Handbook of Genetic Counseling/Prader-Willi Syndrome-2

Prader-Willi Syndrome Contracting and Introduction Establish rapport with small talk and introduce myself What concerns do you have that you would like to discuss today? Briefly discuss the topics to be covered during the appointment Follow up- changes since last visit? Prenatal counseling Amnio/CVS Recurrence risks (<1% for UPD) Elicit Interim Medical History Definition Prader-Willi syndrome (PWS) is a disorder caused by the inheritance of a paternally derived deletion of the long arm of chromosome 15 and is characterized by abnormalities in physical and mental development. Historical significance First recognized microdeletion syndrome identified with high-resolution chromosome analysis Most common recognized genetic form of obesity First recognized human genomic imprinting disorder First recognized disorder resulting from uniparental disomy Etiology Deletion of the long arm of chromosome 15 at q11-q13 (~75% of cases) Detectable by high-resolution chromosome analysis or FISH with specific probes Paternally derived chromosome has been deleted (maternal genes are inactive due to genomic imprinting) Maternal disomy- receiving 2 copies of the maternal 15th chromosome and no paternal copies of the 15th chromosome (~24% of cases) Clinical differences exist between deletion patients and those with maternal disomy. Maternal disomy patients are less likely to have typical facial characteristics, slightly higher IQs and milder behavior problems.* A defect in the imprinting process occurs due to problems associated with the imprinting center, such as a mutation or deletion resulting in the biparental inheritance and a maternal-only pattern (1% of cases) In all cases where there has been a recurrence of Prader-Willi syndrome, there has been an imprinting mutation. Molecular Genetics The actual genes that cause the phenotypic changes have not been identified. Several imprinted and nonimprinted genes have been found to exist in the deletion region (called the PWS/AS critical region). A deletion in the nonimprinted P gene, which codes for tyrosinase-positive albinism, is associated with hypopigmentation seen in 33% of patients with PWS. The SNRPN is the best described gene likely to cause some of the PWS features This ribosome-associated protein functions by controlling gene splicing and may therefore be involved in the control of the synthesis of some proteins SNRPN is known to be imprinted in the brain SNURF is upstream of SNRPN is a putative imprinting control element for the critical region Very small deletions in this gene have been identified in a few cases Many other genes have been identified from the critical region, but the function of these genes has yet to be elucidated Associated Risks Patients with PWS usually have an unremarkable family history PWS that is caused by a deletion has a recurrence risk of 1% or less. Uniparental disomy is caused by nondisjunction thus the recurrence risk is 1% or less When counseling patients with a detected imprinting mutation, a recurrence risk of up to 50% pertains because the mutation is likely dominant and occurred in the paternal grandmother's germ line. Incidence Approximately 1: 10,000-15,000 live births Both sexes and all races are affected The majority of affected individuals are the only family member affected Diagnostic Criteria These criteria were developed before the availability of diagnostic testing and are still valuable in suggesting diagnosis and the need for a diagnostic test. Major criteria (1 point each) Infantile central hypotonia Infantile feeding problems and failure to thrive Characteristic facial appearance Early-childhood-onset of obesity (2-3 years of age) Hypogonadism with genital hypoplasia Developmental delay and mild cognitive impairment Mild short stature Characteristic behavior disorder Minor Criteria (1/2 point each) Decreased movement and infantile lethargy Typical behavior problems Sleep apnea Short stature Hypopigmentation Small hands and feet for height and age Esotropia, myopia Thick, viscous saliva Speech articulation defects Skin picking Supportive criteria (no points) High pain threshold Decreased vomiting Temperature control problems Scoliosis Early adrenarche Osteoporosis In children under 3 with 5 points (at least 3 from major criteria) or those above 3 with 8 points (at least 4 from major criteria) a diagnosis should be suspected Clinical Features Hypotonia Prenatal in onset and present in nearly 100% of cases Causes decreased fetal movement and abnormal fetal position The fetus is often breeched in position at the time of delivery, thus delivery is often via a caesarian section. The infant usually has a poor suck reflex and fails to awake to feed leading, in many cases, to failure to thrive Infantile lethargy and a weak cry are also associated with hypotonia Motor milestones are delayed and average age of sitting is ~12 months and walking at 24 months Hypotonia results in a decrease in lean body mass leading to a high ratio of fat to lean body mass in children. Hypotonia gradually improves, although the adult with PWS remains mildly hypotonic with decreased muscle tone and bulk All newborns with persistant hypotonia are suggested to have PWS testing. Developmental delay and intelligence Motor milestones are delayed in 90-100% of cases (see above) Language development is also delayed Verbal skills are a strength in most patients but.. Speech is often poorly articulated, nasal and slurred. Cognitive abnormalities are present and most patients are mildly mentally retarded with an IQ of 60s-low 70s ~40% have borderline MR or low normal intelligence ~20% have moderate MR Academic performance is poor for cognitive ability Strengths are in reading, long-term memory, and visual-spatial skills Weaknesses are in math, sequential processing, and short-term memory Patients often have an unusual skill with jigsaw puzzles and word-find puzzles. Hypogonadism Prenatal in onset and persists throughout life At birth it is evident by genital hypoplasia Cryptorchidism is present in 90-100% of male patients Sexual activity is uncommon in both sexes and fertility is rare (one case reported) Early-childhood-onset of obesity Significant obesity is not found in young infants Onset is usually