Download HED - National Foundation for Ectodermal Dysplasias

The Multi-Syndrome Guide
to the
Ectodermal Dysplasias
National Foundation for
Ectodermal Dysplasias
Dedication
This booklet is dedicated to the individuals who
have served on our Scientific Advisory Board.
Under the leadership of Dr. Ronald J. Jorgenson,
this group has been paramount to the success of the
NFED and to the well being of individuals affected
by ectodermal dysplasia syndromes.
Copyright by NFED 1999
Revision 2003
This book was authored by the
National Foundation for Ectodermal Dysplasias
Scientific Advisory Board.
(Members are listed on page 32.)
Products and methods of treatment are mentioned in this booklet as
examples. Their inclusion should not be considered as endorsement
or approval by NFED.
1
National Foundation for Ectodermal Dysplasias
Multi-Syndrome Guide
Section
Page
1. Introduction
4
2. Embryology
5
3. Genetics
Special Considerations About Inheritance
5
8
4. What Type of ED Is It?
9
5. Ectodermal Dysplasia
11
6. Ectodermal Dysplasia Syndromes
Christ-Siemens-Touraine Syndrome
Clouston Syndrome
Tooth and Nail Syndrome
11
12
13
14
7. Complex Ectodermal Dysplasia Syndromes
Ectrodactyly-Ectodermal Dysplasia-Clefting
Syndrome
Hay-Wells Syndrome
Rapp-Hodgkin Syndrome
Tricho-Dento-Osseous Syndrome
15
8. Other Syndromes with Ectodermal Defects
Goltz Syndrome
Keratitis-Ichthyosis-Deafness Syndrome
Trichorhinophalangeal Syndrome
Cranioectodermal Dysplasia
Ellis-van Creveld Syndrome
Oculodentodigital Syndrome
Hallermann-Strieff Syndrome
Growth Retardation-Alopecia-PseudoanodontiaOptic Atrophy
20
20
21
22
24
24
25
26
2
15
17
19
20
26
9. Other Syndromes of Interest
Incontinentia Pigmenti
Epidermolysis Bullosa
Ichthyosis
27
27
28
29
10. Conclusion
29
11. Where Can I Learn More About ED?
30
12. ED Syndrome Identification By Photo
31
13. Acknowledgements
34
Photo 1
A big hello from all of us.
*Photo identification, by ectodermal dysplasia syndrome, is located on page
31.
3
Introduction
The ectodermal dysplasia syndromes (EDs) are a group of inherited
disorders that involve defects of the hair, nails, teeth, and sweat glands.
The types of EDs are recognized by the combination of physical features
that an affected person has and the way they are inherited. More than
100 types of ED are described in the book by Drs. Friere-Maia and
Pinhiero from Brazil (Ectodermal Dysplasias: A Clinical and Genetic
Study. New York, AR Liss, 1984), and a short list is included in A Family
Guide to the Ectodermal Dysplasias, published by the National
Foundation for Ectodermal Dysplasias (NFED) in 1992.
Many physicians do not know how many EDs there are and may not
appreciate the wide effect they have on affected individuals. When these
physicians think about EDs, they have in mind the rather distinctive features
of the type of ED that is called hypohidrotic ED or the Christ-SiemensTouraine (AED) syndrome. This booklet, however, describes many other
types of ED, types that are not as common or as easily recognized.
Hopefully, a reader of this booklet will walk away with a better
understanding of the EDs and with information about the type of ED that
exists in a particular family.
This booklet does not describe each type of ED but does give a brief
overview of several types frequently found in the families of members of
the NFED. In this booklet, we discuss some aspects of development and
genetics and
describe ED
and different
types of ED
syndromes.
S o m e
syndromes
described may
not
be
considered
EDs in the
strictest sense
but are included Photo 2 Life is something to smile about.
4
here because they are of interest to the NFED and because they complete
the picture of how the EDs fit into the overall scope of birth defects and
genetic disorders.
Embryology
To understand the EDs, it is necessary to know a little about biology. The
following description is intended to help understand both the terms used
by physicians who work with the EDs and the logic for separating the EDs
into the several groups discussed in this booklet.
Shortly after a human egg is fertilized, it begins to change; the single egg
develops into all the cells, tissues, and organs that comprise the human
body. The process by which a fertilized egg changes is quite predictable.
The egg goes through a number of steps during which it doubles in size
and splits in half, leading to a mass of cells that are very much like the
original egg. Eventually, some of the cells in the mass take on characteristics
of their own. One of the earliest steps in this process is the formation of
three distinct layers of cells: the cells on the “inside” of the mass become
the endoderm and will eventually form the internal organs and linings of
the inner body; the cells on the “outside” of the mass become the ectoderm
and will eventually form the outer covering of the body; and the cells
between the “inside” and “outside” of the mass become the mesoderm,
which will eventually form the muscles and bones.
This booklet discusses the ectoderm: skin, nails, hair, sweat glands, teeth,
and some other parts of the body. The ectoderm, however, does not exist
in a vacuum. The ectoderm, mesoderm, and endoderm interact with one
another in complex ways during growth and development. This interaction,
although poorly understood, is the basis for some of the syndromes
described.
Genetics
We must know only a few things about genetics in order to understand
how the EDs are inherited. First, the hereditary material is called DNA
(short for deoxyribonucleic acid). DNA is passed from one generation to
the next in sperm cells from fathers and egg cells from mothers. Thus, we
5
have two copies of every DNA molecule, one from our mother and one
from our father. Despite the importance of DNA (it makes us what we
are), it is delicate and may change as it passes from one generation to the
next. Many of the changes in DNA, called mutations, are harmful; that is,
they may lead to abnormal development or function.
Second, short segments of DNA control specific developmental events
and are called genes. Genes are arranged on a strand of DNA in much
the way that beads are strung along necklaces. If a DNA mutation affects
a gene, we say the gene has mutated. Since we inherit two copies of
every gene, it is possible to have two normal genes, one normal gene
coupled with one mutated gene, or two mutated genes.
