Neonatal features

Neonates with EB may present at birth with large ulcers, usually on the lower extremities, called congenital localized absence of skin (CLAS) (Fig. 11.2). The edges of such ulcers are well-demarcated and the base is red and shiny. Bart and colleagues⁴ originally described the association of CLAS, mucosal blistering, and nail dystrophy and proposed that this triad represented a distinct syndrome, later termed Bart syndrome. Since that description, however, CLAS has been reported as a presenting sign in all types of EB, and Bart’s original kindred was further examined and found to have DDEB.⁵ CLAS likely results from intrauterine friction, such as the leg rubbing against the uterine wall, and is not specific for any one type of EB. The use of the term Bart syndrome is now discouraged.

With or without CLAS, neonates with EB develop friction-induced blistering and erosions after birth. Skin changes may initially correlate with areas traumatized during birthing, such as the scalp and face in cases of vaginal birth. In many instances, blistering may be generalized. After birth, areas that are most subject to friction, such as the hands, diaper area, extensor extremities, and back, are most likely to blister (Fig. 11.3). Intact blisters are filled with serous or hemorrhagic fluid. In JEB and RDEB, the bullae can be quite large, and the pressure of fluid within the blister cavity can cause the lesion to extend (Fig. 11.4). More superficial blisters may rupture easily, leaving open erosions.

The blisters in EBS and JEB often heal without scarring, but macular hypo- or hyperpigmentation may be a transient change after blisters heal. DEB blisters heal with scarring that is often atrophic. Milia are most suggestive of DEB but can be seen in all forms of EB (Fig. 11.5). Granulation tissue, which is often described as ‘exuberant’ or ‘hyper-’ in JEB, can be seen in any EB erosion that has been slow to heal but is not often seen in the neonatal period.

Oral involvement is most often seen in neonates with JEB or DEB but can be seen in EBS as well. Open erosions or intact vesicles can occur on the lips, gums, and palate. These lesions probably result from the trauma of sucking and may result in pain with feeding. In any form of EB, trauma to the periungual skin can result in nails that are absent, dystrophic, or may be shed.

Blisters and erosions are at risk of becoming infected, signaled by the formation of crusts and foul-smelling or purulent drainage. Neonates with EB and extensive erosions are at risk for developing fluid and electrolyte abnormalities as well as sepsis. Neonates with EB and pyloric atresia may present with gastrointestinal obstruction at birth.⁶ In these cases, polyhydramnios and gastric distension may have been noted on prenatal ultrasound, and genitourinary strictures and obstruction may be present as well. Airway involvement is uncommon in neonates with EB, but can occur. Although it is most often associated with JEB-Herlitz (JEB-H), laryngeal involvement can occur in infants with certain forms of EBS and with RDEB.⁷ An early sign of blisters and erosions of the larynx is hoarseness, which can progress to stridor as airway obstruction worsens.

Basal epidermolysis bullosa simplex

Basal EBS is the most common and often mildest form of EB. Most forms are transmitted in an autosomal dominant manner. Individuals with localized forms of EBS may not present for medical evaluation, thus precise estimates of the true prevalence of EBS are lacking. For example, the NEBR calculated the prevalence of EBS to be 4.60 cases/million, but also estimated that the registry probably captured only 10% of all individuals affected with EBS.³ Population-based data from Scotland show a prevalence of 28.6 cases/million in 1992.¹³

EBS, localized (EBS-loc, formerly Weber–Cockayne) is characterized by blisters of the hands and feet. Other than mild oral disease, extracutaneous involvement does not occur. Patients may first develop blisters at any age, including birth, but it is common for the first signs to present in the toddler years, or sometimes as late as adolescence, after a period of marked frictional stress.

