Congenital and Hereditary Disorders of the Skin

Collodion Baby

The term collodion baby refers to a neonate born encased in shiny, thickened skin that resembles parchment or plastic wrap ( Fig. 92.2 ). The taut skin leads to various distorting features such as ectropion (eversion of eyelids), eclabium (eversion of lips), flattening or hypoplasia of the nose and ears, and pseudocontractures of the digits. These infants have an ineffective cutaneous barrier against transepidermal water loss and invasion of pathogenic organisms and are at risk of multiple complications, including temperature instability, dehydration, electrolyte instability, infections, poor sucking, failure to thrive, keratitis, ear canal obstruction, percutaneous toxicity from topical medications, pneumonia from aspiration of squamous material in amniotic fluid, and distal limb or digital ischemia.

These neonates need diligent supportive care in a humidified incubator with close monitoring of temperature, fluid and electrolyte balance, and caloric intake. Surveillance for signs of cutaneous or systemic infection is important, but prophylactic antibiotics or antifungals are not recommended. Skin care is somewhat controversial, but many advocate application of a bland petroleum-based or water-in-oil emollient at least every 6 to 8 hours. Caution is advised with use of topical medications or keratolytics because of increased percutaneous absorption and risk of toxicity. If there are erosions or fissures, bathing with normal saline may be more comfortable than with plain water. Ophthalmology and otolaryngology consultations should be considered for eye and ear involvement.

Collodion baby refers not to a specific disease but rather to an initial phenotype seen in several forms of ichthyosis ( Table 92.4 ). Ichthyosis prematurity syndrome, Netherton syndrome (NS), and Sjögren–Larsson syndrome must also be considered in the differential diagnosis. The collodion membrane is typically shed in 3 to 4 weeks, and the eventual phenotype depends on the underlying genetic mutation. More than half of collodion babies have autosomal recessive congenital ichthyosis (ARCI), discussed in more detail below. About 10% have almost normal skin after the collodion membrane sheds, which has been referred to as self-healing collodion baby . It is difficult to predict the long-term prognosis during the neonatal period. The diagnostic work-up should include a detailed family history and consideration of microscopic examination of scalp and eyebrow hair to look for tiger-tail banding seen on polarized microscopy in trichothiodystrophy (TTD). The role of skin biopsy before the collodion membrane has shed is controversial, and the underlying diagnosis may become evident with time, which will help determine appropriate genetic testing or the need for biochemical or metabolic assays.

Autosomal Recessive Congenital Ichthyosis: Harlequin Ichthyosis, Lamellar Ichthyosis, and Nonbullous Congenital Ichthyosiform Erythroderma

ARCI encompasses a spectrum of nonsyndromic autosomal recessive ichthyoses that includes phenotypes ranging from lamellar ichthyosis (LI) to nonbullous congenital ichthyosiform erythroderma (CIE) to harlequin ichthyosis (HI). ARCI is caused by mutations in more than a dozen different genes.

The classic LI phenotype is characterized by coarse, yellow to brown-black, platelike scales ( Fig. 92.3 ) with varying degrees of underlying erythema, ectropion, and eclabium. Many patients with LI are born with a full or partial collodion membrane, discussed earlier. The classic CIE phenotype is characterized by more prominent erythroderma and finer, white scales that may not be apparent until the collodion membrane sheds. Neonates with CIE often have a less severe collodion membrane or may be born without a membrane. The principles of neonatal management for these phenotypes are the same as those discussed earlier for a collodion baby.

HI is the most severe clinical phenotype of ichthyosis in a newborn and is rarely diagnosed by prenatal ultrasound. These neonates are born with an “armor” of thick, fissured, platelike scales ( Fig. 92.4 ). They have severe ectropion and eclabium and flattened, hypoplastic nose and ears. Constricting bands lead to contractures and digital ischemia. They are at high risk of the complications discussed earlier for collodion babies but have a higher rate of infant mortality. Historically, almost 50% of babies with HI have died in the neonatal period, more than half in the first 3 days of life. The cause of death is most commonly attributed to sepsis and/or respiratory failure. Intensive, multidisciplinary, supportive care is critical for neonates with HI, with detailed recommendations for neonatal care available. Early initiation of therapy with a systemically acting retinoid (such as isotretinoin, 0.5 to 1 mg/kg per day, or acitretin, 0.5 mg/kg per day) before day of life 7 may improve the survival rate. Patients who survive infancy have a lifelong ichthyosis that resembles CIE.

Epidermolytic Ichthyosis

The term keratinopathic ichthyoses encompass ichthyoses that are a result of keratin mutations, most of which are autosomal dominant. Epidermolytic ichthyosis (EI), previously referred to as epidermolytic hyperkeratosis or bullous CIE , is the most common and presents with generalized erythroderma and bullae. The term epidermolytic hyperkeratosis describes the histopathologic or ultrastructural features seen on skin biopsy characterized by marked hyperkeratosis (thickened stratum corneum) with clumping and lysis (disintegration) of the epidermal cells above the basal layer. Newborns with EI typically present with widespread erythema and superficial blistering, as a result of the fragility of the epidermis from abnormal keratin production ( Fig. 92.5 ). These neonates may receive a misdiagnosis of epidermolysis bullosa (EB) or staphylococcal scalded skin syndrome. Subtle skin thickening over the elbows, knees, palms, or soles may be diagnostic clues. During the first few months of life, the phenotype gradually evolves into more pronounced skin thickening with verruciform, ridged scales, accentuated in areas of friction, including flexural and intertriginous areas. Malodorous bacterial colonization is common.

Treatment of neonates with EI requires supportive care with attention to gentle handling to minimize blister formation, including use of nonadherent dressings. They are at risk of temperature instability, dehydration, and electrolyte instability and should be closely monitored for bacterial infections.

