TAMISON JEWETT, MDPROFESSOR, DEPARTMENT OF PEDIATRICS

SECTION ON MEDICAL GENETICSWAKE FOREST BAPTIST HEALTH

Down Syndrome Update2014

Down syndrome (as we know it today) has existed since the

beginning of humankind.

Down syndrome history

Pottery artifacts from the Tumaco-La Tolita culture from 2500 years ago depict individuals with features of Down syndrome (DS).

DS features are evident in a terra cotta sculpture carved by the Toltecs in Mexico (500-1200 AD).

Esquirol, a French psychiatrist, wrote a description of the DS facial appearance in 1838.

Flemish, 1515, Artist unknown

Filippo Lippi, 1400’s

Down syndrome history (cont.)

First described in the medical literature in 1866 by Dr. John Langdon Down in England; he coined the term “Mongoloid.”

In 1956, scientists discovered that the typical human cell has 46 chromosomes.

In 1958, Lejeune discovered that the cells from an individual with DS had an extra chromosome 21.

In 1959, 9 people with DS were found to have an extra chromosome 21.

Syndrome:

a recognizable pattern of features, usually owing to a specific cause, e.g., Down syndrome, wherein the cause is extra

chromosome 21 material

Down syndrome features

Brachycephaly (short skull front-to back)

Excess nuchal (back of neck) skin

Hypoplastic (underdeveloped) midface

Upslanting palpebral fissures (eyelids)

Small ears w/ over-folded helices

Down syndrome features (cont.)

5th finger clinodactyly (incurving)

Wide gap between 1st and 2nd toes

Single transverse palmar crease(s) (40%)

Heart defect (45%)

Fine, soft hair

It is important to remember that individuals with DS look mainly like their families; it is the characteristic pattern of features that

causes them to resemble one another.

Typical Female Chromosomes

Typical Male Chromosomes

Ideogram of the human chromosomes

p-arm=>

q-arm=><= centromere

autosomes

Sex chromosomes

Acrocentric=>

From the NIH Image Bank

Trisomy 21 Female Chromosomes

Trisomy 21 Male Chromosomes

Typical gamete formation and fertilization

Nondisjunction (abnormal cell division) and fertilization

Abnormal cell division leading to abnormal chromosome distribution can occur in EITHER PARENT. As women age, our risk for this to

occur increases, as follows:

Maternal Age Incidence of DS at delivery

15-29 1 in 1500

30-34 1 in 800 35-39 1 in 270 40-44 1 in 100 45 and over 1 in 50

Chromosomal translocations…

…can result in Down syndrome.

Down syndrome

Occurs in ~1:650 live births

The underlying causes:

94% due to nondisjunction (unequal cell division) resulting in 47 chromosomes with an extra #21

3.3% due to an unbalanced translocation

~2.4% are mosaic (some cells have the typical 46 chromosomes, and some have 47)

<1% have a duplication of a portion of chromosome 21

Extra chromosomes mean extra genes.

Genes are recipes that direct our cells to make something our bodies

need.

From the NIH Image Bank

From the NIH Image Bank

The genes of chromosome 21: what do we know?

There are more than 400 genes on chromosome 21.

Of these, ~170 code for proteins that are also encoded by genes in mice and other animals.

When genes are conserved across species, it is typically because they are important.

Chromosome 21

Not all genes on chromosome 21 cause problems when occurring in a triple dose.

2/3 of these genes are “compensated,” meaning that the amount of their product is similar to that seen in a typical population

Chromosome 21 (cont.)

1/3 of the genes on chromosome 21 are over-expressed in people with DS and are

referred to as being “dosage sensitive.”

Most of these are expressed at 1.5 x the typical amount (as expected).

Some of these actually have amplified expression (more than 1.5 x the typical amount).

Chromosome 21 (cont.)

Examples of genes on chromosome 21 that are dosage sensitive and may cause problems:

COL6A1 heart defects CRYA1 cataracts DYRK1A intellectual disability; Alzheimer disease ETS2 leukemia; skeletal anomalies IFNAR immune dysfunction SOD1 premature aging APP Alzheimer disease

What’s New?

In 2013

905 articles were published in medical journals on some aspect of Down syndrome

Of these, the majority focus on Prenatal physical findings Prenatal testing Physiology of brain function Research in a mouse model of Down syndrome Organ function (heart, lung, eye, and more) Disorders of blood Social science

Delivering the diagnosis of Down syndrome: what is essential?

933 parents of children with DS and 389 genetic counselors were polled regarding information believed to be

Essential

Important

Not important

when giving a new diagnosis of DS, both prenatally and postnatally

Delivering the diagnosis (cont.)

100 features of DS were rated as belonging in one of the three categories

254/389 genetic counselors completed the survey Prenatal Postnatal

687/993 parents completed the survey Parents who learned of the diagnosis prenatally Parents who learned of the diagnosis postnatally

Delivering the diagnosis—the parents

Most parents were female, Caucasian, married, and had more than a high school education.

They were from 49/50 of the U.S. states.

The majority belonged to a DS advocacy group (77.3%).

The parents (cont.)

