Three cases seen by a busy dermatologist illustrate how to make a correct diagnosis and direct management for patients affected by these genetically inherited conditions. The ectodermal dysplasias are a diverse group of disorders with more than 250 subtypes distinguished by widely variable defects in the embryonic ectodermal structures, including the hair, nails, teeth and sweat glands. Many classification schemas have developed and evolved over the years — the original purely descriptive, while newer approaches have utilized both clinico-genetic and functional subgroups to help organize these complex conditions. With all of the clinical variability and classification perplexity, how can correctly diagnosis and direct management for your patients affected by these genetically inherited conditions that affect up to 1 in 5,000 to 10,000 people? It’s easier than you think.
Three Cases
Case 1:Young Boy with Facies Similar to his Mother’s (Figure 1) First, a 5-year-old boy and his mother appear in your office. The child has sparse light-colored hair and a decreased number of teeth that the pediatrician called “milk bottle caries;” he also has dry sensitive skin. The mom says her son turns “really red,” with limited perspiration, when outside on a hot day. You also learn that as an infant, the patient had fevers for which the doctors could never find a cause and has been to the pediatrician for cerumen impaction on several occasions. Upon examination, you notice he has dry, diffusely eczematous skin. His nails are normal, but he has conical teeth, and his facial features are notable for a prominent forehead, depressed nasal bridge, periocular hyperpigmentation, recessed small chin, and slightly prominent lips. You notice his mother also has thin, blond hair and facial features that are more subtle, but similar to her son’s facies. What is your patient’s diagnosis? How do you confirm it? How do you treat it? What guidance can you provide? Case 2: Young Woman with ‘Ugly Nails’ Next you enter the room of a 20-year-old woman who has a chief complaint of “ugly nails.” You immediately notice her pale, wiry hair that seems to have a mind of its own. In talking with her, you learn that she is very troubled by her nails, which she reports have always been “funny looking.” She thinks she may have developed a fungal infection after a manicure. She notes she rarely goes to the salon for a haircut, going about once a year. She says she is planning to move back to Canada, where she was born, after she completes college and knows that it will be more difficult to get antifungal medication there due to their socialized healthcare system. As she stands to get on the examination table, you notice she is somewhat short for her age. You notice her hair is coarse and wiry with focal patches of alopecia (Figure 2). Her nails are very thick, dark and hyperconvex with micronychia and no subungual debris (Figure 3). She also has palmoplantar hyperkeratosis. Her teeth are normal. You ask her if she sweats normally, and she says she does. What is your patient’s diagnosis? How do you counsel her? Case 3: Baby Girl with Scalp Erosions, Erythema and Eyelid Fusion You just finished a mound of charts after a busy morning and your nurse stops you in the hallway as you are on your way out. She says the hospital just called and needs you to see a 2-day old baby with possible epidermolysis bullosa or an infection. When you arrive, the baby is in an isolette and anxious-looking parents are at the bedside. You find out this is the couple’s first child, that the mother had regular prenatal care, was healthy, with no illnesses, throughout her pregnancy, and had no history of sexually transmitted diseases. Looking at the baby, you immediately notice erosions covering the surface of her scalp. She is diffusely red with a shiny collodian-like membrane but no blistering (Figure 4). She has a cleft lip but no eclabium or ectropion and that the lateral canthi of both of her eyes appear to have subtle fusion of the eyelids. Her hands and feet are normal aside from the erythema. What is your diagnosis? What can be done for their baby?
Case 1: Diagnosis and Treatment
Diagnosis — Hypohidrotic Ectodermal Dysplasia (HED) For your patient in Case 1 (Figure 1), you astutely appreciate all of the clinical features of the child and his mother. From this, you know this patient has hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, which is the classic ectodermal dysplasia and is the prototype that most physicians think of when they consider this category of disorders. You also know that his mother is likely a carrier for this syndrome. The term hypohidrotic ectodermal dysplasia is the preferred name for this condition, not anhidrotic ectodermal dysplasia, as most individuals with HED can sweat, albeit to a severely limited degree — a symptom that does tend to improve with age. More rarely affected individuals are completely unable to sweat. Clinical Presentation and Etiology In HED, there can be varying degrees of clinical presentation due to incomplete penetrance and lyonization. Female carriers classically have subtle features. The case illustrates the most common inheritance pattern for HED, which is X-linked. HED can less often be inherited as an autosomal dominant (AD) and autosomal recessive (AR) condition. X-linked HED is due to mutations in ectodysplasin (EDAR), a TNF ligand that is a signaling molecule involved in the cell differentiation pathway of NF-kB. The AR and AD types are due to mutations in the ectodysplasin receptor and signal mediator. HED is more difficult to diagnosis in infancy, but the diagnosis is appropriate to consider in infants who are born with “peeling skin” and periorbital hyperpigmentation. These infants are more often fussy due to heat intolerance and often present with fevers of unknown origin. Diagnosis is often made at 6 to 9 months of age due to the failure of tooth eruption or presence of conical teeth. During childhood, most affected children are also recognized to have thin, light, slow-growing hair, along with a significantly reduced ability to sweat causing hyperthermia. Other classic signs are periorbital hyperpigmentation and wrinkling, depressed nasal bridge, thick nasal secretions, cerumen impaction, raspy voice, fragile-appearing and eczematous skin changes. Physical growth, development and intelligence are normal. Management and Support Families should be counseled regarding the genetic nature and management of the condition, which cannot be cured. The family should be congratulated on having a healthy baby, especially if first-time parents. It should be stressed that while this condition may cause them to alter their lives to a degree, their child