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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