Chapter 142. Ectodermal Dysplasias

The ectodermal dysplasias (EDs) are a group of inherited disorders that share in common developmental defects involving at least two of the major structures classically held to derive from the embryonic ectoderm—hair, teeth, nails, and sweat glands. Freire-Maia and Pinheiro1 published an exhaustive review and classification system for these disorders using a numeric system of 1 (hair), 2 (teeth), 3 (nail), and 4 (sweat glands) for characterization. This system has little use in practice, although it did allow for a rational approach to a previously chaotic field. Freire-Maia and Pinheiro laid claim to more than 150 ectodermal disorders in their most recent compilation.2 Several other classification schemes have been suggested. Each has limited clinical application but can help in ordering thinking about these disorders.3,4 In an attempt to move to a more useful and unified system, an international classification conference was convened in 2008 to initiate this process which is still ongoing.5

This chapter covers only the more common of these conditions and those in which ectodermal defects are likely to bring them to a dermatologist for diagnosis and medical attention. Fig. 142-1 is an algorithm showing the approach to the diagnosis of EDs. The first step in the algorithm for making a specific diagnosis of an ED is to determine the presence of sweating (hidrotic) or absence of sweating (hypohidrotic/anhidrotic). The involvement of other ectodermal structures and of nonectodermally derived tissues provides further branching points in a diagnostic hierarchy. Mode of inheritance may differ within a seemingly uniform diagnostic group, and care must be taken in evaluating family members before providing recurrence risks.

Within the last few years, causal genes have been identified for many of the EDs. Given continuing discoveries, the reader is directed to the following resources: http://www3.ncbi.nlm.nih.gov/OMIM (Online Catalog of Mendelian Inheritance in Humans) and http://www.ncbi.nlm.nih.gov/sites/GeneTests (an up-to-date listing of laboratories offering molecular testing). The National Foundation for Ectodermal Dysplasias (http://www.nfed.org) is a lay support group that has numerous informative pamphlets for families and physicians, as well as a strong advocacy program for dental care, insurance coverage, and research.

Historical Aspects

One of the earliest descriptions of hypohidrotic ectodermal dysplasia involving male first cousins and their grandmother with sparse hair, missing teeth and dry skin was described in 1848 by Thurnam.6 Darwin described this condition in his writings from 1875.

Epidemiology

X-linked hypohidrotic ED (XLHED) occurs in all racial groups and is thought to have an incidence at birth of anywhere from 1 in 5,000–17,000 births.7 Accurate prevalence and incidence data are not available.

Etiology, Pathogenesis,and Genetics

XLHED results from alterations in the gene ectodysplasin (EDA, EDA1, HED) located at Xq12-13.8 It codes for a transmembrane protein, ectodysplasin, which is composed of 391 amino acids and has alternative splicing forms, the significance of which is not known. A multitude of mutations in this gene causing XLHED have been identified. There does not appear to be a correlation between the nature of the mutation and the clinical features9 (i.e., to date, there have been no phenotype–genotype correlations). Interfamilial and intrafamilial variation occurs to a mild degree. Ectodysplasin belongs to the tumor necrosis factor family and plays a role in regulation of the formation of ectodermal structures. It forms trimers and is expressed in keratinocytes, the outer root sheath of hair follicles, and sweat glands. It localizes to the lateral and apical surfaces of cells.

As is typical of X-linked recessive disorders, expression is full blown in affected males, and carrier females may express none, some, or all of the features of the disorder, often in a patchy distribution. Between 60% and 80% of carrier females express some clinical signs of the disorder; the most frequent are patchy hypotrichosis and hypodontia. The disorder can be inherited from a carrier mother or occur in an affected individual as the result of a de novo mutation. Approximately 70% of affected males inherited the mutation from a carrier mother.

