text:
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)

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.

Web References

 * www.geneclinics.org


text:
Handbook of Genetic Counseling/Protein S Deficiency

Protein S Deficiency

(pregnancy loss)

Introduction and contracting

 * Introduction
 * What is your understanding about why you were referred for genetic counseling?
 * Do you have any questions or concerns you would like to discuss?
 * Address immediate concerns
 * Explain that we will be taking a detailed pregnancy and family history
 * Then we will answer your questions and talk a little more about protein S deficiency including how it is inherited and how it may increase the risk for pregnancy loss as well as other causes of multiple pregnancy losses

Medical History

 * Who was referring physician
 * How many pregnancies have you had?
 * Confirm when the losses were and use EMPATHY
 * Why do you believe you had the miscarriages?
 * Sometimes women who have miscarriages are concerned that it might be due to something they did or did not do during the pregnancy
 * What were you told you about the pregnancy losses?
 * What types of testing did they do to find a reason for the miscarriages?
 * Were you sick at all during the pregnancies?
 * Did you drink, smoke or use drugs?
 * Any medications during the pregnancies
 * Did you take prenatal vitamins?
 * Any concerns about anything you might have been exposed to during any of your pregnancies?
 * Have you had any other chronic health problems except those due to the protein S deficiency?
 * Could you describe how you first found out you had protein S deficiency
 * Have you had any complications related to the protein S deficiency?

Family History

 * Take a family history to see if there are any hereditary diseases that may run in your family that may or may not be related to your history of pregnancy losses
 * Miscarriages in other family members
 * Infertility
 * Mental retardation/learning difficulties
 * Birth defects (heart defects, CL/CP, spina bifida)
 * Chronic illnesses such as diabetes or heart disease
 * Anyone else with protein S deficiency
 * Any other blood clotting problems in the family
 * Sickle cell anemia
 * Specifically ask about symptoms of blood clotting see below
 * Consanguinity

Psychosocial considerations and assessment

 * How are you handling the pregnancy losses?
 * Have family members or friends been supportive?
 * What do your plans for the future look like?
 * Are you currently working outside the home?
 * Are you in touch with a perinatal loss support group?
 * Would you like to be in touch with a support group?
 * Is your insurance covering the testing that has been performed?
 * Are there any other concerns or questions?

What is protein S

 * A protein that is involved in stopping the blood clotting process
 * (Protein S is a vitamin K-dependent anticoagulant protein)
 * (Major function is as a cofactor to facilitate the action of activated protein C (APC) on its substrates, activated factor V (FVa), and activated factor VIII (FVIIIa) )
 * (Normally forms a complex with protein C to inhibit coagulation)
 * Not having enough protein S may lead to problems with blood clotting in the veins (venous thromboembolism or pulmonary embolism in the lungs, but does not appear to increase risk for arterial thrombosis)
 * Also associated with increased risk for miscarriage (studies have focused mostly on miscarriages that occur in 2nd and 3rd trimesters)

How does protein S deficiency occur (Inherited vs. Acquired)

 * Inherited risk factors
 * Caused by mutation in one of the two copies of the genes that instruct the body on how to make protein S (located on chromosome 3 at locus 3p11.1-q11.2 near a protein S pseudogene)
 * Discuss genes and AD inheritance
 * Incomplete penetrance (some individuals with protein S deficiency remain completely healthy and asymptomatic and there are other risk factors that may also contribute to the blood clotting in some individuals)
 * VTE develops in 60-80% of patients who are heterozygous for protein S deficiency. The remaining patients are asymptomatic, and some heterozygous individuals never develop VTE.
 * Occasionally a person can inherit two mutated copies
 * This results in purpura fulminans (characterized by small vessel thrombosis with cutaneous and subcutaneous necrosis, and it appears early in life, usually during the neonatal period or within the first year of life)
 * Acquired risk factors for thrombophilia
 * Age - 1 in 10,000 in young before age 40 and 1 in 1,000 in elderly
 * Malignancy -Tumor cells increase coagulant activity and so do chemotherapy drugs
 * Antiphospholipid antibodies - may be associated with lupus or other autoimmune disease and increases risk 9 fold
 * Surgery or major trauma-without prophylactic treatment risk may be as high as 45-70% with total hip or knee replacement surgery and increased risk continues for several weeks
 * Pregnancy -RR is 10 increases to 1 in 1,000 from 1 in 10,000
 * HRT and oral contraceptives-- risk depends on estrogen content and type of progesterone some studies show 2-3 fold increase
 * Acquired thrombophilia
 * usually due to liver disease
 * vitamin K
 * systemic lupus erythematosus
 * Protein S levels decrease in pregnancy and can fall into the abnormal-low laboratory range, but the low levels of protein S in pregnancy do not cause thrombosis by themselves

Special Concerns During Pregnancy

 * Pregnancy can result in falsely low protein S assays, especially functional assays. In addition, pregnancy increases the risk of thrombosis in patients who are heterozygous for protein S deficiency
 * A female patient who is on warfarin for prior thrombosis should not continue warfarin during pregnancy due to teratogenic effects
 * Heparin should be started during pregnancy and for 4-6 weeks postpartum in patients with protein S deficiency
 * One case control study suggested that fetuses with a prothrombotic risk factor may have an increased incidence of low birth weight, but only statistically significant when fetus carried multiple thrombotic risk factors or was homozygous for risk factors
 * Women with pre-eclampsia/eclampsia and intrauterine growth restriction, were more likely to have protein S deficiency than controls, but too small to assess strength of association
 * Feb 2002 article in Seminars in Perinatology stated that not all studies have found association between inherited thrombophilias and adverse pregnancy outcomes. It is limited by lack of well designed studies and therefore no clear evidence to determine when to test, whom to test, and what to test for

Protein S deficiency and risk of miscarriage

 * French case control study of 232 instances of women experiencing stillbirth (> 22 weeks gestation) and 464 controls (cases were referred patients which may add bias because 84% had more than one stillbirth)
 * Independently protein S deficiency and factor V Leiden were correlated with stillbirth
 * MTHFR mutation frequency alone was no greater
 * However, with homozygosity for the MTHFR mutation plus an additional thrombophilic risk factor, and in the absence of supplementation with folic acid, the risk for stillbirth was 100% (28/28)
 * This study also confirmed that those with the assessed risk factors and stillbirth virtually always showed maternal vascular markers when the placenta was thoroughly evaluated
 * Study in Israel (May 2002) demonstrated among 40 women with unexplained intrauterine fetal death at >27 wks matched with 80 healthy women demonstrated significantly higher rate of protein S deficiency than controls (OR 3.2, 2.4-4.1 CI) biased sample may not be representative of women of other ethnicities
 * Prospective study in US of 145 patients with idiopathic pregnancy loss and 145 matched controls
 * 1 or greater thrombophilic defect in 66% of study group and 28% of controls
 * 21% of women with loss had combined thrombophilic defects compared to 5.5% controls
 * late pregnancy wastage more common in women with thrombophilia

Prevention?

 * Individuals with homozygosity for the MTHFR mutation and any other predisposing factor (protein S deficiency, protein C deficiency, antithrombin III deficiency, the thrombophilic prothrombin mutation, factor V Leiden, or antiphospholipid antibodies), high dose folate supplementation beginning preconceptually may have a protective effect.
 * Those who have had one or more stillbirths and are found to have a thrombophilic mutation (not including MTHFR homozygosity in isolation) heparin and low dose aspirin may be appropriate

Testing for Protein S Deficiency

 * Absent /reduced protein S and normal total proteins in heterozygote
 * Protein S antigen testing:
 * Functional protein S:
 * Assays for functional protein S are difficult to perform, indirect and are based on prolongation of blood clotting by the generation of APC and its function
 * Several other factors can alter the interpretation of test results falsely low protein S functional assay value can be observed in patients with factor V Leiden genetic defect and some pregnant women

Incidence of Protein S Deficiency

 * based on 9000 blood donors 1 in 700 had protein S deficiency
 * unknown if deficiency varies by race, but thrombotic disease in general less frequent in Asians
 * No clear difference in male to female ratio

Associated symptoms

 * Symptoms related to protein S deficiency include those associated with deep venous thrombosis (DVT), thrombophlebitis, or pulmonary embolus.
 * Venous thrombosis of the lower limbs: Lower limb swelling and discomfort are the usual symptoms. Occasionally, redness or discoloration also is present, with or without associated cellulitis.
 * A family history of thrombosis is an important finding, which suggests inherited thrombophilia.
 * Thrombosis at an early age (e.g., usually <40 y) or recurrent thrombosis also is indicative of an inherited thrombophilic state (e.g., protein S deficiency).
 * Deep vein thrombosis
 * The most common manifestation is venous thrombosis of the lower extremities (accounts for approximately 90% of all events)
 * Superficial veins that are thrombosed usually appear distended, firm, and noncompressible (cords), with or without associated redness or pain.
 * Superficial thrombophlebitis can be observed in some cases, with or without DVT
 * Classic presentation of DVT is a triad of calf pain, edema, and pain on dorsiflexion of the foot (less than a third of DVT cases exhibit these 3 findings)
 * Physicians observe unilateral leg or calf swelling with mild or moderate pain more often, which suggests DVT
 * Rarely, calf discomfort without swelling is the only sign of DVT
 * The differential diagnosis of DVT includes muscle strains and tears, passive swelling of a paralyzed or immobilized limb, Baker cyst, cellulitis, knee trauma or derangement, lymphatic obstruction, and the postphlebitic syndrome
 * Pulmonary embolism
 * Some patients may have associated or isolated pulmonary embolism and may experience dyspnea, chest pain, syncope, or cardiac palpitations
 * Classic pleuritic chest pain, cough, or hemoptysis suggests an embolism with pleural involvement
 * Acute right-sided heart failure occurs rarely and is associated with massive embolus
 * Findings of right ventricular dysfunction include bulging neck veins, a left parasternal lift, and an accentuated pulmonic component of the second heart sound.
 * These findings in the chest also are not specific for pulmonary embolism.

