Dementia in a woman with Prader–Willi syndrome

We report on a 58-year-old woman with Prader–Willi syndrome (PWS) and dementia.This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dementia forms indeed occur more prevalent in people with PWS.     

The importance of gynecological examination in adolescent girls and adult women with Prader–Willi syndrome

Current published guidelines for routine care of women with Prader–Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020–2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3–39], BMI 30.4 kg/m² [IQR 23.5–37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16–39. Median spine T score was −1.3 (range between 0.5 and −3.7), and hip T score was −1.2 (range between 0.8 and −3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = −0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.     

The use of medical care and the prevalence of serious illness in an adult Prader–Willi syndrome cohort

IntroductionAdults with Prader–Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness.MethodParticipants were contacted via the Dutch Prader–Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS.ResultsThe need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions.DiscussionPeople with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing conditions and recognizing conditions in an early stage. Adequate preventive management and treatment of PWS related morbidity, could reduce medical care use in the long term and could improve quality adjusted life years.     

Mosaicism for maternal uniparental disomy 15 in a boy with some clinical features of Prader–Willi syndrome

Prader–Willi syndrome (PWS) is caused by the lack of paternal expression of imprinted genes in the human chromosomal region 15q11.2–q13.2, which can be due to an interstitial deletion at 15q11.2–q13 of paternal origin (65–75%), maternal uniparental disomy (matUPD) of chromosome 15 (20–30%), or an imprinting defect (1–3%). The majority of PWS-associated matUPD15 cases represent a complete heterodisomy of chromosome 15 or a mixture of hetero- and isodisomic regions across the chromosome 15. Pure maternal isodisomy is observed in only a few matUPD15 patients. Here we report a case of an 18-year-old boy with some clinical features of Prader–Willi syndrome, such as overweight, muscular hypotonia, facial dysmorphism and psychiatric problems, but there was no reason to suspect PWS in the patient based solely on the phenotype estimation. However, chromosomal microarray analysis (CMA) revealed mosaic loss of heterozygosity of the entire chromosome 15. Methylation-specific multiplex ligation-dependant probe amplification (MS-MLPA) analysis showed hypermethylation of the SNRPN and NDN genes in the PWS/AS critical region of chromosome 15 in this patient. Taking into consideration the MS-MLPA results and the presence of PWS features in the patient, we concluded that it was matUPD15, although the patient's parents were not enrolled in the study. According to CMA and karyotyping, no trisomic or monosomic cells were present. To the best of our knowledge, only two PWS cases with mosaic maternal isodisomy 15 and without trisomic/monosomic cell lines have been reported so far.     

Highly restricted deletion of the SNORD116 region is implicated in Prader–Willi Syndrome

The SNORD116 locus lies in the 15q11-13 region of paternally expressed genes implicated in Prader–Willi Syndrome (PWS), a complex disease accompanied by obesity and severe neurobehavioural disturbances. Cases of PWS patients with a deletion encompassing the SNORD116 gene cluster, but preserving the expression of flanking genes, have been described. We report a 23-year-old woman who presented clinical criteria of PWS, including the behavioural and nutritional features, obesity, developmental delay and endocrine dysfunctions with hyperghrelinemia. We found a paternally transmitted highly restricted deletion of the SNORD116 gene cluster, the shortest described to date (118 kb). This deletion was also present in the father. This finding in a human case strongly supports the current hypothesis that lack of the paternal SNORD116 gene cluster has a determinant role in the pathogenesis of PWS. Moreover, targeted analysis of the SNORD116 gene cluster, complementary to SNRPN methylation analysis, should be carried out in subjects with a phenotype suggestive of PWS.     

Spatial Competences in Prader–Willi Syndrome: A Radial Arm Maze Study

The present study was aimed at investigating the spatial abilities in Prader–Willi syndrome (PWS) by using the Radial Arm Maze (RAM) task. We trained PWS individuals with the deletion subtype in two different RAM paradigms that tapped different aspects of spatial memory. To evaluate the extent of spatial deficit in PWS individuals, it seemed interesting to compare their performances with those of individuals with Williams syndrome (WS) in which deficits in spatial abilities have been well described. The two syndromic groups were compared to typically developing (TD) individuals mental-age and gender matched. The findings evidenced the impairment of PWS individuals in solving the RAM task with variable severity depending on the paradigm requests. Since the RAM is a task that allows the acquisition of spatial competences through the movement, we advance that the spatial deficits observed in PWS individuals may be related to the malfunctioning of spatial and motor integrative processing.     

Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution?

Does the manipulation of gametes and embryos as practised in human IVF invoke perturbations in fetal and neonatal phenotype? There is increasing evidence that the answer is 'yes', although the degree of perturbation may be less acute than observed in other species. However, the long-term consequences are not known, and may prove to be considerable. There is now a substantial body of evidence from animal models suggesting that assisted reproductive technologies (ART) are associated with altered outcomes in fetal and neonatal development. Epigenetic modification of gene expression is an attractive hypothesis that accounts for these differences and is one of a number of causal pathways that may be activated by cellular stress invoked during manipulation. Here we widen the debate to propose that environment-induced cellular stress also acts to modify fetal and placental gene expression, potentially also contributing to phenotype skewing after ART.     

Do placentae of term singleton pregnancies obtained by assisted reproductive technologies differ from those of spontaneously conceived pregnancies?

The study was conducted to investigate the association of placental morphological and histopathological features with term, singleton pregnancies obtained by assisted reproductive technologies (ART). The study group comprised 45 consecutive women with a singleton pregnancy, obtained by ART, who delivered at term. For each subject in the study group, the consecutive, matched-for-age-and-parity woman, with a term singleton, spontaneously conceived pregnancy served as the controls. The placentae of both groups were subject to a detailed morphological and histopathological investigation by one pathologist, who was blinded to specimen origin. Pregnancy complications, fetal weight and perinatal outcome were similar in both groups. No differences in morphological or histopathological features of the placenta were observed between the groups. Nevertheless, the placentae of the study group showed a borderline, significantly higher placental weight and placental:fetal weight ratio, and placental thickness was significantly higher. Abnormal umbilical cord insertion was significantly more prevalent in the study group. Neither the specific ART method employed, nor the infertility factor affected the results, suggesting that multiple embryo transfers and/or ovulation induction protocols may account for these differences.     

Artificial intelligence–assisted phenotype discovery of fragile X syndrome in a population-based sample

PurposeFragile X syndrome (FXS), the most prevalent inherited cause of intellectual disability, remains underdiagnosed in the general population. Clinical studies have shown that individuals with FXS have a complex health profile leading to unique clinical needs. However, the full impact of this X-linked disorder on the health of affected individuals is unclear and the prevalence of co-occurring conditions is unknown.MethodsWe mined the longitudinal electronic health records from more than one million individuals to investigate the health characteristics of patients who have been clinically diagnosed with FXS. Additionally, using machine-learning approaches, we created predictive models to identify individuals with FXS in the general population.ResultsOur discovery-oriented approach identified the associations of FXS with a wide range of medical conditions including circulatory, endocrine, digestive, and genitourinary, in addition to mental and neurological disorders. We successfully created predictive models to identify cases five years prior to clinical diagnosis of FXS without relying on any genetic or familial data.ConclusionAlthough FXS is often thought of primarily as a neurological disorder, it is in fact a multisystem syndrome involving many co-occurring conditions, some primary and some secondary, and they are associated with a considerable burden on patients and their families.     

Frequency of de novo variants and parental mosaicism in vascular Ehlers–Danlos syndrome

PurposeVascular Ehlers–Danlos syndrome (vEDS) is a rare inherited autosomal dominant disorder caused by COL3A1 pathogenic variants. A high percentage of de novo cases has been suggested. Part of it could be due to parental mosaicism, but its frequency is unknown.MethodsThis retrospective study included a large series of COL3A1-confirmed vEDS probands with family information. The frequency of de novo cases was evaluated and the distribution of the type of variants was compared according to the mode of inheritance. The COL3A1 mosaicism was studied by deep targeted next- generation sequencing (NGS) from parental blood DNA.ResultsOut of 177 vEDS probands, 90 had a negative family history, suggesting a high rate (50.8%) of de novo pathogenic variants, enriched in the more severe COL3A1 variants (no null variant). Among those, both parental DNA were available in 36 cases and one parental DNA in 18 cases. NGS detected only one mosaicism from maternal blood DNA (allelic ratio 18%), which was confirmed in saliva (allelic ratio 22%).ConclusionvEDS is characterized by a high frequency of de novo pathogenic variants. Parental mosaicism is rare (2–3%), but should be systematically searched with targeted NGS, taking into account its importance in genetic counseling.     

Do monochorionic dizygotic twins increase after pregnancy by assisted reproductive technology?

