Effectiveness

of

health-related

quality-of-life

measurement

in

clinical

practice

a

prospective

randomized

controlled

trial

in

patients

with

chronic

liver

disease

and

their

physicians

Background

This

study

assessed

the

effectiveness

of

computerized

measurement

and

feedback

of

health-related

quality

of

life

-LRB-

HRQoL

-RRB-

in

daily

clinical

practice

in

patients

with

chronic

liver

disease

Introduction

Health-related

quality

of

life

-LRB-

HRQoL

-RRB-

or

psychological

social

and

physical

functioning

-LSB-

-RSB-

has

become

an

important

outcome

measure

in

medical

care

Standardized

assessment

of

HRQoL

preceding

each

consultation

may

potentially

provide

physicians

with

valuable

information

Several

studies

have

shown

that

physicians

vary

in

their

ability

to

elicit

psychosocial

information

or

that

they

underestimate

patients

HRQoL

-LSB-

-RSB-

Furthermore

various

studies

have

shown

that

when

communication

with

the

physician

encompasses

both

physical

and

psychosocial

issues

patients

have

better

treatment

compliance

are

more

satisfied

with

the

consultation

and

report

less

symptoms

-LSB-

-RSB-

Nevertheless

relatively

few

studies

have

assessed

the

value

of

HRQoL

measurement

in

clinical

practice

Some

have

shown

positive

results

with

regard

to

acceptance

by

patients

and

physicians

or

a

significant

increase

in

the

identification

and/or

discussion

of

HRQoL

issues

-LSB-

-RSB-

Less

consistent

and

favorable

results

have

been

obtained

with

regard

to

the

effectiveness

of

standardized

HRQoL

measurement

in

actually

improving

HRQoL

or

psychosocial

outcomes

Even

though

decreased

depression

-LSB-

-RSB-

improved

overall

and

emotional

functioning

-LSB-

-RSB-

improved

mental

health

-LSB-

-RSB-

and

a

decrease

in

disease-specific

debilitating

symptoms

of

patients

undergoing

chemotherapy

-LSB-

-RSB-

have

been

associated

with

HRQoL

measurement

in

clinical

practice

several

other

studies

found

no

significant

improvement

in

HRQoL

or

psychosocial

outcomes

-LSB-

-RSB-

A

possible

explanation

might

be

that

the

majority

of

existing

studies

assessing

the

effectiveness

of

HRQoL

measurement

in

clinical

practice

with

regard

to

patients

psychosocial

functioning

or

HRQoL

have

included

oncological

patients

or

patients

from

general

practice

Oncological

patients

can

be

considered

a

special

group

due

to

the

life-threatening

nature

of

the

disease

Patients

from

general

practice

on

the

other

hand

may

be

too

diverse

and

often

present

with

generally

minor

complaints

which

may

hamper

the

discovery

of

beneficial

effects

Both

groups

impede

generalization

of

results

to

other

chronic

patient

populations

Two

important

studies

-LSB-

-RSB-

used

designs

in

which

physicians

were

part

of

both

the

control

and

the

experimental

group

either

by

using

a

crossover

design

-LRB-

physicians

were

first

assigned

to

one

group

then

crossed

over

to

the

other

group

halfway

through

the

study

-RRB-

-LSB-

-RSB-

or

by

assigning

patients

rather

than

physicians

to

the

different

groups

-LSB-

-RSB-

This

may

possibly

have

caused

bias

Two

systematic

reviews

have

stressed

the

need

for

further

research

evaluating

the

effectiveness

of

repeated

measurements

of

HRQoL

in

clinical

practice

-LSB-

-RSB-

and

the

need

for

further

research

to

help

health

care

professionals

identify

patients

who

would

benefit

most

from

such

interventions

-LSB-

-RSB-

The

study

reported

here

differs

from

previous

studies

by

including

a

patient

population

with

chronic

liver

disease

-LRB-

CLD

-RRB-

in

order

to

study

the

effects

of

HRQoL

use

in

clinical

practice

in

a

population

that

is

more

representative

of

other

patients

with

a

chronic

disease

CLD

is

one

of

the

most

prevalent

diseases

in

the

world

The

most

common

causes

of

CLD

hepatitis

B

virus

-LRB-

HBV

-RRB-

and

hepatitis

C

virus

-LRB-

HCV

-RRB-

have

been

estimated

to

affect

million

and

million

people

worldwide

respectively

-LRB-

-RRB-

In

addition

alcohol

is

another

main

cause

of

end-stage

liver

disease

worldwide

and

the

second

most

common

reason

for

liver

transplantation

in

the

United

States

-LSB-

-RSB-

CLD

is

a

serious

disease

that

is

associated

with

significant

physical

and

psychological

symptoms

such

as

impaired

cognition

hepatic

coma

fluid

in

the

abdomen

abdominal

pain

joint

pain

fatigue

depression

and

anxiety

-LSB-

-RSB-

Not

surprisingly

HRQoL

in

patients

with

CLD

has

been

shown

to

be

impaired

-LSB-

-RSB-

CLD

is

an

appropriate

example

of

a

typical

chronic

disease

with

patients

experiencing

substantial

comorbidity

and

possibly

mortality

as

is

the

case

in

other

chronic

diseases

such

as

kidney

disease

and

chronic

obstructive

pulmonary

disease

Our

study

also

differs

from

previous

studies

by

assessing

the

benefits

of

HRQoL

measurement

for

patients

with

different

demographic

characteristics

-LRB-

e.g.

