Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1.

Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with a pathogenic or suspicious rare variant in LRP5, PLS3, or WNT1. In addition, the aim was to compare their medical care utilization to both the overall Dutch population and the Dutch Osteogenesis Imperfecta (OI) population. The Amsterdam UMC Genome Database was used to match 92 patients with the Statistics Netherlands (CBS) cohort. Patients were categorized based on their harbored variants: LRP5, PLS3, or WNT1. Hospital admissions, outpatient visits, medication data, and diagnosis treatment combinations (DTCs) were compared between the variant groups and, when possible, to the total population and OI population. Compared to the total population, patients with an LRP5, PLS3, or WNT1 variant had 1.63 times more hospital admissions, 2.0 times more opened DTCs, and a greater proportion using medication. Compared to OI patients, they had 0.62 times fewer admissions. Dutch patients with an LRP5, PLS3, or WNT1 variant appear to require on average more medical care than the total population. As expected, they made higher use of care at the surgical and orthopedic departments. Additionally, they used more care at the audiological centers and the otorhinolaryngology (ENT) department, suggesting a higher risk of hearing-related problems.

Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers.

BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers. METHODS: In order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms. RESULTS: Preclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset. CONCLUSIONS: EBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3.

Further audiovestibular characterization of DFNB77, caused by deleterious variants in LOXHD1, and investigation into the involvement of Fuchs corneal dystrophy.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

Informed consent for exome sequencing in diagnostics: exploring first experiences and views of professionals and patients.

Next-generation sequencing is increasingly being chosen as a diagnostic tool for cases of expected genetic, but unresolved origin. The consequential increased need for decisions on disclosure of unsolicited findings poses a challenge for the informed consent procedure. This study explored the first experiences with, and needs for, the informed consent procedure in diagnostic exome sequencing, with the stakeholders involved. Semi-structured interviews were conducted with 11 professional experts and one professional gave a written response. Furthermore, the counseling process was observed in three cases where exome sequencing was offered, followed by interviews with the patient (representative) and the genetic counselor. The respondents not only preferred an opt-out for unsolicited findings but also identified many challenges and therefore more experiences with exome sequencing was considered needed. Context-dependent decision-making was observed and an Advisory Board for unsolicited findings was considered helpful while doubts were raised about the feasibility and the possibility of undermining patients' autonomy. Finally, respondents brought up the complexity of information provision, and division of responsibilities between clinicians and the lab. These challenges and needs, raised by stakeholders involved, provide more insight in the next steps needed for an optimal informed consent procedure for exome sequencing in diagnostics.

Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

[Maternal uniparental disomy 14; differential diagnosis with Prader-Willi syndrome]. / Maternale uniparentale disomie 14. In de differentiaaldiagnose bij Prader-Willi-syndroom.

BACKGROUND: Maternal uniparental disomy 14 is a rare genetic disorder in which both chromosomes 14 are maternally inherited. The disorder is characterised by neonatal hypotonia and feeding difficulties, intrauterine or later growth retardation, truncal obesity and precocious puberty. During the neonatal period its clinical phenotype shows great similarities with that of Prader-Willi syndrome. CASE DESCRIPTION: We describe two patients with dysmaturity, neonatal hypotonia and feeding difficulties who initially showed clinical signs of Prader-Willi syndrome. However, molecular testing for this disorder was normal. Some years later, additional molecular testing confirmed the diagnosis of maternal uniparental disomy 14. CONCLUSION: Maternal uniparental disomy 14 shows many phenotypic similarities with Prader-Willi syndrome. In a hypotonic neonate, molecular testing for maternal uniparental disomy 14 should therefore be considered if Prader-Willi syndrome has been excluded.

The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries.

