroid carcinoma].

The RET gene encodes a receptor tyrosine kinase involved in normal and neoplastic development of neural crest cell lineages. Activating RET mutations are present in patients with multiple endocrine neoplasia types 2A and 2B (MEN2A, 2B) and in familial medullary thyroid carcinoma (FMTC) patients, whereas inactivating RET mutations are found in patients with Hirschsprung (HSCR) disease. In particular for MEN2A and FMTC, the clinical management largely depends on the specific mutation found.

Carcinoma, Medullary↗

[Lump in the neck: 4 patients with a medullary thyroid carcinoma].

In a 25-year-old man, medullary thyroid carcinoma (probably a solitary sporadic form) was diagnosed following investigation of a small lump in the patient's neck. This was removed and followed up with further treatment. In a 27-year-old man, episodes of headache, palpitations and excessive perspiration (due to a pheochromocytoma) and a positive family history of thyroid problems led to further investigations and the subsequent diagnosis of multiple endocrine neoplasia (MEN) type 2A. The patient died at 48 years of age as the result of liver metastases. A total thyroidectomy had been carried out on a 19-year-old man with familial medullary thyroid carcinoma. The calcitonin levels remained elevated, but no tumour residues could be found. A 16-year-old girl with MEN type 2B had also previously undergone surgery. Her main complaint consisted of persistent constipation. Thyroid carcinomas usually present as a nodule in the neck. In 25% of cases, medullary thyroid carcinoma is part of the MEN2 syndrome. The clinical approach for medullary thyroid carcinoma is based on pathological findings following fine needle aspiration biopsy. The results of DNA tests determine the course of treatment and the need for family testing. In families with a hereditary form, there is a clear genotype-phenotype correlation. Early diagnosis and treatment can improve life expectancy.

Adolescent↗

Efficacy of high therapeutic doses of iodine-131 in patients with differentiated thyroid cancer and detectable serum thyroglobulin.

Serum thyroglobulin (Tg) is usually the best marker of residual or metastatic disease after treatment of differentiated thyroid cancer. We evaluated the effect of so-called blind therapeutic doses of iodine-131 in patients with detectable Tg during suppressive levothyroxine treatment (Tg-on), and in patients with a negative diagnostic scintigram but detectable Tg during the hypothyroid phase (Tg-off). Twenty-two patients with differentiated thyroid carcinoma underwent total thyroidectomy and radioiodine ablation. During the follow-up, six patients with detectable Tg-on and 16 patients with detectable Tg-off were identified. All patients were treated with a blind therapeutic dose of 7,400 MBq iodine-131. Diagnostic scintigrams were compared with post-treatment scintigrams. Tg-off was measured in 16 cases, 1 year after the administration of the blind therapeutic dose, at the time of the follow-up diagnostic scintigram. Six patients were followed up by Tg-on only. Post-therapy scintigrams revealed previously undiagnosed local recurrence or distant metastases in 13/22 cases (59%); the remaining nine post-therapy scintigrams were negative. At the time of the blind therapeutic doses, Tg-off values ranged from 8 to 608 microg/l. After 1 year of follow-up, Tg-off decreased in 14/16 (88%) patients. In all patients who were followed by Tg-on only (n=6), a decrease in Tg values was measured. It is concluded that blind therapeutic doses resulted in a decrease in Tg levels in the majority of patients with suspected recurrence or metastases. The post-treatment scintigrams revealed pathological uptake in 59% of patients.

Adult↗

Molecular genetic aspects of Von Hippel-Lindau (VHL) disease and criteria for DNA analysis in subjects at risk.

Von Hippel-Lindau (VHL) disease is an autosomal, dominantly inherited tumour syndrome. Carriers of a germline mutation in the VHL tumour suppressor gene tumours are predisposed to develop tumours that are multicentric or bilateral, and manifest at a younger age than in situations without a VHL germline mutation. The mutation spectrum is heterogeneous, with mutations scattered throughout most of the VHL gene. Although some recurrent mutations have been reported, most families have their own unique germline mutation. Tested individuals are no longer uncertain regarding their risk for developing the disease and family members who are non-carriers are relieved of the burden of repeated clinical monitoring.VHL germline mutations are identified in virtually all families and sporadic patients with classic VHL disease, but also in patients who do not meet clinical diagnostic criteria. The chance of finding a VHL germline mutation in (apparently) sporadic patients not fulfilling the criteria increases with: young age at diagnosis, the presence of multi-centric or bilateral tumours, involvement of multiple organs and a positive family history of VHL associated tumours.