triggered by hyperphagia between 1-6 years of age, but can occur as early as 6 months Hyperphagia is due to a hypothalamic abnormality resulting from lack of satiety There is a decreased caloric requirement, related to hypotonia and associated decreased activity Food-seeking behavior with hoarding and foraging of food is often common in patients with PWS Patients often eat unappealing substances such as garbage, frozen food and pet food Patients have decreased vomiting activity The obesity is central in location Abdomen Buttocks Thighs Obesity is the major cause of morbidity and mortality in PWS and longevity can be nearly normal if obesity is avoided. Obesity results in complications such as: Cardiopulmonary compromise Diabetes mellitus type II Hypertension Chronic leg edema Sleep apnea Characteristic Facial Features that are present at birth or appear over time for MOST patients: Narrow bi-frontal diameter Almond-shaped palpebral fissures Narrow nasal bridge Down-turned mouth with a thin upper lip Other characteristic physical findings Small narrow hands with a straight ulnar border Short broad feet, present by age 10 *African Americans are less likely to have small hands and feet* Shoulders are usually sloping Hypopigmentation manifests as fairer skin, hair, and eye color and occurs in about 1/3 of patients Scoliosis and/or kyphosis are common (about 40-80% of cases) Short stature is almost always present by the 2nd half of the 2nd decade for 90-95% of patients due to lack of pubertal growth spurt Strabismus is found in 60-70% of cases Behavior profile is present in 70-90% of cases A characteristic profile becomes evident in early childhood, with temper tantrums, stubbornness, controlling and manipulating behavior, OCD, and difficulty with change in routine Lying, stealing, and aggressive behavior are also common. These behavioral problems interfere with the quality of life for adults Others: Thick viscous saliva Predispose to dental caries Can result in articulation problems High pain threshold Skin picking Sleep disturbances, especially daytime sleeping Osteoporosis, frequent but poorly studied Diagnostic Testing Methylation analysis PCR test that can detect all three causes of PWS All three causes result in the genes for PWS being methylated Methylated DNA is cut differently by restriction enzymes than unmethylated DNA The differences in the sizes of DNA can be detected This test can be used for both prenatal and postnatal testing Chromosome analysis using the FISH probe for SNRPN High resolution chromosome analysis alone is insufficient due to false positives and false negatives Uniparental disomy can be identified using microsatellite repeat sequences from chromosome 15 in the patients and the parents; if none of the variants of these repeats that are present in the father are seen in the child, then all the genetic information from chromosome 15 has been maternally derived. The presence of a normal FISH test plus abnormal methylation analysis indicates a probable imprinting center error Management and Treatment Options Intervention and management of PWS can significantly impact the health, functional abilities, and life of patients. Infantile FTT- Special feeding techniques are required because breast feeding is usually inhibited by the hypotonia Short Stature- Growth hormone has been shown to increase height and muscle tone Good results have been shown for adolescents. Development and behavior- Closely monitor development and behavior in infancy and toddler-hood. Developmental assessments should be conducted on patients and they should have early intervention services as soon as possible. Educational intervention should occur throughout school years. Most children require special education classes, speech therapy, and physical/occupational therapies. It is important to apply specific and consistent limits at home and school. Most individuals require consistency in daily routines and should be prepared in advance for changes in routine or activities. Those with severe behavioral problems may respond to psychotherapy. Medication for treatment of psychiatric problems is often needed. Obesity- Avoidance of obesity is extremely important, yet very difficult to achieve. Close monitoring of weight percentiles and height to weight ratio is critical throughout life Those who are extremely obese should have an assessment of glycosylated hemoglobin levels Decrease caloric intake, to1000-1200 Kcal/day or less. Vitamins and calcium should be taken everyday (100% of daily recommended) Keeping food under lock and only keeping healthy low calorie food in the house is critical Involve teachers and employers of individuals with PWS in food monitoring Regular exercise is extremely important; a program should be initiated as early as possible. Hypotonia- Physical therapy is appropriate Evaluation of hypothyroidism if hypotonia is persistant Hypogonadism (endocrine)- Administration of hCG may stimulate testicular descent Administration of testosterone in males or estrogen in females to improve secondary sex characteristics Ophthalmologic- Exams to monitor strabismus, myopia and hyperopia Dental- Emphasis placed on good dental hygiene Products that increase saliva flow can be used as necessary Musculoskeletal- Scoliosis should be monitored and treated as in the general population Calcium and vitamin D levels should be assured Dermatologic- Examination of the skin should occur to monitor the presence of sores from skin picking Keep lesions moist and covered Behavior modification techniques may be necessary Psychosocial Issues Parents often must monitor children with PWS 24 hours a day to control symptoms such as obesity; this is draining for the parents. Fathers often struggle with guilt, blaming themselves for the occurrence of the syndrome. Important for counselors to ask how the parents are coping and how they are handling the situation. References Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company. Allanson JE, Cassidy SB (2001). Management of Genetic Syndromes. New York: Wiley-Liss, Inc. Jorde LB, Carey JC, Bamshad MJ, White RL (1999). Medical Genetics. 2nd ed. Philadelphia: Mosby. 8iryjk75ikm nuryezry Web References www.geneclinics.org Notes The information in this outline was last updated in 2002.