Handbook of Genetic Counseling/Prader-Willi Syndrome - Prenatal

Prader-Willi Syndrome - Prenatal Introduction Discuss the reason for referral. Elicit prior knowledge about Prader-Willi syndrome. Elicit prior knowledge about prenatal diagnosis. Assess concerns and set goals for the session. Provide overview of topics for counseling session. Client & Partner Information Discuss why it's important to get pregnancy, personal, and family history. Explain that it is a way to identify other potential risk factors Use examples: seizure medication, diabetes, etc. Go over pregnancy history: How has the pregnancy been going? G1P1? Any stillbirths? Spontaneous or elective abortions? Was the pregnancy planned? If so, how long did it take to become pregnant? LMP? EDC? Any bleeding? Any illnesses during the pregnancy? Infection, cold, rash, fever? Any chronic illnesses? Any exposures during the pregnancy? X-rays, smoking, alcohol, recreational drugs? Medications: Currently? Earlier in the pregnancy? Personal background: Occupation? Do you have a religious preference? Psychosocial assessment Financial, insurance concerns? Support system? Information about the father: Name, age, occupation? Any exposures? Any chronic illnesses? Elicit History Construct pedigree: Abnormal # miscarriages, stillbirths, infant deaths? Previous children with chromosome abnormality, Down syndrome, birth defects, mental retardation? Consanguinity? Ethnicity? Other concerns/risk factors? What is Prader-Willi Syndrome? A complex, multi-system mental retardation disorder The first recognized microdeletion syndrome identified when high-resolution chromosome analysis was introduced Now known to be one of the most common microdeletion syndromes Also one of the most common recognized genetic forms of obesity Caused by several different genetic alterations of proximal chromosome 15q Etiology & Incidence History Prader-Willi syndrome was first described in 1956. The basis of Prader-Willi syndrome Caused by the lack of expression of normally active paternally inherited genes at chromosome 15q11-q13 The maternally inherited genes are normally inactive due to genetic imprinting Imprinting is a phenomenon by which some genes are modified in different ways depending on the genederof the parent from whom they were inherited There are 3 ways in which P-W syndrome can be caused. Small deletion in the paternally contributed chromosome 15 This is seen in 75% of patients Usually the deletion is 4-Mb or smaller Uniparental disomy 15 (UPD) Inheritance of 2 maternal chromomes 15 but no paternal chromosome 15 Defect in the imprinting process Seen in approximately 1% of patients Very small deletion or other abnormality in the imprinting center All studied families in which there has been a recurrence of P-W have had an imprinting mutation. The actual genes whose deficiency that cause the phenotype have not yet been identified One-third of patients with P-W exhibit hypopigmentation due to deletion of a gene associated with tyrosinase-positive albinism Incidence 1 in 10,000 - 15,000 Occurs in both sexes and all races Diagnosis is often delayed or missed in many cases Clinical Features & Natural History Neonatal hypotonia and failure to thrive Hypotonia is prenatal in onset and nearly uniformly present Causes decreased fetal movement, frequent abnormal fetal position, and difficulty at time of delivery State of hypoarousal are associated with poor suck and lack of awakening to feed Hypotonia gradually improves Motor milestones are delayed Average age of sitting is 12 months Average age of walking is 24 months It is recommended that all newborns with persistent hypotonia be tested for P-W Developmental delay and mild cognitive impairment Language development is delayed Speech is often poorly articulated, having a nasal and/or slurred character Most patients are mildly retarded Mean IQ 60s to low 70s Approximately 40% have borderline retardation or low normal intelligence 20% have moderate retardation Characteristic facial appearance Narrow bifrontal diameter Almond-shaped palpebral fissures Narrow nasal bridge Downturned mouth with a thin upper lip Early-childhood-onset obesity Hyperphagia begins generally between ages 2 and 4 leading to significant obesity Hypothalamic abnormality results in lack of satiety There is a decreased caloric requirement likely related to hypotonia and decreased activity Food seeking behavior with hoarding or faraging for food and stealing food or money to buy food are common High threshold for vomiting may complicate binging on spoiled food The obesity is central in distribution, with relative sparing of the distal extremities Obesity is the major cause of morbidity and mortality in P-W syndrome Hypogonadism with genital hypoplasia Hypogonadism is prenatal in onset and persists throughout life Genital hypoplasia is evident at birth Pubertal development is abnormal In both males and females, sexual activity is uncommon and fertility is rare Mild short stature If not apparent in childhood, it is almost always present by the second half of the second decade Average height is 155cm for males and 148cm for females African-Americans tend to be taller Characteristic behavior profile Becomes evident in early childhood Tempor tantrums, stubbornness, controlling and manipulative behavior Obsessive-compulsive characteristics Difficulty with change in routing Lying, stealing, and aggressive behavior True psychosis is evident in young adulthood in approximately 5-10% Sleep disturbances Excessive daytime sleepiness and oxygen desaturation in REM sleep These are common even in the absence of obesity Inheritance P-W is caused by a lack of expression of the paternally derived PWS/AS region of chromosome 15q11-q13 by one of several genetic mechanisms Deletion of PWS/AS region 70% of patients have P-W syndrome by this genetic mechanism <1% risk to siblings of an affected proband Most of these cases are de novo deletions A small number of cases are due to translocation with a concomitant deltion If a parent has a balanced chromosomal translocation the recurrence risk could be as high as 25% Uniparental disomy 25% of patients have P-W syndrome by this genetic mechanism <1% risk to siblings of an affected proband Imprinting defect <5% of patients have P-W syndrome by this genetic mechanism The risk to siblings