Early Pregnancy Loss

 * establishing pregnancy is more difficult than many people realize
 * clinically recognized pregnancy loss occurs in ~15% of pregnancies
 * 40-60% of all conceptions may be lost, but most of these (3/4) are estimated to be lost before it is recognized clinically
 * most miscarriages occur between 6-8 weeks and expulsion between 10-12 weeks
 * after 3 consecutive clinical abortions the empiric risk of aborting next pregnancy is 20-55%

Late Pregnancy Loss

 * seem to be associated with thrombophilia

Possible causes of pregnancy losses
o anticardiolipin antibodies -- type of a group of antiphospholipid antibodies that may be associated with miscarriage o circulating antibodies to cardiolipin and/or inappropriate coagulation parameters, plus poor reproductive outcome, SLE, or spontaneous thrombosis (the antibodies can react with phospholipids that are required for coagulation) o SLE - an autoimmune disease thought to be related to SA's (Antichromatin IgG is useful in diagnosing SLE antinuclear antibody testing can indicate many at risk for SLE or some other autoimmune diseases)
 * chromosomal abnormalities (most common 70% of first trimester loss)
 * balanced translocation carrier (2.7-4.8% of couples with recurrent losses)
 * trisomies and other chromosomal anomalies
 * Hormonal causes
 * Inadequate luteal phase
 * Deficient progesterone
 * Endometrial factors (endometrial protein expression)
 * Uterine abnormalities
 * septate uterus
 * bicornate uterus
 * uterine myomas or fibroids
 * DES exposure in utero
 * Environmental exposures
 * Alcohol (women who drink 2X's week had sig. higher SA than other women but drinkers also tend to smoke also - possible confounding?)
 * tobacco ( if ½ pack a day or greater and appears to be dose dependent)
 * very heavy caffeine intake (moderate intake is not associated with SA)
 * chemical solvent exposure in either sex may increase risk
 * Immune Causes
 * autoimmune problems -- estimated to be cause of multiple SA's in up to 30% of women (woman makes antibodies that will attack her own proteins and those that she has in common with the fetus)
 * alloimmune causes -- (response to tissues from another individual of the same species)
 * Diabetes (controlled or unsuspected is not thought to cause SA)
 * Infection
 * chlamydia trachomatous causes acute and chronic infection of the endometrium which could interfere with implantation (more chlamydia antibodies in women with recurrent SA's but not all studies confirmed this)
 * Mycoplasma hominis and ureaplasma urealyticum (controversy over importance in losses)
 * CMV but suggests this is rare and causation not proven
 * Herpes simplex virus (importance in SA's debated)
 * HIV does not increase rates of loss in asymptomatic women
 * Psychological factors-two studies showed significant reduction in SA among women who have 3 or more SA's when undergoing counseling once per week during pregnancy

Patient Resources

 * www.fvleiden.org (information of many thrombophilias and online support group)
 * support group for pregnancy loss (There is one at Christ hospital)

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/


text:
Handbook of Genetic Counseling/Reciprocal Translocation

Reciprocal Translocation

Contracting

 * What were you told about why you were referred to Genetics?
 * What did they tell you about the results of the chromosome studies?
 * What are your main concerns? Do you have any questions?
 * Overview of session

Intake

 * Follow intake questions
 * What doctors are they seeing?
 * Has she had any surgeries, or is she scheduled for any?
 * What have they been told about the Dandy-Walker malformation and hydrocephalus?
 * What have they been told about her heart defect?
 * Has anyone talked with them about what to expect in the future?
 * Updates to family history?
 * Ask again about mental retardation, learning problems, birth defects
 * Ask again about miscarriages and stillbirths in family

Genes and Chromosomes

 * Chromosomes are instruction books for bodies - genes located all along chromosomes
 * One copy of each from mother, one from father

Explanation of Chromosomes

 * Show her karyotype to parents and point out rearrangement
 * This is what we call a reciprocal translocation
 * Parts of two different chromosomes break off and redistributed to different chromosomes
 * Her chromosomes look a little bit different than what we would expect
 * This happens to about 1 in 500 people
 * We don't know why this happens sometimes
 * This is not something that we can change or fix
 * Nothing that anyone did or didn't do caused this to happen - it is a random event

What Does this Mean

 * We don't really know right now - but there are some ways that we can try to find out
 * It looks like the translocation is balanced
 * All of the genetic material is still there, it is just rearranged (show yellow and pink chromosomes)
 * Most of the time, this does not cause a problem so it would not explain why was born with Dandy-Walker malformation and a heart problem
 * Remember that there are genes along the length of the chromosomes?
 * There are spaces between those genes
 * If the chromosomes broke in those spaces, it should not have disrupted any genes and all of the body functions should still work
 * We would expect a child with a balanced reciprocal translocation to be healthy
 * This would mean that her health complications are caused by something other than the translocation
 * BUT . ..
 * If one or both of the chromosomes broke in the middle of a gene, or if a small piece of one of the chromosomes is missing, that could cause problems (5%)
 * Unfortunately, we can't look any closer at her chromosomes right now, so we can't tell if this is the case
 * If a gene is interrupted or a piece is missing, this COULD explain her problems
 * To help us determine whether the translocation is balanced or not, we need to look at BOTH of her parents chromosomes

Importance of Looking at Parent's Chromosomes

 * If you both have normal chromosomes:
 * The balanced translocation is something new
 * If might explain the Dandy-Walker malformation and heart defect
 * If one of you has the same balanced translocation as_____
 * We know that you both do NOT have Dandy-Walker malformation or a heart defect
 * Because you both don't have any health complications, we know that all of the genetic information is there - nothing is missing or interrupted
 * This means that her problems may have another cause

What Does this Mean for her's Future?

 * At this point, it is hard to say
 * Once we know more about parents chromosomes, we will have a better idea about what caused the Dandy-Walker malformation and heart defect
 * If the translocation does appear to be the cause of the problems, we still may not be able to predict what will happen to her in the future
 * As mentioned before, we can't always look close enough at the chromosomes to know exactly what genes might not be working right
 * We can be sure that her gets the care that she needs, including tests to rule out any possible problems and physical, occupational, speech therapies if needed
 * If the translocation is not the cause of the problems, we may be able to identify another cause
 * Either way, the important thing is that her gets the medical care that she needs

Reproductive Risks of a Balanced Reciprocal Translocation

 * As we have already talked about, a balanced reciprocal translocation usually does not cause any physical differences
 * Does have impact on reproduction
 * Four possible outcomes for any pregnancy:
 * A child with normal chromosomes
 * Would expect child to be healthy
 * They cannot pass on the translocation to their children
 * A child that is a balanced translocation carrier
 * If the parents are healthy, we would expect the child to be too
 * Child would have same four possible outcomes for a pregnancy as we are discussing now
 * A child with an unbalanced translocation causing a physical or mental handicap
 * Unbalanced translocation means that there is extra or missing chromosomal material
 * Could lead to physical differences, medical problems like heart defects, etc.
 * An unbalanced translocation that leads to miscarriage or stillbirth
 * Usually if the piece that is extra or missing is large (contains a lot of chromosomal material)
 * There are too many changes in genetic material to allow a conception to grow
 * Some people with balanced translocations have problems with infertility

Risk Assessment

 * The exact risk assessment depends on where the chromosome breaks
 * Overall, there is 5-30% risk to have child born with physical or mental handicaps (general population is 3-5%)
 * There is a 20-30% risk for miscarriage (general population 15%)