Although monochorionic (MC) dizygotic twins (DZT) are extremely rare in natural pregnancy, six pairs of such twins have successively been reported in a recent short period. All six cases of MC DZT were the products of pregnancy by assisted reproductive technology (ART). In this overview, we summarize these six cases and discuss possible mechanisms of this twinning and clinical implications of confined blood cell chimerism (CBC). The placental MC membrane was diagnosed ultrasonographically in all cases and pathologically in four. The presence of CBC was confirmed in four cases by haplotyping at polymorphic marker loci in peripheral blood leukocytes, karyotyping of lymphocytes and skin fibroblasts, and/or ABO blood group typing. As CBC is attributable to placental vessel anastomosis between DZT, it may become a risk factor for twin–twin transfusion syndrome (TTTS), mortality, and for other complications in twins. MC DZT may produce psychological trauma, especially in a girl/woman when she grows up and is known to be chimeric for a male karyotype and vice versa, although genital organs are generally normal—unlike freemartin in cattle. In addition, CBC in twins may mislead physicians when genotyping for a disease-susceptibility test is performed in medical practice in the near future. Blood group chimera may also cause confusion if a blood transfusion is necessary. Therefore, sufficient informed consent prior to ART and genetic counseling before/after birth are absolutely necessary for improved quality of life. It is most likely that all six cases are the consequence of fusion between two outer cell masses from two zygotes. The ART used in the six MC DZT included in vitro fertilization-embryonic transfer (IVF-ET) into the uterus, FSH-induced superovulation followed by intrauterine insemination, and/or intracytoplasmic sperm injection (ICSI). The use of an ovulation-inducing agent and implantation of several fertilized eggs at close sites are probably the events common among these cases. Assisted hatching, simultaneous ET, the use of eggs that have developed to the blastcyst stage, and cell culture procedures that lead to changes of the nature of cell surface, all may increase the chance of a cell fusion. This chance hypothesis can simply explain why MC DZT are very rare in natural pregnancy. Large-scale research on the prevalence of ART-associated MC DZT and long-term follow-up of the twins are essential.     

Anti-Müllerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology

BACKGROUND: Recently, a new marker, the anti-Müllerian hormone (AMH), has been evaluated as a marker of ovarian response. Serum AMH levels have been measured at frequent time-points during the menstrual cycle, suggesting the complete absence of fluctuation. The aim of this study was to evaluate whether serum AMH measurement on any day of the menstrual cycle could predict ovarian response in women undergoing assisted reproductive technology (ART). METHODS: This study included 48 women attending the IVF/ICSI programme. Blood withdrawal for AMH measurement was performed in all the patients independently of the day of the menstrual cycle. RESULTS: Women in the lowest AMH quartile (<0.4 ng/ml) were older and required a higher dose of recombinant FSH than women in the highest quartile (>7 ng/ml). All the cancelled cycles due to absent response were in the group of the lowest AMH quartile, whereas the cancelled cycles due to risk of ovarian hyperstimulation syndrome (OHSS) were in the group of the highest AMH quartile. This study demonstrated a strong correlation between serum AMH levels and ovarian response to gonadotrophin stimulation. CONCLUSION: For the first time, clinicians may have a reliable serum marker of ovarian response that can be measured independently of the day of the menstrual cycle.     

What is the most relevant standard of success in assisted reproduction? Singleton live births should also include preterm births

An intensive debate is ongoing in this journal concerning themost appropriate endpoint after assisted reproduction techniques.The endpoint suggested by the first authors was Birth Emphasizinga Successful Singleton at Term (BESST). We have evaluated themost appropriate endpoint from different perspectives: patients,public, health authorities, obstetric and IVF clinics. We findsingleton live birth highly relevant as an outcome parameteras multiple pregnancies are the main factor responsible forthe overall poorer obstetric and neonatal outcome in IVF pregnancies,and multiple pregnancies are mostly an avoidable iatrogeniccomplication. However, our proposal is that both preterm andterm singletons should be included since the prematurity rateis an outcome that is largely uninfluenced by the IVF clinics.In conclusion, we propose singleton live birth per cycle initiatedas the most appropriate main outcome after assisted reproduction.Prematurity should in addition be reported separately as a secondaryoutcome.     

Practitioner reporting of birth defects in children born following assisted reproductive technology: Does it still have a role in surveillance of birth defects?