Third, the DNA doesn’t exist as long thread-like material inside of cells; it
coils and folds upon itself into structures called chromosomes. The DNA
packages itself, in fact, into 46 paired chromosomes. Twenty-three of the
chromosomes come from the DNA of the mother, the other 23 which are
virtual replicas of the mother’s, come from the DNA of the father. Twentytwo of the pairs have nothing to do with determining the gender (male or
female) of the individual and are called autosomes. The members of the
twenty-third pair (the sex pair) are not as similar as the members of the
other pairs and determine gender: males have an unmatched XY pair,
while females have a matched XX pair.
These three simple concepts come together in our notion of inheritance. If
the DNA we inherit has no mutations, we are programmed to develop
normally. If there is a mutation in one of the genes along the length of
either DNA strand (our mother’s or our father’s), we are programmed to
develop abnormally. A mutation in the DNA of one of the 22 pairs that
have virtually nothing to do with determining gender, is said to be autosomal.
A mutation in the DNA of the sex pair is said to be X-linked. The only
other thing we need to complete our understanding of inheritance is to
know whether a single mutation (on the mother’s DNA or on the father’s
DNA) is sufficient to cause abnormal development, or two mutations (on
both sets of DNA) are necessary. If a single mutation is sufficient, we say
the mutation (or for convenience the gene or the disorder) is dominant; if
two mutations are necessary, we say the mutation (or for convenience the
gene or disorder) is recessive.
6
How does this apply to the EDs? As you read through this booklet, you’ll
see that a pattern of inheritance is usually specified for each type of ED.
The Christ-Siemens-Touraine syndrome, for example, is said to be Xlinked recessive, while the Clouston syndrome is said to be autosomal
dominant. The pattern of inheritance is crucial to understand whether or
not there is a risk for relatives of an affected individual to be affected, so it
becomes an important component in the description of each type of ED.
The patterns and their associated risks are listed below for those readers
who are interested in knowing precisely how risks are calculated.
1. The inheritance pattern of an autosomal dominant disorder is the
following.
• Males and females may be affected.
• Affected males and affected females may transmit the
disorder to their children.
• Each child born to an affected person has a 50% chance
to be affected.
2. The inheritance pattern of an autosomal recessive disorder is as
follows.
• Males and females may be affected.
• The parents of affected children usually do not appear to
be affected, although they probably are carriers of the
mutation.
• Each child born to carrier parents has a 25% chance to
be affected.
3. The inheritance pattern of an X-linked recessive disorder is as
follows.
• Males only are fully affected, though females who are
carriers may show mild signs of the disorder.
• All daughters of affected males are carriers.
• None of the sons of affected males is affected.
• Each child born to a carrier female has a 50% chance to
inherit the gene; sons who do will be affected, daughters
who do will be carriers.
7
Special Considerations About Inheritance
The most important thing for you to remember is that there are exceptions
to all rules. The inheritance pattern in your family may not match those
listed above because of some unexpected event or unlikely combination
of genes. Or, it may be that your family is not large enough for the rules to
be obvious. The best example of the impact of small family size on
inheritance pattern relates to gender determination. Most people know
that is as likely (50% chance) that a pregnancy will result in the birth of a
boy as a girl. Yet, a given couple may have three, four or even five sons,
but no daughters. The
chance that the next child will
be boy is still only 50%; the
rules don’t change depending
on a relatively small number
of outcomes. Similarly,
having one or more children
affected by an ED does not
change the inheritance
pattern; each pregnancy faces
Photo 3 Special Friends
the risk predicted by the
inheritance pattern for the ED
in the family.
It is equally important to remember that genetic disorders, including the
EDs, “breed true” in families. If there is an abnormal gene (a mutation) in
a family, it will cause the same disorder in whomever inherits the gene.
There may be a small amount of variation in the way the mutation expresses
itself (relatively mild or relatively severe), but it suddenly will not cause
another type of ED or another type of genetic disorder. The predictable
way the mutations for the EDs shows up in different people should give
some comfort to families of affected individuals; for the most part, they
know what they are dealing with from the very start since the physical
features of the EDs are easily seen and relatively well documented in the
literature or in the files of organizations such as the NFED.
The following table lists a few types of ED and related disorders to illustrate
how diverse the physical features may be and to emphasize that each type
of ED or related disorder had a predictable set of features.
8
Syndrome
Affected Areas
Hair Sweat Nails Teeth
CST
Clouston
Tooth and Nail
Rapp-Hodgkin
Ellis-van Creveld
X
X
X
X
X
X
Other
X
X
X
X
X
X
X
X
Inheritance
XL,AD,AR
AD
AD, AR
cleft lip/ palate
AD
AR
dwarfism
polydactyly
EEC
X
X
X
X
cleft lip/ palate
ectrodactyly
AD
Hay-Wells
X
X
X
X
cleft lip/ palate
AD
ankyloblepharon
Key XL=X-Linked AD=Autosomal Dominant AR=Autosomal Recessive
What Type of ED Is It?
One of the most frustrating experiences for parents of a young child with
ED is not knowing what their child has. Frequently, no one tells the parents
anything because no one recognizes that the problems the child has are
not part of growing up. Many children, for instance, have fevers, complain
about the heat, or have rashes. Physicians and nurses who see children
with these problems are more apt to think about common diseases of
childhood rather than a rare genetic disorder.
Parents of children with one of the most common type of ED, ChristSiemens-Touraine syndrome, get some relief after a diagnosis of ED is
made; they gain comfort in knowing what their children have, and their
physicians have access to a great deal of information about the disorder.
Parents of other children may not find a diagnosis, however, and may
remain concerned and confused. These parents often become angry with
their physicians, but cannot be blamed for their anger; they only want to
know what their children have and what to do about it.
To make a diagnosis of ED, physicians and dentists evaluate which
ectodermal structures are involved. The doctors may also look for physical
features that do not develop from the ectoderm (the bones, for instance).
By noticing patterns of physical features in children, doctors are often able
9
to make correct diagnoses and help
families cope with their situations and seek
proper medical care.