can live a happy, healthy, relatively normal life with certain precautions. They should be counseled that many of the signs and symptoms can be managed appropriately to improve quality of life and reduce limitations. While hypotrichosis is difficult to address, they should know wigs are an option. The hypohidrosis requires special attention to minimize the consequences of potential overheating. Damp towels or bandanas to the neck, wet T-shirts, spray bottles of water, water bottle fans, and small insulated coolers with ice, bottled water and dampened washcloths are all useful items for families and children to have available. Parents may need to advocate for their children so special accommodations can be utilized at school. It is also important to let families know that many people affected by HED participate in athletics with the appropriate safety measures in place; while swimming is an ideal sport for such patients. Genetics Evaluation A referral that may be appropriate for these patients is for genetics evaluation. This consultation is very useful for genetic counseling and as a source of information for families. Most cases of HED do not require confirmatory genetic testing, as 95% of patients affected by HED have classic X-linked disease, which is often quite obvious based on clinical features. There are no genotype-phenotype correlations in HED. The utility of genetic testing can be to assist in diagnosis when the clinical presentation and inheritance pattern is suggestive but not classic for the diagnosis. Confirmatory testing is also helpful to determine carrier status and for prenatal diagnosis when this may impact family planning issues and decisions. Diagnostic Tests Other helpful diagnostic tests that can be performed by you as a dermatologist are trichograms of pulled hairs, starch iodide testing for palmar sweating and skin biopsies. In one study by Rouse et al,1 it was found that trichogram results, while not sensitive or specific, could help support a diagnosis of HED if there is variable hair shaft thickness, trichorrhexis nodosa or pili torti. This same study also found starch iodide testing to be supportive of the diagnosis if there was minimal to no sweating, although some affected individuals were found to have intense palmar sweating. It was additionally found that scalp or palmar skin biopsies that lacked eccrine structures were diagnostic of HED. On the other hand, if eccrine structures were present in the scalp biopsy, the patient was not likely to be affected by HED. Overall, scalp biopsies were found to be more sensitive than palmar biopsies for making a diagnosis. Referrals Dermatologist. Atopy, including atopic dermatitis, is known to be more common in people affected by HED. Atopic dermatitis is managed as it would be for a person who is not affected by HED, preferably by a dermatologist. Pediatric dentist. Referral to a pediatric dentist is also very important to manage the hypodontia, which can lead to speech, salivary and chewing problems if not addressed. Dentures or other dental appliances can be utilized as early as 3.5 years of age and help maintain normal facial and dental development. Emotional and social support services. Support for these families is also a key to good management. Some may require emotional and social support from a professional in psychology. Another important referral is to the National Foundation for Ectodermal Dysplasias (NFED; www.nfed.org), which provides affected individuals and their families with physical, emotional, social and informational resources. Of significant excitement for scientists, physicians and affected individuals is the very real potential for future gene therapies to correct the manifestation of HED. In the HED mouse model,2 Tabby, the classic phenotypic findings can be rescued by ectodysplasian injection prenatally. Additionally, a HED-affected dog model3 administered postnatal recombinant ectodysplasin developed with normalization of dentition, improved sweating ability and lacrimation, along with decreased eye and airway infections. While this is years from use in humans, the impressive success seen in animal models offers future hope.
Case 2: Diagnosis and Treatment
Diagnosis — Hidrotic Ectodermal Dysplasia (Figures 2 and 3) Another patient with an ectodermal dysplasia in the same day?!?! But, you are correct in your assumption that the patient in case 2 has hidrotic ectodermal dysplasia, also known as Clouston syndrome. This ectodermal dysplasia syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expressivity. The mutation is found in the GJB6 gene, which encodes connexin-30. Clinical Presentation and Etiology The patient typifies many of the common findings in hidrotic ectodermal dysplasia, including French-Canadian ancestry, along with her hair and nail changes without the presence of associated teeth or sweating abnormalities. The hair findings in hidrotic ectodermal dysplasia can be quite variable and range from fine, brittle, slow-growing hair that can be unruly to patchy or total alopecia. There can also be sparse to absent eyebrows, eyelashes, axillary hair and pubic hair. The nails are classically small, thick and discolored with severe onychodystrophy and occasional onycholysis. The skin can also reveal palmoplantar hyperkeratosis, as well as hyperpigmentation of the axillae, elbows, knuckles, areolae and pubic area. Additionally, affected individuals can have short stature, as well as ophthalmologic involvement, including cataracts, photophobia, strabismus, conjunctivitis and blepharitis. Management and Support Good news — You share with the patient that she does not require a prescription for any medications, that she has normal teeth and sweating ability, and is otherwise healthy. Bad news — The unfortunate news you have to share is that these changes are permanent and that there are no available treatments that are routinely effective to treat her hair, nail or skin changes. Topical medications with salicylic and/or lactic acid have been tried to treat the hyperkeratosis and to flatten the nails, but are not highly efficacious. In addition, the patient needs to know 50% of her children may be affected. Referrals — The patient would benefit from a referral to the NFED and patient education that focuses on the positive aspects of this condition. It is advisable to have the patient seen by an ophthalmologist due to the associated ocular manifestations that can occur. As genetic testing is not necessary for this condition, you are certainly qualified to share this information with the patient if you desire. However, if you don’t want to share the bad news that 50% of her children may be affected, you can also refer her to a geneticist.