Reproductive Options for Balanced Translocation Carrier

 * Just be aware of risks
 * Prenatal testing - amniocentesis or CVS
 * Adoption
 * Sperm or egg donor
 * PGD or IVF

Psychosocial

 * How do you feel about what we talked about?
 * Do you have any new concerns?
 * Give patient literature about translocations
 * Feelings of guilt or blame if either parent is translocation carrier
 * Frustration over inability to offer an explanation right now
 * Fear, worry, anxiety about the future


text:
Handbook of Genetic Counseling/Renal Cell Carcinoma

Renal Cell Carcinoma

Introduction

 * Renal (comprising most kidney) cancer is usually sporadic or randomly occurring
 * Some individuals with renal cancer have a genetic predisposition to developing cancer and we call these hereditary cancers
 * There are a couple of things that sometimes make us wonder if a cancer is due to an inherited genetic predisposition. One of these is early age of onset of cancer.
 * ______ was diagnosed at a young age (most individuals with renal carcinoma are diagnosed in their 40's-60's)
 * Two most common types of renal carcinomas
 * Most common is clear cell renal carcinomas (comprise 80% of sporadic cases and are the type seen in Von Hippel Lindau, which rules this genetic cancer syndrome out)
 * Second most common is papillary renal cell carcinomas (PRCCs) I WON'T GO INTO ALL OF THE FOLLOWING DETAILS ONLY THOSE STARRED
 * generally accepted that it has a better prognosis than other types of renal cancer
 * appears to be sporadic in majority of cases
 * accounts for about 5-10% of sporadic renal cell carcinoma and is seen in Hereditary Papillary Renal Carcinomas (HPRC)
 * estimated that male to female ratio for PRCC is between 5:1 and 8:1 (however when 9 families were studied they found 28:12 (2.33:1 ratio)
 * Sporadic PRCC are usually solitary tumors (but multiple papillary adenomas were described in surrounding renal parenchyma in some cases)
 * In one study all 29 patients from the 6 families with HPRC studied had multiple bilateral tumors
 * Suggestion to subdivide PRCC into type 1 and type 2 tumors
 * Those with family history and those with met mutation share features of type 1, but not all individuals with tumors characteristic of type 1 had an identified met mutation
 * Trisomy 7 characteristic of sporadic and hereditary papillary renal carcinomas (shown in 95% of PRCCs)
 * Also characterized by trisomy or tetrasomy 17, and trisomy 16, 20, and 12 and loss of Y in males
 * Suggested that those with tri or tetrasomy 7 and 17 correspond to papillary adenomas and more complex karyotypic changes are papillary carcinomas

Review genes and chromosomes

 * In order to understand the difference between hereditary and sporadic cancer it can be helpful to review some genetic information because it is not something most people think about all the time.
 * Some genes help control when cells divide and how fast they divide.
 * Essentially there are genes that act like the breaks of a car and there are genes that function like the gas pedal to accelerate cell growth and division.
 * If these genes are changed it can sometimes cause a cell to keep dividing and dividing and develop into cancer.

HPRC

 * Recently described form of hereditary cancer
 * Genetic predisposition to develop multiple tumors in both kidneys (bilateral, multifocal)
 * Median age of onset is 45, but ranges from 18-79 with most between 35 and 55 years old
 * Explain AD inheritance with reduced penetrance
 * Associated with (germline) mutation of a gene present in all of the cells of affected family members
 * gene is called MET and is found at 7q31
 * the gene is involved with regulating cell division
 * this gene is called a proto-oncogene which just means that when it has a change or a mutation in the gene, it can cause cell division to become accelerated (it is kind of like pressing down harder on the gas pedal and not releasing the it so the car can stop)
 * met mutations have also been found in 13% of tumors of PRC patients without a family history but all but one had bilateral disease and may be ascertainment bias
 * half had somatic mutation and half were shown to have germline mutation so rate of met mutation in true sporadic mutations may be 7% or even lower due to bias
 * In those with germline mutation it is possible that these are de novo mutations or may be possible that family members are not picked up because in known families, tumors not always detected until intense radiologic screening is done
 * Germline mutation screening for met does not appear to be clinically indicated in patients with PRCC without additional evidence for genetic predisposition, which includes positive family history, unusual age at onset, bilateral disease (Mary Liebert 2001 found in Genetic Testing)
 * Tumors are predominantly PRCs in HPRC but also breast, pancreas, lung, skin and stomach have been described in some of these families

Management in those with HPRC

 * Use of partial nephrectomy due to risk of tumor in other kidney
 * Those at high risk might benefit from earlier and aggressive site-specific surveillance

Differential Causes

 * 1;X translocations
 * may have prominent papillary architecture
 * may seem to be widely metastatic and poor prognosis
 * TFE3 gene identified at breakpoint
 * Hereditary leiomyomatosis and renal cell cancer (HLRCC)
 * Described in large Finnish family
 * Along with PRCs, uterine leiomyomas, skin leiomyomas, breast cancers, and bladder cancers also found
 * Mapped to 1q42-q44

Facts about renal cell carcinoma

 * accounts for about 3% of adult malignancies and 90-95% of neoplasms in the kidney
 * more common in individuals of Northern European descent but incidence increasing most rapidly in African Americans
 * twice as common in men
 * lack of early warning signs
 * 25-30% are asymptomatic

Symptoms and presentation

 * hematuria (40%)
 * flank pain (40%)
 * palpable mass in the flank or abdomen (25%)
 * weight loss (33%)
 * fever (20%)
 * hypertension (20%)
 * hypercalcemia (5%)
 * night sweats
 * malaise
 * variocele, usually left sided, due to obstruction of the testicular vein (2% of males)
 * cytokine release by tumor frequently causes paraneoplastic conditions

metastasis

 * lung 75%
 * soft tissues 36%
 * bone 20%
 * liver 18%
 * cutaneous sites 8%
 * CNS 8%

Risk factors

 * Smoking doubles risk and contributes to as many as 1/3 of cases
 * Obesity also seems to increase risk especially in women
 * Risk increased also with
 * Abuse of phenacetin-containing analgesics
 * Acquired cystic kidney disease
 * Renal dialysis
 * Renal transplantation

MET function

 * proto-oncogene that encodes met receptor (receptor for hepatocyte growth factor/scatter factor)
 * triggers autophosphorylation of critical tyrosines in the intracellular tyrosine kinase domain of MET, activating a signal cascade


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Handbook of Genetic Counseling/Retinoblastoma

Retinoblastoma

What is Retinoblastoma?

 * a rare, malignant tumor of the retina (nerve-rich, light-sensitive layer that enables us to see) of one or both eyes that occurs in children, usually before 3 years of age

Incidence

 * affects 1 in every 15,000 to 20,000 live births
 * represents about 2% of all childhood malignancies
 * approximately 350 new cases are diagnosed in the U.S. each year
 * affects both sexes in all races

Types of Retinoblastoma

 * Unilateral - when the tumors are present in one eye
 * 50-70% of cases
 * mean age of diagnosis is 24 months
 * Bilateral - when the tumors occur in both eyes
 * 30-50% of cases
 * mean age of diagnosis is 15 months
 * "Trilateral" - the occurrence of bilateral RB plus a pinealoma
 * Unifocal - when a single RB tumor is present
 * Multifocal - when more than one tumor is present in one eye

Mode of Inheritance

 * 90% of patients have no family history of retinoblastoma
 * most cases arise spontaneously for no apparent reason (sporadic)
 * 20% of cases are transmitted as an autosomal dominant trait
 * patients heterozygous for a cancer-predisposing mutation in one RB1 allele are said to have a germline mutation & have a hereditary predisposition to RB
 * a combo. of clinical presentation, family history, and mutation analysis is used to determine if a proband has a germline (heritable) mutation or 2 somatic mutations
 * occurs in cells that have cancer-predisposing mutations in both copies of the gene
 * "Two hit model" - if a child inherits a gene predisposing it to get Retinoblastoma, a second event must take place to change the other gene, causing Retinoblastoma to occur. The nature of the 2nd event is unknown, but research is trying to determine which factors can precipitate the onset of this disorder.