A correct diagnosis is necessary for
prognosis. To anticipate what kinds of
problems an individual with ED may have
or to reduce concern about what
problems may or, indeed may not arise,
doctors must know the natural history of
the specific condition. A correct diagnosis
is also important to predict the chance
that the condition will appear again in the Photo 4 Off to school.
same family. Parents of affected children
should ask how the ED is inherited. Are they at risk to have other affected
children? Can the children with ED pass it on to their children? Can other
individuals in the family be more severely affected? What other relatives
are at risk to have affected children? These questions cannot be answered
without a diagnosis and without knowledge of the inheritance pattern in
the family.
Many individuals with ED may be given a correct diagnosis eventually.
There are, however, some individuals who do not fit neatly into one or
another recognized category. In other words, there always seem to be
individuals with the label “ectodermal dysplasia - type unknown”. This
situation may be frustrating for families. Failure to reach diagnosis has
several explanations. First, some genetic conditions are unique; they result
from a change in a gene that has occurred only in the one individual and
for which there is no precedent. Second, some diagnoses are not clear
because the affected individual has a physical feature that is not generally
considered part of ED. An incidental congenital heart defect in a child
with Christ-Siemens-Touraine syndrome, for instance, may steer the doctor
away from the correct diagnosis unless proper consideration is given to
the possibility that the two conditions coexist by coincidence. Third, even
within a specific type of ED, not all affected individuals will have exactly
the same features to the same degree. Fourth, the medical literature may
be biased and may describe only severely affected individuals or those
10
with unusual findings; as a result, individuals with mild features of a known
ED may escape notice or may not be diagnosed promptly.
Ectodermal Dysplasia
The word “dysplasia” refers to abnormal organization of cells in the organs
of the body. Any organ of the body may be dysplastic (affected by a
dysplasia), when the dysplasia involves an organ derived from the ectoderm
(see above), it is proper to say the end result is an ectodermal dysplasia
(ED) without further qualification. For example, abnormal development
of the hair only is an ED (trichodysplasia), abnormal development of teeth
only is an ED (dental dysplasia), and abnormal development of the nails
only is an ED (onychodysplasia).
Two things must be remembered about the EDs. First, to qualify as an
ED, there must be an intrinsic developmental abnormality in the part of the
body involved. Graying of the hair with age or age-related hair loss in
males, for instance, does not qualify as trichodysplasia (ED involving the
hair only); these characteristics are physiological, not developmental. For
the same reason, dental cavities do not qualify as dental dysplasia (ED
involving the teeth only), and thick nails from fungal infection do not qualify
as onychodysplasia (ED involving the nails only). Second, there may be
several different types of developmental defects of a part of the body that
qualify as a dysplasia. For instance, absence of the hair, excessively thin
hair shafts, or twisting of hair shafts are each different types of
trichodysplasia.
Ectodermal Dysplasia Syndromes
The suggestion to include abnormal development of a single part of the
body as an ED is a new idea. Most papers and books about EDs define
them as hereditary disorders that affect two or more parts of the body that
are derived from the ectoderm. This traditional definition is not wrong but
has limitations for those people who are trying to sort out the EDs and
trying to develop a meaningful system for classification.
In medicine, the word “syndrome” is used when referring to the consistent
association of two or more physical traits, a practice that is accommodated
11
by the system used here. Thus abnormal development of one part of the
body only is a dysplasia, whereas consistent abnormal development of
two or more parts is a syndrome. If parts of the body derived from the
ectoderm only are involved in the syndrome, it is called an “ED syndrome.”
If parts of the body derived from other embryonic layers of tissue (the
mesoderm or the endoderm) are consistent parts of a syndrome whose
primary features also involve the ectoderm, it is called a “complex ED
syndrome.”
For thoroughness, this booklet also describes “other syndromes with
ectodermal defects” and “other syndromes” that are found in the families
of members of the NFED or which some doctors may call an ED.
Christ-Siemens-Touraine Syndrome
The Christ-Siemens-Touraine (CST) syndrome is often called anhidrotic
or hypohidrotic ectodermal dysplasia because of the inability of affected
individuals to sweat normally. Physicians may abbreviate this as “AED”
or “HED”. It is, perhaps, the most common type of ED, and for decades
has received a great deal of attention because of its striking physical features.
Individuals affected by the CST syndrome have sparse hair that is lightly
pigmented, congenital absence of most teeth, and a greatly reduced ability
to sweat. Diagnosis is sometimes possible at birth. In many cases,
newborns have dark circles around their eyes because that skin is thin and
the underlying blood vessels create a bluish
shadow. The skin also may appear to be
“peeling” at birth. Infants may not be able
to tolerate heat and may be irritable in warm
environments or may have unexplained
fevers. More often, the diagnosis is not
made until the teeth do not erupt at the
expected age or the teeth appear to be
pointed when they do erupt. Eruption may
Photo 5 A face all can
be delayed, or only a few teeth may erupt.
love.
With the exception of heat intolerance,
general health and overall development, including intelligence, is within
normal limits. Affected individuals may have a higher than average
12
frequency of ear wax impaction, dry nasal concretions, respiratory illness,
sinusitis, or sparseness of tears and saliva. Nails, facial hair in males, and
the appearance of pubic hair in adolescence are normal.
Treatment for the CST syndrome involves maintaining a cool environment,
dental treatment to replace missing teeth, and the use of wigs, if desired,
to mask sparseness of hair.
The CST syndrome is inherited as an X-linked recessive disorder in most
families, although autosomal dominant and autosomal recessive forms of
the disorder exist. Female carriers of the X-linked form may show no
signs or only mild signs of the disorder: peg-shaped teeth, absence of a
few teeth, patchy sweat distribution, or mild sparseness of scalp hair.
Carriers of the autosomal recessive form of the disorder do not have any
of the features of the disorder; the autosomal dominant form is milder than
the other two. Since the gene for the X-linked form of the CST syndrome
has been identified, accurate diagnosis is possible in many families. The
autosomal forms of the disorder are caused by a gene on chromosome 2,
different mutations in the DL gene.
Parent’s Perspective
“At the time of diagnosis, our family was full of fear for the future of
our child. The support of friends, family, and those responsible for
our son’s medical and dental care was invaluable to his growth and
development. But, perhaps most important was giving our son the
opportunity to be an active participant in the process, whether it
pertained to his oral health care, socialization, education, or athletic
activities. He has become a self-assured, responsible young man who
is successful in every respect, in spite of ED. We are enormously
proud of his many achievements and the joy he has brought to our
family.”
