[Is there more to hypodontia then missing teeth?] / Ernstige hypodontie: meer dan alleen ontbrekende gebitselementen?

Dental care professionals regularly see patients with hypodontia. Hypodontia can be acquired, for example through chemotherapy or radiation at a young age, but is hereditary in most patients. Due to an error (pathogenic variant) in one of the many genes that control odontogenesis, the formation of the tooth germ is disrupted at an early stage. The genes involved are not only crucial for tooth development, but they also play an important role in other physical processes. This article provides background information on hypodontia. Based on an inventory of gastrointestinal complaints in patients with hypodontia and a case description of the simultaneous occurrence of a coagulation disorder and hypodontia, the importance of a broad view of this patient group is illustrated. It is concluded that, in addition to a dental assessment, examination of these patients should include a limited physical examination and the medical history of the patient and his close relatives.

Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity.

BACKGROUND: Mutations in the leptin-melanocortin pathway genes are known to cause monogenic obesity. The prevalence of these gene mutations and their effect on weight loss response after bariatric surgery are still largely unknown. OBJECTIVE: To determine the prevalence of genetic obesity in a large bariatric cohort and evaluate their response to bariatric surgery. METHODS: Mutation analysis of 52 obesity-associated genes. Patient inclusion criteria were a BMI > 50 kg/m2, an indication for revisional surgery or an early onset of obesity (< 10 years of age). RESULTS: A total of 1014 patients were included, of whom 30 (3%) were diagnosed with genetic obesity, caused by pathogenic heterozygous mutations in either MC4R, POMC, PCSK1, SIM1, or PTEN. The percentage total body weight loss (%TBWL) after Roux-en-Y gastric bypass (RYGB) surgery was not significantly different for patients with a mutation in MC4R, POMC, and PCSK1 compared with patients lacking a molecular diagnosis. Of the confirmed genetic obesity cases, only patients with MC4R mutations receiving a sleeve gastrectomy (SG) showed significantly lower %TBWL compared with patients lacking a molecular diagnosis, during 2 years of follow-up. CONCLUSIONS: In this cohort of morbid obese bariatric patients, an estimated prevalence of monogenic obesity of 3% is reported. Among these patients, the clinical effects of heterozygous mutations in POMC and PCSK1 do not interfere with the effectiveness of most commonly performed bariatric procedures within the first 2 years of follow-up. Patients with MC4R mutations achieved superior weight loss after primary RYGB compared with SG.

Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines.

BACKGROUND: Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. METHODS: In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85-100% of all MADB patients and minor criteria as those present in 70-84% of patients. RESULTS: All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria. CONCLUSIONS: We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency.

STUDY QUESTION: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? SUMMARY ANSWER: No association was found between CGG repeats of intermediate size and POI compared with controls. WHAT IS KNOWN ALREADY: CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. STUDY DESIGN, SIZE: A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause ≥40 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause ≥40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher's exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (ß = -0.018, P = 0.74). LIMITATIONS, REASONS FOR CAUTION: FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. WIDER IMPLICATIONS OF THE FINDINGS: We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. STUDY FUNDING/COMPETING INTERESTS: The Prospect-EPIC study was funded by 'Europe Against Cancer' Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association.

The association of CGG repeats in the FMR1 gene and timing of natural menopause.