Case 3: Diagnosis and Treatment
Diagnosis — Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome (Figure 4) Now considering that third patient, you remember that scalp erosions at birth are highly suggestive, almost pathognomonic, for ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, which is caused by mutations in gene p63. Clinical Presentation and Management Your suspicion of this condition is also supported by the presence of her ankyloblepharon, which can present as intrapalpebral strands of tissue, or incomplete to complete fusion of the eyelids. This is often a subtle feature and spontaneous lysis can happen before birth or during the birthing process. Therefore, absence of ankyloblepharon does not rule out this diagnostic consideration. Cutaneous features — The diagnosis is also supported by the presence of congenital erythroderma with a collodian-like membrane, which is a common finding in these infants, and may be associated with more widespread erosions. This often leads many to consider a diagnosis of epidermolysis bullosa. The lack of vesicles or bullae makes this consideration less likely. Ichthyosisform scaling can also accompany these diffuse skin changes with congenital ichthyosis often considered in the differential diagnosis. The absence of ectropion or eclabium argues against this group of conditions. While erosions, with associated crusting, granulation tissue and secondary infection, are most often found on the scalp, the palms and soles are also commonly affected. The erosions may even be more extensive and involve the entire skin surface. When severe, the erosions can be life-threatening, and this manifestation of AEC syndrome is the most challenging aspect to manage. Scalp erosions often lead to scarring alopecia, but not in all patients. Additional cutaneous findings include progressive pigmentary changes, variable hypohidrosis and dystrophic nails. Additional features — Patients have a typical facies with maxillary hypoplasia, broadened nasal root and cleft lip and/or palate. Other common hair changes include sparse, wiry hair with an uncombable hair phenotype. Other less common findings include supernumerary nipples, hypospadia and micropenis. Limb defects, which help to differentiate AEC syndrome from ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, can also be seen. These, when present, are less severe than in EEC syndrome, but syndactyly is quite common and more pronounced limb defects have been appreciated in AEC-affected patients. Therefore, the presence of limb defects does not rule out a diagnosis of AEC syndrome. Fortunately, intelligence in these individuals is normal and most affected individuals have a normal life expectancy. Newborn care — Supportive care with a high suspicion for secondary infection is the most important in the newborn period. Gentle wound care is best, as aggressive measures are uniformly met with failure and an overall worse outcome. Referrals — In addition to social service support and patient education, consultation with specialists including an ophthalmologist, dentist and otolaryngologist may be needed for other conditions that are commonly present, such as conjunctivitis and blepharitis, conductive hearing loss, and hypodontia. The understanding of this autosomal dominant disorder is increasing, as is the knowledge regarding the causative gene, p63. Hopefully the future holds therapies that are not just supportive and targeted at symptoms, but curative.
Conclusion
Regardless of your clinical acumen for making a definitive diagnosis in these sometimes difficult cases, it is helpful to categorize these conditions within the spectrum of ectodermal dysplasias. This will be a starting point for making referrals and managing symptoms, as well as providing anticipatory guidance to your patients and their families. It will also help you provide your support and allow you to direct these patients to the NFED, which will undoubtedly provide a wonderful resource and support network for these affected individuals and their families. Dr. Bree is an Assistant Professor of Dermatology and Pediatrics at Baylor College of Medicine and practices pediatric dermatology at Texas Children's Hospital in Houston, TX. Disclosure: Dr. Doctor has no conflict of interest with any material presented in this month’s column.
Three cases seen by a busy dermatologist illustrate how to make a correct diagnosis and direct management for patients affected by these genetically inherited conditions. The ectodermal dysplasias are a diverse group of disorders with more than 250 subtypes distinguished by widely variable defects in the embryonic ectodermal structures, including the hair, nails, teeth and sweat glands. Many classification schemas have developed and evolved over the years — the original purely descriptive, while newer approaches have utilized both clinico-genetic and functional subgroups to help organize these complex conditions. With all of the clinical variability and classification perplexity, how can correctly diagnosis and direct management for your patients affected by these genetically inherited conditions that affect up to 1 in 5,000 to 10,000 people? It’s easier than you think.