men

and

women

young

and

old

-RRB-

which

is

essential

for

determining

which

patients

are

most

likely

to

benefit

from

HRQoL

measurement

in

clinical

practice

a

point

recently

reiterated

in

a

systematic

review

on

this

topic

-LSB-

-RSB-

In

addition

in

our

study

physicians

rather

than

patients

were

assigned

to

the

control

or

the

experimental

group

This

assigning

of

physicians

to

only

one

group

prevents

bias

of

physicians

being

focused

on

discussing

HRQoL

when

seeing

patients

in

the

control

group

The

aims

of

the

study

were

twofold

the

first

was

to

assess

the

effectiveness

of

real-time

computerized

measurement

of

HRQoL

in

various

patients

with

CLD

and

presentation

of

the

results

to

physicians

before

the

consultation

in

terms

of

improvement

in

patient

HRQoL

patient

management

and

patient

satisfaction

with

the

consultation

by

means

of

a

randomized

trial

with

repeated

measurements

The

second

aim

was

to

assess

hepatologists

experiences

with

the

availability

of

real-time

HRQoL

patient

data

and

to

measure

the

possible

effect

-LRB-

s

-RRB-

it

had

on

their

consultations

Patients

and

methods

Patient

recruitment

This

study

was

performed

at

the

Department

of

Gastroenterology

and

Hepatology

of

the

Erasmus

Medical

Centre

Rotterdam

where

HRQoL

measurement

on

a

regular

basis

was

implemented

for

the

duration

of

year

All

patients

older

than

years

of

age

with

CLD

visiting

the

department

between

September

and

January

were

invited

to

participate

Written

information

about

the

study

was

sent

to

the

patients

days

before

their

consultation

at

the

outpatient

department

Patients

interested

in

participating

informed

their

physician

who

consequently

directed

them

to

the

researcher

for

further

explanation

of

the

study

and

to

sign

informed

consent

For

this

effectiveness

study

we

included

all

patients

with

two

or

more

measurement

moments

All

physicians

working

at

the

Department

of

Hepatology

participated

The

protocol

was

in

accordance

with

the

ethical

guidelines

of

the

modified

Declaration

of

Helsinki

and

approved

by

the

Medical

Ethics

Committee

of

the

Erasmus

MC

Study

objectives

The

primary

aim

of

this

study

was

to

assess

the

effectiveness

of

computerized

measurement

of

HRQoL

in

clinical

practice

The

primary

outcome

measures

were

patients

generic

HRQoL

-LRB-

physical

and

mental

component

score

separately

-RRB-

and

disease-specific

HRQoL

Secondary

outcome

measures

were

patient

satisfaction

with

the

consultation

and

patient

management

The

secondary

aim

of

this

study

was

to

assess

hepatologists

experiences

with

the

availability

of

real-time

HRQoL

patient

data

Study

design

and

intervention

Physicians

Physicians

were

randomly

assigned

to

either

the

experimental

or

control

group

by

means

of

a

restricted

randomization

procedure

called

blocking

To

ensure

an

equal

number

of

physicians

in

each

group

it

was

decided

to

include

six

in

the

experimental

group

and

five

in

the

control

group

We

used

a

random

sequence

table

to

assign

physicians

to

one

of

the

conditions

Due

to

the

nature

of

the

intervention

it

was

impossible

to

blind

physicians

to

group

assignment

Physicians

in

the

experimental

group

were

able

to

obtain

an

instant

computerized

graphical

output

of

HRQoL

patient

data

which

also

included

data

from

previous

measurement

moments

so

that

changes

in

patients

HRQoL

could

be

monitored

-LRB-

Fig.

-RRB-

Prior

to

the

study

physicians

received

instructions

from

a

psychologist

with

expertise

in

the

field

of

HRQoL

measurement

on

how

to

interpret

this

output

First

physicians

were

shown

the

questionnaires

in

order

to

familiarize

them

with

the

content

Second

they

were

informed

that

the

red

line

in

the

graph

was

the

average

score

of

patients

with

CLD

on

the

Short

-LRB-

-RRB-

measuring

generic

HRQoL

and

that

scores

under

this

line

were

to

be

considered

low

They

were

also

told

that

the

average

score

of

healthy

people

on

this

questionnaire

was

The

physicians

were

instructed

to

interpret

the

disease-specific

Liver

Disease

Symptom

Index

-LRB-

LDSI

-RRB-

at

item

level

with

scores

ranging

from

-LRB-

not

at

all

-RRB-

to

-LRB-

to

a

large

extent

-RRB-

The

physicians

were

asked

to

use

the

HRQoL

data

in

all

consultations

for

year

No

recommendations

for

specific

responses

were

given

Instead

they

were

instructed

to

use

their

clinical

experience

to

choose

an

appropriate

treatment

After

seeing

a

participating

patient

physicians

in

both

groups

completed

a

checklist

about

the

content

of

the

consultation

Physicians

in

the

control

group

conducted

their

consultations

as

usual

Fig.

of

the

graphical

output

of

patients

health-related

quality

of

life

as

presented

to

physicians

in

the

intervention

group

A

score

of

is

the

average

score

of

a

healthy

norm

population

The

dashed

line

represents

the

mean

score

for

patients

with

chronic

liver

disease

Patients

Through

the

random

assignment

of

physicians

patients

were

indirectly

allocated

to

either

group

Patients

were

initially

blinded

to

the

group

assignment

All

patients

participating

in

the

study

completed

a

computerized

generic

and

disease-specific

HRQoL

questionnaire

and

the

first

part

of

a

pen-and-paper

questionnaire

on

patient

satisfaction

with

the

consultation

before

each

consultation

at

the

outpatient

Department

of

Hepatology

for

year

They

also

completed

the

second

part

of

the

satisfaction

questionnaire

after

the

consultation

More

specific

information

on

the

content

of

the

questionnaires

is

provided

in

Study

measures

To

ascertain

good

questionnaire

completion

a

researcher

was

always

available

to

answer

questions

about

the

computer

and/or

questionnaires

at

the

patient

's

request

Study

measures

HRQoL

Disease-specific

HRQoL

This

was

assessed

by

means

of

the

LDSI

which

measures

severity

and

hindrance

of

nine

symptoms

itch

joint

pain

pain

in

the

right

upper

abdomen

decreased

appetite

jaundice

fatigue

depressed

mood

worries

about

family

situation

and

fear

of

complications

-LSB-

-RSB-

Because

of

time

constraints

only

items

measuring

symptom

severity

were

included

in

this

study

-LRB-

n

-RRB-

The

physicians

were

instructed

to

interpret

the

questionnaire

at

item

level

with

scores

ranging

from

-LRB-

not

at

all

-RRB-

to

-LRB-

to

a

large

extent

-RRB-

For

data

analysis

a

total

score

ranging

from

to

was

computed

by

summing

the

scores

of

each

item

The

reliability

of

the

LDSI

is

good

-LRB-

internal

consistency

α

-RRB-

as

is

the

construct

validity

-LSB-

-RSB-

Generic

HRQoL

This

was

assessed

by

means

of

the

Short

version

-LRB-

-RRB-

The

produces

a

Physical

Component

Summary

-LRB-

PCS

-RRB-

and

Mental

Component

Summary

-LRB-

MCS

-RRB-

representing

physical

and

emotional

functioning

respectively

The

mean

score

of

the

PCS

and

MCS

in

the

general

population

is

-LSB-

standard

deviation

-LRB-

SD

-RRB-

-RSB-

with

higher

scores

representing

better

HRQoL

Mean

scores

and

SD

of

the

PCS

and

MCS

of

CLD

patients

was

calculated

from

a

large

database

-LRB-

n

-RRB-

-LSB-

-RSB-

-LRB-

PCS

mean

SD

MCS

mean

SD

-RRB-

These

means

were

used

as

a

reference

point

-LRB-

red

line

-RRB-

in

the

graphical

representation

for

physicians

so

they

could

easily

identify

patients

scoring

below

average

within

the

CLD

group

The

has

been

shown

to

be

reliable

between

test

and

retest

-LRB-

MCS

r

PCS

r

-RRB-

and

median

relative

validity

estimates

of

for

the

PCS

and

MCS

respectively

have

been

found

-LSB-

-RSB-

Patient

satisfaction

with

the

consultation

Patients

satisfaction

with

the

consultation

was

measured

with

the

QUOTE-Liver

a

newly

developed

questionnaire

consisting

of

items

that

assesses

the

discrepancy

between

patients

needs/expectations

-LRB-

importance

measured

before

the

consultation

-RRB-

and

the

actual

care

that

they

receive

-LRB-

performance

measured

after

the

consultation

-RRB-

The

internal

consistency

of

the

overall

QUOTE-Liver

was

excellent

-LRB-

α

-RRB-

as

was

the

face

validity

all

patients

-LRB-

n

-RRB-

in

the

validation

study

and

three

psychologists

and

a

hepatologist

agreed

that

the

items

of

the

QUOTE-Liver

adequately

reflected

the

most

important

aspects

of

care

for

CLD

patients

Construct

validity

as

measured

by

the

correlation

between

a

visual

analog

scale

-LRB-

VAS

-RRB-

measuring

overall

satisfaction

and

the

total

score

on

the

QUOTE-Liver

was

good

-LRB-

r

P

-RRB-

Content

validity

was

also

good

of

the

patients

in

the

validation

study

suggested

new

items

to

be

included

-LRB-

Gutteling

et

al.