-M.R.
Clouston Syndrome
Clouston was the name of the physician who described for the first time a
type of ED characterized by thick nails that grow slowly, sparse hair,
thickness of the skin over the palms and soles, dark skin over the knees
and elbows, white patches on the inside of the cheeks, thin eyebrows
(outer portion only), and a reduced number of eyelashes. Individuals with
this type of ED have normal teeth and sweat normally. Intelligence is
13
normal. Clouston
syndrome
is
frequently called
hidrotic ED because
affected individuals
sweat normally and
exhibit no heat
intolerance.
Although most
affected individuals Photo 6 These two girls became friends at
an NFED regional conference.
are of French
ancestry,
the
Clouston syndrome has been reported in individuals from many ethnic
backgrounds. The number of people with Clouston syndrome in the
general population is not known, probably because many do not come to
medical attention.
The Clouston syndrome is inherited as an autosomal dominant disorder.
The gene that causes Clouston syndrome, the GJB6 gene, is on chromosome
13; molecular testing is available.
Tooth and Nail Syndrome
Individuals with the “tooth and nail” syndrome sweat and tolerate heat
normally. Nails are spoon-shaped (concave), thin, and grow slowly. Many
teeth are congenitally absent, but rarely are more than 20 permanent teeth
missing. The teeth which are present may be peg-shaped or smaller than
normal. Baby teeth may be retained until adulthood if they have no
permanent successors. The density of scalp hair varies from normal to
sparse, and the hair itself may be lightly pigmented. No other medical
problems have been noted in patients affected by “tooth and nail” syndrome.
Intelligence is normal.
There are at least two types of “tooth and nail” syndrome: the Fried
syndrome (pronounced “freed”) and the Witkop syndrome. The difference
between the Fried syndrome and the Witkop syndrome is inheritance.
The Fried syndrome is an autosomal recessive disorder, while the Witkop
14
syndrome is an autosomal dominant disorder.
Consequently, family history may be necessary
to know the type a particular individual has.
The gene for the Witkop type of “tooth and
nail” syndrome, the MSX1 gene, is located
on chromosome four, but molecular testing is
not yet available.
Parent’s Perspective
“It’s been very important to not only
address treatment concerns as they
develop but to remember to compliment
each positive step. We’ve always
discouraged demeaning remarks with
appropriate correction and provided our
daughter with lots of family support.
Perhaps the most important thing we’ve
done is to continue our social activities and
our life style as it’s always been.” -V.L.
Photo 7
Mom’s little
helper.
Parent’s Perspective
“It’s been very helpful to learn as much as we could from the NFED,
our physicians, dentists, and geneticists. We’ve always emphasized
what our son does well and encouraged him in other areas. We do
not at all emphasize aspects of his disorder like his unusual teeth.
Gaining knowledge and experience along with the passage of time
has eliminated our initial anxieties and worries. We’re thrilled with
(him) just as he is.”
-D.J.
Complex Ectodermal Dysplasia Syndromes
Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome
Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome is a type
of ED in which there is congenital absence of some of the fingers or toes,
features of ED, and cleft lip or palate. While both hands and both feet are
usually involved, exceptions have been noted: only one hand or foot may
be involved. Abnormalities in the development of tear ducts can cause
excessive tearing or a failure of the tear glands to develop may cause
inflammation of the eyelids, cornea, and conjunctiva. Intolerance of light
(photophobia) may occur. Skin and hair may be more lightly pigmented
15
than normal,
and a variety of
hair problems
may
be
experienced,
from sparse
hair to thick,
unruly hair. The
nails in some,
but not all,
people with the
disorder may
Photo 8 Lots of hours can be spent in a dentist
be abnormal.
chair, but a good dentist can be a good
Various renal
friend, too.
problems have
been identified in individuals affected by EEC, but great variation in the
type and severity exist.
The most obvious abnormalities of the oral cavity include cleft palate with
or without cleft lip; cleft lip may occur on one or both sides of the upper
lip. Congenital absence of teeth and pointed teeth are common. Conductive
hearing loss (not nerve deafness) even without ear malformations has been
noted in some individuals. Mental retardation may be an occasional feature.
The EEC syndrome is a group of autosomal dominant disorders that
resemble one another. There is considerable variation in expression
between affected members of the same family; that is, some members
may have the condition in mild form, while relatives are more severely
affected. Thus, careful examination of the affected individual, as well as
his or her parents and siblings, is essential before genetic counseling can
be provided. The gene for the EEC syndrome is located on chromosome
7. Molecular testing is available.
Parents’ Perspectives
“This EEC thing is not what I would have chosen for (her) or us. But
it is real and could be much worse. It is a part of our life, and we
must embrace and cherish every moment of our lives... even the hard
parts. My only regret is not always making sure surgery was really
medically necessary. Out of 40 procedures, there are three that could
16
have been omitted. We learned to take each challenge one little bit
at a time, and before we knew it, it was over. Now we look back and
marvel at how well our daughter copes.”
-M.S.
“I don’t pretend it’s a bed of roses bringing up a child with special
needs, but there are a lot of good things as well. I feel perhaps I am
a stronger person because of (him). It can be distressing to see your
child have endless operations—21 so far in (his) case. You feel you
can’t face another operation or appointment with specialists. I suppose
it’s nice having two other children as well because you then tend to
rear all your children the same; otherwise you will be accused of
favoritism. It’s a good thing because your child with a syndrome will
eventually go out into the big world and you must not “baby” them.
The hardest part is letting go, letting them make mistakes and realize
their own limitations. Above all, take time out to have a good
chuckle.”
-M.C.
Hay-Wells Syndrome
The Hay-Wells syndrome is also
known as the ankyloblepharonectodermal defects-clefting
(AEC) syndrome. The scalp hair
in affected individuals is sparse
and wiry, while the eyelashes are
sparse or absent. The nails may
be absent or malformed. The
teeth and sweat glands may also
be affected. The teeth may be
small and malformed or prone to
tooth decay, while sweat
production may be low.