Risks to family members

 * Parents of a proband -
 * Cytogenetically detectable chromosome 13 deletion or rearrangement. Recommendation: Parental cytogenetic studies to determine if either parent carries a balanced chromosome translocation or rearrangement
 * Positive family history (i.e., the parent had retinoblastoma or a close relative of one parent had retinoblastoma). Conclusion: The parent has an RB1 cancer-predisposing germline mutation
 * Negative family history. Recommendation: Examination of apparently unaffected parents by an ophthalmologist knowledgeable about retinoblastoma, retinoma, and retinoblastoma-associated eye lesions. If such a lesion is detected, the parent has an RB1 cancer-predisposing germline mutation
 * Presence of a germline RB1 cancer-predisposing mutation. Recommendation: Molecular genetic testing of a blood sample of both parents.
 * If a germline mutation is identified in either parent, the parent is at risk of developing non-ocular second primary tumors and is at-risk to transmit the mutation to other offspring.
 * If a germline RB1 mutation is not identified in either parent, two possibilities exist: 1) the index case has a de novo RB1 germline mutation (90-94% chance); or 2) one parent has mosaicism (which includes the germline) for the RB1 cancer-predisposing mutation (6-10% chance).
 * Mosaicism for an RB1 cancer-predisposing mutation. Recommendation: Molecular genetic testing of the parents is not necessary.
 * Sibs of a proband - The risk to sibs of an index case depends on the genetic status of the parents of the index case.
 * If a parent is determined to have a germline RB1 cancer-predisposing mutation either by positive family history, by an eye examination that reveals a retinoblastoma-associated eye lesion, or by molecular genetic testing that reveals the presence of a cancer-predisposing RB1 mutation, the risk to each sib of the index case is 50% (or lower if the carrier parent is a mutational mosaic) of inheriting the cancer-predisposing RB1 mutation. Given the approximately 99% penetrance of most RB1 cancer-predisposing mutations, the actual risk for retinoblastoma in these individuals is about 50% (or lower if the carrier parent is a mutational mosaic). (Note: In rare families with "familial-low penetrance retinoblastoma," the risk of tumor development is less than 40%)
 * If neither parent has the cancer-predisposing RB1 mutation that was identified in the index case, germline mosaicism in one parent is possible and the risk to each sib of having retinoblastoma is 3-5%
 * If the index case has mosaicism for an RB1 cancer-predisposing mutation, it is assumed that the mutation arose as a post-zygotic event and that neither parent has an RB1 germline mutation. The risk to the sibs is not increased.
 * If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (i.e., unifocal or multifocal) and family history can be used. The low, but not negligible, risk to sibs of an index case with a negative family history presumably reflects the presence of either a germline RB1 mutation with reduced penetrance in one parent or somatic mosaicism (that includes the germline) for an RB1 mutation in one parent.
 * Offspring of a proband -
 * If the index case has sporadic bilateral RB, a germline RB1 cancer-predisposing mutation has to be assumed and the risk to each offspring is close to 50%.
 * If the index case has had sporadic unilateral multifocal RB, recurrence risk for offspring is lower. (Note: In rare families with "familial-low penetrance retinoblastoma," the risk of tumor development is less than 40%).
 * The low (~1%), but not negligible, risk to the offspring of index cases with unifocal disease and a negative family history reflects the possibility of a germline RB1 mutation with low penetrance or mutational mosaicism.

Chromosome location

 * chromosome 13q14
 * cytogenetic analysis (600-650 bands for at least 30 metaphases) detects deletions or rearrangements in approx. 5% of patients with unilateral RB and 7.5% of patients with bilateral RB -may also result in DD and facial dysmorphism
 * with a normal cytogenetic study? 10% of cases have a positive family history and unilateral or bilateral RB; 30% of cases have a negative family history and multifocal RB; 60% of cases have a negative family history and unifocal RB
 * mosaic aberrations are present in about 1% of patients

Molecular genetics

 * gene RB1
 * Normal gene product: The RB1 gene encodes a ubiquitously expressed nuclear protein that is involved in cell cycle regulation (G1 to S transition). The RB-protein is phosphorylated by members of the cyclin-dependent kinase (cdk) system prior to the entry into S-phase. Upon phosphorylation, the binding activity of the pocket domain is lost, resulting in the release of cellular proteins
 * 80% of patients have a point mutation in the coding regions of RB1 gene; 15% have a partial deletion in the RB1 gene; 5% are unknown (mo mutation found)
 * recessive oncogene - gene that appears to prevent retinoblastoma
 * Two kinds of oncogenes - can cause cancer either by their presence or their absence. Both are mutants/incomplete versions of ordinary genes that normally regulate cell growth. One is dominant and causes out-of-control cell growth (cancer). The other kind is recessive and normally limits or stops the growth of cells. When they are lost, cells can proliferate wildly, causing cancer.

Penetrance

 * incomplete (90%; including all bilateral cases and about 15% of unilateral cases)
 * up to 10% of gene carriers will not develop the tumor but may pass on the gene

Signs/Symptoms

 * leukocoria (white pupil reflex or "cat's eye reflex") - distinctive white mass in the pupil area behind the lens
 * strabismus
 * eye may become red and painful
 * unusual: glaucoma (increased pressure in the eyeball), orbital cellulites, uveitis, hyphema, vitreous hemorrhage
 * some retinal tumors (retinocytoma, retinoma) may undergo spontaneous growth arrest, leading to retinal lesions and scars

Testing:
tumors appear as gray-yellow elevations on the retina ("tumor seeds" - the beginnings of tumors may be visible in the vitreous body of the eye)
 * Diagnostic -
 * clinical ophthalmoscopic examination of the fundus of the eye with dilated pupils
 * imaging studies may be used to support the diagnosis and stage the tumor
 * ultrasound, CAT scan, or MRI may detect calcifications in the tumors
 * probes may be used to identify newborns with a genetic predisposition in order to diagnose earlier
 * Molecular - used in patients with RB with normal cytogenetic studies for risk prediction in relatives
 * mutation analysis of RB1 gene in white blood cell DNA and tumor cells
 * 40% of patients have an abnormal RB1 gene
 * can detect a germline mutation in 80% of the patients with hereditary RB
 * Testing available at several labs, including Retinoblastoma Solutions, University of Pennsylvania, Vermont, etc.
 * detection depends on whether the tumor is unifocal or multifocal, whether the family history is positive or negative, and the sensitivity of the methodology
 * if a germline mutation is identified in the proband, RB1mutation analysis can be used to determine the status of at-risk siblings and offspring
 * indirect testing using linkage analysis (microsatellite markers) can be used in some families
 * Prenatal - RB1 mutations can be detected in utero through CVS or amnio if the RB1 mutation is known or if linkage was informative
 * Screening - ASCO classifies RB as a Group 1 disorder (genetic testing is considered part of the standard management for at-risk family members). Therefore, asymptomatic at-risk children are tested for early identification to improve diagnostic certainty and also to reduce the need for costly screening procedures in those members who have not inherited the mutation.

Treatment

 * 9 of 10 children are treated successfully (goal is preservation of sight and life)
 * enucleation - excision of the tumor and the eye, removal of some of the optic nerve
 * bilateral? more involved eye is removed, other treated in another way
 * photocoagulation
 * cryotherapy
 * radiation
 * systemic chemotherapy
 * follow-up ophthalmological exams every 3 months
 * radiologic surveys for bony metastases
 * studies of spinal fluid & bone marrow for malignant cells

Future prognosis

 * early diagnosis and treatment can reduce morbidity and increase longevity
 * patients with hereditary RB are at an increased risk of developing other (non-ocular) tumors, including pinealomas in the brain which are usually fatal
 * may be at risk of developing osteosarcoma (rare form of bone cancer) - same gene involved in both disorders, soft tissue sarcomas, or melanomas

Differential diagnosis

 * sporadic congenital disorders such as persistent hyperplastic primary vitreous & Coat's disease
 * hereditary disorders such as tuberous sclerosis, Norrie disease, incontinentia pigmenti, and familial exudative vitreoretinopathy
 * ocular infestation by Toxocara canis

Resources

 * www.geneclinics.org
 * www.retinoblastoma.com
 * NORD
 * Retinoblastoma Genetics


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Handbook of Genetic Counseling/Rett Syndrome

Rett Syndrome

Contracting

 * What were you told about why you were referred to genetics?
 * What would you like to learn today?
 * Do you have any questions that you would like us to be sure to address?

Intake and Family History

 * Development during first 6-18 months (should be normal)?
 * Recent development - will see rapid regression in language and motor skills?
 * Loss of purposeful hand use? Repetitive hand movement?
 * Screaming fits and inconsolable crying (18-24 months)?
 * Autistic features?
 * Apnea or hyperpnea?
 * Tremors and acquired microcephaly?
 * Seizures?