Mutations in an autosomal gene, EDAR, mapped to 2q11-q13, have been implicated in an autosomal dominant form of hypohidrotic ectodermal dysplasia (HED; OMIM #129490) and in an autosomal recessive form (OMIM #224900)10 that are clinically similar to XLHED. Both these entities are much rarer. EDAR acts as a receptor for ectodysplasin. Mutations in yet another gene, EDARADD, have been identified recently in autosomal recessive HED and autosomal dominant HED.11,12 EDARADD is an intracellular adaptor protein that assists in transmitting the signal from the activated EDA receptor to the nucleus of the cell. Individuals with autosomal dominant HED appear to have a milder defect in the ability to sweat.

Certain mutations in the X-linked NEMO gene, which causes incontinentia pigmenti (IP) in females, have been shown to result in HED and immune defects in males (see Chapter 143).13,14

Clinical Manifestations

Dermatologic

Affected males may present at birth with a collodion membrane or with marked scaling of the skin,15 similar to congenital ichthyosis. Scalp hair is usually sparse, fine, and blonde. It may thicken and darken at puberty, and secondary sexual hair is typically normal. Other body hair is usually sparse or absent.

The ability to sweat is significantly compromised, and most affected males have marked heat intolerance. Sweat pores are usually undetectable on physical examination, and fingerprint ridges are effaced. The inability to sweat adequately in response to environmental heat results in an elevation of core temperature and bouts of unexplained high fevers, usually leading to an extensive workup for infectious disease, malignancy, or autoimmune disease before the correct diagnosis is recognized. In an older series of patients, mental retardation was reported as a feature of XLHED. Currently, this is believed to have been due to damage from prolonged high fevers and seizures and not to be an intrinsic feature of the disorder.16

The nails are usually normal; reports of thin, fragile nails are not convincing.17 Periorbital wrinkling and hyperpigmentation are typical and often present at birth (Figs. 142-2A–142-2C). Eczema affects more than two-thirds of affected males and is often difficult to manage. Hyperplasia of sebaceous glands, particularly on the face, can develop over time and appear as small, pearly, flesh-colored to white papules that may resemble milia.

Systemic Associations

Hypodontia, oligodontia, or anodontia are invariable features of XLHED in affected males. Hypoplastic gum ridges in an affected infant can be an early clue to the diagnosis of the disorder. Teeth that do erupt are usually peg-shaped and small (see Fig. 142-2B). The facies of the disorder are characterized by frontal bossing and a depressed midface with a saddle nose and full, everted lips. Otolaryngologic manifestations include thick nasal secretions and impaction, ozena, sinusitis, recurrent upper respiratory tract infections and pneumonias, decreased saliva production, hoarse voice, and an increased frequency of asthma. The increased frequency of respiratory tract infections has been attributed to hypoplastic or absent mucus secreting glands in the bronchial tree.18 Gastroesophageal reflux and feeding difficulties may be a problem in infancy. The basis for this is unknown. Preliminary studies suggest that there may be failure to thrive in infancy and early childhood in as many as 20% to 40% of affected boys, with catch-up growth seen later.19 Although several reviews have suggested that infant mortality may be increased, unbiased confirmatory data are lacking.

Female carriers for XLHED may be affected as severely as males or show few, if any, signs of the disorder (Fig. 142-3). Heat intolerance, if present, is usually mild; adult carrier women comment that they do not sweat much or that they do not like very warm weather, but it is unusual for a female to experience fever due to inability to sweat. Typically, a few teeth may be peg-shaped or missing and scalp hair may be patchy or thin. Careful examination of the skin of carrier females often reveals a diminution in or patchy distribution of sweat pores. This sometimes can be appreciated readily just by magnification of fingertip pads or may require more sophisticated sweat testing.

Variants

As noted in Section “Etiology, Pathogenesis, and Genetics,” the autosomal dominant and autosomal recessive forms of HED are similar, although the autosomal dominant form may be milder. The X-linked form is by far the most common and always should be the diagnosis of default in a sporadic case.

Histopathology

The epidermis is thinned and flattened. There is a reduction in the number of sebaceous glands and hair follicles. Eccrine glands are absent or incompletely developed. Histologic evaluation of the skin is usually not necessary.

