Are You Confident of the Diagnosis?

p63 disorders are allelic and include ankyloblepharon-ectodermal defects-clefting (AEC) syndrome, ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, split hand/foot malformation, acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, limb-mammary syndrome, Rapp Hodgkin syndrome, and nonsyndromic orafacial clefting.

AEC syndrome is also known as Hay-Wells syndrome. Rapp Hodgkin is now felt to represent a variable manifestation of AEC and is not considered a separate disease entity

What you should be alert for in the history

AEC syndrome

  • Neonatal erythema

  • History of skin erosions, especially of the scalp

  • Recurrent skin infections

  • Palmoplantar changes (superficial erosions with overlying hyperkeratosis)

  • Pigmentary alteration of the skin (mask-like facial hypopgimentation that improves with age in dark-skinned individuals and progressive flexural reticulate hyperpigmentation in light-skinned individuals) of the skin

  • Ankyloblepharon at birth

  • Dry eyes with irritation

  • Cleft lip and/or palate

  • Hearing loss

  • Speech delay

  • Nail changes (most commonly pseudoptyerigium, frayed distal edge with resorption of the nail plate and hyperconvexity)

  • Abnormal and decreased number of teeth

  • Subjective decreased sweating with symptoms of overheating

  • Feeding difficulties and poor weight gain

  • Need for a gastrostomy tube

EEC syndrome

  • Congenital hand and foot malformations

  • Cleft lip and/or palate

  • Eye problems with dry eyes, irritation, photophobia and recurrent infections

  • Hearing loss

  • Urogenital problems

  • Mammary gland/nipple changes (hypoplasia or supernummerary

  • Subjective decreased sweating

Characteristic findings on physical examination

AEC syndrome

  • Facial features with maxillary hypoplasia, small mandible, broad nasal root, hypoplastic alae nasi, thin vermillion border, short philtrum (Figure 1)

    This child has characteristic facies seen in AEC syndrome including thin upper lip, short philtrum, evidence of repaired cleft lip, broad nasal bridge as well as light, wiry hair with uncombable hair phenotype. (Courtesy of the National Foundation for Ectodermal Dysplasias)

  • Ankyloblepharon at birth

  • Lacrimal duct atresia with resultant xerophthalmia, conjuctivitis and blepharitis

  • Congenital erythroderma with diffuse skin erosions

  • Scalp erosions

  • Scarring alopecia secondary to extensive scalp erosions

  • Atrophic, cribiform and stellate scarring of the skin often in a shawl distribution

  • Masked hypopigmentation in dark-skinned individuals (Figure 2)

    This infant has characteristic facial hypopigmentation seen in African-American infants with AEC syndrome that typically improves with age. (Courtesy of the National Foundation for Ectodermal Dysplasias)

  • Reticulate hyperpigmentation especially of the intertriginous areas in light skinned individuals

  • Hair is fair, brittle, coarse and wiry with patchy alopeia (Figure 3)

    These two unrelated females with AEC reveal different aspects of the syndrome. The younger girl had significant scalp erosions leading to scarring alopecia, while the teenager who did not have significant scalp erosions has light, wiry hair typical of AEC. Also note the younger girl is wearing hearing aids as she has associated hearing loss related to AEC. (Courtesy of the National Foundation for Ectodermal Dysplasias)

  • Sparse eyebrows and eyelashes

  • Nail abnormalities are variable (micronychia, hyperconvexity, thickened nail plates, frayed distal edge with nail plate resorption, pseudopterygium formation)

  • Palmoplantar changes including erosions, hyperkeratosis and effaced dermatoglyphics

  • Cleft lip and/or palate

  • Conductive hearing loss

  • Hypodontia

  • Limb anomalies including syndactyly

  • Supernumerary nipples

  • Hypospadias

EEC syndrome

  • Ectrodactyly of the hands and feet (Figure 4)

    These EEC-affected individuals show the variable ectrodactyly of the hands seen in this autosomal dominant condition. (Courtesy of the National Foundation for Ectodermal Dysplasias)