Polycystic ovaries contain a larger number of antral follicles than control ovaries. The aim of this study was to test whether the increase in estradiol (E(2)) and inhibin B after stimulation with 300 IU recombinant FSH in the early follicular phase and the ovarian volume can predict the size of the follicle cohort in polycystic ovary syndrome (PCOS) patients (n = 10), patients with polycystic ovaries detected by ultrasound but with regular menstrual cycles (PCO; n = 10), and regularly menstruating patients with normal ovaries (n = 10). The follicle cohort size was measured as the FSH-sensitive follicles growing during a standardized in vitro fertilization stimulation. Linear regression analysis showed that the slopes of the regression lines of the E(2) increment and the inhibin B increment in relation to the number of follicles were not significantly different among the three groups, meaning that an increased sensitivity for FSH of the granulosa cells of polycystic ovaries was not found. For the total group (n = 30) we calculated that an E(2) increment of 100 pmol/L predicts 5.5 follicles (95% confidence interval, 2.8--8.2; r = 0.617; P < 0.001), and an inhibin B increment of 100 ng/L predicts 6.2 follicles (95% confidence interval, 3.5--9.0; r = 0.665; P < 0.001). The ovarian volume could not be used in a prediction model because the association with the number of follicles was different in the PCO group compared with the PCOS and the control group. Women with PCO and women with PCOS both had a follicle cohort twice as big as the cohort in control women (P < 0.01). The differences in menstrual cycle pattern between the PCO and PCOS groups cannot be explained by differences in cohort size.

Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study was to investigate if ageing women with polycystic ovary syndrome (PCOS) who gained regular menstrual cycles differed from women who continued to menstruate irregularly with regard to risk factors for developing diabetes mellitus and atherosclerosis. DESIGN AND PATIENTS: In the original study of a population of 346 PCOS patients, defined in the past as having oligo- or amenorrhoea and elevated LH concentrations, we had sent out a questionnaire to investigate changes in the pattern of their menstrual cycles while ageing. From this cohort of patients, a significantly older group of 53 women (mean age: 41.3 years, range: 33.3-49.4) who were not using oral contraceptives or other hormones visited the outpatient clinic. These women did not differ from the non-participating group in BMI, ethnic origin, the proportion with regular menstrual cycles by age group, parity or the use of clomiphene citrate or gonadotrophins in the past. MEASUREMENTS: A physical examination and a transvaginal ultrasound were performed. The size of the follicle cohort was determined by counting the number of small follicles in the ovaries. Thirty-four women were also willing to give two fasting blood samples for measuring their glucose, insulin and lipid status. RESULTS: Forty-one of the 53 (77.4%) women had a regular menstrual cycle (shorter than 6 weeks) and 12 (22.6%) had an irregular cycle (longer than 6 weeks). The body mass index (BMI), waist: hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of diabetes (1-9%) and hypertension (11.3%) did not differ between the two menstrual cycle groups. Also, the fasting glucose, insulin, glucose/insulin ratio, total cholesterol, HDL-c, and LDL-c concentrations did not show any significant difference between the two groups. Instead, these parameters all were significantly higher in women with a BMI > 27 kg/M2 compared to women with a BMI < or = 27 kg/m2. Regularly menstruating PCOS women were older (P < 0.01), showed less follicles in their ovaries (n = 48, P < 0.01) and had lower androgens (n = 34, P < 0.05) than the irregularly menstruating women. Logistic regression analysis showed a second significant influence, after age, of the BMI on the menstrual cycle pattern (age, P < 0.01; BMI, P < 0.05). If age was excluded from the analysis, only the follicle count significantly predicted the menstrual cycle pattern (P < 0.02). CONCLUSIONS: We conclude that hyperinsulinaemia, dyslipidaemia and hypertension in our population of ageing women with polycystic ovary syndrome are not related to the menstrual cycle pattern but rather to obesity. Age and the size of the follicle cohort are the main factors determining the menstrual cycle pattern in ageing women with polycystic ovary syndrome, although an association with the BMI was also found.

Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population.