EBS, other generalized (EBS, gen-nonDM, formerly Koebner) presents at birth and is characterized by intraepidermal blistering in a generalized distribution. Oral involvement can be seen in infancy but improves with age. Atrophic scarring, dyspigmentation, and nail dystrophy may be seen. Extracutaneous involvement in this type of EB is uncommon. For both EBS-loc and EBS, gen-nonDM, life expectancy is normal and the overall prognosis is good. However, affected adults report that acral blistering can be painful and limits daily activities such as walking, thereby affecting quality of life.^14,15

EBS Dowling–Meara (EBS-DM), on the other hand, is more severe and can even be fatal in the newborn period.^14,16,17 Blistering presents at birth or within the first days of life. Skin involvement ranges from generalized to localization of blisters and erosions to areas of friction. A clinical clue to the diagnosis of EBS-DM is the occurrence of blisters in grouped or annular configurations (Fig. 11.6). This feature, however, is not always reliable and may not be present until after 1 year of age. Milia and atrophic scarring may occur, and nail dystrophy in which nails may be thickened, ridged, or shed, is fairly common. In childhood, a confluent palmoplantar keratoderma develops and becomes more prominent with age, persisting into adulthood. This hyperkeratosis can interfere with ambulation, and joint contractures may be a subsequent complication.^14,17 Oral blistering is often present and varies in severity. Laryngeal involvement, presenting as hoarseness, has been reported, but unlike in JEB, does not signal a poor prognosis.¹⁸ Gastroesophageal reflux and constipation may also be seen as complications.¹⁹ The severity of EBS-DM generally improves over time, with less blistering in adolescence, and rare blistering in adulthood in many cases. Patients may also report reduced blistering during febrile illnesses.

EBS with mottled pigmentation (EBS-MP) is a rare subtype.²⁰ It is characterized by acral, nonscarring blistering that presents in infancy. In addition, 2–5 mm hypo- and hyperpigmented macules occur in a reticulate pattern around the neck, axillary, and groin areas. This mottled pigmentation may be congenital or can develop later in infancy.

EBS with muscular dystrophy (EBS-MD), EBS with pyloric atresia (EBS-PA), and EBS, Ogna (EBS-Og) are all due to mutations in PLEC1, encoding plectin, although EBS-MD and EBS-PA are inherited recessively and EBS-Og is autosomal dominant.²¹ EBS-MD is a rare disorder that begins at or shortly after birth with mild generalized blistering and mucous membrane involvement. Other cutaneous findings include milia, atrophic scarring, and nail dystrophy.²² Nonmucosal findings can include respiratory involvement and dental enamel hypoplasia, leading to prominent caries. In most cases, progressive muscle weakness begins in adolescence or adulthood, although onset in infancy has been reported.²³ The presentation of neonates with EB with pyloric atresia is discussed below.

Junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is the least common type of EB. Data from the NEBR suggests an incidence of two cases/million live births.³ Inheritance of all forms of JEB is autosomal recessive, and a spectrum of clinical phenotypes can be seen. The JEB–Herlitz (JEB-H) and JEB with pyloric atresia (JEB-PA) subtypes, however, are often incompatible with survival beyond infancy.

JEB-H is characterized by generalized skin and mucosal erosions with a propensity for wounds to form exuberant granulation tissue. Other associated findings include nail dystrophy (Fig. 11.7), dental enamel hypoplasia, and involvement of the respiratory epithelium. Blistering and erosions are seen at, or shortly after, birth (Fig. 11.8A), although the amount of blistering is not predictive of outcome, as infants with little skin involvement can do poorly. Severe involvement of the back and buttocks is common but not pathognomonic (Fig. 11.8B). In neonates who survive into infancy, the development of exuberant or hypergranulation tissue within erosions is a finding with high specificity for JEB-H. The central face, especially the periorificial areas (Fig. 11.9), periungual skin (paronychial inflammation), and nape of the neck are commonly affected. Absent or dystrophic nails or nail shedding are often present. Ocular erosions can also occur.⁷ Oral blistering and erosions are often present in the neonatal period and can make feeding difficult. The laryngeal and respiratory epithelia may also be affected, typically first presenting as a weak or hoarse cry.²⁹ Stridor suggests worsening airway obstruction, which can be fatal. Involvement of the gastrointestinal and urinary epithelia can also occur. Anemia, probably due to a combination of iron deficiency and chronic inflammation, is common. Patients with JEB-H typically die in the first few years of life due to failure to thrive, sepsis, pneumonia or respiratory failure. Data from the NEBR reported a cumulative risk of death of ~45% in the first year of life,³⁰ while the Dutch EB registry found that over 23 years, all 22 subjects with JEB-H passed away in the first 3 years, with the average age of death being 5.8 months.³¹