Etiology

 * Progressive neurological disorder characterized by normal birth and normal psychomotor development until 6-18 months when see rapid regression
 * Affects girls
 * Diagnosis based on clinical or molecular basis
 * X-linked dominant inheritance
 * About 99.5% of cases are sporadic
 * Result from de novo mutation or from one parent who has somatic or germline mosaicism
 * Mother may have favorable skewed X-inactivation that results in her being unaffected or only slightly affected
 * Risks to siblings depends on status of parents
 * When mother of affected has MECP2 mutation, risk to inherit mutation is 50%
 * If mutation is not identified in parents, risk to low but germline mosaicism cannot be excluded
 * Healthy sisters of girl with Rett syndrome could be carriers with no symptoms due to skewed X-inactivation
 * Females who reproduce have 50% chance of passing on mutation
 * Daughters who inherit mutation at high risk to develop classic Rett syndrome
 * Skewed X inactivation in girls may result in milder phenotype
 * Sons who inherit mutation may suffer severe neonatal encephalopathy or have severe mental retardation syndrome - usually result in miscarriage
 * Due to mutations in MECP2 gene
 * Located at Xq28
 * Methyl-CpG-binding protein 2 (MeCP2)
 * Expressed in all tissues
 * Thought to be global transcriptional repressor, and mutation disrupts gene expression during development
 * Most active in brain tissue
 * Prevalence is estimated to be 1:10,000 to 1:15,000

Clinical Features

 * Normal course of development but may have mild hypotonia
 * Poor suck or weak cry
 * Generally very placid
 * Stage I (early onset)
 * Generally begins between 6 and 18 months of age
 * Symptoms are vague and often overlooked
 * Lasts for a few months to a year
 * Infants show less eye contact and less interested in toys
 * Delays in gross motor skills such as crawling or sitting
 * Handwringing and decreasing head growth are mild
 * Stage II (rapid destructive stage)
 * Begins between ages 1 and 4 years old
 * Lasts for weeks or months
 * May have rapid or gradual onset
 * Purposeful hand skills and spoken language lost
 * May being wringing, washing, clapping, tapping, or hand-to mouthing
 * Hands sometimes clasped behind back or at sides with random touching, grasping, and releasing
 * Movements persist while awake but disappear during sleep
 * Often screaming fits and inconsolable crying
 * May see breathing irregularities
 * Apnea and hyperventilation
 * Breathing normal during sleep
 * Autistic-like behaviors
 * Loss of social interaction and communication
 * General irritability and sleep irregularities
 * Gait patterns unsteady and difficult to initiate movements
 * Slowing of head growth is noticeable
 * Brain size may eventually be 30% smaller than normal
 * May begin to notice change as early as 3 months
 * Gastrointestinal findings
 * About 85-90% of girls have general growth failure and wasting
 * Oropharyngeal and gastroesophageal incoordination may result in poor food intake
 * Bowel dysmotility, constipation, and functional megacolon common
 * Fecal impaction, volvulus, and intussusception can occur
 * May also involve gallstones
 * Stage III (plateau or pseudostationary stage)
 * Begins between ages 2 and 10
 * Can last for years
 * Many girls remain in this stage for most of their lives
 * Apraxia, motor problems common during this stage
 * Seizures occur in about 50% of girls
 * Tonic-clonic and partial complex are most common
 * Occur more frequently once disease stabilizes
 * Improvement in behavior with less irritability, crying, and autistic-like features
 * May show more interest in her surroundings
 * Alertness and attention span may improve
 * Communication skills may also improve
 * Osteoporosis is problem, possibly due to poor bone formation - results in fractures
 * Stage IV (late motor deterioration stage)
 * Can last for years or decades
 * Characterized by reduced mobility
 * Muscle weakness, rigidity (stiffness), spasticity, dystonia (increased muscle tone with abnormal posturing of extremity or trunk), and scoliosis
 * Girls may stop walking
 * Generally no decline in cognition, communication, or hand skills
 * Repetitive hand movements may decrease
 * Eye gaze usually improves
 * Girls typically survive into adulthood
 * Incidence of sudden, unexplained death significantly higher
 * May be due to reduced heart rate variability and neurological differences
 * Atypical Rett syndrome
 * Females have mild learning disability or a few women with no symptoms and skewed X-inactivation
 * Mutations have been found in those previously diagnosed with autism, mild learning disability, and Angelman syndrome
 * Males
 * Males meeting clinical phenotype have been found with 47,XXY and mosaicism for MECP2 mutations
 * Males with 46,XY can also (rarely) be affected

Diagnosis/Testing Options

 * Clinical diagnosis
 * Requires following:
 * Apparently normal prenatal and perinatal period
 * Normal head circumference at birth
 * Apparently normal development through age six months
 * Deceleration of head growth occurring anytime between ages three and 48 months
 * Loss of acquired hand skills and purposeful hand use between ages five and 30 months, with subsequent development of stereotyped hand movements
 * Severe impairment of expressive and receptive language together with severe psychomotor retardation
 * Development of gait apraxia and truncal ataxia between ages 12 and 48 months
 * Limitations
 * May be considered tentative until patient is 2-5 years old
 * Broad clinical variability
 * Some girls do lose purposeful hand motion and have seizures but can walk and retain some speech
 * Some girls severe with no period of normal development
 * Some girls have less dramatic regression and milder mental retardation
 * Biochemical laboratory studies not helpful
 * Mutation analysis
 * Used to confirm diagnosis in patients or family members of patients
 * Bi-directional sequencing
 * Detects mutations in about 80% of patients
 * Can also do PCR based DHPLC or combination of both
 * Must be sure mutation is disease-causing and not polymorphism (truncating or previously reported)
 * Baylor College of Medicine
 * MECP2 testing using PCR amplification of 3 exons
 * 14cc for adults or 6cc for child in purple top EDTA tube
 * CPT codes 83891, 83898x5, 83904x5, 83912 for index case; 83891, 83898x1, 83904x1, and 83912 (for other family members)
 * X-chromosome inactivation
 * Useful in family with several children having various MECP2 mutation phenotypes but asymptomatic mother
 * Mother may have mutation but XCI pattern causes her to have no clinical signs
 * Not used for diagnosis in at-risk family members
 * Prenatal testing
 * Prenatal diagnosis offered to women with known MECP2 mutations
 * Male fetus will at best survive with severe mental retardation
 * Phenotype in female difficult to predict since depends on X-inactivation
 * Also offered whether or not disease-causing mutation is identified in parent because of germline mosaicism

Treatment/Management

 * No treatment known to improve neurologic outcome
 * Several trials have had questionable efficacy and outcomes
 * Tried naltrexone (oral opiate agonist) and L-carnitine
 * Management is supportive and symptomatic therapy
 * Low dose risperidone for agitation or other selective seratonin uptake inhibitors
 * May also try chloral hydrate, hydroxyzine, or diphenhydramine with melatonin
 * Carbidopa/levodopa for rigidity but benefit not proven
 * Melatonin may help sleep disturbances
 * Try controlling diet to help with constipation
 * Ample fluid intake and high fiber diet can help prevent crisis
 * May use stool softeners
 * Anti-reflux agents, smaller and thickened feedings, and positioning can help with reflux
 * Video/EEG studies can give definitive information about seizures and need for antiepileptic
 * Occupational and physical therapy to maintain function and prevent scoliosis
 * Music therapy may be beneficial to girls to improve receptive and expressive language
 * Mental function is not impaired!

Differential Diagnosis

 * Infantile neuronal ceroid lipofuscinosis
 * Loss of motorskills and seizures, dementia, and spasticit
 * Have retinal dystrophy with blindness not seen in Rett syndrome
 * Relies on electron microscopic findings on tissue biopsy, analysis of PPT-1 enzyme, or mutation analysis of CLN1 gene
 * Autism
 * Common diagnosis of girls with Rett syndrome without microcephaly, seizures, kyphoscoliosis
 * No clinical criteria can distinguish between them
 * Angelman syndrome
 * Mental deficiency, seizures, ataxia, hand stereotypes, and microcephaly
 * Developmental regression should distinguish Rett syndrome
 * Seizures more difficult to manage in Angelman Syndrome
 * Molecular genetic testing identifies about 90% of Angelman mutations
 * Older patients may have been diagnosed with cerebral palsy

Psychosocial Issues

 * Lifelong care for a child who may never be able to take care of herself
 * Feelings of guilt, anger, fear, sadness, sense of loss surrounding new diagnosis
 * Concern about risk for future children
 * Worry, frustration about what future holds since may not be able to predict
 * One child that requires extra care and attention, detracting from other children or family relationships

Support Resources

 * International Rett Syndrome Association
 * (800) 818-7388
 * www.rettsyndrome.org

 * Rett Syndrome Research Foundation
 * 4600 Devitt Drive
 * Cincinnati, OH 45246
 * (513) 874-3020
 * www.rsrf.org

 * Easter Seals
 * (800) 221-6827
 * www.easter-seals.org


text:
Ruby Programming/Syntax/Method Calls

A method in Ruby is a set of expressions that returns a value. With methods, one can organize their code into subroutines that can be easily invoked from other areas of their program. Other languages sometimes refer to this as a function. A method may be defined as a part of a class or separately.

Method Calls
Methods are called using the following syntax:

With or without parameters, Ruby allows method calls without parentheses:

Parentheses are needed to chain method calls; for example:

Method Definitions
Methods are defined using the keyword  followed by the method name. Method parameters are specified between parentheses following the method name. The method body is enclosed by this definition on the top and the word  on the bottom. By convention method names that consist of multiple words have each word separated by an underscore.