Three Cases
Case 1:Young Boy with Facies Similar to his Mother’s (Figure 1) First, a 5-year-old boy and his mother appear in your office. The child has sparse light-colored hair and a decreased number of teeth that the pediatrician called “milk bottle caries;” he also has dry sensitive skin. The mom says her son turns “really red,” with limited perspiration, when outside on a hot day. You also learn that as an infant, the patient had fevers for which the doctors could never find a cause and has been to the pediatrician for cerumen impaction on several occasions. Upon examination, you notice he has dry, diffusely eczematous skin. His nails are normal, but he has conical teeth, and his facial features are notable for a prominent forehead, depressed nasal bridge, periocular hyperpigmentation, recessed small chin, and slightly prominent lips. You notice his mother also has thin, blond hair and facial features that are more subtle, but similar to her son’s facies. What is your patient’s diagnosis? How do you confirm it? How do you treat it? What guidance can you provide? Case 2: Young Woman with ‘Ugly Nails’ Next you enter the room of a 20-year-old woman who has a chief complaint of “ugly nails.” You immediately notice her pale, wiry hair that seems to have a mind of its own. In talking with her, you learn that she is very troubled by her nails, which she reports have always been “funny looking.” She thinks she may have developed a fungal infection after a manicure. She notes she rarely goes to the salon for a haircut, going about once a year. She says she is planning to move back to Canada, where she was born, after she completes college and knows that it will be more difficult to get antifungal medication there due to their socialized healthcare system. As she stands to get on the examination table, you notice she is somewhat short for her age. You notice her hair is coarse and wiry with focal patches of alopecia (Figure 2). Her nails are very thick, dark and hyperconvex with micronychia and no subungual debris (Figure 3). She also has palmoplantar hyperkeratosis. Her teeth are normal. You ask her if she sweats normally, and she says she does. What is your patient’s diagnosis? How do you counsel her? Case 3: Baby Girl with Scalp Erosions, Erythema and Eyelid Fusion You just finished a mound of charts after a busy morning and your nurse stops you in the hallway as you are on your way out. She says the hospital just called and needs you to see a 2-day old baby with possible epidermolysis bullosa or an infection. When you arrive, the baby is in an isolette and anxious-looking parents are at the bedside. You find out this is the couple’s first child, that the mother had regular prenatal care, was healthy, with no illnesses, throughout her pregnancy, and had no history of sexually transmitted diseases. Looking at the baby, you immediately notice erosions covering the surface of her scalp. She is diffusely red with a shiny collodian-like membrane but no blistering (Figure 4). She has a cleft lip but no eclabium or ectropion and that the lateral canthi of both of her eyes appear to have subtle fusion of the eyelids. Her hands and feet are normal aside from the erythema. What is your diagnosis? What can be done for their baby?
Case 1: Diagnosis and Treatment
Diagnosis — Hypohidrotic Ectodermal Dysplasia (HED) For your patient in Case 1 (Figure 1), you astutely appreciate all of the clinical features of the child and his mother. From this, you know this patient has hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, which is the classic ectodermal dysplasia and is the prototype that most physicians think of when they consider this category of disorders. You also know that his mother is likely a carrier for this syndrome. The term hypohidrotic ectodermal dysplasia is the preferred name for this condition, not anhidrotic ectodermal dysplasia, as most individuals with HED can sweat, albeit to a severely limited degree — a symptom that does tend to improve with age. More rarely affected individuals are completely unable to sweat. Clinical Presentation and Etiology In HED, there can be varying degrees of clinical presentation due to incomplete penetrance and lyonization. Female carriers classically have subtle features. The case illustrates the most common inheritance pattern for HED, which is X-linked. HED can less often be inherited as an autosomal dominant (AD) and autosomal recessive (AR) condition. X-linked HED is due to mutations in ectodysplasin (EDAR), a TNF ligand that is a signaling molecule involved in the cell differentiation pathway of NF-kB. The AR and AD types are due to mutations in the ectodysplasin receptor and signal mediator. HED is more difficult to diagnosis in infancy, but the diagnosis is appropriate to consider in infants who are born with “peeling skin” and periorbital hyperpigmentation. These infants are more often fussy due to heat intolerance and often present with fevers of unknown origin. Diagnosis is often made at 6 to 9 months of age due to the failure of tooth eruption or presence of conical teeth. During childhood, most affected children are also recognized to have thin, light, slow-growing hair, along with a significantly reduced ability to sweat causing hyperthermia. Other classic signs are periorbital hyperpigmentation and wrinkling, depressed nasal bridge, thick nasal secretions, cerumen impaction, raspy voice, fragile-appearing and eczematous skin changes. Physical growth, development and intelligence are normal. Management and Support Families should be counseled regarding the genetic nature and management of the condition, which cannot be cured. The family should be congratulated on having a healthy baby, especially if first-time parents. It should be stressed that while this condition may cause them to alter their lives to a degree, their child can live a happy, healthy, relatively normal life with certain precautions. They should be counseled that many of the signs and symptoms can be managed appropriately to improve quality of life and reduce limitations. While hypotrichosis is difficult to address, they should know wigs are an option. The hypohidrosis requires special attention to minimize the consequences of potential overheating. Damp towels or bandanas to the neck, wet T-shirts, spray bottles of water, water bottle fans, and small insulated coolers with ice, bottled water and dampened washcloths are all useful items for families and children to have available. Parents may need to advocate for their children so special accommodations can be utilized at school. It is also important to let families know that many people affected by HED participate in athletics with the appropriate safety measures in place; while swimming is an ideal sport for such patients. Genetics Evaluation A referral that may be appropriate for these patients is for genetics evaluation. This consultation is very useful for genetic counseling and as a source of information for families. Most cases of HED do not require confirmatory genetic testing, as 95% of patients affected by HED have classic X-linked disease, which is often quite obvious based on clinical features. There are no genotype-phenotype correlations in HED. The utility of genetic testing can be to assist in diagnosis when the clinical presentation and inheritance pattern is suggestive but not classic for the diagnosis. Confirmatory testing is also helpful to determine carrier status and for prenatal diagnosis when this may impact family planning issues and decisions. Diagnostic Tests Other helpful diagnostic tests that can be performed by you as a dermatologist are trichograms of pulled hairs, starch iodide testing for palmar sweating and skin biopsies. In one study by Rouse et al,1 it was found that trichogram results, while not sensitive or specific, could help support a diagnosis of HED if there is variable hair shaft thickness, trichorrhexis nodosa or pili torti. This same study also found starch iodide testing to be supportive of the diagnosis if there was minimal to no sweating, although some affected individuals were found to have intense palmar sweating. It was additionally found that scalp or palmar skin biopsies that lacked eccrine structures were diagnostic of HED. On the other hand, if eccrine structures were present in the scalp biopsy, the patient was not likely to be affected by HED. Overall, scalp biopsies were found to be more sensitive than palmar biopsies for making a diagnosis. Referrals Dermatologist. Atopy, including atopic dermatitis, is known to be more common in people affected by HED. Atopic dermatitis is managed as it would be for a person who is not affected by HED, preferably by a dermatologist. Pediatric dentist. Referral to a pediatric dentist is also very important to manage the hypodontia, which can lead to speech, salivary and chewing problems if not addressed. Dentures or other dental appliances can be utilized as early as 3.5 years of age and help maintain normal facial and dental development. Emotional and social support services. Support for these families is also a key to good management. Some may require emotional and social support from a professional in psychology. Another important referral is to the National Foundation for Ectodermal Dysplasias (NFED; www.nfed.org), which provides affected individuals and their families with physical, emotional, social and informational resources. Of significant excitement for scientists, physicians and affected individuals is the very real potential for future gene therapies to correct the manifestation of HED. In the HED mouse model,2 Tabby, the classic phenotypic findings can be rescued by ectodysplasian injection prenatally. Additionally, a HED-affected dog model3 administered postnatal recombinant ectodysplasin developed with normalization of dentition, improved sweating ability and lacrimation, along with decreased eye and airway infections. While this is years from use in humans, the impressive success seen in animal models offers future hope.