JEB-non-Herlitz, generalized (JEB-nH gen) has features similar to JEB-H, although it is generally less severe and its overall prognosis tends to be better.³² In the neonatal period, however, clinical signs and pathologic analysis may not fully distinguish between JEB-H and JEB-nH gen, and a final diagnosis may be based on long-term outcome and/or results of genetic mutation analysis. Generalized blistering and mucous membrane involvement are seen in the neonatal period, and both improve as the child ages. Healing with granulation tissue is less common and less pronounced than in JEB-H, but can occur. Cutaneous lesions may heal with atrophy and pigmentary alterations. In hair-bearing areas, progressive alopecia may result, although this finding is most pronounced in adulthood. Likewise, nail dystrophy can begin in infancy and is progressive and marked with increasing age. Laryngeal involvement may occur, sometimes resulting in respiratory failure. Although the overall prognosis for JEB-nH gen is generally better than for JEB-H, the fatalities in the neonatal period and infancy are not uncommon. Data from the NEBR reported a cumulative risk of death of 40% and 49% in the first year and 2 years of life, respectively.³⁰

EB with pyloric atresia (EBS-PA or JEB-PA) presents at birth with upper gastrointestinal obstruction, most often affecting the pylorus. The degree of skin involvement is variable and ranges from extensive CLAS to normal skin, with the onset of blistering at several months of age.³³ Prenatal signs of an affected fetus include polyhydramnios and abdominal masses appreciated on ultrasound.³⁴ The ocular, respiratory, and urogenital epithelia are often affected. The prognosis for neonates with EB with pyloric atresia is generally poor, but nonlethal cases are reported.³⁵ Infants with extensive erosions often expire quickly due to fluid and electrolyte imbalances as well as sepsis. If surgical correction of the pyloric atresia is successful, infants may still succumb to sepsis, feeding intolerance, failure to thrive, and respiratory or renal disease before 1 year of age.³⁶

Dystrophic epidermolysis bullosa

DDEB may be more common than reported, as individuals with mild phenotypes may not seek medical attention. The NEBR estimated the prevalence of DDEB to be approximately 1/million,³ while Scottish data suggests a point prevalence of 1/14.6 per million.¹³ Infants with DDEB may present with CLAS and/or with blistering in the newborn period. As the child ages, the tendency for blistering decreases. Blistering most commonly affects areas predisposed to trauma, such as the hands, feet, elbows, and knees, and heals with atrophy and milia. Oral erosions occur but are often mild. Nail dystrophy is common and may be the only clinical sign of disease.⁴³ Extracutaneous complications such as esophageal strictures are uncommon. Transient bullous dermolysis of the newborn is a distinctive variant of DEB that is benign and self-limited. Blistering begins at birth or in the newborn period and dramatically improves or even remits completely, usually within the first year of life. Most reported cases are sporadic, but familial cases are described.^44,45

The incidence of RDEB is approximately 1–2/million live births.^3,13 The current classification includes RDEB, severe generalized (RDEB-sev gen, formerly Hallopeau–Siemens), RDEB, generalized other (RDEB-O, formerly non-Hallopeau–Siemens), and several rare subtypes with more limited involvement (Table 11.1).

In RDEB, blistering and erosions begin at birth and can be extensive. The compromised skin barrier is a risk for infection, and during the neonatal period sepsis is the most worrisome complication. Although death can occur, infants with RDEB generally do fairly well, especially compared with infants with JEB. Affected areas heal with scarring that can lead to the development of joint contractures over time. Recurrent scarring of the hands and feet leads to loss of the interdigital spaces and eventual contracture of the digits, called pseudosyndactyly or ‘mitten’ deformities (Fig. 11.10).⁴⁶ Joint contractures and pseudosyndactyly may begin in the first year of life. Nail involvement is common with anonychia due to nail shedding and scarring of the nail bed at an early age.