Diagnosis and Differential Diagnosis

(Box 142-1)

The scaling skin at birth may result in a misdiagnosis of congenital ichthyosis. Repeated bouts of fever may be thought to have an infectious source. The diagnosis of HED is recognized readily when expected, such as when an at-risk male is born into a family in which the disorder is known to segregate. Examination for sweat pores and a Panorex view of the jaw leads quickly to the correct diagnosis. Absence of eccrine structures in skin biopsies of the scalp and/or palmar region may help confirm a diagnosis,20 but are rarely necessary. In an isolated, fully expressing female, the autosomal dominant and recessive forms of HED need to be considered. Family history is mandatory, and mothers always should be examined fully to detect mild manifestations of the X-linked form. Molecular testing may be helpful but is not indicated for clinical diagnosis in most instances. Referral to a pediatric dermatologist may be helpful if the diagnosis is in question.

Treatment

Maintenance of cool ambient temperatures is vital to prevent hyperpyrexia. Most children do well with simple measures, such as wet T-shirts, air conditioning in home and school, wet headbands, etc. Occasionally, cooling vests allow a broader range of participation in sports and vigorous physical activity in warm climates.

Dental restoration is of primary importance, and early implementation of dentures and ultimate use of dental implants are mainstays of treatment.

Management of otolaryngologic complications, asthma, and recurrent infections needs to be individualized. The eczema may be quite refractory to care.

Although infancy and childhood are complicated by many problems, most individuals with HED lead adult lives that allow them to function successfully in society. Heat intolerance seems to decrease due to the development of some ability to sweat in adolescence or to the development of common sense and adaptation of lifestyle, or both.

Recombinant ectodysplasin protein injections of pregnant affected (Tabby) mice led to permanent rescue of the phenotypic features in the offspring.21 Further, early postnatal injections were also shown to ameliorate the developmental defects. Similar results have been seen in affected canine models who were infused with recombinant ectodysplasin protein in the postnatal period, with resultant normalization of teeth, lacrimation and sweating ability, as well as decreased eye and respiratory infections.22,23 These developments in animal models have been encouraging and human trials are planned. An international patient registry has been established by the NFED to facilitate these clinical trials.

Epidemiology

Hidrotic ED was first described in a French–Canadian kindred.24 It has been reported in other ethnic groups, but the majority of affected individuals can trace their ancestry back to an original French–Canadian settler.

Etiology, Pathogenesis, and Genetics

Hidrotic ED is autosomal dominant with variable expression (the degree of severity can vary within and between families). Males and females are affected in equal numbers and to equal degree. The gene maps to the centromeric region of the long arm of chromosome 13.

The disorder is caused by mutations in a connexin gene, GJB6 or connexin-30.25 Different mutations in the same gene are responsible for a form of nonsyndromic autosomal dominant deafness and at least one patient with keratitis-ichthyosis-deafness (KID syndrome) (see Chapter 49). Other connexin genes show similar variability in mutation: disease correlations [e.g., mutations in connexin-31 (GJB3)] can cause either erythrokeratodermia variabilis (see Chapter 49) or late-onset autosomal deafness.

Clinical Manifestations

The scalp hair is wiry, brittle, and pale, and there is often patchy alopecia (Fig. 142-4A). This progresses in adult life and may lead to total alopecia. Body and facial hair are affected. The nails may be milky white in infancy and early childhood, gradually thickening and becoming dystrophic. The nail plates in adults are thick, short, and slow growing. They separate distally from the nail bed (see Fig. 142-4C), and may cause pain. Anonychia has been reported. Not all the nails are necessarily affected to the same degree. Progressive palmar/plantar hyperkeratosis is common (see Fig. 142-4B). In contrast to HED, sweating is normal, as are the teeth. Oral leukoplakia has been reported. Conjunctivitis and blepharitis, possibly due to poor function of sparse eyelashes, are common.