unpublished

-RRB-

A

reduced

version

consisting

of

the

nine

items

ranked

by

patients

as

most

important

and

the

two

liver-disease-specific

items

was

used

in

our

study

Using

a

formula

applied

for

all

QUOTE-Liver

instruments

-LRB-

performance

-RRB-

a

total

satisfaction

score

can

be

computed

ranging

from

to

with

meaning

not

satisfied

at

all

and

meaning

completely

satisfied

-LSB-

-RSB-

Patient

management

The

effect

of

the

intervention

on

patient

management

was

measured

by

means

of

a

checklist

that

physicians

completed

after

each

consultation

with

a

study

participant

including

the

question

Have

you

changed

your

treatment

in

any

way

and

a

subquestion

If

so

what

have

you

done

followed

by

several

options

Prescription

of

antidepressants

Referral

to

psychosocial

care

Altering

the

frequency

of

consultations

and

Other

Physicians

experiences

Experiences

of

physicians

with

the

experimental

condition

were

assessed

through

the

checklists

that

they

completed

after

each

consultation

with

a

study

participant

asking

the

question

Did

you

find

the

HRQoL

information

useful

Why

with

the

answering

options

Yes

it

provided

new

information

Yes

it

saved

time

Yes

No

the

patient

is

doing

well

No

I

know

this

patient

well

enough

No

the

patient

tells

me

a

lot

No

Also

a

semistructured

interview

was

conducted

months

into

the

study

and

at

the

end

of

the

study

The

interview

included

questions

about

the

effort

to

request

HRQoL

information

the

usefulness

of

the

information

whether

the

availability

of

HRQoL

information

increased

the

duration

of

the

consultation

and

whether

participating

patients

addressed

HRQoL

issues

more

often

than

patients

who

did

not

participate

Physicians

were

also

asked

whether

there

were

certain

subgroups

of

patients

whose

HRQoL

information

they

found

particularly

useful

Opinions

of

physicians

in

the

control

group

toward

possible

future

availability

of

HRQoL

information

during

the

consultation

were

assessed

by

means

of

the

same

semistructured

interview

at

months

only

Statistical

analysis

Sample

size

A

nonclustered

power

analysis

based

on

a

medium

effect

size

-LRB-

Cohen

's

D

-RRB-

with

a

significance

level

and

power

indicated

that

at

least

patients

were

needed

in

each

group

to

detect

a

statistically

significant

difference

Data

selection

For

patients

who

were

included

in

both

groups

because

they

had

consultations

with

physicians

from

the

control

group

as

well

as

physicians

from

the

experimental

group

during

the

year

of

the

study

data

from

the

condition

in

which

they

had

most

often

been

was

included

-LRB-

n

-RRB-

For

patients

who

had

been

in

both

conditions

equally

-LRB-

n

-RRB-

all

data

were

excluded

The

first

measurement

moment

of

all

patients

-LRB-

-RRB-

was

considered

a

baseline

measure

as

no

HRQoL

data

had

yet

been

presented

to

the

physicians

Data

analysis

Differences

on

the

variables

gender

diagnosis

disease

severity

and

age

between

participants

and

nonparticipants

were

assessed

by

means

of

χ2

tests

or

t

tests

The

same

was

done

for

assessing

differences

between

patients

in

the

control

group

and

the

intervention

group

Scores

of

participating

patients

on

measurement

moments

-LRB-

Ti

-RRB-

were

summarized

into

one

overall

score

per

variable

in

the

study

Univariate

analyses

of

variance

were

performed

in

SPSS

Fixed

factors

were

age

gender

disease

severity

presentation

of

HRQoL

data

to

the

clinicians

-LRB-

feedback

-RRB-

and

interactions

between

these

variables

Differences

in

diagnoses

between

patients

in

both

groups

were

controlled

for

by

entering

one

propensity

score

of

the

variable

diagnosis

as

a

covariate

in

the

analyses

Propensity

scores

were

especially

designed

for

situations

in

which

study

participants

could

not

be

randomly

assigned

to

groups

and

their

characteristics

were

therefore

not

balanced

among

the

groups

A

propensity

score

was

defined

as

the

conditional

probability

of

assignment

to

a

certain

treatment

group

given

a

set

of

observed

pretreatment

characteristics

and

was

usually

estimated

by

means

of

a

logistic

regression

analysis

-LSB-

-RSB-

Thereby

the

background

characteristic

-LRB-

s

-RRB-

in

this

case

diagnosis

was

reduced

to

one

single

score

the

propensity

score

We

calculated

the

propensity

score

by

entering

the

different

diagnoses

-LRB-

HBV

HCV

cholestatic

liver

disease

pretransplantation

posttransplantation

autoimmune

hepatitis

and

other

-RRB-

as

dummy

variables

-LRB-

-RRB-

in

a

logistic

regression

analysis

The

unstandardized

logistic

regression

weights

were

then

multiplied

by

the

relevant

dummy

variable

and

summed

together

with

the

constant

This

score

was

used

in

the

univariate

analysis

to

adjust

for

baseline

confounding

Univariate

analyses

of

variance

were

performed

for

each

outcome

variable

-LRB-

disease-specific

HRQoL

and

generic

HRQoL

MCS

and

PCS

-RRB-

separately

A

forward

technique

was

used

in

which

the

main

effects

of

the

fixed

factors

were

assessed

in

the

first

block

and

the

interactions

between

feedback

of

HRQoL

data

and

each

of

the

other

fixed

factors

-LRB-

age

gender

severity

of

the

disease

-RRB-

were

explored

in

the

second

block

Differences

between

the

two

groups

on

patient

management

variables

and

satisfaction

with

the

consultation

were

assessed

by

means

of

Mann

Whitney

tests

Hepatologists

experiences

with

the

availability

of

real-time

patient

HRQoL

data

was

assessed

by

means

of

semistructured

interviews

and

checklists

These

data

were

of

a

descriptive

nature

and

are

presented

as

such

Results

Characteristics

of

patients

and

physicians

in

the

study

Of

the

patients

that

agreed

to

participate

in

the

study

completed

the

questionnaires

more

than

once

Of

these

were

included

in

the

experimental

and

control

conditions

equally

often

and

were

therefore

excluded

from

the

analyses

One

hundred

and

sixty-two

patients

-LRB-

control

group

n

experimental

group

n

-RRB-

were

included

-LRB-

Fig.