79% received the diagnosis after birth (65% in the last decade)

Most were told by a pediatrician (35%) or obstetrician (26%) Genetic counselors delivered the information only ~8% of the time

35% received no genetic counseling

57% felt they were not sufficiently informed about Down syndrome at the time of diagnosis

51% were somewhat or extremely dissatisfied with the experience

Delivering the diagnosis (cont.)

34 essential information items were identified, with most agreed upon by parents and genetic counselors.

Of these, the following 22 were felt to be most important.

Essential information items

Genetic information Caused by extra chromosome 21 material Diagnosis confirmed by chromosome analysis Recurrence risk for future pregnancies

Physical features Hypotonia

Associated medical complications Heart defect possibly requiring open heart surgery

Essential information (cont.)

Intellectual disability and developmental delay Mild-to-moderate intellectual disability Developmental delay in achieving milestones Need for physical, occupational, and speech therapies Need for early intervention and case management

Essential information (cont.)

Long-term prognosis Inclusion in regular classes Special education classes Participate in community sports, activities Have friends More like other children than different

Essential information (cont.)

Informational resources and referrals Local support groups Advocacy organizations and websites Early intervention centers Printed or written material Fact sheets or brochures Books Contact with families raising a child with DS

Further findings

Prenatal genetic counselors tend to focus more on clinical information and potentially “negative” aspects (intellectual disability, heart defect, developmental delay)

Postnatal counselors focus on treatment and management, with more of a balance between positive and negative information

A finding of particular interest…

There was a significant difference placed on the importance of discussing “options for pregnancy management” (to continue or terminate a pregnancy) following a diagnosis of DS. Of the 100 items ranked, it was ranked 11th for prenatal genetic counselors 65th for postnatal genetic counselors 96th for prenatal parents 92nd for postnatal parents

Further findings (cont.)

Parent perspectives were pretty much the same, regardless of whether their child’s diagnosis was made before or after birth.

Parents especially value information that addresses ability and potential for people with DS.

Parents want information about what life is like for a child with DS, including examples of positive outcomes.

Social Conditions for People with Down Syndrome: a study from Denmark

Information was obtained from Danish Cytogenetic Register (founded in 1968, contains

3,530 persons with DS) Civil Registration System (number assigned to each

resident) IDA (info on education, employment, income, and marital

status) Medical Birth Register and Civil Registration System (info on

children and spouses)

Final group studied (after elimination of those with incomplete data)= 1,998 individuals All were born from 1968-2007

Results—basic information

Of the 1,998 individuals with DS,

45% female; 55% male

93% have a free-standing extra chromosome 21

4% have an unbalanced translocation

3% have mosaic DS

Results-education

Of those 18 years old or greater,

More than 80% finished at least 10 years of primary school (one year of preschool through 9th grade in Denmark)

2% had a secondary or post-secondary education, including High school Vocational school College

More persons with mosaic DS obtained an education beyond primary school than those with other karyotypes

Results-employment

4% of those aged 18 and over had a job as their main source of income for some period of time

Those with mosaic DS had a job more often than persons with other karyotypes (28% vs. 3%)

The remainder received a disability pension

Results-income

Average yearly gross income for persons with DS aged 18 or older was $25,000.00 (US dollars)

Income increased with age of the individual

Same for males and females

Results-marital status

14 persons with DS married during the period studied

Average age at marriage was 28 years

None of them divorced during this period

Equal numbers of males and females married

Persons with mosaic DS were more often married than those with other karyotypes

Results-having a child

13 persons in the group studied had at least one child 11 children (including one pair of twins) were born to

7 women with DS 8 children were reportedly fathered by men with DS None of the children had DS Persons with mosaic DS had a child more often than

persons with other karyotypes Average age at delivery was 31 for moms with DS and

28 for dads with DS

USA’s First National Down Syndrome Registry

2006- director of NIH asked the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to form a Down Syndrome Working Group To include scientists from across NIH To coordinate ongoing research supported by NIH and

related to DS To enhance new NIH-supported research

U.S. DS Registry (cont.)

2007- the Working Group created the NIH Research Plan on DS To focus on genetic and neurobiological research on

cognitive aspects of DS To build upon ongoing NIH research on DS To reflect the lives of families and individuals with DS To connect the DS community with emerging scientific

opportunities

U.S. DS Registry (cont.)

After working to achieve the goals of the Research Plan, NIH created the Down Syndrome Consortium to foster communication between NIH Individuals with DS and their families National organizations interested in DS Pediatric and other groups

One of its first activities was to create a Down Syndrome Registry, now called

DS-Connect: The NIH Down Syndrome Consortium Registry

DS-Connect

Was launched in September, 2013

Is a centralized, secure database

Stores and shares health care information

Links persons with DS and their families to doctors and scientists working to improve their quality of life

DS-Connect

Participation is free and voluntary

Is designed to remain confidential

Is for people with DS of all ages and their families

“If participants give permission to be contacted, the registry coordinator can inform them of research studies in which they may be interested. Results from these studies will help researchers better understand Down syndrome and how to treat its accompanying health problems across the lifespan.”

DS-Connect

DS-Connect

To register, go to

http://DSConnect.nih.gov