Histopathology

The thickened palms and soles show orthohyperkeratosis with a normal granular layer. On electron microscopy, an increase in the number of desmosomes in the cells of the stratum corneum is found. The hair shows nonspecific changes.

Diagnosis and Differential Diagnosis

(See Box 142-1)

The diagnosis is straightforward. The involvement of nails and hair and palmar/plantar thickening, in the absence of other signs of ED, are reasonably specific. Other palmar/plantar hyperkeratoses do not have similar hair changes. Orofacial clefting differentiates other forms of autosomal dominant hidrotic ED, such as ankyloblepharon–ED–cleft palate (AEC) syndrome or Rapp–Hodgkin syndrome. Although the nail changes are similar to those of pachyonychia congenita, the hair changes are distinctive.

Treatment

Occasionally, ablation of the nail matrix is necessary for relief of pain. Wigs may provide cosmetic benefit. Treatment of the thickened palms and soles is not specific and minimally successful.

Epidemiology

Described first in 1976,26 Hay–Wells syndrome has been found in ethnically and geographically disparate families. Described in 1968, Rapp–Hodgkin syndrome, with many clinical similarities to Hay–Wells syndrome, was once thought to be a distinct clinical entity. More recently, it has become evident that Rapp–Hodgkin syndrome is allelic to Hay–Wells syndrome.27–30 Although there are some clinical differences, the genotype–phenotype correlations are limited at best and it is reasonable to consider these disorders to be the same.

Etiology, Pathogenesis, and Genetics

The disorder is caused by mutations in the tumor-suppressor gene p63, a gene that has been implicated in the pathogenesis of ectrodactyly–ED–cleft lip/palate (EEC) syndrome, limb–mammary syndrome, acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, and other autosomal dominant forms of ED. Mutations that cause EEC and AEC cluster in different regions of the gene.31,32 AEC syndrome is an autosomal dominant disorder with complete penetrance and variable expression.

Clinical Features

Dermatologic

Eighty percent to 90% of affected infants present at birth with shiny red, cracking, peeling skin, and superficial erosions, similar to the appearance of a collodion membrane (Fig. 142-5A).17 This sheds within a few weeks, and the skin underneath is dry and thin. The scalp is almost invariably affected by recurrent erosions, and many individuals are plagued by a chronic erosive dermatitis with abnormal granulation tissue on the scalp (see Figs. 142-5B and 142-5C).33 Recurrent bacterial infection of the scalp is common. Patchy alopecia is the rule, and the scalp hair that is present is often wiry, coarse, and light in color with an uncombable hair appearance. Sparseness to absence of body hair is typical. Dyspigmentation, both hypo- and hyperpigmentation, can be quite striking and is seen universally in affected patients.34,35 Ankyloblepharon filiforme adnatum (AFA)—strands of skin between the eyelids—is seen in approximately 70% of affected infants (see Fig. 142-5D). These may tear spontaneously prior to birth, minimally involve the lateral eyelids or require surgical lysis. Lacrimal duct atresia or obstruction is common. The nails may be normal, hyperconvex and thickened, absent, or partially dystrophic, and all changes can be found in a single individual. Effaced dermatoglyphics and palmoplantar erosive changes are also quite common. Sweating may be normal, although most affected individuals describe subjective heat intolerance. Supernumerary nipples and ectopic breast tissue are seen occasionally, as is mild cutaneous syndactyly of toes two and three. More prominent limb defects, including ectrodactyly, have recently been observed.36,37

In Rapp–Hodgkin, hypohidrosis usually without episodes of frank hyperpyrexia, abnormal hair with pili torti or pili trianguli et canaliculi and progressive balding, along with nail dystrophy, similar to Hay–Wells, are seen.38,39 The face in Rapp–Hodgkin syndrome is striking, with a short nasal columella and maxillary hypoplasia, thin upper lip, and full lower lip (Figs. 142-6A and 142-6B). The nails are thick and short, worsening with age (see Fig. 142-6C). The teeth may be conical and prone to caries (see Fig. 142-6D). The lacrimal puncta are aplastic in almost one-third of affected individuals. Scalp involvement with breakdown and granulation tissue formation appears to be far less common in patients with Rapp–Hodgkin than in AEC syndrome, and AFA is rare.