Example:

Return Values
Methods return the value of the last statement executed. The following code returns the value.

An explicit return statement can also be used to return from function with a value, prior to the end of the function declaration. This is useful when you want to terminate a loop or return from a function as the result of a conditional expression.

Note, if you use "return" within a block, you actually will jump out from the function, probably not what you want. To terminate block, use break. You can pass a value to break which will be returned as the result of the block:

In this case, six will have the value 6.

Default Values
A default parameter value can be specified during method definition to replace the value of a parameter if it is not passed into the method.

The method call above will output:

The following is a syntax error in Ruby 1.8

The above code will work in 1.9.2 and will be logically equivalent to the snippet below

Variable Length Argument List, Asterisk Operator
The last parameter of a method may be preceded by an asterisk(*), which is sometimes called the 'splat' operator. This indicates that more parameters may be passed to the function. Those parameters are collected up and an array is created.

In the example above the output would be ['a', 'b', 'c'].

The asterisk operator may also precede an Array argument in a method call. In this case the Array will be expanded and the values passed in as if they were separated by commas.

has the same result as:

Another technique that Ruby allows is to give a Hash when invoking a function, and that gives you best of all worlds: named parameters, and variable argument length.

You see, the arguments for accepts_hash got rolled up into one hash variable. This technique is heavily used in the Ruby On Rails API.

Also note the missing parenthesis around the arguments for the accepts_hash function call, and notice that there is no { } Hash declaration syntax around the :arg1 => '...' code, either. The above code is equivalent to the more verbose:

Now, if you are going to pass a code block to function, you need parentheses.

In versions of Ruby since Ruby 2.0, it is also possible to use the new built-in keyword arguments that make above technique somewhat easier. The new syntax is as follows: Above function can now be called as test_method(1,2), test_method(1,2, c: somevalue), test_method(1,2, d:someothervalue), test_method(1,2, c:somevalue, d:someothervalue) or even test_method(1,2, d: someothervalue, c: somevalue). In this example, parentheses are again not required unless you want to chain the result to another function or method right away. Note that this does mean that you 'have' to pass on names for (in this case) the 'c' and 'd' values you pass into the function, whenever you want to include them Calling the method like test_method(1,2,3,4) will not work.

Keyword Arguments are especially helpful whenever there is a lot of non-required options that might be passed into a function. Specifying the names whenever they are used makes the resulting function calls very readable.

The Ampersand Operator
Much like the asterisk, the ampersand(&) may precede the last parameter of a function declaration. This indicates that the function expects a code block to be passed in. A Proc object will be created and assigned to the parameter containing the block passed in.

Also similar to the ampersand operator, a Proc object preceded by an ampersand during a method call will be replaced by the block that it contains. may then be used.

Introduction
Ruby provides the programmer with a set of very powerful features borrowed from the domain of functional programming, namely closures, higher-order functions, and first-class functions [1]. These features are implemented in Ruby by means of code blocks, Proc objects, and methods (that are also objects)—concepts that are closely related and yet differ in subtle ways. In fact, I found myself quite confused about this topic, having difficulty understanding the difference between blocks, procs, and methods as well as unsure about the best practices of using them. Additionally, having some background in Lisp and years of Perl experience, I was unsure of how the Ruby concepts map to similar idioms from other programming languages like Lisp’s functions and Perl’s subroutines. Sifting through hundreds of newsgroup posts, I saw that I am not the only one with this problem and, in fact, quite a lot of “Ruby Nubies” struggle with the same ideas.

In this article I lay out my understanding of this facet of Ruby, which comes as a result of extensive research of Ruby books, documentation, and comp.lang.ruby, in sincere hope that other people will find it useful as well.

Procs
Shamelessly ripping from the Ruby documentation, Procs are defined as follows: Proc objects are blocks of code that have been bound to a set of local variables. Once bound, the code may be called in different contexts and still access those variables.

A useful example is also provided:

Procs play the role of functions in Ruby. It is more accurate to call them function objects, since like everything in Ruby they are objects. Such objects have a name in the folklore - functors. A functor is defined as an object to be invoked or called as if it were an ordinary function, usually with the same syntax, which is exactly what a Proc is.

On Wikipedia, a closure is defined as a function that refers to free variables in its lexical context. From the example and the previous definitions, it is obvious that Ruby Procs can also act as closures. Note how closely it maps to the Ruby definition blocks of code that have been bound to a set of local variables.

More on Procs
Procs in Ruby are first-class objects, since they can be created during runtime, stored in data structures, passed as arguments to other functions and returned as the value of other functions. Actually, the gen_times example demonstrates all of these criteria, except for “passed as arguments to other functions”. This one can be presented as follows:

There is also a shorthand notation for creating Procs - the Kernel method lambda [2] (we’ll come to methods shortly, but for now assume that a Kernel method is something akin to a global function, which can be called from anywhere in the code). Using lambda the Proc object creation from the previous example can be rewritten as:

Actually, there are two slight differences between lambda and Proc.new. First, argument checking. The Ruby documentation for lambda states: Equivalent to Proc.new, except the resulting Proc objects check the number of parameters passed when called. Here is an example to demonstrate this:

Second, there is a difference in the way returns are handled from the Proc. A return from Proc.new returns from the enclosing method (acting just like a return from a block, more on this later):

While return from lambda acts more conventionally, returning to its caller:

With this in light, I would recommend using lambda instead of Proc.new, unless the behavior of the latter is strictly required. In addition to being a whopping two characters shorter, its behavior is less surprising.

Methods
Simply put, a method is also a block of code. However, unlike Procs, methods are not bound to the local variables around them. Rather, they are bound to some object and have access to its instance variables [3]:

A useful idiom when thinking about methods is that you are sending messages to the object that the method is defined for. Given a receiver - an object that has some method defined - we send it a message, which contains the name of the method, and optionally provides the arguments that the method would receive. In the example above, calling the method arbo without any arguments, is akin to sending a message with just “arbo” as the argument.

Ruby supports the message sending idiom more directly, by including the send method in class Object (which is the parent of all objects in Ruby). So the following three lines are equivalent to the arbo method call:

Note that methods can also be defined in the so-called “top-level” scope, which is not inside any user-defined class. For example:

While it seems that the method say is “free-standing”, it is not - Ruby silently tucks it into the Object class, which represents the scope of your application:

But this doesn’t really matter, and for all practical purposes say can be seen as an independent method. Which is, by the way, just what’s called a “function” in some languages (like C and Perl). The following Proc is, in many ways similar:

The [] construct is a synonym to call in the context of Proc [4]. Methods, however, are more versatile than procs and support a very important feature of Ruby, which I will present right after explaining what blocks are.

Blocks
Blocks are so closely related to Procs that it gives many newbies a headache trying to decipher how they actually differ. I will try to ease on comprehension with a (hopefully not too corny) metaphor. Blocks, as I see them, are unborn Procs. Blocks are the larval, Procs are the insects. A block does not live on its own - it prepares the code for when it will actually become alive, and only when it is bound and converted to a Proc, it starts living:

Is that it, is that what all the fuss is about, then ? No, not at all. The designer of Ruby, Matz saw that while passing Procs to methods (and other Procs) is nice and allows high-level functions and all kinds of fancy functional stuff, there is one common case that stands high above all other cases - passing a single block of code to a method that makes something useful out of it, for example iteration. And as a very talented designer, Matz decided that it is worthwhile to emphasize this special case, and make it both simpler and more efficient.

Passing a block to a method
No doubt that any programmer who has spent at least a couple of hours with Ruby has been shown the following examples of Ruby glory (or something very similar):

(Note that  is equivalent to  .)

Such code is, in my opinion, the part of what makes Ruby the clean, readable, and wonderful language it is. What happens here behind the scenes is quite simple, or at least may be depicted in a very simple way. Perhaps Ruby may not implement it exactly the way I am going to describe it, since there are optimization considerations surely playing their role, but it is definitely close enough to the truth to serve as a metaphor for understanding.

Whenever a block is appended to a method call, Ruby automatically converts it to a Proc object but one without an explicit name. The method, however, has a way to access this Proc, by means of the yield statement. See the following example for clarification:

The method do_twice is defined and called with an attached block. Although the method did not explicitly ask for the block in its arguments list, the yield can call the block. This can be implemented in a more explicit way using a Proc argument:

This is equivalent to the previous example but using blocks with yield is cleaner and better optimized since only one block is passed to the method. Using the Proc approach, any amount of code blocks can be passed:

This is important to note that many people frown at passing blocks and prefer explicit Procs instead. Their rationale is that a block argument is implicit and one has to look through the whole code of the method to see if there are any calls to yield there, while a Proc is explicit and can be immediately spotted in the argument list. While this is simply a matter of taste, understanding both approaches is vital.