EI is caused by autosomal dominant mutations in KRT1 or KRT10 , either inherited or caused by a spontaneous mutation. It is also possible that the parent of a child with EI may have a congenital epidermolytic epidermal nevus caused by a somatic mosaic keratin mutation in KRT1 or KRT10 . Gonadal involvement of the keratin mutation, more common in those with widespread epidermal nevi, results in an offspring affected by generalized EI.

Diagnosis of Ichthyoses

Cutaneous and extracutaneous clinical features are critical in narrowing down the differential diagnosis for a neonate born with scaly or hyperkeratotic skin and can sometimes be sufficient for diagnosis. Family history may be helpful, particularly for ichthyoses with a dominant inheritance pattern. The gold standard for diagnosis is genetic mutation analysis.

Histopathologic findings from a skin biopsy in many patients with ichthyosis are nonspecific, with a few exceptions. EI has characteristic histologic findings of “epidermolytic hyperkeratosis” discussed earlier. Biopsy specimens from an individual with ichthyosis vulgaris, NS, TTD, Refsum syndrome, or Conradi-Hünermann-Happle syndrome (chondrodysplasia punctate X-linked dominant type 2) may show reduced or absent stratum granulosum. Histopathology of loricrin keratoderma is notable for parakeratosis and hypergranulosis. Special immunohistochemical stains or ultrastructural analysis by electron microscopy may be considered in certain cases.

Examination of hair shafts can be helpful for diagnosing NS and TTD. Trichorrhexis invaginata (“bamboo hair” or “ball-and-socket” deformity) is characteristic of NS but is not usually present until after 1 year of age and even then is invariably present. The hair of patients with TTD may show trichoschisis (clean transverse fracture) or trichorrhexis nodosa (nodes from longitudinal splitting of fibers) on light microscopy and characteristic tiger-tail banding on polarized microscopy from low sulfur content.

Further work-up for syndromic ichthyoses is typically based on extracutaneous findings.

Prognosis and Treatment of Ichthyoses

Distinguishing the type of ichthyosis is crucial for offering prognostic information to the family, as prognosis is highly variable. Neonatal care for severe phenotypes, including collodion baby, LI, HI, and EI, was discussed earlier. For all types of ichthyosis, skin care typically involves application of bland emollients to hydrate the stratum corneum. Emollients with keratolytics such as urea, salicylic acid, α-hydroxy acids, and propylene glycol are usually avoided in infancy because of risk of toxicity from absorption. Oral retinoids are primarily considered for patients with HI or rarely in those with severe collodion membrane with delayed shedding.

Classification of Epidermolysis Bullosa

EB classification and nomenclature have evolved over many years and were most recently updated at a 2013 international consensus meeting, although additional subtypes and genes have been identified since. EB is classified into three major types: EB simplex, junctional EB, dystrophic EB, and Kindler syndrome. EB type is determined by the level of the skin at which mechanical fragility and blister formation occur. EB simplex is the most superficial form, with the level of skin cleavage occurring in the epidermis, usually in basal keratinocytes. In junctional EB, blisters form deeper, within the midportion (lamina lucida) of the skin's BMZ. Skin cleavage in dystrophic EB occurs just below the BMZ in the most superficial layer of the dermis (the sublamina densa). In Kindler syndrome, which is very rare, fragility and blister formation are seen at multiple depths within the skin. EB is further subdivided into more than 39 subtypes on the basis of clinical presentation, ultrastructural features, immunohistochemical findings, and the presence of specific genetic mutations. Only the more common or more notable subtypes are discussed in this chapter ( Tables 92.5–92.7 ).

Epidermolysis Bullosa Simplex

EB simplex most commonly results from genetic mutations affecting keratins 5 and 14 in the basal layer of the epidermis (see Table 92.5 ). Blisters typically heal without scarring. Most patients with EB simplex have autosomal dominantly inherited forms and a normal life span. However, some of the recessive forms, including those associated with muscular dystrophy and pyloric atresia, carry a poor prognosis and are associated with early death. Patients with generalized subtypes of EB simplex (intermediate and severe types) present with blistering in the newborn period. Severe generalized EB simplex is characterized by extensive blistering in herpetiform (herpes-like) or arcuate clusters. Mucosal involvement may be seen, nail dystrophy is common, and progressive palmoplantar keratoderma is characteristic. In the intermediate subtype of generalized EB simplex, bullae are most common over pressure points such as the elbows, knees, legs, feet, and hands and may be widespread following the trauma of birth. Mucosal involvement may occur during the newborn period but reduces with age. Nails may be lost but regrow. Localized EB simplex is the most common form of EB. Patients with localized EB simplex are usually asymptomatic during the newborn period, with onset of acral blisters in early childhood.

Junctional Epidermolysis Bullosa

Junctional EB is caused by gene mutations that affect expression of proteins integral to the lamina lucida of the BMZ. All known subtypes of junctional EB are autosomal recessive, and clinical severity is highly variable (see Table 92.6 ). Tooth enamel hypoplasia is characteristic. Generalized severe junctional EB, previously known as Herlitz subtype , is the most severe form and carries the highest risk of early death of all forms of EB. Patients present at birth with widespread mucosal and skin blistering, most pronounced over pressure points ( Fig. 92.6 ). Nails are dystrophic or absent. Exuberant granulation tissue often develops periorally and on the upper back. Airway involvement is typical, and the eyes and gastrointestinal and genitourinary systems are also commonly affected. Prognosis is extremely poor. Most patients die during the first 2 years of life secondary to failure to thrive, sepsis, or respiratory failure. The presentation of the generalized intermediate subtype of junctional EB is variable and less severe than that of the generalized form. Localized subtypes are also seen.