STUDY QUESTION: Is there an association between the number of CGG repeats in the FMR1 gene in the normal and intermediate range and age at natural menopause? SUMMARY ANSWER: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. WHAT IS KNOWN ALREADY: Excessive triple CGG repeats in the FMR1 gene have been widely associated with primary ovarian insufficiency. Recently, the number of CGG repeats in the normal and intermediate range (up to 55 repeats) was found to be associated with serum levels of anti-Müllerian hormone and follicle-stimulating hormone, as markers for ovarian ageing. This suggests that repeats in the normal and intermediate range could be involved in the rate of exhaustion of the ovarian primordial follicle pool and ultimately the timing of menopause. STUDY DESIGN, SIZE: Cross-sectional study in a population-based sample of 3611 Caucasian women with natural menopause. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in 3611 women with a known age at natural menopause. A possible relation between CGG repeats in the normal and intermediate range (up to 55 repeats) and menopausal age were analysed in various ways, including linear regression analysis and analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The number of CGG repeats in the normal and intermediate range in the FMR1 gene was not associated with age at natural menopause. The mean age at menopause was 50.30 (± 4.2) years for women with <45 repeats and 50.64 (± 3.4) years for women with intermediate-sized repeats (P = 0.37). Linear regression analysis of the number of CGG repeats showed no association with menopausal age (ß = 0.019, P = 0.16). LIMITATIONS, REASONS FOR CAUTION: In our cohort, age at menopause was self-reported and determined retrospectively. WIDER IMPLICATIONS OF THE FINDINGS: Earlier observations suggesting that the number of CGG repeats in the normal and intermediate range is associated with the individual variation of the ovarian ageing process could not be confirmed in the current, large sample size study. A relation between the number of CGG repeats in the normal and intermediate range and age at natural menopause appeared to be absent. This finding questions the role of CGG repeat sizes in the ovarian ageing process.

A novel germline mutation of PTEN associated with brain tumours of multiple lineages.

We have identified a novel germline mutation in the PTEN tumour suppressor gene. The mutation was identified in a patient with a glioma, and turned out to be a heterozygous germline mutation of PTEN (Arg234Gln), without loss of heterozygosity in tumour DNA. The biological consequences of this germline mutation were investigated by means of transfection studies of the mutant PTEN molecule compared to wild-type PTEN. In contrast to the wild-type molecule, the mutant PTEN protein is not capable of inducing apoptosis, induces increased cell proliferation and leads to high constitutive PKB/Akt activation, which cannot be increased anymore by stimulation with insulin. The reported patient, in addition to glioma, had suffered from benign meningioma in the past but did not show any clinical signs of Cowden disease or other hereditary diseases typically associated with PTEN germline mutations. The functional consequences of the mutation in transfection studies are consistent with high proliferative activity. Together, these findings suggest that the Arg234Gln missense mutation in PTEN has oncogenic properties and predisposes to brain tumours of multiple lineages.

Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families.

BACKGROUND: Autosomal dominant cerebellar ataxias (ADCAs), or spinocerebellar ataxias (SCAs), are a heterogeneous group of neurodegenerative disorders. Mild CAG repeat expansions in the alpha(1A) voltage-dependent calcium channel gene are associated with SCA type 6 (SCA6). OBJECTIVE: To obtain further insight into the contribution of SCA6 mutations to the phenotypic variability in Dutch patients with ataxia. DESIGN: Survey and case series. SETTING: Hospitalized care, referral center. PATIENTS AND METHODS: The SCA6 locus was analyzed for CAG repeat expansions in a referred sample of 220 Dutch families with progressive cerebellar ataxia. Clinical characteristics of patients with SCA6 were investigated and correlated with molecular findings. RESULTS: The diagnosis SCA6 was confirmed in 24 families comprising 30 familial and 4 sporadic cases. Mean +/- SD age at onset was 50.1 +/- 11.1 years. Expanded CAG repeats with sizes 22, 23, and 25 were found. These sizes correlated inversely with age at onset. No intergenerational changes in CAG repeat size were detected. Despite this, 2 families showed clinical anticipation. CONCLUSIONS: This study provides the first detailed description of Dutch patients with SCA6. Clinical analysis identifies SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early manifestations. No single clinical sign can be considered specific for SCA6. Some patients have ataxia combined with episodic headaches or nausea, suggesting an overlap among SCA6, eposidic ataxia type 2, and familial hemiplegic migraine. Spinocerebellar ataxia type 6 accounts for approximately 11% of all Dutch families with ADCA. Analysis of SCA6 contributes further to the genetic classification of patients with ADCA, including patients without a clear family history of the disease.