-RRB-

Differences

in

age

gender

diagnosis

and

disease

severity

between

patients

in

the

study

and

nonrespondents

are

presented

in

Table

Demographic

characteristics

of

the

patients

are

presented

in

Table

Patients

in

the

control

and

experimental

groups

were

comparable

except

for

the

variables

diagnosis

and

disease

severity

-LRB-

Table

-RRB-

In

the

analyses

these

differences

between

conditions

were

controlled

for

All

physicians

working

at

the

Department

of

Hepatology

-LRB-

n

ten

men

-RRB-

agreed

to

participate

Their

mean

age

was

-LRB-

range

-RRB-

years

and

their

average

working

experience

was

-LRB-

range

-RRB-

years

Fig.

in

the

studyTable

in

age

gender

diagnosis

and

disease

severity

between

patients

in

the

study

and

nonrespondentsPatients

in

the

analyses

-LRB-

n

-RRB-

Patients

excluded

from

the

analyses

-LRB-

n

-RRB-

P

valuePatients

excluded

from

the

study

-LRB-

n

-RRB-

P

valueAge

mean

-LRB-

range

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Gender

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Diagnosis

n

-LRB-

-RRB-

Hepatitis

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Hepatitis

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Cholestatic

liver

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Autoimmune

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Disease

severity

n

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Compensated

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Decompensated

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Differences

were

assessed

by

means

of

χ2

tests

-LRB-

except

for

age

t

test

-RRB-

Reference

group

for

comparison

of

both

P

values

is

the

group

of

patients

in

the

analysesTable

of

patients

included

in

the

data

analysisControl

group

-LRB-

n

-RRB-

Experimental

group

-LRB-

n

-RRB-

P

valueGender

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Age

mean

-LRB-

range

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Diagnosis

n

-LRB-

-RRB-

Hepatitis

-LRB-

-RRB-

-LRB-

-RRB-

Hepatitis

-LRB-

-RRB-

-LRB-

-RRB-

Cholestatic

liver

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Autoimmune

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Disease

severity

n

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

Compensated

-LRB-

-RRB-

-LRB-

-RRB-

Decompensated

-LRB-

-RRB-

-LRB-

-RRB-

Differences

were

assessed

by

means

of

χ2

tests

-LRB-

except

for

age

t

test

-RRB-

Descriptives

The

number

of

times

that

patients

in

the

control

and

experimental

groups

completed

the

questionnaires

varied

between

two

and

-LRB-

Table

-RRB-

Mean

scores

of

patients

at

and

Ti

on

the

outcome

variables

generic

HRQoL

and

disease-specific

HRQoL

are

presented

in

Table

Table

completion

rate

of

patients

in

the

control

and

experimental

groupsNumber

of

times

questionnaires

were

completedTotal

-LRB-

n

-RRB-

-LRB-

n

-RRB-

-LRB-

n

-RRB-

adjusted

means

and

confidence

intervals

at

and

TiP

valueControl

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

LDSI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Male

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

LDSI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Female

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

LDSI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Older

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

LDSI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Younger

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

LDSI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

The

means

at

and

Ti

were

obtained

from

the

univariate

analyses

of

variance

with

fixed

factors

age

gender

severity

of

the

disease

study

group

-LRB-

control

or

experimental

-RRB-

and

interactions

between

these

variables

Differences

in

diagnoses

between

patients

in

both

groups

were

controlled

for

The

significance

level

reflects

the

group

for

which

the

largest

difference

on

the

variable

was

Short

PCS

Physical

Component

Summary

MCS

Mental

Component

Summary

LDSI

Liver

Disease

Symptom

Index

Effects

of

the

experimental

condition

on

patients

HRQoL

and

satisfaction

with

the

consultation

Disease-specific

HRQoL

There

was

no

main

effect

for

the

experimental

condition

on

disease-specific

HRQoL

There

was

a

statistically

significant

interaction

effect

for

the

variables

age

and

feedback

of

HRQoL

data

on

the

outcome

variable

disease-specific

HRQoL

-LRB-

Table

-RRB-

older

patients

-LRB-

years

of

age

as

determined

by

the

median

split

-RRB-

in

the

experimental

group

had

significantly

lower

total

scores

on

the

LDSI

-LRB-

meanAdj

CI

-RRB-

-LRB-

F

P

-RRB-

indicating

better

disease-specific

HRQoL

than

other

patients

especially

older

patients

in

the

control

group

-LRB-

meanAdj

CI

-RRB-

This

difference

between

older

patients

in

the

experimental

group

and

the

control

group

on

disease-specific

HRQoL

is

equivalent

to

a

Cohen

's

D

of

reflecting

a

medium

difference

-LSB-

-RSB-

Table

effects

between

age

gender

disease

severity

and

feedback

on

the

outcome

variable

disease-specific

HRQoL

controlled

for

diagnosisSourceF

valuedfP

Diagnosis

-LRB-

propensity

score

-RRB-

Disease

Gender

Severity

Age

Dependent

variable

mean

total

score

of

the

Liver

Disease

Symptom

Index

-LSB-

disease-specific

health-related

quality

of

life

-LRB-

HRQoL

-RRB-

-RSB-

for

the

measurement

moments

Ti

Generic

HRQoL

Mental

Component

Summary

score

No

main

effect

for

the

experimental

condition

on

mental

HRQoL

was

found

However

a

significant

interaction

effect

for

the

variables

age

and

feedback

of

HRQoL

data

was

found

Older

patients

in

the

experimental

group

had

higher

scores

on

the

MCS

-LRB-

meanAdj

CI

-RRB-

-LRB-

F

P

-RRB-

reflecting

better

HRQoL

than

other

patients

especially

older

patients

in

the

control

group

-LRB-

meanAdj

CI

-RRB-

-LRB-

Table

-RRB-

Furthermore

a

significant

interaction

effect

was

found

for

the

variables

gender

and

feedback

of

HRQoL

data

with

male

patients

in

the

experimental

group

showing

higher

scores

on

the

MCS

-LRB-

meanAdj

CI

-RRB-

-LRB-

F

P

-RRB-

than

other

patients

especially

male

patients

in

the

control

group

-LRB-

meanAdj

CI

-RRB-

-LRB-

Table

-RRB-

Table

analysis

of

variance

with

the

variables

age

gender

disease

severity

and

feedback

on

the

outcome

variable

mental

generic

HRQoL

controlled

for

diagnosisSourceF

valuedfP

Diagnosis

-LRB-

propensity

score

-RRB-

Disease

Gender

Severity

Age

Dependent

variable

mean

total

score

of

Short

Mental

Component

Summary

-LRB-

MCS

-RRB-

-LSB-

generic

mental-health-related

quality

of

life

-LRB-

HRQoL

-RRB-

-RSB-

for

the

measurement

moments

Ti

Physical

Component

Summary

score

No

significant

main

effect

or

interaction

effects

were

found

for

the

variables

feedback

of

HRQoL

data

and

age

gender

and

disease

severity

on

the

PCS

Patients

satisfaction

with

the

consultation

The

scores

on

patient

satisfaction

did

not

differ

significantly

between

the

experimental

and

control

groups

-LRB-

z

P

-RRB-

Also

no

interaction

effects

of

age

gender

and/or

disease

severity

were

found

on

this

outcome

variable

Effects

of

the

experimental

condition

on

the

consultation

and

on

patient

management

Physicians

in

the

experimental

group

requested

information

of

their

patients

in

of

consultations

and

they

discussed

it

with

their

patients

in

of

consultations

They

indicated

finding

the

HRQoL

information

useful

in

of

consultations

which

is

generally

in

accordance

with

the

percentage

of

patients

in

the

experimental

group

scoring

below

average

on

the

MCS

-LRB-

-RRB-

and

PCS

-LRB-

-RRB-

They

mostly

found

the

HRQoL

useless

when

a

patient

was

doing

well

Physicians

in

the

experimental

group

indicated

significantly

more

often

than

physicians

in

the

control

group

that

they

spent

more

time

than

usual

discussing

psychosocial

issues

-LRB-

vs.