Ethics, Medical↗

Clinical management of Von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an autosomal, dominant inherited tumour syndrome with an estimated prevalence of 2-3 per 100,000 persons. A germline mutation in the VHL gene predisposes carriers to tumours in multiple organs. These tumours may include haemangioblastoma in the retina and central nervous system (CNS), renal cell carcinoma, phaeochromocytoma, islet cell tumours of the pancreas, and endolymphatic sac tumours, as well as cysts and cystadenoma in the kidney, pancreas, epididymis and broad ligament. Penetrance of VHL disease is high, most carriers of a VHL germline mutation develop one or more tumours by the age of 60 years. The most common symptoms include: loss of vision, raised intracranial pressure, neurological deficits, paroxysmal raised blood pressure and local pain. At present, metastases from renal cell carcinoma and neurological complications from cerebellar haemangioblastoma are the most common causes of death. However, it is anticipated that intensive radiological and clinical monitoring, and advanced operation techniques will reduce both morbidity and mortality in patients with VHL disease.

Humans↗

Acute dyspnoea resulting from pulmonary oedema as the first sign of a phaeochromocytoma.

The day after undergoing neck dissection, a 42-year-old woman developed acute dyspnoea due to pulmonary oedema. Measurements with a Swan-Ganz catheter revealed not only cardiac depression but also a greatly increased peripheral vascular resistance: 5,400 dyn x s x cm(-5)/m2. A phaeochromocytoma with acute cardiac failure leading to pulmonary oedema was considered. Treatment with alpha- and beta-blockers was complicated by severe hypotension and later ventricular fibrillation. Mechanical ventilation was required for 6 days following resuscitation. Investigation of the urine subsequently showed greatly increased catecholamine concentrations, while imaging revealed bilateral adrenal tumours. Our case history shows that acute pulmonary oedema may be the presenting manifestation of a phaeochromocytoma. The pulmonary oedema resulted partly from backward failure following tachycardia, myocyte necrosis and the greatly increased peripheral vascular resistance, and partly from increased permeability of the capillary network in the lungs.

Adrenal Gland Neoplasms↗

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Humans↗

Medullary thyroid carcinoma: role of genetic testing and calcitonin measurement.

All patients with a thyroid nodule should have their plasma CT measured. Stimulated CT is generally better than basal, but in the lower ranges false negatives and false positives still occur. In families with hereditary MTC, RET gene mutation analysis has superseded measurement of plasma CT in the detection of asymptomatic disease gene carriers. All individuals with apparently sporadic MTC, but in whom there is some suspicion of familial disease, should also have RET genetic analysis. A negative DNA result practically excludes the possibility of hereditary MTC in families where an index case has been investigated and obviates the need for further biochemical evaluation. Disease gene carriers may be divided into three distinct risk groups depending on the specific RET gene mutation in the family. The age at which presymptomatic surgery has to be performed depends on the risk group to which the patient belongs. Compared with the results of DNA analysis, the results of CT stimulation tests have become less important in the assessment of timing of surgery. During follow-up of patients who underwent surgery, measurement of plasma basal CT is still useful. The high sensitivity of measuring stimulated CT levels does not outweigh the burden of life-long periodic stimulation tests and the limited clinical consequences of slightly elevated levels. Stimulation tests are inevitable for persons at risk who prefer not to have genetic testing.

Calcitonin↗

[Diverse expression of multiple endocrine neoplasia type 1].

MEN-1 is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland and the adrenal glands, as well as by neuroendocrine carcinoid tumours. Various clinical manifestations are presented by description of three patients harbouring a MEN1 gene germline mutation. A 44-year-old man had symptoms of hyperparathyroidism and in addition to parathyroid adenomas proved to have tumours in the thymus, adrenal and pituitary glands. A 48-year-old woman from a family with MEN-1 had suffered since her 40th year from headache and heartburn; she appeared to have adenomas in the parathyroid glands and gastrinomas in the pancreas, leading to a Zollinger-Ellison syndrome. One of her relatives, a man aged 29, had suffered from childhood from convulsions due to attacks of hypoglycaemia, and an insulinoma was assessed. In all patients, surgical and/or medical treatment alleviated symptoms. Clearly, the position or nature of the mutations in the MEN1 gene do not correlate with the clinical expression of the disease. Family investigation, DNA analysis and periodic examination improve quality of life and the life expectancy.