Case 2: Diagnosis and Treatment
Diagnosis — Hidrotic Ectodermal Dysplasia (Figures 2 and 3) Another patient with an ectodermal dysplasia in the same day?!?! But, you are correct in your assumption that the patient in case 2 has hidrotic ectodermal dysplasia, also known as Clouston syndrome. This ectodermal dysplasia syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expressivity. The mutation is found in the GJB6 gene, which encodes connexin-30. Clinical Presentation and Etiology The patient typifies many of the common findings in hidrotic ectodermal dysplasia, including French-Canadian ancestry, along with her hair and nail changes without the presence of associated teeth or sweating abnormalities. The hair findings in hidrotic ectodermal dysplasia can be quite variable and range from fine, brittle, slow-growing hair that can be unruly to patchy or total alopecia. There can also be sparse to absent eyebrows, eyelashes, axillary hair and pubic hair. The nails are classically small, thick and discolored with severe onychodystrophy and occasional onycholysis. The skin can also reveal palmoplantar hyperkeratosis, as well as hyperpigmentation of the axillae, elbows, knuckles, areolae and pubic area. Additionally, affected individuals can have short stature, as well as ophthalmologic involvement, including cataracts, photophobia, strabismus, conjunctivitis and blepharitis. Management and Support Good news — You share with the patient that she does not require a prescription for any medications, that she has normal teeth and sweating ability, and is otherwise healthy. Bad news — The unfortunate news you have to share is that these changes are permanent and that there are no available treatments that are routinely effective to treat her hair, nail or skin changes. Topical medications with salicylic and/or lactic acid have been tried to treat the hyperkeratosis and to flatten the nails, but are not highly efficacious. In addition, the patient needs to know 50% of her children may be affected. Referrals — The patient would benefit from a referral to the NFED and patient education that focuses on the positive aspects of this condition. It is advisable to have the patient seen by an ophthalmologist due to the associated ocular manifestations that can occur. As genetic testing is not necessary for this condition, you are certainly qualified to share this information with the patient if you desire. However, if you don’t want to share the bad news that 50% of her children may be affected, you can also refer her to a geneticist.
Case 3: Diagnosis and Treatment
Diagnosis — Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome (Figure 4) Now considering that third patient, you remember that scalp erosions at birth are highly suggestive, almost pathognomonic, for ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, which is caused by mutations in gene p63. Clinical Presentation and Management Your suspicion of this condition is also supported by the presence of her ankyloblepharon, which can present as intrapalpebral strands of tissue, or incomplete to complete fusion of the eyelids. This is often a subtle feature and spontaneous lysis can happen before birth or during the birthing process. Therefore, absence of ankyloblepharon does not rule out this diagnostic consideration. Cutaneous features — The diagnosis is also supported by the presence of congenital erythroderma with a collodian-like membrane, which is a common finding in these infants, and may be associated with more widespread erosions. This often leads many to consider a diagnosis of epidermolysis bullosa. The lack of vesicles or bullae makes this consideration less likely. Ichthyosisform scaling can also accompany these diffuse skin changes with congenital ichthyosis often considered in the differential diagnosis. The absence of ectropion or eclabium argues against this group of conditions. While erosions, with associated crusting, granulation tissue and secondary infection, are most often found on the scalp, the palms and soles are also commonly affected. The erosions may even be more extensive and involve the entire skin surface. When severe, the erosions can be life-threatening, and this manifestation of AEC syndrome is the most challenging aspect to manage. Scalp erosions often lead to scarring alopecia, but not in all patients. Additional cutaneous findings include progressive pigmentary changes, variable hypohidrosis and dystrophic nails. Additional features — Patients have a typical facies with maxillary hypoplasia, broadened nasal root and cleft lip and/or palate. Other common hair changes include sparse, wiry hair with an uncombable hair phenotype. Other less common findings include supernumerary nipples, hypospadia and micropenis. Limb defects, which help to differentiate AEC syndrome from ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, can also be seen. These, when present, are less severe than in EEC syndrome, but syndactyly is quite common and more pronounced limb defects have been appreciated in AEC-affected patients. Therefore, the presence of limb defects does not rule out a diagnosis of AEC syndrome. Fortunately, intelligence in these individuals is normal and most affected individuals have a normal life expectancy. Newborn care — Supportive care with a high suspicion for secondary infection is the most important in the newborn period. Gentle wound care is best, as aggressive measures are uniformly met with failure and an overall worse outcome. Referrals — In addition to social service support and patient education, consultation with specialists including an ophthalmologist, dentist and otolaryngologist may be needed for other conditions that are commonly present, such as conjunctivitis and blepharitis, conductive hearing loss, and hypodontia. The understanding of this autosomal dominant disorder is increasing, as is the knowledge regarding the causative gene, p63. Hopefully the future holds therapies that are not just supportive and targeted at symptoms, but curative.