Intelligence is normal. Like some
other EDs, cleft lip or palate is a
consistent feature, but what sets
Photo 9 Smiles and balloons
AEC syndrome apart is the
go hand in hand.
associated fusion of the upper
and lower eyelids (ankyloblepharon). The eyelid fusion is seldom complete;
it frequently involves narrow bands of skin-like tissue connecting the lids.
Some individuals with the AEC syndrome have a chronic dermatitis of the
scalp that is difficult to treat and may cause scarring and loss of hair.
17
AEC is an autosomal
dominant disorder. The
gene responsible for the
AEC syndrome, the P63
gene, is located on
chromosome
13.
Molecular testing is
available.
The AEC syndrome, like
the EEC syndrome, is a Photo 10 A smile says it all.
good example of a
complex ED syndrome; each of these syndromes involves structures that
doctors may not recognize as ectodermal in origin, making it unlikely that
they will be categorized properly as an ED. Furthermore, they are each
rare, making it unlikely that a given doctor has ever seen a case and limiting
the potential for diagnosis early in life.
Parents’ Perspectives
“We’ve always been open about her uniqueness if they stare or ask
questions. Somehow it makes her differentness more acceptable when
we acknowledge it rather than not talking about it. She goes to
ballet, takes gymnastics, and loves preschool. It was very comforting
to meet another ED child and to discuss our concerns with another
mom. I was very hesitant to pursue that the first year or so. I would
encourage other families to take this step right away.”
-L.V.C.
“Take life with your child one step at a time. Concentrate on each
hurdle and don’t look too far down the road. Educate those around
you as best you can. The more people understand, the less fearful
they are. If we have a negative attitude, the person we hurt the most
is Kevin. Life is going to be OK; we remember that our situation
isn’t the worst case. Things could be better and things could be worse
but whatever comes, we’ll make the best of it. (He) has to live with
this syndrome, and we have to be there for him.”
-C & J. K.
“No one in my life has brought as much knowledge, inspiration, and
pride to me as my son. Levi touches everyone he meets. I feel it’s
very important to help your child find something he or she excels in
to help develop self esteem. Although he’s only 7 years old, he is
state champion in his weight class in free-style wrestling. I’ve always
18
treated him as though he wasn’t affected by a syndrome. We have
very good communication, which has really helped.”
-K.H.
Rapp-Hodgkin Syndrome
The Rapp-Hodgkin syndrome
(RHS) is another type of ED
associated with cleft lip and
palate; in this way, RHS is
similar to the EEC syndrome
and the AEC syndrome.
RHS, however, does not share
the hand defects of the former
or lid defects of the latter.
Problems with sweating in
RHS are not as severe as in
the CST syndrome, and some
affected people sweat through
their scalp. The hair in RHS Photo 11 Very much alike, but still
grows slowly and is coarse.
an individual.
Some affected individuals have
a persistent scalp dermatitis that responds poorly to treatment. As a rule,
individuals with RHS have more teeth than those with the CST syndrome.
Because of the associated cleft lip and palate, individuals with RHS also
may have speech problems and repeated ear infections. General health,
intelligence, and life span are within normal expectations.
RHS is inherited as an autosomal dominant trait. Not everyone with RHS
shows the same pattern of features; some people may be very mildly
affected or not even have one or another of the features that constitute the
syndrome. While the gene responsible for RHS has been located on
chromosome three, there are no molecular tests and the evidence does
not yet show how the AEC syndrome and RHS may be related.
Parent’s Perspective
“Trust your intuition and knowledge about your child; then go to a
medical center that you trust. The support of the craniofacial team
we see has been a big help. Rosie’s innate shyness has been tempered
with friendliness and curiosity. She is a great mediator/diplomat,
19
and all the kids want to be with her. We call her our junior Henry
Kissinger.”
-C.E.
Tricho-Dento-Osseous Syndrome
The tricho-dento-osseous (TDO) syndrome involves the hair, teeth, and
bones. There are three different types of TDO syndrome, differing in
severity and the pattern of bony involvement; the three types may be caused
by defects in the same gene. Individuals with this syndrome are born with
a full head of kinky hair, which tends to straighten with age. Nails are thin
and likely to peel or split. Sweating is not a problem. The bones of
individuals with TDO syndrome appear excessively dense on x-ray films.
The apparent density is of no consequence and should cause no problems
for affected individuals, although it is essential in making a diagnosis. Teeth
are prone to caries and may become abscessed during the first few years
of life. The teeth have thin, pitted, and yellow-brown enamel. On dental xray films, large pulp chambers (taurodontia) are found. In addition, teeth
may be impacted. Intelligence and life span are normal.
The TDO syndrome is an autosomal dominant disorder. The gene has
been located on chromosome 17, but molecular testing is not yet available.
Other Syndromes with Ectodermal Defects
Goltz Syndrome (also called Goltz-Gorlin Syndrome)
Goltz syndrome is sometimes called “focal dermal hypoplasia” because of
characteristic findings in the skin, ranging from small areas of absent skin
to small areas of thin skin, especially on the scalp. The areas of defective
skin may be abnormally pigmented, and fatty tissue may protrude through
them. Frequently, affected individuals have lumps of raised tissue on the
lips, gums, and base of tongue and around the mouth, anus, vulva, groin,
and arm pits. Affected individuals have absent, poorly developed, spoonshaped, or grooved nails. While some affected individuals do not sweat
normally over their entire bodies, their palms and soles may sweat
excessively. Individuals with Goltz syndrome may have patches of hair
loss on the scalp and pubis. Dental abnormalities may include irregular
position of teeth, poor enamel, and malformed teeth.
20
Other findings include
asymmetry of the face,
malformed ears, pointed chin,
and wide-set eyes. Abnormal
development of the eye, small
eyes, and colobomas of the
iris and the choroids, may
occur. Frequently, fusion of
fingers and toes and other
abnormalities of the fingers or
toes may be noted. Hearing
loss has been reported, as have
heart and kidney defects.
Hernias and mental retardation
may be occasional features.