of

consultations

z

P

-RRB-

Treatment

policy

was

altered

significantly

more

often

in

the

experimental

group

-LRB-

of

consultations

vs.

of

consultations

in

the

control

group

z

P

-RRB-

Most

commonly

frequency

of

consultations

was

increased

-LRB-

n

-RRB-

Other

alterations

concerned

prescription

of

medication

-LSB-

-RSB-

increased

attention

for

physical

complaints

-LSB-

-RSB-

referral

to

psychosocial

care

-LSB-

-RSB-

or

occupational

health

physician

-LSB-

-RSB-

and

increased

attention

to

explanations/reassurance

-LSB-

-RSB-

Physicians

experiences

with

the

availability

of

HRQoL

information

in

clinical

practice

Experiences

of

physicians

in

the

experimental

group

at

months

and

at

the

end

of

the

study

did

not

differ

All

physicians

in

the

experimental

condition

found

the

HRQoL

information

useful

except

for

one

older

physician

who

claimed

to

know

his

patients

very

well

They

indicated

being

better

able

to

understand

some

of

their

patients

through

the

extra

information

that

was

provided

by

the

questionnaires

These

physicians

did

not

perceive

requesting

the

information

as

an

extra

effort

on

their

part

Furthermore

they

did

not

think

that

using

the

information

lengthened

their

consultations

All

physicians

in

the

experimental

group

indicated

that

they

wanted

to

continue

using

the

HRQoL

information

in

the

future

Physicians

in

the

control

group

were

similarly

positive

toward

the

possible

availability

of

HRQoL

information

during

their

consultations

in

the

future

on

the

condition

that

it

would

not

be

time

consuming

This

specifically

concerned

patients

awaiting

liver

transplantation

patients

with

hepatitis

C

and

nonnative

speakers

-LRB-

mostly

patients

with

hepatitis

B

-RRB-

Discussion

Computerized

real-time

measurement

of

HRQoL

at

our

busy

outpatient

Department

of

Hepatology

and

presentation

of

the

results

to

physicians

before

each

consultation

did

not

show

a

main

effect

on

patients

overall

HRQoL

However

secondary

analyses

showed

that

the

HRQoL

measurements

positively

affected

disease-specific

HRQoL

and

generic

mental

HRQoL

of

older

patients

-LRB-

years

of

age

-RRB-

with

CLD

and

also

generic

mental

HRQoL

of

male

CLD

patients

The

results

of

our

study

are

among

the

first

to

show

a

beneficial

effect

of

presenting

HRQoL

data

to

physicians

in

clinical

practice

Most

other

studies

have

failed

to

show

evidence

for

the

actual

improvement

in

HRQoL

or

psychosocial

outcomes

-LSB-

-RSB-

Of

the

studies

that

did

find

a

beneficial

effect

one

showed

a

decrease

in

disease-specific

debilitating

symptoms

-LSB-

-RSB-

and

another

showed

improved

emotional

functioning

-LSB-

-RSB-

which

is

in

line

with

findings

of

our

study

It

should

be

noted

that

due

to

the

cross-sectional

data

analyses

a

causal

relationship

between

intervention

and

HRQoL

could

not

be

demonstrated

Future

studies

should

address

this

in

further

detail

Our

study

found

no

differences

between

patients

in

the

experimental

and

control

groups

with

regard

to

satisfaction

with

the

consultation

which

is

in

line

with

findings

from

previous

studies

-LSB-

-RSB-

The

lack

of

observed

differences

between

the

study

groups

may

have

been

due

to

high

levels

of

satisfaction

resulting

in

a

ceiling

effect

This

study

was

among

the

first

to

show

a

significant

difference

in

patient

management

between

experimental

and

control

groups

with

physicians

in

the

experimental

group

mostly

reporting

a

significant

increase

in

the

frequency

of

consultations

Our

findings

were

statistically

significant

and

in

accordance

with

the

findings

of

a

systematic

review

-LSB-

-RSB-

and

subscribe

to

the

increasingly

acknowledged

importance

of

using

HRQoL

information

for

the

improvement

of

physician

consultations

-LSB-

-RSB-

However

it

should

be

noted

that

even

though

the

differences

in

patient

management

between

control

experimental

groups

were

statistically

significant

the

absolute

numbers

were

small

Therefore

the

results

should

be

interpreted

cautiously

and

further

studies

using

more

elaborate

methods

of

data

collection

for

instance

monitoring

patients

medical

records

or

administering

more

detailed

checklists

are

recommended

Physicians

experiences

with

using

HRQoL

information

during

the

consultation

were

generally

positive

requesting

the

information

was

not

considered

an

extra

effort

on

their

part

and

they

found

the

information

especially

useful

for

certain

groups

of

patients

such

as

those

awaiting

liver

transplantation

those

with

hepatitis

C

and

nonnative

speakers

All

physicians

but

one

found

the

information

useful

for

at

least

some

-LRB-

-RRB-

of

their

patients

Physicians

indicated

finding

the

information

least

useful

when

patients

were

doing

well

in

terms

of

HRQoL

or

when

they

knew

the

patient

well

These

generally

positive

experiences

are

in

accordance

with

findings

from

previous

studies

-LSB-

-RSB-

which

assessed

oncologists

attitudes

toward

using

HRQoL

information

in

clinical

practice

The

confirmation

of

these

results

in

hepatologists

suggests

that

HRQoL

information

may

also

be

well

accepted

by

physicians

treating

patients

with

other

chronic

conditions

Another

result

of

our

study

was

that

when

HRQoL

information

was

available

more

time

was

spent

discussing

psychosocial

issues

and

more

treatments

were

altered

Interview

and

checklist

data

were

contradictory

regarding

the

duration

of

consultations

when

HRQoL

information

was

available

In

a

previous

study

in

which

the

duration

of

consultations

was

timed

no

increase

in

consultation

time

was

found

-LSB-

-RSB-

Future

studies

should

shed

more

light

on

whether

the

availability

of

HRQoL

information

increases

the

length

of

consultations

in

hepatology

The

strength

of

our

study

lies

in

the

analyses

performed

where

benefits

for

specific

groups

of

liver

patients

were

explored

by

entering

interactions

between

gender

age

disease

severity

and

feedback

of

HRQoL

data

rather

than

solely

investigating

main

effects

between

the

intervention

and

control

groups

Also

this

study

included

patients

with

CLD

rather

than

patients

with

cancer

or

patients

from

general

practice

making

it

especially

relevant

to

a

more

general

population

of

patients

with

a

chronic

illness

We

are

aware

of

several

limitations

of

this

study

First

physicians

rather

than

patients

were

randomly

assigned

to

either

the

intervention

or

control

group

Randomization

is

a

complicated

issue

in

these

kinds

of

implementation

studies

and

both

methods

are

subject

to

limitations

An

important

advantage

of

the

randomization

of

physicians

is

that

the

control

group

was

not

biased

toward

mentioning

HRQoL

topics

more

often

than

usual

Future

studies

using

the

same

design

but

including

more

physicians

are

needed

to

further

explore

possible

main

effects

of

HRQoL

measurement

on

patients

overall

HRQoL

A

second

limitation

was

the

high

number

of

nonparticipants

Part

of

the

explanation

may

lie

in

the

fact

that

patients

were

responsible

for

contacting

their

physician

if

they

were

interested

in

participating

in

the

study

In

addition

the

number

of