Conclusion
Regardless of your clinical acumen for making a definitive diagnosis in these sometimes difficult cases, it is helpful to categorize these conditions within the spectrum of ectodermal dysplasias. This will be a starting point for making referrals and managing symptoms, as well as providing anticipatory guidance to your patients and their families. It will also help you provide your support and allow you to direct these patients to the NFED, which will undoubtedly provide a wonderful resource and support network for these affected individuals and their families. Dr. Bree is an Assistant Professor of Dermatology and Pediatrics at Baylor College of Medicine and practices pediatric dermatology at Texas Children's Hospital in Houston, TX. Disclosure: Dr. Doctor has no conflict of interest with any material presented in this month’s column.
Three cases seen by a busy dermatologist illustrate how to make a correct diagnosis and direct management for patients affected by these genetically inherited conditions. The ectodermal dysplasias are a diverse group of disorders with more than 250 subtypes distinguished by widely variable defects in the embryonic ectodermal structures, including the hair, nails, teeth and sweat glands. Many classification schemas have developed and evolved over the years — the original purely descriptive, while newer approaches have utilized both clinico-genetic and functional subgroups to help organize these complex conditions. With all of the clinical variability and classification perplexity, how can correctly diagnosis and direct management for your patients affected by these genetically inherited conditions that affect up to 1 in 5,000 to 10,000 people? It’s easier than you think.
Three Cases
Case 1:Young Boy with Facies Similar to his Mother’s (Figure 1) First, a 5-year-old boy and his mother appear in your office. The child has sparse light-colored hair and a decreased number of teeth that the pediatrician called “milk bottle caries;” he also has dry sensitive skin. The mom says her son turns “really red,” with limited perspiration, when outside on a hot day. You also learn that as an infant, the patient had fevers for which the doctors could never find a cause and has been to the pediatrician for cerumen impaction on several occasions. Upon examination, you notice he has dry, diffusely eczematous skin. His nails are normal, but he has conical teeth, and his facial features are notable for a prominent forehead, depressed nasal bridge, periocular hyperpigmentation, recessed small chin, and slightly prominent lips. You notice his mother also has thin, blond hair and facial features that are more subtle, but similar to her son’s facies. What is your patient’s diagnosis? How do you confirm it? How do you treat it? What guidance can you provide? Case 2: Young Woman with ‘Ugly Nails’ Next you enter the room of a 20-year-old woman who has a chief complaint of “ugly nails.” You immediately notice her pale, wiry hair that seems to have a mind of its own. In talking with her, you learn that she is very troubled by her nails, which she reports have always been “funny looking.” She thinks she may have developed a fungal infection after a manicure. She notes she rarely goes to the salon for a haircut, going about once a year. She says she is planning to move back to Canada, where she was born, after she completes college and knows that it will be more difficult to get antifungal medication there due to their socialized healthcare system. As she stands to get on the examination table, you notice she is somewhat short for her age. You notice her hair is coarse and wiry with focal patches of alopecia (Figure 2). Her nails are very thick, dark and hyperconvex with micronychia and no subungual debris (Figure 3). She also has palmoplantar hyperkeratosis. Her teeth are normal. You ask her if she sweats normally, and she says she does. What is your patient’s diagnosis? How do you counsel her? Case 3: Baby Girl with Scalp Erosions, Erythema and Eyelid Fusion You just finished a mound of charts after a busy morning and your nurse stops you in the hallway as you are on your way out. She says the hospital just called and needs you to see a 2-day old baby with possible epidermolysis bullosa or an infection. When you arrive, the baby is in an isolette and anxious-looking parents are at the bedside. You find out this is the couple’s first child, that the mother had regular prenatal care, was healthy, with no illnesses, throughout her pregnancy, and had no history of sexually transmitted diseases. Looking at the baby, you immediately notice erosions covering the surface of her scalp. She is diffusely red with a shiny collodian-like membrane but no blistering (Figure 4). She has a cleft lip but no eclabium or ectropion and that the lateral canthi of both of her eyes appear to have subtle fusion of the eyelids. Her hands and feet are normal aside from the erythema. What is your diagnosis? What can be done for their baby?