The inheritance of Goltz
Photo 12 Blowing bubbles is just
syndrome is not as clear as that
one of many wonderful
of other disorders discussed
things to do.
above. Most reported cases
have been female, making X-linked dominant inheritance with lethality in
males the most likely pattern of inheritance.
Keratitis-Ichthyosis-Deafness Syndrome
Keratitis-ichthyosis-deafness (KID) involves the skin, eyes, and hearing.
The skin findings include red, thick areas of skin on the face, elbows,
knees, and backs of hands and feet. There is also marked thickening of
the skin of the palms and soles, especially on the pads of the fingers and
toes, and prominent ridges of the fingerprints. Decreased tear production
leads to scarring and vascularization of the cornea of the eye is common
and may lead to loss of vision. Affected individuals frequently need to
lubricate their eyes with artificial tears, sterile petrolatum ointment, and
occasionally with vitamin A ointment. Individuals with KID syndrome
should be seen by an ophthalmologist (a medical eye doctor) early in life,
and the doctor’s instructions must be followed carefully since overuse of
some of the lubricating products or inappropriate use of antibiotics in the
absence of infection may worsen the eye problems.
21
The profound hearing impairment in the KID syndrome is sensorineural
(nerve) deafness and is typically severe enough to limit speech development.
Other associated findings have
included thin hair shafts on the
scalp and thin eyebrows or
eyelashes. Teeth tend to erupt
late and may be prone to
cavities. Sweat glands are
reduced in number, leading to
decreased sweating and heat
intolerance. Some affected
individuals have frequent
infections of the skin and nails.
Nails may be absent or small
at birth and may become thick
Photo 13 Happiness is a frame
as time passes. Individuals with
of mind.
the KID syndrome occasionally
are unable to extend or bend
their elbows and knees completely and may have tight heel cords. Some
affected individuals are shorter than average. Intelligence is normal.
KID syndrome seems to be an autosomal dominant disorder, but very
few affected individuals have reproduced, making a study of inheritance
difficult. The gene responsible for KID syndrome, connexin-26, has been
located on chromosome 13, but molecular testing is not yet available.
Parent’s Perspective
“Don’t give up. Find others who care both for you and for the child.
Remember to take care of yourself so you don’t burn out and then
give up. Parents need to nurture each other so they can nurture their
special child. And don’t forget your other children as they are special,
too.”
-K.G.
Trichorhinophalangeal Syndrome
There are at least three types of trichorhinophalangeal syndromes. All
three types have abnormalities of the bones and hair. In Type I, some of
the finger joints are enlarged, and the thumbs and big toes are usually
short; other fingers and toes also may be short. Scalp hair is fine, sparse,
22
and brittle; scalp hair is especially scant in the front, simulating male pattern
baldness and some individuals are completely bald. Eyebrows are thick
near the nose, but sparse in their lateral aspects. In addition, the tip of the
nose is bulbous, the mid-portion of the upper lip is long, and the upper lip
is thin. Extra teeth may be present. Nails may be thin. About 50% of
affected individuals are shorter than normal. Intelligence is normal.
TRP-II is also called the Langer-Giedion syndrome (LGS), named after
the physicians who described the condition first. The facial appearance
and hair abnormalities in individuals with TRP-II are similar to those found
in TRP-I. Unlike TRP-I, mild to moderate mental retardation is present in
most individuals with TRP-II. Hearing loss has been seen, although the
tones affected, age of onset, and the severity of the loss have not been
documented well. Speech delay has also been reported. Another feature
that differentiates TRP-II from TRP I is the presence of bumps on the
long bones, called exostoses. These bumps usually appear by the third or
fourth year of life, although they may be found as early as the end of the
first year. The bumps are located primarily near the ends of the bones of
the arms and legs, although other bones may also be affected.
TRP-III is similar to TRP-I but much more severe.
In most families with TRP-I, the inheritance pattern is autosomal dominant
and associated with mutation in a zinc finger transcription factor gene on
chromosome 8. However, a few families have been reported in which the
condition is inherited as an autosomal recessive. Most patients with LGS
do not have affected relatives, making a study of inheritance difficult.
Evidence suggests that LGS is in reality a contiguous gene syndrome in
which the TRPS1 gene and DNA in the same region has been lost from
the end of Chromosome 8. This led to the localization of the TRP gene, a
zinc finger protein gene, to chromosome 8 and an explanation for the
diversity of the syndrome. Mutations in the responsible gene are thought
to cause TRP-I and TRP-III, with the latter being nothing more than more
serious mutations, while mutations that cause TRP-II are thought to overlap
into an adjacent gene, one that causes the exostoses.
23
Parent’s Perspective
“Our biggest challenge has been
keeping (him) healthy and free from
pneumonia. However, we don’t give
up, nor do we settle for negative news.
We believe in our child and the
milestones she has accomplished.
We’ve learned to keep an open mind,
to be positive, and to answer any
questions that she has. Concentrating
on positive energy and knowing that
God hasn’t given us anything we can’t
handle has been enormously helpful.”
-S.D.
Cranioectodermal Dysplasia Photo 14 I’m not alone,
and neither are
(Sensenbrenner Syndrome)
you.
Individuals with cranioectodermal
dysplasia have problems with their
bones, teeth, and hair. Sweating is normal. The hair is generally thin,
sparse, and slow-growing. Several teeth may be missing; those that are
present are small, widely-spaced, and have poor enamel. The nails are
often broad and short. The arms and legs may be shorter than average,
particularly the arms. Fingers and toes may be short also. The forehead
is prominent, and the head is long and narrow. The chest is often short
and narrow with a prominent breast bone (pigeon chest). The bones
seem to be under-calcified on x-ray studies. Other findings in individuals
with cranioectodermal dysplasia include heart defects, eye abnormalities,
and poor muscle tone. Intelligence is normal. Cranioectodermal dysplasia
is an autosomal recessive disorder.
Ellis-van Creveld Syndrome (Chondroectodermal Dysplasia)
The Ellis-van Creveld (EVC) syndrome is particularly common in North
America among the Amish, a religious group who live primarily in Indiana,
Ohio, and Pennsylvania. The EVC syndrome has abnormalities of the
hands, short stature, and defects of the nails and teeth. Sweating is normal.