non-Dutch-speaking

patients

visiting

the

department

is

relatively

large

-LRB-

hepatitis

B

for

example

is

most

common

among

people

from

North

Africa

-RRB-

These

patients

were

also

invited

to

participate

but

were

less

likely

to

respond

The

relatively

large

number

of

patients

who

completed

the

questionnaires

only

once

may

be

explained

by

the

small

window

of

opportunity

to

complete

the

questionnaires

before

each

consultation

In

addition

for

such

implementation

endeavors

cooperation

of

all

staff

members

is

essential

and

future

research

should

explore

this

further

A

last

limitation

of

this

study

was

that

the

checklists

used

to

assess

consultation

content

were

not

very

detailed

This

was

done

on

purpose

as

longer

inventories

would

have

compromised

physician

participation

However

considering

the

positive

outcomes

of

this

study

it

is

advisable

that

future

studies

consider

ways

to

obtain

a

more

detailed

view

of

how

the

HRQoL

information

affects

consultation

content

for

example

by

recording

consultations

In

conclusion

although

a

main

effect

of

the

intervention

was

not

found

this

study

showed

a

beneficial

effect

of

implementation

of

HRQoL

measurement

in

clinical

practice

on

the

HRQoL

of

older

and

male

patients

with

CLD

and

on

patient

management

Nevertheless

the

study

had

several

shortcomings

and

further

studies

are

needed

to

substantiate

these

findings

Physicians

experiences

with

the

availability

of

HRQoL

information

were

positive

especially

for

patients

awaiting

liver

transplantation

patients

with

hepatitis

C

and

nonnative

speakers

They

expressed

an

interest

in

continued

use

of

HRQoL

information

These

results

advocate

the

continued

use

of

measuring

HRQoL

in

a

clinical

practice

of

hepatology

Including

older

patients

and

male

patients

who

have

been

shown

to

benefit

most

from

such

a

procedure

should

be

aimed

for

O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O

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Noonan syndrome and related disorders : Alterations in growth and puberty Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies , short stature and congenital heart disease , most commonly pulmonary stenosis -LRB- Noonan , Clin Pediatr , 33:548 -- 555 , 1994 -RRB- . Recently , a mutation in the PTPN11 gene -LRB- Tartaglia , Mehler , Goldberg , Zampino , Brunner , Kremer et al. , Nat Genet , 29:465 -- 468 , 2001 -RRB- was found to be present in about 50 % of individuals with Noonan syndrome . The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD -LRB- Gorlin , Anderson , Blaw , Am J Dis Child , 17:652 -- 662 , 1969 -RRB- , Cardio-facio-cutaneous syndrome -LRB- Reynolds , Neri , Hermann , Blumberg , Coldwell , Miles et al. , Am J Med Genet , 28:413 -- 427 , 1986 -RRB- and Costello syndrome -LRB- Hennekam , Am J Med Genet , 117C -LRB- 1 -RRB- : 42 -- 48 , 2003 -RRB- . All three of these syndromes share similar cardiac defects and all have postnatal short stature . Very recently , HRAS mutations -LRB- Aoki , Niihori , Kawame , Kurosawa , Ohashi , Tanaka et al. , Nat Genet , 37:1038 -- 1040 , 2005 -RRB- have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes -LRB- Rodriguez-Viciana , Tetsu , Tidyman , Estep , Conger , Santa Cruz et al. , Nat Genet ,2006 ; Niihori , Aoki , Narumi , Neri , Cave , Verloes et al. , Nat Genet , 38:294 -- 296 , 2006 -RRB- in the Cardio-facio-cutaneous syndrome . Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway . This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis . Introduction Noonan Syndrome -LRB- NS -RRB- has been recognized for about 40 years -LSB- 1 -RSB- but the genetic cause was not found until 2003 when mutations in the PTPN11 gene were reported -LSB- 2 -RSB- . Shortly afterwards LEOPARD syndrome -LRB- LS -RRB- , a rare alleic variant of NS was found to have specific mutations in the PTPN11 gene -LSB- 25 -RSB- . Cardio-facio-cutaneous -LRB- CFC -RRB- syndrome and Costello syndrome -LRB- CS -RRB- , both rare syndromes , share significant phenotypic overlap with NS especially in infancy . The common features of facial dysmorphism , short stature and similar cardiac findings in all four conditions suggest a similar underlying pathogenesis . In 2005 -LSB- 6 -RSB- , mutations in the HRAS oncogene were found to be the cause of CS and in 2006 mutations in KRAS , BRAF , MEK1 and MEK2 genes -LSB- 7 , 8 -RSB- were identified in CFC . All of these germline mutations are components of the RAS-MAPK pathway which plays an important role in growth factors and cytokine signaling . In this review , the clinical findings of the four syndromes will be reviewed . NS will be discussed in more detail since it is common and more clinical studies are available . Noonan syndrome NS is one of the more common non-chromosomal syndromes seen in children with congenital heart disease with an estimated incidence of 1 in 1,500 -LSB- 1 -RSB- . Although there is wide phenotypic variation in NS , distinctive facial features include hypertelorism , down-slanting palpebral fissures , a high arched palate , low set posteriorly rotated ears , malar hypoplasia , ptosis and often a short neck . The phenotype changes significantly with time . In the newborn , there is excessive nuchal skin which is the result of prenatal cystic hygroma . During infancy , the head is relatively large , the eyes are often prominent and round , there is a high nasal bridge which may be flat , and the neck appears short . At 3 to 4 years of age , the body becomes more stocky and the chest more prominent . The chest deformities often become significant . In later childhood , the facial appearance begins to show coarse features and becomes more triangular as the chin lengthens . The eyes become less prominent and the ptosis may be more apparent . In the teenager and young adult , as the neck lengthens webbing may become more apparent , the facial features are more triangular and become sharper , the nose has a pinched root and a thin high bridge . An older adult has prominent nasal labial folds , a high anterior hairline and the skin often appears rather transparent and wrinkled . In most , the prenatal history is unremarkable but polyhydramnios is frequent . Height and weight are within normal limits at birth but height begins to drop off within a few months and over 70 % of patients with NS have significantly short stature . Some patients with NS have significant feeding difficulties with resulting failure-to-thrive and require tube feedings . Although this may contribute to the poor gain in weight , short stature occurs equally in children who have no feeding problems in infancy . Other important findings include a chest deformity which may be in the form of a pectus carinatum or pectus excavatum , apparent widely spaced nipples and a relatively broad chest . Scoliosis and kyphosis occur in about 15 % of patients . Muscle hypotonia is frequent and may account for some of the motor delay . Significant mental retardation is uncommon but some degree of learning disability is frequent and may require special help in school . Eye findings , especially strabismus and refractive errors are common and an occasional patient will have a coloboma . All children with NS should have a complete eye examination . Since conductive hearing loss is rather frequent , children should have a hearing evaluation . Over half of the males with NS have either one or both testes undescended and delay in puberty is common for both males and females . Easy bruising is common in NS and a variety of bleeding problems have been reported -LSB- 9 -RSB- . These include deficiency of Factor XI , Von Willebrand 's disease , thrombocytopenia and platelet function defects . In addition , low levels of Factor VIII and XII have also been noted . Hepatosplenomegaly , usually unexplained , is present in about 25 % of patients particularly in infancy . Lymphatic abnormalities occur in less than 20 % of patients but may present serious problems . Over 80 % of patients with NS have a cardiac finding . Pulmonary stenosis is , by far , the most common but nearly every cardiac lesion has been reported . In addition , hypertrophic cardiomyopathy may occur . It was recognized early on that NS could be transmitted in an autosomal dominant manner . In 1994 , Jamieson et al -LSB- 10 -RSB- was able to map the gene for NS to the distal part of chromosome 12q . Not all families with NS studied showed this linkage suggesting that more than one gene was likely to be involved in the etiology . In 2002 , Tartaglia -LSB- 2 -RSB- found a mutation in the PTPN11 gene to be present in about 50 % of patients with NS . This gene regulates the production of a protein called SHP-2 which is essential in several intracellular signal transduction pathways and controls a number of developmental processes including cardiac semilunar valvulogenesis . The protein is expressed throughout the body and it is an important player in cellular response to growth factors , hormones , cytokines and cell adhesion molecules . The PTPN11 mutations in NS are clustered in interacting portions of the N-SH2 in PTTP domains . This mutation results in a gain of function for SHP-2 . Children with NS often present to the endocrinologists because of the short stature , delayed puberty or undescended testes in males . Although height and weight are usually in the normal range at birth , height drops off within the first few months . In general , there is at least a 2-year delay between bone age and chronological age . Continued growth may occur until the early 20s . In both males and females , there is a delay in puberty . Females seem to possess normal fertility . Males , as expected due to undescended testes , appear to have decreased fertility but male transmission is well described and not uncommon . The cause of short stature in NS is really not clear . After pharmacological stimuli , growth hormone secretion was usually normal in patients studied but a small number showed a subnormal response . Others have shown a neurosecretory growth hormone dysfunction to be present in some patients but this did not appear to have any effect on the response to growth hormone -LSB- 11 -RSB- . There have been previous studies looking at the IgF-1 levels which have been below normal for the majority reported . A considerable number of children have undergone treatment with human biosynthetic growth hormone . The majority of studies have shown similar results . There is a significant increase in growth velocity in the first and second year of growth hormone treatment -LSB- 12 -- 16 -RSB- . The velocity in growth tends to diminish in succeeding years . Several authors claim that the predicted adult height has been increased in patients treated with growth hormone but there have been no real controlled studies to document the long-term effect of growth hormone on adult height . In those studies where bone age as well as actual height were measured , the increase in bone age was equal or slightly greater than the overall increase in height . If the bone age acceleration exceeds the acceleration in height , it is even possible that growth hormone therapy could actually decrease the adult height . Since there was little data available regarding adult height in NS , we recently -LSB- 17 -RSB- published a study of 73 adults who were all over 21 years of age at the time of their last measurement . Thirty-one percent of males and 32 % of females achieved an adult height that was at the tenth percentile or greater which would be considered within a normal range . The remainder all fell below the tenth percentile but importantly 38 % of males and 54.5 % of females had an adult height below the third percentile . Adult height was unrelated to the presence or severity of cardiac disease and none of the adults achieving a normal height had been treated with growth hormone . Dr. Municchi et al -LSB- 16 -RSB- suggests that long-term serial height measurement over years comparing treated and untreated patients is needed to clearly show the benefit of growth hormone therapy on final adult height . There is no question that adult height can be achieved at an earlier age with the use of growth hormone . With the discovery of the PTPN11 mutation , it is now possible to study patients with NS positive for a mutation and compare them with NS patients who do not carry a mutation of the PTPN11 gene . The large cohort reported by Ranke -LSB- 18 -RSB- suggested that weight and length were normal in 119 newborns with NS . With the availability of genetic testing , several recent studies have shown that mean birth length for NS patients with a mutation is slightly below normal and is less than that of the non-mutated NS newborns -LSB- 19 , 20 -RSB- . In a study by Zenker -LSB- 20 -RSB- , 88 % of PTPN11 positive mutated children older than 3 years of age had a height less than two standard deviations and were significantly shorter than non-mutated children . All recent studies -LSB- 21 -RSB- suggest that there is a more severe mechanism acting on growth retardation in NS patients carrying a PTPN11 mutation . A recent study from France -LSB- 19 -RSB- evaluated 35 patients with NS , 20 of whom had a PTPN11 mutation . There was a trend to a shorter birth length in mutated versus non-mutated newborns and small for gestational age tended to be more frequent in mutated versus non-mutated patients . By 6 years of age , patients with mutations were significantly shorter than patients without mutations . The results of hormonal studies showed a normal growth hormone secretion after pharmacological stimuli and a low serum IgF-1 and ALS concentrations which is in contrast with a normal IgFBP-3 level . Since the PTPN11 gene has a negative effect on intracellular signaling downstream from several growth factor receptors , a growth hormone post receptor signaling resistance could represent the mechanism of stunted growth in NS . They felt that the lower growth response to growth hormone treatment observed in mutated versus non-mutated patients suggests some degree of resistance to growth hormone . Another recent study by Binder et al -LSB- 22 -RSB- showed a similar pattern . Data from these two studies would be in favor of growth hormone resistance by a late post receptor signaling defect specific for IgF-1 and ALS that does not effect IgFBP-3 stimulation . Changes in height during the first 2 years of growth hormone therapy in the pre-pubertal group show catch-up growth was less pronounced in patients with a mutation compared to those without a mutation . Fortunately , in all the studies using growth hormone , no adverse results have been observed . Many patients have undergone serial echocardiograms and none have shown an increase in their left ventricular mass index during growth hormone treatment -LSB- 23 -RSB- . These recent studies suggesting that there may be a primary IgF-1 deficiency in NS has stimulated and been incorporated into a phase II clinical study which will investigate the use of IPLEXtm -LRB- mecasermin rinfabate -RRB- -LRB- rDNA origin -RRB- which will be given by injection to treat growth failure due to insulin-like growth factor IgF-1 deficiency . Although we still do not understand how the mutation in the PTPN11 gene affects SHP-2 , the result apparently is a disruption in the growth hormone IgF-1 axis and IgF-1 deficiency which could be the cause of growth failure . LEOPARD syndrome -LRB- LS -RRB- Gorlin -LSB- 3 -RSB- , in 1969 , introduced the acronym LEOPARD -LRB- LS -RRB- to describe a rare syndrome that shares many features similar to NS . These include autosomal