Systemic Associations

Cleft palate, with or without cleft lip, occurs in 80% to 100% of reported cases, with some cases displaying submucosal clefts alone.40 There is typically hypodontia with missing or misshapen teeth, and maxillary hypoplasia is also common.41 Malformed auricles have been described in some. Recurrent otitis media and secondary conductive hearing loss are common and may be consequence of the cleft palate. Hypospadias has been described in several affected males with AEC syndrome. In Rapp–Hodgkin, hypospadias has been reported in two-fifths of affected males; labial hypoplasia and absence of the opening of the vagina have been reported in a single female. These features are also reminiscent of the EEC syndrome.

Histopathology

Consistent histopathologic changes include mild epidermal atrophy, focal orthokeratosis, prominent superficial vascular plexus, and pigment incontinence with melanophages.42 Electron microscopy of hairs shows a defective cuticular structure, atrophy and loss of melanin, along with structural abnormalities including pili torti and pili trianguli et canaliculi. There is a decrease in the keratins of the basal and suprabasal layers of the epidermis and disorganized keratin filaments in the stratum corneum.

Diagnosis and Differential Diagnosis

(See Box 142-1)

Among the autosomal dominant EDs associated with clefting, EEC syndrome is characterized by bony hand and foot abnormalities not typically seen in AEC and also lacks the ankyloblepharon. The peeling, eroded skin of the newborn can lead to misdiagnosis of epidermolysis bullosa or congenital ichthyosis. AFA can occur in the absence of syndromic associations, and strands of tissue between the eyelids have been seen in several forms of arthrogryposis, in association with chromosomal aneuploidy, and in CHANDS (curly hair, ankyloblepharon, and nail dysplasia syndrome), an autosomal recessive form of ED.

Treatment and Prognosis

Light emollients should be used until the collodion membrane sheds. Ankyloblepharon may require surgical lysis. Ongoing ocular hygiene is important. Vigorous and meticulous but gentle scalp care with prompt treatment of infection is extremely important. Grafting of skin to the scalp has not proven successful in most instances. Clefting requires a team approach for repair and follow-up for secondary issues, such as feeding difficulties, speech defects, orthodontia, and ear infections.

Historical Aspects and Epidemiology

EEC syndrome is an ED classified as a multiple congenital anomaly syndrome because it has major involvement of structures other than those derived ectodermally. EEC syndrome has occurred in all racial groups worldwide.

Etiology, Pathogenesis, and Genetics

Mutations in p63, a tumor-suppressor gene mapped to 3q27, have been found in most, but not all, individuals with EEC syndrome.43 The gene is expressed widely, including in the basal cells of proliferating epithelial tissues. Mutations in the same gene cause some cases of isolated split hand–split foot disease, limb–mammary syndrome, the ADULT (OMIM #103285) syndrome, and Hay–Wells/Rapp–Hodgkin syndrome. There appear to be some genotype–phenotype correlations.44 The majority of alterations identified thus far in Hay–Wells syndrome have been missense mutations in the sterile α motif domain of p63; in EEC syndrome, the majority of mutations result in single-amino-acid substitutions in the DNA-binding domain of p63.19 Similar mutations in the DNA-binding domain are also found in the split hand–split foot malformation.45 Frameshift mutations in p63 cause limb–mammary syndrome, in which ectodermal structures other than the mammary gland often, but not always, appear normal. Among three unrelated families with ADULT syndrome, all shared the same point mutation in p63.46

EEC syndrome is an autosomal dominant disorder with variable expression and reduced penetrance. Intrafamilial and interfamilial differences in severity are common.