Adult↗

[Multiple endocrine neoplasia type 1: recent developments and guidelines for DNA diagnosis and periodic clinical monitoring].

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours. Since the identification of the responsible gene in 1997, the diagnosis MEN-1 can be assessed easily, and even presymptomatically, by DNA analysis. An early diagnosis is of importance because through periodic clinical monitoring of (putative) MEN1 gene germline mutation carriers, tumour development can be detected and treated at an early stage. Eligible for DNA analysis are MEN-1 patients and their family members, as well as patients with seemingly sporadic MEN-1 related tumours in whom on clinical grounds carriership of a MEN1 gene germline mutation is suspected. Eligible for periodic clinical monitoring are putative and confirmed carriers of a MEN1 germline mutation from the age of 5.

Adult↗

[Islet amyloid and diabetes mellitus type 2].

Type 2 diabetes mellitus is a heterogeneous and multifactorial disorder accompanied by severe complications and a reduced life expectancy. Histopathologically, it is characterized by deposition of protein in the islets of Langerhans in the pancreas ('islet amyloid'). The 37 amino acids 'islet amyloid polypeptide' (IAPP) was discovered in 1986 as the building block of islet amyloid. The identification of IAPP caused an intensification of research on islet amyloid. In the past few years, particularly transgenic mouse technology has shown that islet amyloidosis is a consequence as well as an (additional) cause in the pathogenesis of type 2 diabetes. Islet amyloid has turned out to be a pathogenic factor, which is accompanied by death of beta-cells and reduction of the insulin producing capacity. This knowledge offers opportunities for the development of novel (preventive) therapy and thus for a better life expectancy of persons which develop type 2 diabetes.

Amino Acid Sequence↗

Parents' responses to disclosure of genetic test results of their children.

The psychological reactions of 22 parental couples and 3 single parents were investigated after disclosure of genetic test results of their children. The children were tested for the early-onset, monogenetic cancer disorder multiple endocrine neoplasia type 2. Participants came from 13 different families and were aged between 28 and 47 years. Parents who were informed that their child was a gene carrier reacted with resignation, showed moderate to high levels of test-related and general anxiety, but few psychological complaints. Daily activities were disturbed in 43% of the parents with carrier-children. There was little disruption of the parents' future perspective, apart from some socioeconomic disadvantages and increased parental concern for the carrier-children. Most parents with carrier-children showed restraint with respect to short-term prophylactic treatment. Parents with favorable test results showed significantly less anxiety and no disturbance in their daily activities. They did not, however, seem to be reassured by the DNA test result. These parents questioned the reliability of the DNA test, wanted confirmation of the test results, and were eager to continue screening of their noncarrier children. Parents, especially those with a lower level of education and/or a pessimistic view of the future, were distressed by unfavorable test results. Additional counseling is advised to prevent parents of carrier-children worrying unnecessarily, or parents with children in whom the disease gene was not found being not reassured. Am. J. Med. Genet. 94:316-323, 2000.

Adolescent↗

Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice.

Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome, in which the cardinal feature is medullary thyroid carcinoma (MTC), a malignant tumor arising from the calcitonin producing thyroid C-cells. MEN 2B is associated with a germline point mutation in the RET proto-oncogene, leading to a Met-->Thr substitution at codon 918 in the kinase domain, which alters the substrate specificity of the protein. We used the human calcitonin gene (CALC-I) promoter to generate transgenic mice expressing either the human RET oncogene with the MEN2B-specific 918 Met-->Thr mutation (CALC-MEN2B-RET) or the human non-mutated RET proto-oncogene (CALC-WT-RET) in the C-cells. At 20 - 22 months of age three out of eight CALC-MEN2B-RET transgenic founders presented with macroscopic bilateral MTC. In two founders nodular C-cell hyperplasia (CCH) was observed. Thyroid abnormalities were never observed in CALC-WT-RET transgenic mice or control non-transgenic mice analysed at this age. In some mice from established CALC-MEN2B-RET transgenic lines nodular CCH was observed from 8 months on whereas MTC was detected in 13% of mice from one CALC-MEN2B-RET line, from the age of 11 months on. These results show for the first time that the MEN2B mutation in the RET oncogene predisposes mice for MTC.