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates.

Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 micromol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH4) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH4 loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH4 load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH4 biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1-4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH4.

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.

Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children.

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. METHODS: Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. RESULTS: The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. CONCLUSIONS: These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.

A diagnostic protocol for adult-onset glycogen storage disease type II.

To analyze the diagnostic value of various laboratory tests for the confirmation of adult-onset glycogen storage disease type II (GSD II), we performed a clinical, biochemical, and genetic study of 18 patients with this disease. Measurement of acid alpha-glucosidase (GAA) activity in muscle and histopathologic analysis of muscle tissue appeared to have no additional value when GAA activity in leukocytes was clearly deficient. Our study showed that creatine kinase elevation is a sensitive marker of GSD II. A diagnostic protocol is formulated.

Polymorphic detection of a parthenogenetic maternal and double paternal contribution to a 46,XX/46,XY hermaphrodite.

True hermaphroditism in humans usually is associated with a 46,XX karyotype or with mosaicism in which admixtures of cells with an XX and an XY karyotype are seen. However, the mechanisms that cause such mosaicisms are poorly understood. To date, with rare exceptions, analyses of hermaphrodites have been limited mostly to cytogenetic investigations. In this report, we describe a 5-year-old patient with true hermaphroditism and a 46,XX/46,XY karyotype (ratio 38:12) in lymphocytes, suggesting involvement of two fertilization events. Microsatellite DNA polymorphisms distributed throughout the genome were analyzed, to investigate the origin of the cell lines concerned. The results are consistent with double paternal and single maternal genetic contributions. Possible mechanisms that would explain these findings are discussed. The most likely mechanism involves a single haploid ovum dividing parthenogenetically into two haploid ova, followed by double fertilization and fusion of the two zygotes into a single individual, at the early embryonic stage.

Mutation analysis for prenatal diagnosis of hereditary tyrosinaemia type 1.

Hereditary tyrosinaemia type 1 is a rare but serious metabolic disorder with an autosomal recessive mode of inheritance. We describe the prenatal diagnosis of an affected fetus performed by DNA-mutation analysis and a subsequent pregnancy with a healthy child in the same family.

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype.

Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family.

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Familial MTC (FMTC) is characterized by MTC only. Both MEN 2A and FMTC are caused by germline mutations of the RET proto-oncogene. PURPOSE: To assess genotype/phenotype correlations, large families have to be examined periodically over a long period using an extensive screening program. PATIENTS AND METHODS: Since 1973, we screened a large family with hereditary C cell carcinoma for MTC, pheochromocytoma, and parathyroid disease by clinical tests and imaging methods. A germline codon Cys618 to Ser mutation in the RET proto-oncogene was recently identified in this family. The disease phenotype associated with this mutation was compared with that of Cys634 mutations in some other large MEN 2A families. RESULTS: The distinct course of disease in the family described here is similar to that in other FMTC families and MEN 2A families with a Cys618 mutation of the RET gene, but clearly different from that in families with a Cys634 mutation. The frequency of pheochromocytomas and parathyroid disease is clearly lower, whereas cure rates and life expectancy are higher. However, in families with a Cys618 mutation, pheochromocytoma and parathyroid disease do occur. CONCLUSION: In FMTC families with cysteine codon mutations of the RET proto-oncogene, screening for other endocrinopathies is mandatory, since these may not be MTC-only families. Therefore, we suggest that MEN 2A families should not be subclassified into MEN 2A and FMTC, but rather according to their specific mutation in the RET protein (i.e., for this family MEN 2A RET C618S).

The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

OBJECTIVE: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. DESIGN: Correlative survey study of 477 MEN 2 families. SETTING: Eighteen tertiary referral centers worldwide. PATIENTS: A total of 477 independent MEN 2 families. MAIN OUTCOME MEASURES: Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. RESULTS: There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. CONCLUSIONS: This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.