There usually is an extra finger on the “pinkie” side of each hand; rarely
there are also extra toes. The nails are thin, ridged, or spoon-shaped.
Several teeth may be missing. Teeth which are present are small and
conical in shape. About 25% of individuals with EVC are born with teeth.
24
These teeth are present at birth or erupt during the first several weeks of
life (natal or neonatal teeth). Natal teeth are usually small and malformed.
When natal teeth fall out or are extracted by a dentist, they are not replaced
by more baby teeth. Other abnormalities in the mouth include rough
(washboard-like) gum ridges. Congenital heart problems are common
and are the life-threatening feature of this syndrome. Mental retardation
may be an occasional feature.
The EVC syndrome is an autosomal recessive disorder. The gene that
causes EVC syndrome is on chromosome 4, near the gene that causes
some common forms of dwarfism. Unlike many of the other disorders
discussed in this booklet, the EVC syndrome may be diagnosed prenatally
by ultrasound or fetoscopy.
Parent’s Perspective
Treat them like they are ‘normal’ kids - don’t put them in a box to
‘protect’ them or ‘on a pedestal’ because their life is so tough. If you
make it out as no big deal it helps others adjust and accept your
‘special needs’. Our daughter is a normal 3-year-old as far as she is
concerned. She will show her scars from her heart surgery and where
she had extra fingers removed as though everyone else should have
them, too. Our first challenge was adjusting to the idea of a child
with special needs and realizing it wasn’t our fault. Our biggest
challenge has been finding a doctor who has seen a child with our
syndrome — we just kept following up on leads or ideas until we
found one we were pleased with.”
-M.H.
Oculodentodigital Syndrome
While there is more than one genetic cause for this syndrome, the features
are quite similar. The hair is sparse, dry, brittle, and grows slowly. The
teeth are often normal in number, but the enamel layer is defective. The
eyes tend to be small and are closer together than average. The nose is
narrow and thin and has a “pinched” tip. Two or more of the fingers or
two or more toes may be fused. The fingers may be curved and unable to
extend fully. Mental retardation may be an occasional feature.
The oculodentodigital syndrome is an autosomal dominant disorder in some
families and an autosomal trait (sometimes called oculodentoosseous
dysplasia) in others. The gene responsible for oculodentodigital syndrome,
connexin-43 is on chromosome 6. Molecular testing is not yet available.
25
Parent’s Perspective
“We found it critical to have our daughter’s eyes examined every six
months from birth on and to see a glaucoma specialist. We also
continue our search for information in medical school and hospital
libraries as they remain our best resource for recently published data.
It was helpful to provide information and make our opinions known
to folks at school prior to (her) entering kindergarten. Although it
may be difficult to have a child labeled as “special ectodermal
dysplasia”, in many cases it is the only way to receive any special
consideration or extra services that the child might need. This has
become more evident with each passing year. Our daughter is simply
great and makes all of our efforts worthwhile.”
-L.D.
Hallermann-Streiff Syndrome
The Hallermann-Streiff syndrome (oculo-mandibulo-facial syndrome) has
short stature, congenital or early onset cataracts, distinctive facial features,
sparse hair, dental anomalies, and thin skin over the nose and scalp. The
facial features include a “beaked” nose, a small face in relation to the size
of the skull, small eyes, and a “double chin”. The small jaws may cause
feeding and breathing difficulties in the young child. The hair is generally
thin and light-colored and may be sparse on the scalp, particularly over
the suture lines. Sweat function and nails are normal in affected individuals.
Hearing is also normal. Congenital cataracts may require early surgery.
Some individuals develop glaucoma with or without cataract surgery, a
factor that must be considered prior to treatment. Spontaneous resorption
of cataracts is an unusual event in humans, but occurs more often in the
Hallermann-Strieff syndrome than in other known disorders. Intelligence
is normal.
The inheritance of Hallermann-Strieff syndrome is unclear, since almost all
cases are isolated with no family history.
Growth Retardation-Alopecia-Pseudoanodontia-Optic Atrophy
Growth retardation-alopecia-pseudoanodontia-optic atrophy (GAPO)
syndrome has total absence of hair, although a little may be present at
birth. The teeth of affected individuals are present but impacted. The
lack of tooth eruption may lead people to believe the teeth are not present,
a situation called pseudoanodontia. While the skin is considered dry,
affected individuals may or may not sweat normally. The skin, however,
especially that around the neck, is redundant and corrugated in appearance.
26
There may be hearing loss and
vision problems associated with
atrophy of the optic nerve.
Facial appearance of affected
individuals is characteristic as is
short stature.
The GAPO syndrome is quite
rare. However, it is probably
an autosomal recessive
disorder. It is possible that
mental retardation may be an
occasional feature.
Other Syndromes of Interest
Photo 15
Mom and son enjoying
the day.
Incontinentia Pigmenti
Incontinentia pigmenti (IP) is a skin disorder characterized by blister-like
lesions over the skin shortly after birth. The lesions gradually change
character, and marbled hyperpigmentation appears in early childhood.
The areas of hyperpigmentation may fade during the second and third
decades of life. By mid-life, affected adults have mild pigmentary changes
only, including small areas of decreased pigmentation. In addition to the
skin lesions and pigmentary changes, people with IP may have missing or
malformed teeth, patches of absent scalp hair, some learning disabilities,
occasional seizures, and various problems with their eyes (the retinas) and
their bones. Their nails also may be poorly formed. Mental retardation is
an occasional feature.
IP affects females almost exclusively (99%) and is caused by a gene carried
on the X-chromosome that is lethal to males who inherit it. In other words,
males who inherit the gene from their affected mothers rarely survive
beyond the second trimester of pregnancy. The gene for IP is called a
dominant, and females who inherit it are likely to show its effect. Less
than half of the people affected by IP have affected relatives, indicating
the important role of genetic mutation in establishing the frequency of IP in
the population. With the help of NFED families with IP, the gene was
isolated in 2000. Direct DNA diagnosis is available for about 90% of IP
27
individuals and prenatal diagnosis of the
occasionally devastating disease is possible.
