In association withPrader-Willi syndrome Prader -Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2 -q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.
ABSTRACT. Background. Prader-Willi syndrome (PWS) is a complex, multisystem disorder. Its major clinical features include neonatal hypotonia, developmental delay, short stature, behavioral abnormalities, childhoodonset obesity, hypothalamic hypogonadism, and characteristic appearance. 1,2 The genetic basis of PWS is also complex. It is caused by absence of expression of the paternally active genes in the PWS critical region on 15q11-q13. In approximately 70% of cases this is the result of deletion of this region from the paternal chromosome 15. In approximately 28%, it is attributable to maternal uniparental disomy (UPD; inheritance of 2 copies of a chromosome from the mother and no copies from the father, as opposed to the normal 1 copy from each parent) of chromosome 15, and in <2%, it is the result of a mutation, deletion, or other defect in the imprinting center. [3][4][5][6][7][8] Clinical diagnostic criteria were established by consensus in 1993. 1 Subsequently, definitive molecular genetic testing became available for laboratory diagnosis of PWS. However, identification of appropriate patients for testing remains a challenge for most practitioners because many features of the disorder are nonspecific and others can be subtle or evolve over time. For example, hypotonic infants who are still in the failure to thrive phase of the disorder often do not have sufficient features for recognition of PWS and often are not tested. Initial screening with these diagnostic criteria can increase the yield of molecular testing for older children and adults with nonspecific obesity and mental retardation. Therefore, the purpose of clinical diagnostic criteria has shifted from assisting in making the definitive diagnosis to raising diagnostic suspicion, thereby prompting testing.We conducted a retrospective review of patients with PWS confirmed with genetic testing to assess the validity and sensitivity of clinical diagnostic criteria published before the widespread availability of testing for all affected patients 1 and recommend revised clinical criteria.Methods. Charts of all 90 patients with laboratoryconfirmed PWS were reviewed. For each patient, the presence or absence of the major, minor, and supportive features listed in the published diagnostic criteria was recorded. The sensitivity of each criterion, mean of the total number of major and minor criteria, and mean total score for each patient were calculated.Results. There were 68 patients with a deletion (del 15q11-q13), 21 with maternal UPD of chromosome 15, and 1 with a presumed imprinting defect. Age range at the time of the most recent evaluation was 5 months to 60 years (median: 14.5 years; del median: 14 years; range: 5 months-60 years; UPD median: 18 years; range: 5-42 years).The sensitivities of the major criteria ranged from 49% (characteristic facial features) to 98% (developmental delay). Global developmental delay and neonatal hypotonia were the 2 most consistently positive major criteria and were positive in >97% of the patients. Feeding problems in ...
A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.
Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial appearance, obesity, hypogonadism, and short stature. Obesity and the behavioural problems are the major causes of morbidity and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted region of proximal 15q and results from absence of the normally active paternal genes in this region. Such absence results from paternal interstitial deletion, maternal uniparental disomy, or a mutation or other abnormality in the imprinting process. Diagnostic identification of all causes has become available in recent years, permitting early detection and institution of appropriate management. This testing has permitted recent identification of some phenotypic differences among affected subjects of different race and between those with deletions and uniparental disomy as a cause.
Condition Description: Prader-Willi syndrome (PWS) is caused by abnormal expression of genes on chromosome 15 due to abnormal imprinting. 1 This is most commonly due to a deletion of the paternallyderived chromosome 15q11-q13, but can also be due to uniparental disomy 1 (UPD) or a mutation involving the imprinting center on chromosome 15 2 . Recommended testing strategy is presented as an algorithm at the end of the sheet 3 . Diagnostic Criteria:1. Severe Hypotonia 2. Feeding problems until age 2 at which time insatiable appetite develops leading to increased obesity risk 3. Short stature with small hands and feet 4. Hypogonadism (small penis, undescended testes) 5. Characteristic behaviors (obsessive, temper tantrums, skin picking) 6. Global developmental delay, mild to moderate cognitive impairment 7. Hypopigmentation compared to family background Other associated findings: Growth Hormone deficiency, hypogonadotropic hypogonadism, risk for insulin resistance and diabetes, sleep apnea (obstructive and central), high pain threshold Differential diagnosis 3 : Infantile Hypotonia: Spinal Muscular Atrophy, Congenital Myotonic Dystrophy or other myopathy/neuropathy, other chromosomal abnormality. Older children (obesity/cognitive impairment): Fragile X, Bardet Biedl syndrome, chromosomal abnormality Action required: Follow diagnostic algorithm to confirm diagnosis. Consider referral for clinical genetics evaluation (link to clinics) and endocrinology. Follow management recommendations. 2,3
This study examines the nature, severity and correlates of non-food obsessions and compulsions in 91 people with Prader-Willi syndrome (PWS) aged 5-47 years (mean age = 19 years). Prominent symptoms, seen in 37-58% of the sample, included hoarding; ordering and arranging; concerns with symmetry and exactness; rewriting; and needs to tell, know or ask. A remarkably high proportion of participants had moderate to severe symptom severity ratings; 64% showed symptom-related distress, and 80% showed symptom-related adaptive impairment. The study also compared obsessive-compulsive symptoms in 43 adults with PWS to age- and sex-matched non-retarded adults with obsessive-compulsive disorder (OCD). The PWS and OCD groups showed similar levels of symptom severity and numbers of compulsions; they also showed more areas of symptom similarity than difference. Increased risks of OCD in persons with PWS are strongly indicated. Implications are discussed for pharmacotherapy, behavioral therapy and family support.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.
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