Animals↗

Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant early-onset cancer disorder. In the Netherlands presymptomatic genetic testing for MEN 2 is offered to testees from the age of five years. We report on adults requesting testing for themselves (n=90) and on parents who want an at-risk child to be tested (n=26). Sociodemographic, personality, and attitude characteristics, and levels of psychological distress, were determined for applicants and their partners in the predisclosure phase of testing. These participants showed only mildly increased levels of psychological distress, defined as heightened scores on measures of general and test-related anxiety, and of psychological complaints. Compared with a normal population, high levels of anxiety and health complaints were found in applicants who were younger than 25 years and single, and in persons who generally tended to react to distressful situations with anxiety or depression. These characteristics were particularly evident in young applicants (<25 years). Our study shows that people who feel ambivalent towards DNA testing and who are more vulnerable to psychological distress are more likely to agree to participate in the test as part of a collective application by members of a hereditary cancer family.

Adolescent↗

Pseudohypoparathyroidism type Ia. Albright hereditary osteodystrophy: a model for research on G protein-coupled receptors and genomic imprinting.

Pseudohypoparathyroidism type Ia (PHP Ia) is a hereditary endocrine disorder, characterised by resistance to parathyroid hormone (PTH), causing disturbance of calcium homeostasis, and to several other polypeptide hormones. Patients with PHP Ia exhibit a complex of somatic abnormalities, termed Albright hereditary osteodystrophy (AHO). Treatment with vitamin D derivatives alleviates symptoms of hypocalcemia and may prevent bone demineralisation. PTH, like many polypeptide hormones, exerts its effects via a G protein-coupled cell surface receptor. PHP Ia is caused by a heterozygous, inactivating mutation in the gene for the alpha-subunit of the Gs protein, which disrupts Gs-protein-coupled signal transduction pathways. Several mutations have been described. When the mutation is inherited from the mother, the offspring will develop PHP Ia, i.e., both hormonal resistance and somatic abnormalities. When the mutation is derived from the father, children will have normal hormone responses while exhibiting the somatic features of AHO; this form of the disorder is called pseudopseudohypoparathyroidism (PPHP). A combination of tissue-specific genomic imprinting and haploinsufficiency may explain the occurrence of PPHP, and the fact that not all Gs-mediated polypeptide hormone actions are affected equally. PHP may therefore serve as a model in studying the pleiotropic consequences of impaired Gs-mediated signal transduction.

Calcium↗

Criteria for mutation analysis in MEN 1-suspected patients: MEN 1 case-finding.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal, dominantly inherited cancer syndrome, with tumours in various endocrine glands. In 1997 the responsible tumour suppressor gene was identified. MEN1 gene germ-line mutations are detected in the vast majority of MEN 1 patients, however, with regard to case-finding, unfortunately only at a very low frequency in patients with apparently sporadic MEN 1-related tumours. In order to increase the detection rate of disease gene carriers among patients with apparently sporadic MEN 1-related tumours, clinical criteria were needed. DESIGN AND RESULTS: In this study MEN1 gene germ-line mutations were revealed in 16/16 MEN 1 patients/families (100%). Based on our clinical experience with MEN 1 patients/families we formulated clinical criteria to identify disease gene carriers among patients with apparently sporadic MEN 1-related tumours. The criteria for MEN 1-suspected patients are: young age at onset (< 35 years) and/or multiple MEN 1-related lesions in a single organ or two distinct organs affected. Application of these criteria yielded MEN1 gene germ-line mutations in nine of 15 MEN 1-suspected patients (60%), thus identifying novel MEN 1 families. Follow up was also guaranteed for patients not fulfilling these criteria. CONCLUSIONS: The clinical criteria for MEN 1-suspected patients increase the detection rate of germ-line MEN1 gene mutations among patients with apparently sporadic MEN 1-related tumours. These criteria may be used for (presymptomatic) identification of MEN 1 disease gene-carriers, thus enabling early detection of tumour development and timely treatment, as well as genetic counselling.

Adult↗