of an affected proband is up to 50% A healthy parent can carry this imprinting defect But recurrence risk may be lower because imprinting defects can be de novo mutations Balanced chromosome translocation within 15q11-q13 or abnormality <1% of patients have P-W syndrome by this genetic mechanism All of these cases have been de novo Risk to siblings of an affected proband is <1% If a familial case is detected, the theoretical risk of inheritance of the balanced translocation could be as high as 25% Diagnosis Genetic testing Molecular Genetic Testing Testing for the parent-specific methylation imprint detects over 99% of cases and is highly specific Methylation-specific testing is important to confirm the diagnosis in all children The methylation abnormality can be determined by southern blot hybridization using a methylation-sensitive probe (SNRPN or PW71B) or with parent-specific PCR primers If the methylation pattern is characteristic of maternal inheritance only, then the diagnosis is confirmed DNA methylation testing detects all cases caused by deletions, UPD, and imprinting defects Once the diagnosis is established, further tests are done to classify the mutation Deletions can be detected using FISH analysis UPD can be detected with informative microsatellite markers An imprinting defect is presumed to be present in patients with an abnormality in the parent-specific methylation imprint without evidence of a deletion or UPD Cytogenetic Analysis 1% of patients have a detected chromosomal rearrangement resulting in a deletion of bands 15q11-q13 Deletion can be detected using high resolution chromosome studies at the 650 band level and FISH. Clinical diagnosis Consensus diagnostic criteria were developed in 1993 Major Criteria Neonatal and infantile hypotonia with poor suck Feeding problems and/or FTT in infancy Onset of rapid weight gain between 1-6 years of age causing central obesity Hyperphagia Characteristic facial features Hypogonadism Genital hypoplasia Incomplete and delayed puberty Infertility Developmental delay or mild to moderate MR or multiple learning disabilities Minor Criteria Decreased fetal movement and infantile lethargy Typical behavior problems Sleep disturbance/sleep apnea Short stature for the family by 15 years of age Hypopigmentation Small hands and feed for height age Narrow hands with straight ulnar border Esotropia, myopia Thick, viscous saliva Speech articulation defects Skin picking Supportive Findings High pain threshold Decreased vomiting Scoliosis and/or kyphosis Early adrenarche Osteoporosis Unusual skill with jigsaw puzzles Normal neuromuscular studies such as muscle biopsy Differential Diagnosis Hypotonia in infancy Neonatal sepsis CNS depression Congenital myotonic dystrophy Several myopathies and neuropathies Developmental delay/mental retardation, obesity, and hypogonadism Albright hereditary osteodystrophy Bardet-Biedl syndrome Cohen syndrome Borjeson-Forssman-Lehmann syndrome Some patients with Fragile X syndrome Possible 6q or 1p deletions Management Infancy Special feeding techniques, including special nipples or gavage feeding to assure adequate nutrition Physical therapy may improve muscle strength and encourage achievement of milestones Screening for strabismus should start in infancy Childhood Obesity Monitoring of weight and nutritional counseling are critical Low-calorie, well-balanced diet with regular exercise and close supervision to minimize food stealing should be instituted before the onset of excessive weight gain Energy requirement should rarely exceed 1000 to 1200 Kcal/day Learning disabilities should be evaluated, and educational planning instigated Speech therapy is often needed Growth hormone replacement Normalizes height and increases lean body mass Growth hormone evaluation is recommended if growth rate is reduced or height is less than the 3rd percentile Behavioral disturbances Often follow excessive weight gain Firm limit-setting should be instituted Serotonin re-uptake inhibitors have helped many patients with managing behavior Sex hormone replacement is controversial Produces adequate secondary sexual characteristics Testosterone replacement may play a role in male behavior problems Estrogen replacement may increase risk of stroke and osteoporosis in females Scoliosis screening should be routine Adulthood Obesity The major cause of morbidity and mortality in adults Can cause medical complications Cardiopulmonary compromise Type II diabetes mellitus Thrombophlebitis Chronic edema If obesity is avoided, longevity may be nearly normal Psychiatric and behavioral disturbances may require hospitalization and medication Psychosis Manic-depressive illness Obsessive-compulsive disorder Group homes specifically designated for patients with P-W have been successful Prenatal Testing Psychosocial Issues Uncertainty because symptoms and severity vary widely Uncertainly may make goal-setting and future planning problematic Feelings of isolation, loneliness, and despair. Frustration due to ignorance about the disease. Coping with chronic pain and fatigue Burden of dealing with a chronic, rare, progressive disease Body image and self-esteem issues due to spleen or liver enlargement or growth retardation Guilt about passing on the gene to one's children. Family dynamic changes Stress in the marriage Sibling relationships Family members may feel guilty or resentful Depression and frustration about the requirement for lifelong management. Shock, fear, and denial over the diagnosis. Offer Resources Prader-Willi Syndrome Association (800) 926-4797 www.pwsausa.org The Prader-Willi Foundation (800) 253-7993 PWSAUSA@aol.com March of Dimes information on Spina Bifida, Amniocentesis, Folic Acid, and Maternal blood screening www.modimes.org 1-888-MODIMES Review and summarize major points Elicit final questions and concerns Arrange for Follow-up References National Organization for Rare Disorders Online Mendelian Inheritance in Man Geneclinics GeneReviews Living with Gaucher Disease: A guide for patients, parents, relatives, and friends Brochure copyright 1991, Genzyme Corporation Charrow, J. et al. "Gaucher Disease: Recommendations on Diagnosis, Evaluation, and Monitoring." Archives of Internal Medicine; vol 158, p 1754, September 14, 1998. Notes The information in this outline was last updated in 2002.