BACKGROUND: National assisted reproductive technology (ART) data collections that rely on practitioners' reports of birth defects have consistently reported lower proportions of children with birth defects than record linkage studies that link ART infants to birth and malformation registers. METHODS: We compared the birth defect data reported to the national Australian Assisted Conception Data Collection (ACDC) by practitioners at three Western Australian ART clinics with the birth defect data identified on the Western Australian Birth Defects Registry (WABDR) through record linkage of all the pregnancies conceived at these clinics to the WABDR. Cases are reported to the WABDR by multiple statutory and voluntary sources. RESULTS: We found that the national ACDC significantly underestimated the prevalence of birth defects in WA-born ART infants. Less than one-third of ART children identified with a major birth defect on the WABDR were reported to the ACDC. CONCLUSIONS: Although national ART data collections provide valuable information on pregnancy rates and short-term pregnancy outcomes such as multiple birth and birth weight, we strongly recommend that birth defect information used for patient counselling is preferentially drawn from large studies that have used record linkage to high-quality birth defect registers.     

Task-switching deficits and repetitive behaviour in genetic neurodevelopmental disorders: Data from children with Prader–Willi syndrome chromosome 15 q11–q13 deletion and boys with Fragile X syndrome

Prader–Willi syndrome (PWS) and Fragile X syndrome (FraX) are associated with distinctive cognitive and behavioural profiles. We examined whether repetitive behaviours in the two syndromes were associated with deficits in specific executive functions. PWS, FraX, and typically developing (TD) children were assessed for executive functioning using the Test of Everyday Attention for Children and an adapted Simon spatial interference task. Relative to the TD children, children with PWS and FraX showed greater costs of attention switching on the Simon task, but after controlling for intellectual ability, these switching deficits were only significant in the PWS group. Children with PWS and FraX also showed significantly increased preference for routine and differing profiles of other specific types of repetitive behaviours. A measure of switch cost from the Simon task was positively correlated to scores on preference for routine questionnaire items and was strongly associated with scores on other items relating to a preference for predictability. It is proposed that a deficit in attention switching is a component of the endophenotypes of both PWS and FraX and is associated with specific behaviours. This proposal is discussed in the context of neurocognitive pathways between genes and behaviour.     

A case of an atypically large proximal 15q deletion as cause for Prader–Willi syndrome arising from a de novo unbalanced translocation

We describe an 11 month old female with Prader–Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype.     

Serum anti-Müllerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles

BACKGROUND: Anti-Müllerian hormone (AMH) is reported to be a reliable marker of the ovarian response to controlled ovarian stimulation (COS). The objective of this study is to determine whether the serum AMH level can predict ovarian hyperstimulation syndrome (OHSS) prior to selection of COS protocols. METHODS: A cohort of 262 IVF cycles was investigated prospectively, in order to evaluate the predictive value for OHSS by means of certain risk factors, including age, body mass index (BMI), serum estradiol (E2) level, number of retrieved oocytes and basal serum AMH level. RESULTS: The basal serum AMH level predicted OHSS better than age and BMI with a sensitivity of 90.5% and specificity of 81.3%. Both the basal serum AMH level (odds ratio: 1.7856, P = 0.0003) and serum E2 level on the day of HCG administration (odds ratio: 1.0005, P = 0.0455) proved to be significant predictors of OHSS by logistic regression analysis. However, age (odds ratio: 0.9346, P = 0.049) was the only significant factor for prediction of clinical pregnancy. CONCLUSIONS: The basal serum AMH level could be utilized effectively to predict OHSS and thus to direct the selection of mild COS protocols.     

What is the most relevant standard of success in assisted reproduction?: challenges in measuring and reporting success rates for assisted reproductive technology treatments: what is optimal?

For assisted reproductive technology (ART) treatments, measures of success that move beyond traditional measures of pregnancy and live birth and narrow the numerator to infant outcomes with an optimal short- and long-term prognosis are needed. Hence, presentation of singleton live birth delivery rates is warranted. Twins have greatly increased risks for morbidity and mortality in comparison with singletons. Success rates based on singleton live births will more completely inform patients evaluating which ART treatment options will maximize their chance for a healthy infant. Additionally, providers who limit embryos transferred can feel they are on an even playing field in reporting their success rates. Measures of success that narrow the numerator further to exclude preterm or low birth weight singleton births might also be informative. However, the utility of such measures is less clear because the aetiologies of preterm birth and low birth weight among singletons are probably multifactorial. While it may be desirable to consider adverse outcomes such as congenital anomalies in defining treatment success, it is unfeasible to collect complete and accurate data on anomalies in current ART registries. As ART use increases, continual re-examination and critique of the manner in which success is defined and presented to the public is critical.