Mutations in the gene that causes IP, the
NEMO gene, cause a type of hypohidrotic
ectodermal dysplasia that is associated with
severe immune deficiency.
Other disorders similar to IP are the Naegeli
syndrome, the Berlin syndrome, and
hypomelanosis of Ito. Individuals with the
Photo 16 I beat the
Naegeli syndrome have marbled skin
odds!
hyperpigmentation, decreased sweating,
defects of teeth, and thickened skin of the
palms and soles. People with the Berlin syndrome have generalized skin
hyperpigmentation, missing teeth, sparse hair, short stature, and learning
disabilities. Hypomelanosis of Ito is often considered the counterpart of
IP, showing hypopigmentation in much the same pattern as IP shows
hyperpigmentation. The Naegeli syndrome is an autosomal dominant
disorder, the Berlin syndrome is an autosomal recessive, and hypomelanosis
of Ito is probably an autosomal dominant.
Epidermolysis Bullosa
More than 16 types of epidermolysis bullosa (EB) have been described.
Most types of EB are present at birth or become noticeable in early infancy,
although some types do not show up until later in life. While EB is basically
a skin disorder, the mucous membranes may be involved in severe types.
Individuals with EB develop blisters wherever they injure their skin or
expose their skin to high temperatures in the environment. The blisters
tend to cause heat intolerance, although sweat function would be normal
in the absence of blisters. The hair is normal in individuals with EB. If
there is extensive blistering of the skin of the scalp, however, hair may be
absent or sparse. The nails may be affected; any injury may cause the
nails to be lost or become abnormal in appearance. The teeth are usually
normal, but excessive blistering of the linings of the mouth may lead to
poor oral hygiene and subsequent dental decay; the teeth in one type of
EB have defective enamel. Intelligence is normal.
28
The various EBs are inherited as autosomal dominant, autosomal recessive,
and X-linked disorders.
Ichthyosis
The numerous types of ichthyosis have characteristic age of onset,
distribution of scaly skin, microscopic appearance of the skin, and patterns
of inheritance. In virtually all types of ichthyosis, the superficial layer of
the skin is affected; the surface layers proliferate more rapidly than normal,
or the most superficial layer fails to be shed normally. In either case,
scaling and flaking of the skin results.
Individuals with ichthyosis may have dry, scaly skin at birth or later in life.
The sweat glands in individuals with ichthyosis are normally formed, but
the superficial scales plug the sweat pores, creating a mechanical barrier
to normal sweating. The hair is normal in most individuals with ichthyosis,
although hair on the scalp may not penetrate the thick scales, making hair
look sparse. The nails and teeth are also normal in most individuals with
ichthyosis, although either may be affected in rare types or certain
individuals. Intelligence is normal.
The several types of ichthyosis are inherited as autosomal dominant and
autosomal recessive disorders, and one as an X-linked disorder.
Conclusion
The EDs are a distinctive group of syndromes. They vary widely in their
effects with some being mild and others profound. The intent of this booklet
has been to describe the way that the EDs are classified and to provide a
pathway of understanding for affected individuals, their families, and
clinicians.
It is important to remember that not all individuals affected by the EDs will
have physical features that fit the description of a specific syndrome. There
may be a great deal of variation in the physical appearance of the same
type of ED from one affected person to the next. A person may even
have a type of ED that has not been described yet, or have a unique type
of ED. Nonetheless, the EDs share certain features, an understanding of
which makes it possible to understand the ramifications for most affected
29
individuals, and allows everyone involved to respond appropriately to the
individual’s needs. When questions of a diagnosis exist, the expertise of a
geneticist or other physician with experience with the EDs is strongly
recommended.
Photo 17
New friends and old gather at an NFED conference.
Where Can I Learn More About ED?
National Foundation for Ectodermal Dysplasias
410 E. Main Street, P.O. Box 114
Mascoutah, IL 62258-0114
United States of America
Phone - (618) 566-2020
Fax - (618) 566-4718
Web Site - www.nfed.org
E-mail - [email protected]
30
ED Syndrome Identification by Photographs
(All photos are identified from left to right.)
Photo
Page
1. All HED
3
2. HED, HED, AEC
4
3. HED, HED
8
4. Unknown
10
5. HED
12
6. Clouston, Langer Giedion (Trichorhinophalangeal II)
14
7. Tooth and Nail
15
8. EEC
16
9. AEC
17
10. AEC, AEC
18
11. Rapp-Hodgkin, Rapp-Hodgkin
19
12. Goltz
21
13. KID
22
14. Trichorhinophalangeal I
24
15. GAPO
27
16. IP
28
17. All HED
30
The NFED seeks to enrich the lives of
individuals affected by all forms of the
ectodermal dysplasia syndromes.
31
Acknowledgments
The NFED is indebted to the doctors of the Scientific Advisory Board
and the Board of Directors for volunteering their time and expertise to
help all individuals affected by the ED syndromes.
Scientific
Advisory Board
.
Frank H. Farrington, DDS,
MS
Timothy J. Fete, Sr., MD, MPH
Christopher J. Hartnick, MD
Ronald J. Jorgenson, DDS,
PhD
Richard A. Lewis, MD, MS
Kathleen J. Motil, MD, PhD
Jill K. Powell, MD
Lynette L. Rosser, MSW
Elaine C. Siegfried, MD
Clark M. Stanford, DDS,
PhD
Virginia P. Sybert, MD
Barry Tanner, PhD
32
Board of Directors
Leo J. Burke, DDS
Honorable Jerry F. Costello
Frank H. Farrington, DDS,
MS
David Freestone, MD
Jim Gehrs
Keith S. Geismar
John E. Gilster, DDS
Frank C. Hazzard
Donald V. Huebener, DDS,
MS
Martha L. Hyde, MD
Catherine M. Klingelhoefer
Richard F. Moss
Yvette Mulryan
Kevin Pawlow
Beth Pond
Brian F. Randall
Garrett C. Reuter
Mary K. Richter
Sarah Tevis
Keith Throm
Michael A. Woods
National Foundation for Ectodermal Dysplasias