Case 1: Diagnosis and Treatment
Diagnosis — Hypohidrotic Ectodermal Dysplasia (HED) For your patient in Case 1 (Figure 1), you astutely appreciate all of the clinical features of the child and his mother. From this, you know this patient has hypohidrotic ectodermal dysplasia (HED), also known as Christ-Siemens-Touraine syndrome, which is the classic ectodermal dysplasia and is the prototype that most physicians think of when they consider this category of disorders. You also know that his mother is likely a carrier for this syndrome. The term hypohidrotic ectodermal dysplasia is the preferred name for this condition, not anhidrotic ectodermal dysplasia, as most individuals with HED can sweat, albeit to a severely limited degree — a symptom that does tend to improve with age. More rarely affected individuals are completely unable to sweat. Clinical Presentation and Etiology In HED, there can be varying degrees of clinical presentation due to incomplete penetrance and lyonization. Female carriers classically have subtle features. The case illustrates the most common inheritance pattern for HED, which is X-linked. HED can less often be inherited as an autosomal dominant (AD) and autosomal recessive (AR) condition. X-linked HED is due to mutations in ectodysplasin (EDAR), a TNF ligand that is a signaling molecule involved in the cell differentiation pathway of NF-kB. The AR and AD types are due to mutations in the ectodysplasin receptor and signal mediator. HED is more difficult to diagnosis in infancy, but the diagnosis is appropriate to consider in infants who are born with “peeling skin” and periorbital hyperpigmentation. These infants are more often fussy due to heat intolerance and often present with fevers of unknown origin. Diagnosis is often made at 6 to 9 months of age due to the failure of tooth eruption or presence of conical teeth. During childhood, most affected children are also recognized to have thin, light, slow-growing hair, along with a significantly reduced ability to sweat causing hyperthermia. Other classic signs are periorbital hyperpigmentation and wrinkling, depressed nasal bridge, thick nasal secretions, cerumen impaction, raspy voice, fragile-appearing and eczematous skin changes. Physical growth, development and intelligence are normal. Management and Support Families should be counseled regarding the genetic nature and management of the condition, which cannot be cured. The family should be congratulated on having a healthy baby, especially if first-time parents. It should be stressed that while this condition may cause them to alter their lives to a degree, their child can live a happy, healthy, relatively normal life with certain precautions. They should be counseled that many of the signs and symptoms can be managed appropriately to improve quality of life and reduce limitations. While hypotrichosis is difficult to address, they should know wigs are an option. The hypohidrosis requires special attention to minimize the consequences of potential overheating. Damp towels or bandanas to the neck, wet T-shirts, spray bottles of water, water bottle fans, and small insulated coolers with ice, bottled water and dampened washcloths are all useful items for families and children to have available. Parents may need to advocate for their children so special accommodations can be utilized at school. It is also important to let families know that many people affected by HED participate in athletics with the appropriate safety measures in place; while swimming is an ideal sport for such patients. Genetics Evaluation A referral that may be appropriate for these patients is for genetics evaluation. This consultation is very useful for genetic counseling and as a source of information for families. Most cases of HED do not require confirmatory genetic testing, as 95% of patients affected by HED have classic X-linked disease, which is often quite obvious based on clinical features. There are no genotype-phenotype correlations in HED. The utility of genetic testing can be to assist in diagnosis when the clinical presentation and inheritance pattern is suggestive but not classic for the diagnosis. Confirmatory testing is also helpful to determine carrier status and for prenatal diagnosis when this may impact family planning issues and decisions. Diagnostic Tests Other helpful diagnostic tests that can be performed by you as a dermatologist are trichograms of pulled hairs, starch iodide testing for palmar sweating and skin biopsies. In one study by Rouse et al,1 it was found that trichogram results, while not sensitive or specific, could help support a diagnosis of HED if there is variable hair shaft thickness, trichorrhexis nodosa or pili torti. This same study also found starch iodide testing to be supportive of the diagnosis if there was minimal to no sweating, although some affected individuals were found to have intense palmar sweating. It was additionally found that scalp or palmar skin biopsies that lacked eccrine structures were diagnostic of HED. On the other hand, if eccrine structures were present in the scalp biopsy, the patient was not likely to be affected by HED. Overall, scalp biopsies were found to be more sensitive than palmar biopsies for making a diagnosis. Referrals Dermatologist. Atopy, including atopic dermatitis, is known to be more common in people affected by HED. Atopic dermatitis is managed as it would be for a person who is not affected by HED, preferably by a dermatologist. Pediatric dentist. Referral to a pediatric dentist is also very important to manage the hypodontia, which can lead to speech, salivary and chewing problems if not addressed. Dentures or other dental appliances can be utilized as early as 3.5 years of age and help maintain normal facial and dental development. Emotional and social support services. Support for these families is also a key to good management. Some may require emotional and social support from a professional in psychology. Another important referral is to the National Foundation for Ectodermal Dysplasias (NFED; www.nfed.org), which provides affected individuals and their families with physical, emotional, social and informational resources. Of significant excitement for scientists, physicians and affected individuals is the very real potential for future gene therapies to correct the manifestation of HED. In the HED mouse model,2 Tabby, the classic phenotypic findings can be rescued by ectodysplasian injection prenatally. Additionally, a HED-affected dog model3 administered postnatal recombinant ectodysplasin developed with normalization of dentition, improved sweating ability and lacrimation, along with decreased eye and airway infections. While this is years from use in humans, the impressive success seen in animal models offers future hope.