dominant inheritance , similar facial dysmorphism and similar cardiac defects with an overabundance of hypertrophic cardiomyopathy compared to pulmonary stenosis . The characteristic cutaneous finding of lentigines is the main distinguishing characteristic . In addition , unilateral or bilateral hearing loss is frequent . Sarkozy et al -LSB- 24 , 25 -RSB- recently reported clinical and molecular studies in a consecutive study of 30 patients with LS and found mutations in the PTPN11 gene in 27 of the 30 patients studied . Mutations in LS have all occurred in exons 7 , 12 and 13 while the more typical NS have the great majority of mutations occur in exons 3 , 8 and 13 . It is of interest that the mutations in patients with LS show a loss of function rather than gain a function as is found in the more typical NS patients . Zenker -LSB- 20 -RSB- noted a specific mutation T468M in exon 12 which was also reported by Sarkozy in seven of their patients with LS to have less adverse effects on body growth . Only two of the ten patients with the T468M mutation have short stature.A cardiac abnormality was present in 71 % of the patients with LS , with 80 % of those showing hypertrophic cardiomyopathy . Pulmonary stenosis was present in two patients and a partial AV canal in another . Cardio-facio-cutaneous syndrome -LRB- CFC -RRB- It is often difficult to distinguish an infant with CFC from NS although , with time , the phenotype becomes more distinctive . Patients with CFC -LSB- 4 -RSB- have a high forehead , a relatively large head and bitemporal constriction . Like NS , they have a downward slant of the palpebral fissures , posteriorly rotated ears and a flat nasal bridge . The hair is usually sparse , curly and friable and absent eyebrows are frequent . The skin changes are variable but include keratosis pilaris with patchy hyperkeratosis -LSB- 26 -RSB- . In time , the phenotype for CFC becomes more distinctive and less Noonan-like . These patients are significantly delayed in both motor and mental skills and , like NS , they are hypotonic , often have failure-to-thrive with frequent gastrointestinal complaints and often require tube feedings . Cardiovascular abnormalities are similar to NS although hypertrophic cardiomyopathy is more common than in the typical NS patient . Although these children appear to be of normal height and weight at birth , they soon fail-to-thrive and short stature is found in 78 % -LSB- 27 -RSB- . Bone age is significantly delayed and osteopenia is occasionally observed . Very recently , mutations in four separate genes have been found to be associated with CFC -LSB- 3 , 4 -RSB- . These four genes include BRAF , KRAS , MEK1 and MEK2 . All of these genes belong to the same RAS-ERK pathway that regulates cell differentiation , proliferation and apoptosis . It is likely that the mechanism causing short stature in NS may be similar to that causing short stature in CFC . This is a very rare disease and there is little information regarding endocrine studies in patients with CFC . Costello syndrome Costello Syndrome -LRB- CS -RRB- -LSB- 28 -RSB- is a rare condition with a distinctive facial appearance which may be difficult to distinguish from NS and CFC in infancy . Although height and weight are normal or above normal at birth , severe growth retardation is the rule postnatally . Like NS , they have a large head , short wide nose and short neck . Unlike NS or CFC , these patients usually have thick and relatively prominent lips and tongue . They also have loose skin on the hands and feet and deep palmar and plantar creases . There is significant mental and motor delay . Cardiovascular abnormalities are found in about 60 % and they are remarkably similar to that found in NS and CFC . Pulmonary stenosis , atrial septal defect and hypertrophic cardiomyopathy are the most common lesions -LSB- 29 -RSB- . Of particular interest is the high incidence of cardiac arrhythmias noted particularly in infancy -LSB- 30 -RSB- that is not characteristic of either CFC or NS . Recently Aoki et al -LSB- 4 -RSB- reported mutations in HRAS a proto-oncogene to cause CS . Gripp et al -LSB- 31 -RSB- confirmed this finding and reported 33 of 40 patients with a clinical diagnosis of CS to have a HRAS mutation . All the mutations were de novo . Patients with CS are at a significantly increased risk for the development of malignancy , particularly rhabdomyosarcoma , neuroblastoma , ganglioneuroblastoma , and transitional cell carcinoma of the bladder . Although few studies of growth hormone have been carried out in Costello patients , the findings are very similar to that of NS . Response to growth hormone treatment has been variable . Kerr et al -LSB- 32 -RSB- have suggested that in CS , hormone treatment may be harmful because of the propensity to tumor formation and the presence of hypertrophic cardiomyopathy . He described two patients , one who had mild left ventricular hypertrophy with normal function before growth hormone was started . After 3 months of treatment , the cardiomyopathy progressed with significant left ventricular outflow tract obstruction with a gradient of 60 mmHg . He was treated with Propranolol . There was no further progression of the cardiomyopathy in spite of continuation of growth hormone . In the second case , growth hormone was started at 12 months and continued until age 26 months when a large pelvic mass was discovered which was proven to be an embryonal rhabdomyosarcoma . Growth hormone was stopped after the tumor was recognized . In spite of extensive chemotherapy , the patient died . Since CS is associated with both subaortic hypertrophic cardiomyopathy and tumors , the role of growth hormone in these two patients is unknown . At the present time , it is unclear whether growth hormone is beneficial or harmful in CS . Conclusion NS , LS , CFC and CS all have significant phenotypic overlap . Although they may be difficult to distinguish early on in life , in time they can usually be distinguished clinically . Recent studies show that each of these syndromes is caused by a germline mutation in a key component of the highly conserved RAS , RAF-ERK-MAP kinase cascade which is better known for its roles in growth factor and cytokines signaling in cancer pathogenesis . We still do not understand how these specific mutations cause the disease and why there are such distinct phenotypic differences in mutations within the same signaling pathway . Tartaglia et al -LSB- 33 -RSB- recently provided evidence that specificity in amino acid substitution is relevant to the functional deregulation of SHP-2 and disease pathogenesis . They showed NS mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated mutations and that Y279C and T468M amino acid substitutions noted in LS engender a loss of SHP-2 catalytic activity . It is not surprising that a mutation in the HRAS gene associated with CS has an increased incidence of tumors since these mutations are identical to the human tumor associated mutations . So far , CFC syndrome has not been associated with malignancy but the number of reported cases is still quite small with long-term follow-up limited . For the endocrinologist , it is interesting that all of the syndromes have a high incidence of short stature . LS , on the other hand , with loss of function appears to have a lower incidence of short stature but the higher incidence of hypertrophic cardiomyopathy . It will be of interest to see how effective IPLEXtm will be in treating the growth failure in NS and perhaps these related syndromes as well . Since the growth failure starts very soon after birth and may indeed start before birth , it is certainly possible that treatment may be necessary very early in life to achieve anywhere near a normal growth stature .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

noonan syndrome
leopard syndrome
costello syndrome
short stature
growth hormone