  • Cleft lip and/or palate

  • Dry skin

  • Erosions of the skin are very rare

  • Thickening of the palmar and plantar skin

  • Coarse, dry, light colored sparse hair or may be normal

  • Sparse secondary sexual hair

  • Sparse eyebrows and eyelashes

  • Lacrimal duct atresia

  • Blepharitis and dacrocystitis

  • Corneal scarring

  • Hypodontia

  • Conductive hearing loss

  • Bladder diverticula

  • Ureterocele and vesicoureteral reflux

  • Hydronephrosis

  • Renal agenesis or dysplasia

  • Duplicated renal collecting system

  • Hypospadia and micropenis

  • Cryptorchidism

  • Transverse vaginal septum

Expected results of diagnostic studies

AEC syndrome

  • Palmar impressions on starch iodide paper reveal decreased sweating

  • Scanning electron microscopy of the hair reveals flattening with angulation and triangular shape of the hair shaft with canaliculi, pili torti and variable pigmentation including pallor, absence of pigment, bicolored hair and pili annulati

  • Skin biopsy reveals a paucity of eccrine glands and hair follicles, epidermal atrophy variable basilar pigmentation, scattered melanophages in the superficial dermis, and mild perivascular lymphocytic infiltrate

  • Mutational analysis of p63 can confirm the diagnosis and testing is commercially available

EEC syndrome

  • Scanning electron microscopy of the hair reveals longitudinal grooves (pili canaliculi), irregular torsion (pili torti) and focal cuticular defects

  • Mutational analysis of p63 can confirm the diagnosis and testing is commercially available

Diagnosis confirmation

Diagnosis is typically based on the constellation of skin, hair, and nail findings, along with the other congenital malformations. Molecular genetic testing can confirm a diagnosis in question.

AEC syndrome

  • Erosions at birth can be misdiagnosed as epidermolysis bullosa, but there is no actual blistering in AEC as opposed to EB

  • Diffuse erythroderma can be misdiagnosed as a congential ichthyosis but ichthyosis has a true collodion membrane and more significant scaling

  • Aplasia cutis congenita presents with congenital absence of skin but does not have associated malformations such as the cleft lip/palate

  • EEC syndrome although the limb anomalies are unusual and not a prominent feature in AEC syndrome

EEC syndrome

  • Limb-mammary syndrome but there is no associate cleft lip/palate in this condition

  • AEC syndrome although the skin/scalp erosions are unusual and not a prominent feature of EEC syndrome

ADULT (Acro-Dermato-Ungual-Lacrimal-Tooth) syndrome

  • Autosomal dominant

  • Manifested by ectrodactyly or syndactyly; dry, freckled skin, dystrophic nails, lacrimal duct atresia, primary hypodontia and loss of permanent teeth (Figure 5, Figure 6, Figure 7)

Figure 5.

X-Ray image of bony anomalies of ADULT syndrome. (Courtesy of Rhonda E. Schnur, MD)

Figure 6.

Tooth enamel defects in ADULT syndrome. (Courtesy of Rhonda E. Schnur, MD)

Figure 7.

Nail dystrophy in ADULT syndrome. (Courtesy of Rhonda E. Schnur, MD)

Who is at Risk for Developing this Disease?

Both AEC and EEC syndromes are quite rare. Males and females are equally affected due to the autosomal dominant inheritance pattern. There appears to be no racial or ethnic predilection.

What is the Cause of the Disease?
Etiology

Mutations in the p63 gene on chromosome 3q27 leading to defective p63 protein are responsible for both AEC and EEC syndrome.

AEC syndrome is most often associated with missense mutations in the sterile alpha (SAM) domain of p63 although more rare frameshift mutations in the transactivation inhibitory domain of p63 have been noted. EEC syndrome is caused by point mutations in the DNA binding domain of p63 in 95% of cases

Pathophysiology

p63 is a transcription factor expressed as six isoforms. One of the isoforms, deltaNp63alpha, is expressed in the skin and is known to affect barrier formation, terminal differentiation, adhesion, proliferation and basment membrane formation. Disrupted or mutated deltaNp63 alpha leads to perturbed skin function on many levels. Downstream genes are also not properly expressed when p63 is mutated since it is an important transcription factor. p63 is also known to be important in craniofacial and limb formation

Systemic Implications and Complications

Both AEC and EEC syndromes are complex ectodermal dysplasias with involvement of multiple organ systems. Both conditions are associated with a high incidence of cleft lip and/or palate. This is associated with facial dysmorphology, dental anomolies, hearing loss, speech delay, feeding difficulties and failure to thrive.