The ampersand (&)
The ampersand operator can be used to explicitly convert between blocks and Procs in a couple of cases. It is worthy to understand how these work.

Remember how I said that although an attached block is converted to a Proc under the hood, it is not accessible as a Proc from inside the method ? Well, if an ampersand is prepended to the last argument in the argument list of a method, the block attached to this method is converted to a Proc object and gets assigned to that last argument:

Another (IMHO far more efficacious) use of the ampersand is the other-way conversion - converting a Proc into a block. This is very useful because many of Ruby’s great built-ins, and especially the iterators, expect to receive a block as an argument, and sometimes it’s much more convenient to pass them a Proc. The following example is taken right from the excellent “Programming Ruby” book by the pragmatic programmers:

The collect method expects a block, but in this case it is very convenient to provide it with a Proc, since the Proc is constructed using knowledge gained from the user. The ampersand preceding calc makes sure that the Proc object calc is turned into a code block and is passed to collect as an attached block.

The ampersand also allows the implementation of a very common idiom among Ruby programmers: passing method names into iterators. Assume that I want to convert all words in an Array to upper case. I could do it like this:

This is nice, and it works, but I feel it’s a little bit too verbose. The upcase method itself should be given to map, without the need for a separate block and the apparently superfluous x argument. Fortunately, as we saw before, Ruby supports the idiom of sending messages to objects, and methods can be referred to by their names, which are implemented as Ruby Symbols. For example:

This, quite literally, says send the message/method upcase to the object “Erik”. This feature can be utilized to implement the map {|x| x.upcase} in an elegant manner, and we’re going to use the ampersand for this! As I said, when the ampersand is prepended to some Proc in a method call, it converts the Proc to a block. But what if we prepend it not to a Proc, but to another object? Then, Ruby’s implicit type conversion rules kick in, and the to_proc method is called on the object to try and make a Proc out of it. We can use this to implement to_proc for Symbol and achieve what we want:

Dynamic methods
You can define a method on "just one object" in Ruby.

Or you can use define_(singleton_)method, which preserves the scope around the definition, as well.

Special methods
Ruby has a number of special methods that are called by the interpreter. For example:

This does something silly but  is an important part of meta-programming in Ruby. In Ruby on Rails it is used extensively to create methods dynamically.

Another special method is  that ruby calls whenever a class instance is created, but that belongs in the next chapter:  Classes.

Conclusion
Ruby doesn’t really have functions. Rather, it has two slightly different concepts - methods and Procs (which are, as we have seen, simply what other languages call function objects, or functors). Both are blocks of code - methods are bound to Objects, and Procs are bound to the local variables in scope. Their uses are quite different.

Methods are the cornerstone of object-oriented programming, and since Ruby is a pure-OO language (everything is an object), methods are inherent to the nature of Ruby. Methods are the actions Ruby objects do - the messages they receive, if you prefer the message sending idiom.

Procs make powerful functional programming paradigms possible, turning code into a first-class object of Ruby allowing to implement high-order functions. They are very close kin to Lisp’s lambda forms (there’s little doubt about the origin of Ruby’s Proc constructor lambda)

The construct of a block may at first be confusing, but it turns out to be quite simple. A block is, as my metaphor goes, an unborn Proc - it is a Proc in an intermediate state, not bound to anything yet. I think that the simplest way to think about blocks in Ruby, without losing any comprehension, would be to think that blocks are really a form of Procs, and not a separate concept. The only time when we have to think of blocks as slightly different from Procs is the special case when they are passed as the last argument to a method which may then access them using yield.

That’s about it, I guess. I know for sure that the research I conducted for this article cleared many misunderstandings I had about the concepts presented here. I hope others will learn from it as well. If you see anything you don’t agree with - from glaring errors to small inaccuracies, feel free to amend the book.

title: Ruby Programming/Syntax/Method Calls


text:
Budget Watch Collecting/Tool list

Essentials That You Can't Do Without

 * Screwdrivers : 0.5mm, 1mm and 1.5mm at least. A full set (nine screwdrivers, from 0.6 to 3 mm) is much better. The USD 50 AF (which is a French-made one, but rebranded) is a sure bet. Bergeon makes a nice set, but a bit overpriced. Do not get the anti-magnetic ones, as these are way too soft.

 * Tweezers : Quality makes a difference. I'd get one quality pair (Dumont is a very good brand), and a couple of less expensive ones to start. An anti-magnetic steel pair (size 1 or 2; whereas a fine size 5 is for hairspring work only), and any brass one, as brass is softer than steel, so it won't leave any mark on the steel, and brass is anti-magnetic (AM is always obviously written on these).

 * Watch oil and oiler : I like fountain oilers, because they save oil, especially if you don't do all that many watches at a time.  Dip oilers will work, but it is likely that your oil will be contaminated before you use much of it.  A reasonable substitute is an insulin syringe with a blunted tip. Depends on local rules; here I can get them without a prescription.

 * Movement holder or movement rings : It's just barely possible to work without them, but only barely. The genuine Bergeon 4040 is a classic. Do not get the Chinese/Indian ones, their sides are not parallel.

Nearly Essential Tools

 * Digital camera : Unless your memory is a lot better than mine. Take pictures of the movement.  If your camera won't take close-ups, you can probably hold a jeweler's loupe in front of the lens to get closer.  Generally best with the flash off.

 * Screwdriver sharpener : Possibly not right away if you get a very high quality screwdriver set, you'll need it if you get a $15 screwdriver set, and you'll need it eventually no matter what. I'd rather have cheap screwdrivers and a sharpener than a good set without. You'll need a sharpening stone: buy a double-sided USA Norton "India" stone (orange/brown): one side is coarse, the other one is fine. Always put some PETROL on it BEFORE sharpening anything on it, or the stone will get clogged up with metal fragments. For a last fine sharpening job, you can use an Arkansas stone (they're gray or bluish/white colored). Always use oil with this stone.

 * Loupes : If you're as nearsighted as I am, you can just barely manage without one, but they are too cheap to do without. You'll want a x4 or so to get tools between the loupe and the watch, and a x12 or so to inspect extremely close.  Drill some holes in the body to reduce fogging. Good brands : Asco, Bergeon.  An Optivisor (headband mounted stereo magnafyer) is nice. The real ones have a prism that helps with close vision.   Cheaper ones just have the lens, you wind up having to go cross-eyed to see.

 * Case wrench : Jaxa-style is the best cheap version. If you go for the Asian copy of the Jaxa tool, remember you can still buy a good Bergeon set of replacement bits.

 * Case knife : One of the easiest tools to substitute, but inexpensive.

 * Crystal press : For installing crystals and bezels, and for closing stubborn snap-on backs.

 * Crystal lift : For installing and removing plastic crystals, the only way to access some watches with one-piece cases

 * Pin vise : For holding stems and similar.

 * Rubber dust blower : To remove dust, or to dry a part.

 * A tool to remove the strap/bracelet from the watch : I like the cheap Bergeon 6767 (the one with fine tip).

 * Parts trays : I use artist's watercolor trays from WalMart, less than $1.

 * Rodico cleaning putty : Putty-like thumbtack substitutes can work, but the real stuff isn't expensive. The older Green one is okay, but the Premium gray leaves no residues at all.

 * Watch tissue : Basically like wrapping tissue, but pre-cut in 3-4 inch squares.

 * Hand puller : Go for the black Bergeon one, expensive, but do not take a risk with those fragile hands !

 * Small containers for movements : I like 2 oz condiment containers with lids from a restaurant supply store.

 * Watchmaker's bench : I started with a footstool on my desk to get close to the right level, built a custom bench later. Always clean it well before doing any watchmaking job, that's a priority.

Advanced Tools

 * Cleaning machine : A mechanical watch cleaner (spins the parts around in jars of cleaner) does nearly as good a job as a good ultrasonic, a better job than a cheap ultrasonic, and is far easier.

 * Chemicals : L and R watch cleaning chemicals may cost more than a used mechanical machine, but make a huge difference. Non-ammoniated will last longer for occasional use, the ammonia will evaporate.  If you can't afford both wash and rinse, get the wash and substitute Naptha (lighter fluid) or paint thinner for the rinse.