Clinical Manifestations

Dermatologic

The ED may be quite mild. The hair is usually blond, coarse, and dry. It may be sparse and slow growing. Axillary and pubic hair also may be affected. The nails are dystrophic in approximately four-fifths of individuals with transverse ridging, pitting, and slow growth. Dry skin and thickening of the palms and soles can occur. Sweating is usually normal.

Systemic Associations

The major distinguishing feature of EEC syndrome is ectrodactyly—abnormal development of the median rays of the hands and feet (Figs. 142-7A–142-7C). The feet are involved more frequently than the hands, and there may be asymmetry of involvement (see Figs. 142-7A–142-7C).

Cleft palate, with or without cleft lip, occurs in 70% to 100% depending on the series.47,48 Hypodontia and premature loss of secondary teeth and the dental abnormalities associated with clefting are found in most affected individuals. Lacrimal gland abnormalities are common. Secondary conductive hearing loss is frequent. Genitourinary abnormalities that include hydronephrosis, and structural renal or genital malformations affect one-third or more of persons with EEC syndrome. Although mental retardation has been reported, it is not believed to be an inherent feature of the disorder.

Diagnosis and Differential Diagnosis

Among disorders with limb defects that need to be considered in the differential diagnosis of EEC syndrome are the odontotrichomelic syndrome (OMIM #273400), in which there are severe absence deformities of the limbs, and aplasia cutis congenita with limb defects (Adams–Oliver syndrome, OMIM #100300), which does not have clefting or ectodermal defects other than absence of skin. Cutis marmorata telangiectatica congenita (see Chapter 107) has been described in some individuals with Adams–Oliver syndrome. Other EDs with clefting include Hay–Wells syndrome, and limb–mammary syndrome, all of which, in at least some families, appear to be allelic to EEC syndrome. Ectrodactyly with cleft palate without ED (OMIM #129830) also may be a distinct entity. There appear to be some families with EEC in whom linkage studies have suggested other causal genes located at different chromosomal loci. These genes have not yet been identified, but Dlx protein regulation by p63 may play an important role in the development of limb abnormalities. Prenatal diagnosis by ultrasound for detection of limb abnormalities is unreliable; molecular testing may prove useful in some families.

Treatment

As for other EDs with orofacial clefting and ophthalmologic involvement, management requires a team approach. Similarly, treatment for the limb defects must be individualized. Renal ultrasound and a high index of suspicion for urinary tract problems are appropriate and warranted.

Historical Aspects and Epidemiology

The earliest case was reported by Witkop in 1965 when he described a pedigree demonstrating autosomal dominant inheritance.49 Along with Hudson, he later went on to describe 23 cases in six families in 1975. All demonstrated hypoplastic nails and hypodontia; the latter manifested as failure of permanent teeth to erupt.50

Etiology, Pathogenesis, and Genetics

A nonsense mutation in MSX1, a gene expressed in the developing teeth and nail beds in mice, has been found in one family with Witkop syndrome.51,52 Other mutations in MSX1 have been associated with isolated tooth agenesis or tooth agenesis with cleft palate. Tooth and nail syndrome is autosomal dominant, with variable expression and intrafamilial variability.

Clinical Manifestations

Dermatologic

The nails are thin, small, and friable and may show koilonychia at birth. Toenails are usually more severely involved than fingernails (Fig. 142-8B). Nail changes improve with age and may be unappreciated in affected adults. A few individuals have reported thin, fine hair.

Systemic Associations

The primary teeth usually are unaffected, although they may be small. The secondary teeth may fail to erupt, and there can be partial or total absence (see Fig. 142-8A). The mandibular incisors, second molars, and maxillary canines are missing most often. No other ectodermal structures are affected.

Diagnosis and Differential Diagnosis

This is an easy condition to miss. The nail changes may be subtle. The tooth abnormalities may be mild enough to escape detection by a physician. The lack of associated features, either dermatologic or systemic, readily distinguish Witkop syndrome from other EDs. There is a presumed autosomal recessive disorder characterized by taurodontia (teeth with an elongated body and pulp chamber and short roots), absent teeth, sparse hair, and hypoplastic nails that appears similar.