AEC is associated with skin erosions that can lead to fluid and electolyte imbalance, percutaneous toxicity, secondary infection, sepsis and death in the neonatal period. Therefore this should be managed aggressively with high ambient humidity isolettes, fluid resuscitation and appropriate antimicrobial therapy to reduce the potential motality. Life span is otherwise normal.

EEC is associated with limb defects and genitourinary malformations. Life expectancy is normal.

Treatment Options

Treatment of the erosions in AEC is very challenging and can be frustrating since wound healing is poor. Aggressive wound care managment should be avoided and gentle wound care is advised.

What to avoid

Avoid vigorous/aggressive cleaning.

Avoid keeping the area too moist as this seems to increase the risk of infection.

Avoid debridement and any type of skin grafting procedure as these uniformly fail with increased morbidity and mortality. There is an underlying defect that prevents appropriate wound healing that cannot be corrected by grafting (including synthetic, skin substitutes, split-thicknes and full-thickness grafts), so please don’t try it even if you are desperate. Don’t be tempted to think it will work in your patient. It won’t. Trust me. Results of grafting an consistently negative and can lead to fatal complications.

What to do

Apply gentle wound care with daily cleansing using a mild cleanser and peridoic dilute bleach bathes/soaks/mist Cover the eroded areas during the day with a bland emollient or wound healing gel, followed by a nonadherent contact layer, wrapped by a gauze and held in place with a stretch tubular elastic net. Uncover the area at night.

Treat pruritus with sedating antihistamines Keep a high index of suspicion for infection. Do not use prophylactic antimicrobial therapy, as this will lead to resistant organisms. Culture if concerned for infection and remember the difference between colonization and active infections. Skin infections can be bacterial, yeast, fungal or viral.

Begin with a topical antimicrobial if there are signs of active infection without systemic symptoms. Oral and intravenous antimicrobial therapy should be based on culture and sensitivity whenever possible with avoidance of broad empiric treament. Intermittent use of topical corticosteroids at the edge of the erosion had questionable benefit. Low-dose doxycycline may reduce inflammation and matrix metalloproteinases in chronic wounds and help wound healing. There is risk of enamel hypoplasia if this medication is given in children less than 8 years of age.

Optimal Therapeutic Approach for this Disease

Management of AEC and EEC should be multidisciplinary. There are no uniformly effective therapies or cure for these multisystem genetic syndromes.

Ankyloblepharon in AEC syndrome may lyse spontaneously or may be surgically treated by an ophthalmologist.

Ocular symptoms of dry eyes can be treated with saline eye drops. Prophylactic antibiotics for eye infections are not recommended. Referral to an ophthalmologist and/or oculoplastic surgeon is recommended. Results of lacrimal duct surgery are inconsistent and unpredictable.

Cleft lip and palate should be surgically repaired with standard protocols by plastic surgeons. Speech and hearing evaluations are advised. Good dental hygiene to prevent caries and dental consultation for treatment of the hypodontia is recommended. Renal ultrasound is recommended and malformations should be evaluated and surgically treated as indicated by urology.

Limb anomolies can be surgically improved in most cases by a hand/foot surgeon. Failure to thrive should be evaluated by a gastroenterologist and nutrition team with a high incidence of gastrostomy tube placement in AEC syndrome. Psychological functioning is variable and psychology/psychiatry consultation may be warranted.

Hypohidrosis rarely leads to hyperthermia and can be treated with cooling techniques. Dry skin can be managed with emollients.

There are no good therapies for the hair and nail changes. Wigs can be used for the alopecia and nail sculpting or artifical nails can also be used for cosmesis. There are no effective therapies for the scarring or pigmentary alternation of the skin. Wound care should be gentle with a high index of suspicion and appropriate treatment of secondary infections. DO NOT graft skin erosions as they are NEVER effective.

Patient Management

The patient should be seen on regular 3- to 6-month intervals by dermatology and ophthalmology as these are the most prominent symptoms that affect the daily lives of those affected with AEC and EEC syndromes.

Wound care in AEC should be gentle. Keep an eye out for symptoms of skin infection. Care to protect the eyes is important, as corneal scarring is common in EEC.