 * Staking set

title: Budget Watch Collecting/Tool list


text:
Handbook of Genetic Counseling/Ring Chromosome 22

Ring Chromosome 22

Introduction and contracting

 * Could you explain to me in your own words why you were referred to genetics?
 * What is your understanding of the chromosome results?
 * What are your main questions or concerns?
 * Outline session
 * Explain chromosome results
 * Take family history (ask standard questions i.e.) miscarriage, MR, learning disabilities, birth defects, etc.)
 * Dr. will examine him and may ask more questions about his medical history
 * We will discuss what we know and answer questions if we can

Explain results

 * Briefly explain chromosomes and genes
 * He has 46 chromosomes including an X and Y which indicates what we already knew that he is a boy
 * He also has part of an extra chromosome that has formed a ring
 * The ring contains part of chromosome 22 (show ideogram)
 * a ring usually forms when the ends of a chromosome break off leaving "sticky ends" that then connect.
 * We don't really know why rings form
 * We also don't know where the extra piece of chromosome originally came from
 * The presence of extra chromosomal material can change the way our bodies grow and develop
 * There are no reports in the literature of individuals with an extra ring chromosome 22 that is exactly like the one found in _______.
 * Therefore it makes it difficult to give you a clear idea of what to expect
 * Especially since there are two things we are considering, the extra genetic material and the fact that it is present in a ring form
 * However, we can tell you about what we do know from reports in the literature that are similar in some ways
 * I'd like to address your main concerns the best I can so please jump in with questions

Possibilities with ring chromosomes

 * Extra ring chromosomes have been passed on from parent to child (a case of grandfather, father and son all with extra ring 22 that is much small then _____'s ring)
 * When the ring chromosome is copied before cells divide sometimes there is difficulty separating them and this can result in the ring being altered (new break points or duplication of some of the material)
 * It is thought that if they can't separate the cell dies
 * It tends to be more common to have ring chromosomes present in a certain percentage of a person's cells and not all of them
 * When this is the case the cells with the extra ring are thought to die (evidence for this comes from the fact that sometimes when these individuals are retested there are no longer rings present or they are found in a smaller percentage of cells.)

Discussion

 * It seems that _____ is doing better than nearly all of the individuals that have been reported to have a duplication of all or even part of chromosome 22 in the literature
 * If individuals have an entire extra copy of chromosome 22 (that is not a ring) they generally die before birth or soon after. They also usually have a number of birth defects and characteristic physical features.
 * Individuals with partial deletions have been reported with a number of physical characteristics and health concerns that ______ does not seem to have.

Phenotype seen in other cases

 * Complete trisomy 22 syndrome, der(22) syndrome, and cat eye syndrome (CES) all have some overlapping characteristics (see charts from articles describing characteristics with complete and mosaic trisomy 22 and see chart listing features of CES)

CES

 * Typically associated with supernumerary bisatellited marker chromosome (inv dup 22pter-22q11.2) resulting in 4 copies of that region
 * Highly variable phenotype (same marker results in different phenotype in different generations)
 * 3 copies have been enough to result in CES phenotype (Reiss et al. 1985 and Knoll et al. 1994)
 * Criteria for diagnosis of CES include;
 * Ocular coloboma of the iris and or retina
 * Anal atresia (with or without fistula)
 * Preauricular skin tags and pits
 * Heart defects (especially total anomalous pulmonary venous return
 * Dysmorphic features (hypertelorism, down-slanting palpegral fissures, urogenital defects, mild to moderater MR

Minute supernumerary ring chromosome 22 associated with CES

 * 3 generations had the minute ring derived from 22q11.2
 * ring present in 90% of blood cells over the three generations
 * individual affected with CES has 4 copies of this region in each cell (unaffected father and grandfather have 3 copies)
 * father and paternal grandfather had no clinical features
 * may have been derivative of a dicentric marker chromosome

Case of duplication of 22q11.2-q13.1 and pericentric inversion (Prasher VP et al. 1995)

 * Limited communication skills
 * Persistent self injury
 * Poor mobility
 * Colobomata (common in cat eye syndrome)
 * Prominent forehead
 * Low posterior hairline
 * Prognathism of lower jaw
 * Tongue protrusion
 * Poor vision
 * Needed help with daily living skills
 * Short hands and fingers
 * Moderate thoracic kyphosis
 * Small penis and testes
 * Bilateral single transverse palmar crease

Shares features of another case with duplication of 22q11.1 to q13

 * Absence of speech
 * Persistent self-injury
 * Lack of daily living skills
 * very poor vision

Case of de novo direct duplication of 22q11-q12

 * Milder phenotype than complete trisomy 22 and der(22)t(11:22)
 * Similar in type and severity of cat eye syndrome (CES)

Other case of 22q11.2-q13.1 de novo duplication

 * Minor physical anomalies
 * Bilateral preauricular pits
 * Failure to thrive
 * Highly arched palate
 * Bilateral hydronephrosis
 * Delayed gross motor skills

Mechanisms of ring formation

 * By two DNA breaks, one in each arm of the same chromosome, followed by fusion of the proximal broken ends. The causes of these DNA breaks are usually unknown and so is the mechanism behind ligation of the ends. It is possible that the non-homologous end-joining machinery plays a role in this process (Smith et al. 2001). A ring can also be formed by fusion at two breakpoints in the same chromosome arm. However, only few examples of such rings have been described. Most probably, this is because they are acentric and will lack attachment point for the cell division machinery. Unless there is a different anchorage sequence for the kinetochore complex they will be lost in subsequent mitoses. Such ÒneocentromereÓ sequences have, however, been described in rare cases of constitutional (Slater et al. 1999) and acquired (Gisselsson et al. 1999) ring chromosomes.
 * By fusion of dysfunctional telomeres from the same chromosome. Several in vitro and animal models have shown that shortening of telomeric DNA repeats leads to the detachment of protective proteins from the chromosome ends (Counter et al. 1992). This renders the chromosome ends prone to recombination with DNA either from other chromosomes Ð leading to formation of a dicentric Ð or with the other arm of the same chromosome Ð leading to formation of a ring.
 * Parents carrying acrocentric isochromosomes or homologous Robertsonian translocations have been known to have children with a ring chromosome apparently derived from the parental abnormality (Mears AJ cites de Almeida et al. 1983 and Neri et al. 1983)
 * Extranumerary can form when a marker chromosome breaks and ends of the monocentric fragment fuse

Constitutional ring chromosomes
Supernumary ring chromosomes
 * 1/50,000 human fetuses (Jacobs et al. 1975)
 * In most instances, these rings are formed by breakpoints in both arms, followed by fusion of the proximal ends into a ring with loss of the distal material.
 * Such rings may thus result in clinical features mimicking terminal deletion syndromes.
 * Alternatively, congenital ring chromosomes are supernumerary, i.e. they occur together with two normal homologues of the corresponding chromosome (Anderlid et al. 2001)
 * rare due to:
 * actually are rare in occurrence
 * supernumerary ring chromosomes often gradually disappear in vivo and only cells with normal karyotype are eventually observed (Michalski K et al. 1993 cited Hoo et al. 1980)
 * not very many reports makes it difficult to predict prognosis or provide empiric risk data
 * supernumerary marker chromosomes are more common than supernumerary rings occurring in 1 in 1,500 to 1 in 500 for a (Michalski K et al. 1993 extrapolated this from multiple studies from 1984-1990)
 * the consequences will be similar to partial trisomies or duplications
 * Different characteristics depending on:
 * which chromosome is involved
 * the position of breakpoints within the chromosome.
 * patients with extra rings do not only display diverse symptoms resulting from deletions or duplications
 * In a meta-study including more than two-hundred patients with congenital ring chromosomes it has been demonstrated that the majority of children with rings show a failure to thrive beyond the extent expected from their chromosomal imbalances (Kosztolanyi 1987).
 * suggested that this is due to the mitotic instability of rings, preventing somatic cells from proliferating normally.
 * hypothesis is supported by the fact that growth failure is more common among patients with large ring chromosomes, than among those with small ones (Kosztolanyi 1987).
 * This is in accordance with the BFB model of ring chromosome dynamics.
 * Statistically, large rings will undergo more sister chromatid exchanges per cell cycle than small rings and would thus have a higher propensity for breaking at anaphase.
 * In a normal cell, this provokes a physiological DNA damage response leading to either cell cycle arrest or apoptosis (Cohen-Jonathan et al. 1999).
 * a cell population carrying a ring chromosome would proliferate slower than a population without rings; the population with rings would be less fit and be at a selective disadvantage.
 * Interestingly, ring chromosome loss or size reduction is not uncommon in cases with congenital rings.
 * In particular, cases with small rings often exhibit a subclone without the ring chromosome and these patients are thus ring/monosomy mosaics (Gisselsson et al. 1999).

Ring chromosomes at cell division

 * In contrast to linear chromosomes, rings may undergo cell division in three different ways (McClintock 1938; Lejeune 1968). Which of these pathways a ring chromosome will follow depends on the number of sister chromatid exchanges (SCE) that has occurred in the ring before cell division:
 * No SCE or an even number of SCEs in the same direction will enable normal, symmetrical segregation of the chromatids.
 * An even number of SCEs in different directions will lead to the formation of interlocked rings.
 * An odd number of SCEs will lead to transformation from two parallel chromatids into one continuous ring, with the double size of the original rings (Fig. 2).