The aim of this study was to investigate the prevalence of diabetes mellitus, hypertension and cardiac complaints in a Dutch population with polycystic ovarian syndrome (PCOS) and to compare the results with the prevalence of these conditions in the Dutch female population, as retrieved from the Netherlands Health Interview Survey of Statistics Netherlands. A total of 346 PCOS patients were interviewed by telephone, with a mean age of 38.7 years (range 30.3--55.7) and a mean body mass index of 24.4 (range 17.5--55.8). Diabetes occurred in eight (2.3%), hypertension in 31 (9%) and cardiac complaints in three (0.9%) of the women. The prevalence of diabetes and hypertension differed significantly from the prevalence of these conditions in the Dutch female population (both P < 0.05). In PCOS women aged 45--54 years (n = 32) the prevalence of diabetes was four times higher (P < 0.05) and of hypertension 2.5 times higher (P < 0.01) than the prevalence of these conditions in the corresponding age group of the Dutch female population. Hypertension also occurred significantly (P < 0.05) more in the younger (35--44 years) PCOS group (n = 233), but this age group was significantly more obese (P < 0.01) when compared with figures of obesity of the Dutch female population. In conclusion, our data show that in a follow-up study of a relatively lean PCOS population, the prevalence of diabetes mellitus and hypertension was increased when compared with the Dutch female population, especially in women aged 45--54 years.

Women with polycystic ovary syndrome gain regular menstrual cycles when ageing.

The aim of this study was to investigate if previously oligo- or amenorrhoeic polycystic ovary syndrome (PCOS) patients gain regular menstrual cycles when ageing. Women registered as having PCOS, based on the combination of oligo- or amenorrhoea and an increased LH concentration, were invited by letter to participate in a questionnaire by telephone. In this questionnaire we asked for the prevalent menstrual cycle pattern, which we scored in regular cycles (persistently shorter than 6 weeks) or irregular cycles (longer than 6 weeks). We interviewed 346 patients of 30 years and older, and excluded 141 from analysis mainly because of the use of oral contraceptives. The remaining 205 patients showed a highly significant linear trend (P < 0.001) for a shorter menstrual cycle length with increasing age. Logistic regression analysis for body mass index, weight loss, hirsutism, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy, ethnic origin and smoking showed no influence on the effect of age on the regularity of the menstrual cycle. We conclude that the development of a new balance in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of regular cycles in older patients with PCOS.

Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study.

BACKGROUND: This study was designed to compare endocrine tests [clomiphene citrate challenge test (CCT), exogenous FSH ovarian reserve test (EFORT) and basal FSH, basal estradiol (E(2)) and basal inhibin B as an integral part of all CCT and EFORT], with respect to their ability to estimate the stimulable cohort of follicles in the ovaries (ovarian capacity) and to analyse which test or combination of tests would give the best prediction of ovarian capacity. METHODS: A total of 110 regularly menstruating patients, aged 18-39 years, participated in this prospective study, randomized by a computer-designed 4-block system study into two groups. Fifty-six patients underwent a CCT, and 54 patients underwent an EFORT. In all patients, the test was followed by an IVF treatment. The result of ovarian hyperstimulation during IVF treatment, expressed by the total number of follicles, was used as gold standard. RESULTS: Univariate linear regression analysis showed that the best correlation with the number of follicles after ovarian hyperstimulation (Y) is found by the inhibin B increment (InhB incr.) in the EFORT (Y = 3.957 + 0.081 x InhB incr. (95% CI 0.061-0.101); r = 0.751; P < 0.001). Multiple linear regression analysis showed a significant contributing value of the variables basal FSH, E(2) increment of the EFORT and inhibin B increment to the basic model with the variable age. The best prediction of ovarian capacity (Y) was seen when E(2) increment and inhibin B increment were used simultaneously in a stepforward multiple regression prediction model [Y = 2.659 + 0.052 x InhB incr. (0.026-0.078) + 0.027 x E(2) incr. (95% CI 0.012-0.054); r = 0.796; P < 0.001]. The CCT could not be used in a prediction model. CONCLUSIONS: The EFORT is the endocrine test which gives the best prediction of ovarian capacity.