Early dental evaluation and treatment is recommended with reports of decreased utilization of dental prosthesis in these conditions as opposed to other ectodermal dysplasias; although these patients would similarly benefit from their use. Avoid skin grafting even if recommended by the physician or surgeon as they DO NOT work and will increase the risk of complications that may even be fatal.

Unusual Clinical Scenarios to Consider in Patient Management

Percutaneous toxicity can occur in infants with extensive skin erosions, so care should be taken to avoid this complication. Facial features are consistent and aid in diagnosis.

Skin erosions, especially of the scalp, are the defining feature of AEC but have rarely been seen in EEC. Limb anomalies are the defining feature of EEC but have been seen in AEC. Scalp erosions are the most problematic manifestation for AEC affected individuals. Ocular symptoms are the most problematic manifestation for EEC affected individuals.

Wound care seems paradoxical as an overly moist, occluded wound bed seems to prevent healing and increases the risk of infection in AEC.

Do NOT attempt skin grafting as it will fail!

Pigmentary anomolies in AEC are possibly related to postinflammatory pigmentary alternation although there is not always preceding erosions that are clinically apparent in the affected areas. Scarring is also likely related to prior erosions but these may be subclinical as erosions are not always previously noted in the scarred areas. There is considerable intrafamilial variation in these conditions.

There is some early speculation that AEC may be associated with an underlying immunodeficiency due to increased risk of skin infections and sepsis (but this could also be related to the impaired skin barrier) and one affected child is also known to be affected by autoimmune lymphoproliferative syndrome.

Gastrostomy tube placement for failure to thrive in AEC is out of proportion compared to patients with only oral clefting, therefore there is speculation that there may be mucosal involvement that prevents absorption.

What is the Evidence?

Bree, AF. “Clinical lessons learned from the International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome,?”. Am J Med Genet. vol. 149A. 2009. pp. 1894-9. (Overview and photos in tabular format of the clinical and genetic findings in a cohort of AEC affected individuals.)

Clements, SE, Techanukul, T, Coman, D, Mellerio, JE, McGrath, JA. “Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype-phenotype correlation”. Br J Dermatol . vol. 162. 2010. pp. 201-7. (Review of genetic and clinical findings in EEC syndrome.)

Clements, SE, Techanukul, T, Holden, ST, Mellerio, JE, Dorkins, H, Escande, F. “Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder”. Br J Dermatol . vol. 163. 2010. pp. 624-9. (Review of genetic data linking these two previously separated genetic disorders.)

Julapalli, ME, Scher, RK, Sybert, VP, Siegfried, EC, Bree, AF. “Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome”. Am J Med Genet. vol. 149A. 2009. pp. 1900-6. ([Cutaneous findings from an AEC-affected cohort.)

Koster, MI. “p63 in skin development and ectodermal dysplasias”. J Invest Dermatol. vol. 130. 2010. pp. 2352-8. (Nice discussion of the role of p63 in normal and abnormal skin development.)

Rinne, T, Bolat, E, Meijer, R, Scheffer, H, van Bokhoven, H. “Spectrum of p63 mutations in a selected patient cohort with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome”. Am J Med Genet. vol. 149A. 2009. pp. 1948-51. (Outlines the specific genetic mutations in a cohort of AEC-affected individuals.)

Rinne, T, Brunner, HG, van Bokhoven, H. “p63-associated disorders”. Cell Cycle. . vol. 6. 2007. pp. 1-7. (Overview of the p63 disorders.)

Rinne, T, Hamel, B, van Bokhoven, H, Brunner, HG. “Pattern of p63 mutations and their phenotype-update”. Am J Med Genet A. vol. 140. 2006. pp. 1396-40. (Discussion of the p63 disorders with correlation of the differeing clinical findings in AEC and EEC associated with the area of mutation in p63.)

Roelfsema, NM, Cobben, JM. “The EEC syndrome: a literature study”. Clin Dysmorphol. . vol. 5. 1996. pp. 115-27. (Review of clinical and genetic findings of EEC syndrome.)

Siegfried, E, Bree, A, Fete, M, Sybert, V. “Skin erosions and wound healing in ankyloblepharon-ectodermal defect – cleft lip and/or palate”. Arch Dermatol. vol. 141. 2005. pp. 1591-5. (Discussion of the findings and treatment recommendations for the erosions associated with AEC syndrome.)