Treatment and Prognosis

The nails usually require no treatment. Restorative dentistry is important.

Epidemiology

Focal dermal hypoplasia of Goltz (FDH), first described in 1934, received its name from a report by Goltz and coauthors53 of three patients. Subsequently, there have been over 200 case reports published.

Etiology, Pathogenesis, and Genetics

Focal dermal hypoplasia is an X-linked dominant disorder, usually lethal in males. Case reports of males with the condition are believed to be due to mosaicism for postzygotic mutations (as is true for incontinentia pigmenti); the presence of some normal cells allows survival in the male. The mutated gene is PORCN, the human homolog of the porcupine gene in Drosophila. PORCN is thought to be important for palmitoylation and secretion of Wnt protein, a key regulator of the development of skin and bone.54,55

Clinical Manifestations

Dermatologic

The skin changes of FDH are the primary diagnostic features with considerable phenotypic variability. There is linear, punctate, streaky cribriform atrophy (Fig. 142-9) with telangiectasia. The cribriform atrophy is marked by tiny ice pick-like depressions in the skin. These are distributed along the lines of Blaschko. Areas of thinned to absent dermis are irregularly distributed and the resultant herniations of fat appear as yellow–pink excrescences on the skin surface (see Fig. 142-9C). These are easily depressed. Papillomas that may be fleshy or vascular develop throughout life and favor the perigenital, perioral, intertriginous, and mucosal surfaces. Other dermatologic features include patchy alopecia, brittle or sparse hair, and palmar and plantar hyperkeratoses. Some individuals have had hyperhidrosis and some have had aplasia cutis congenita.

Systemic Associations

The other organ systems most frequently involved in FDH are the skeletal, central nervous system, teeth, and eyes. Microphthalmia and coloboma are common and the diagnosis of FDH should prompt a full ophthalmologic evaluation. Oligodontia, tooth dysplasia, and enamel defects are common. The skeletal abnormalities are too numerous to list; the more common are vertical banding of the bones (osteopathia striata), syndactyly (both cutaneous and bony), asymmetry, and short stature. Mental retardation has been reported in approximately 15% of cases. Defects in other organ systems have been described in a minority of cases, including cardiac defects, abdominal wall defects, and renal malformations. It is not certain that these are inherent features of FDH.

Diagnosis and Differential Diagnosis

(See Box 142-1)

The diagnosis of FDH is relatively straightforward. Cribriform atrophy has been described in X-linked dominant Conradi–Hünermann syndrome (chondrodysplasia punctata), but ichthyosis is not a feature of FDH, and fat herniation is not part of Conradi–Hünermann. The streaky distribution of the atrophic lesions of IP is similar, as are the other system malformations, but the blistering, hyperkeratosis, and hyperpigmentation of IP are not found in FDH. In microphthalmia and linear skin defects/microphthalmia, dermal aplasia, sclerocornea, the skin defects are limited to the head and neck; there is atrophy and scarring of the skin more similar to aplasia cutis congenita and not dermal atrophy alone. The disorders do share similar ocular abnormalities.

Treatment and Prognosis

There is no specific treatment for the dermatologic and systemic features of FDH. Papillomas can be excised if they interfere with function. Use of vascular lasers to decrease the erythema of telangiectatic areas may have cosmetic benefit. As with most X-linked dominant disorders, clinical involvement varies considerably, and the range in severity is marked. This makes prognostic counseling difficult early in infancy, and usually it is wiser to counsel patience and reassurance until the extent to which there is systemic involvement becomes clear. It is important to inquire about the family history of lost pregnancies (a distorted male–female ratio in offspring and increased pregnancy loss are clues to the mother being a carrier). Both mothers and fathers should be examined carefully; fathers may have subtle features, and, presumably, represent individuals with postzygotic mutations for the FDH gene.

(See Chapter 62)

(See Chapter 62)