Case 2: Diagnosis and Treatment
Diagnosis — Hidrotic Ectodermal Dysplasia (Figures 2 and 3) Another patient with an ectodermal dysplasia in the same day?!?! But, you are correct in your assumption that the patient in case 2 has hidrotic ectodermal dysplasia, also known as Clouston syndrome. This ectodermal dysplasia syndrome is inherited in an autosomal dominant fashion with complete penetrance and variable expressivity. The mutation is found in the GJB6 gene, which encodes connexin-30. Clinical Presentation and Etiology The patient typifies many of the common findings in hidrotic ectodermal dysplasia, including French-Canadian ancestry, along with her hair and nail changes without the presence of associated teeth or sweating abnormalities. The hair findings in hidrotic ectodermal dysplasia can be quite variable and range from fine, brittle, slow-growing hair that can be unruly to patchy or total alopecia. There can also be sparse to absent eyebrows, eyelashes, axillary hair and pubic hair. The nails are classically small, thick and discolored with severe onychodystrophy and occasional onycholysis. The skin can also reveal palmoplantar hyperkeratosis, as well as hyperpigmentation of the axillae, elbows, knuckles, areolae and pubic area. Additionally, affected individuals can have short stature, as well as ophthalmologic involvement, including cataracts, photophobia, strabismus, conjunctivitis and blepharitis. Management and Support Good news — You share with the patient that she does not require a prescription for any medications, that she has normal teeth and sweating ability, and is otherwise healthy. Bad news — The unfortunate news you have to share is that these changes are permanent and that there are no available treatments that are routinely effective to treat her hair, nail or skin changes. Topical medications with salicylic and/or lactic acid have been tried to treat the hyperkeratosis and to flatten the nails, but are not highly efficacious. In addition, the patient needs to know 50% of her children may be affected. Referrals — The patient would benefit from a referral to the NFED and patient education that focuses on the positive aspects of this condition. It is advisable to have the patient seen by an ophthalmologist due to the associated ocular manifestations that can occur. As genetic testing is not necessary for this condition, you are certainly qualified to share this information with the patient if you desire. However, if you don’t want to share the bad news that 50% of her children may be affected, you can also refer her to a geneticist.
Case 3: Diagnosis and Treatment
Diagnosis — Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome (Figure 4) Now considering that third patient, you remember that scalp erosions at birth are highly suggestive, almost pathognomonic, for ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, also known as Hay-Wells syndrome, which is caused by mutations in gene p63. Clinical Presentation and Management Your suspicion of this condition is also supported by the presence of her ankyloblepharon, which can present as intrapalpebral strands of tissue, or incomplete to complete fusion of the eyelids. This is often a subtle feature and spontaneous lysis can happen before birth or during the birthing process. Therefore, absence of ankyloblepharon does not rule out this diagnostic consideration. Cutaneous features — The diagnosis is also supported by the presence of congenital erythroderma with a collodian-like membrane, which is a common finding in these infants, and may be associated with more widespread erosions. This often leads many to consider a diagnosis of epidermolysis bullosa. The lack of vesicles or bullae makes this consideration less likely. Ichthyosisform scaling can also accompany these diffuse skin changes with congenital ichthyosis often considered in the differential diagnosis. The absence of ectropion or eclabium argues against this group of conditions. While erosions, with associated crusting, granulation tissue and secondary infection, are most often found on the scalp, the palms and soles are also commonly affected. The erosions may even be more extensive and involve the entire skin surface. When severe, the erosions can be life-threatening, and this manifestation of AEC syndrome is the most challenging aspect to manage. Scalp erosions often lead to scarring alopecia, but not in all patients. Additional cutaneous findings include progressive pigmentary changes, variable hypohidrosis and dystrophic nails. Additional features — Patients have a typical facies with maxillary hypoplasia, broadened nasal root and cleft lip and/or palate. Other common hair changes include sparse, wiry hair with an uncombable hair phenotype. Other less common findings include supernumerary nipples, hypospadia and micropenis. Limb defects, which help to differentiate AEC syndrome from ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, can also be seen. These, when present, are less severe than in EEC syndrome, but syndactyly is quite common and more pronounced limb defects have been appreciated in AEC-affected patients. Therefore, the presence of limb defects does not rule out a diagnosis of AEC syndrome. Fortunately, intelligence in these individuals is normal and most affected individuals have a normal life expectancy. Newborn care — Supportive care with a high suspicion for secondary infection is the most important in the newborn period. Gentle wound care is best, as aggressive measures are uniformly met with failure and an overall worse outcome. Referrals — In addition to social service support and patient education, consultation with specialists including an ophthalmologist, dentist and otolaryngologist may be needed for other conditions that are commonly present, such as conjunctivitis and blepharitis, conductive hearing loss, and hypodontia. The understanding of this autosomal dominant disorder is increasing, as is the knowledge regarding the causative gene, p63. Hopefully the future holds therapies that are not just supportive and targeted at symptoms, but curative.
Conclusion
Regardless of your clinical acumen for making a definitive diagnosis in these sometimes difficult cases, it is helpful to categorize these conditions within the spectrum of ectodermal dysplasias. This will be a starting point for making referrals and managing symptoms, as well as providing anticipatory guidance to your patients and their families. It will also help you provide your support and allow you to direct these patients to the NFED, which will undoubtedly provide a wonderful resource and support network for these affected individuals and their families. Dr. Bree is an Assistant Professor of Dermatology and Pediatrics at Baylor College of Medicine and practices pediatric dermatology at Texas Children's Hospital in Houston, TX. Disclosure: Dr. Doctor has no conflict of interest with any material presented in this month’s column.