Extracutaneous involvement is common in RDEB, and generalized RDEB (and JEB) are effectively multisystem disorders. Mucosal involvement includes the gastrointestinal tract, ocular, and genitourinary system. Oral ulcers are painful and make eating difficult, limiting the ability of the child to take in adequate calories. Oral scarring leads to microstomia, ankyloglossia, and loss of the vestibule.⁴⁷ Esophageal involvement is extremely common; erosions lead to progressive strictures that produce dysphagia and limit adequate caloric intake. Malabsorption is another gastrointestinal complication that is poorly understood.¹⁹ Anal erosions make defecation painful, exacerbating constipation. The cornea and conjunctiva are frequent sites of ocular injury. Recurrent abrasions and ulcers lead to scarring that can affect visual acuity.⁷ Urinary tract involvement may present with dysuria, hematuria, meatal stenosis, or even sepsis. Ureterovesical obstruction and hydronephrosis can occur.⁴⁸

Failure to thrive is a common complication of generalized RDEB and results from unmet nutritional needs. Affected neonates and infants demonstrate failure to gain weight adequately before height velocity drops off. Chronic wound healing, blood and protein losses from erosions, and infection increase the body’s need for calories. Oral, esophageal and intestinal involvement hinders adequate intake and absorption of nutrients. In addition to causing growth failure, chronic malnutrition contributes to poor wound healing, the development of anemia, deficiencies of essential minerals and trace elements, and increased susceptibility to infection.^49,50 Anemia likely results from both iron deficiency and poor iron utilization due to chronic inflammation.⁵¹ Additional long-term complications of RDEB that are most often seen in older children, adolescents or adults include renal failure, osteopenia and osteoporosis, cardiomyopathy, and aggressive squamous cell carcinomas.^7,46

Kindler syndrome

Kindler syndrome (KS) is a rare, autosomal recessive disorder in which trauma-induced blistering begins at birth or early in infancy. Based on clinical and laboratory features, it is often diagnosed as a form of EB in the neonate. However, patients with KS develop progressive poikiloderma and cutaneous atrophy in childhood.⁵³ Photosensitivity is variable. Gingivitis and periodontitis are common mucosal findings. In addition, esophageal and urogenital stenosis can occur. KS is caused by mutations in FERMT1 which encodes fermitin family homolog 1 (kindlin-1), involved in cell–matrix interactions.⁵⁴

Additional considerations

In those cases where neonates present with extracutaneous manifestations requiring surgical intervention, such as pyloric stenosis or respiratory distress in the case of suspected JEB-H, the risks and benefits of surgical intervention must be weighed against the child’s overall prognosis. With careful attention, patients with EB can tolerate intubation (either nasopharyngeal or endotracheal) and anesthesia for procedures.^72,73 Repair of pyloric atresia³⁶ and early placement of tracheostomy tubes²⁹ have been performed successfully in EB patients, but these infants often succumb to other complications of their disease. Thus, comfort care alone is a valid treatment option for infants with EB subtypes that carry a poor prognosis, such as JEB-PA and JEB-H.^31,74

In order to be discharged after birth, infants with EB need to be medically stable. From a dermatologic standpoint, a reasonable goal is no more than 10% skin involvement, minimal development of new blisters, and evidence of adequate feeding and weight gain. In addition, parents or care providers should demonstrate comfort with and competence at changing the baby’s dressings, and support services such as a home health nurse and sufficient medical supplies need to be in place. Infants should have follow-up with care providers who are experienced in managing EB. A multidisciplinary approach is needed to monitor for and treat the many complications that may develop as the child ages.

Protocols for optimal follow-up after discharge are not standardized, but clinic visits at least every 3 months in the first year of life are a good rule of thumb, with more frequent follow-up being needed for infants with severe disease. In addition to monitoring skin involvement, growth and development should be followed closely with the pediatrician. Many infants with EB will lag in motor development, and having a physical therapist and occupational therapist involved in the treatment plan to address gross and fine motor development is important. Due to a high risk for dental complications, visits with a pediatric dentist should also begin in the first year of life.⁷⁵ Any infant with EB and signs and symptoms of anemia, such as fatigue, pallor, and tachycardia, should have blood work performed. However, as anemia is common in severe forms of EB and as the signs and symptoms may be difficult to appreciate, all infants with JEB and RDEB should have a screening complete blood count and iron studies performed by 1 year of age, and repeated every 6–12 months thereafter.

Finally, families of infants with EB should be encouraged to maintain hope as disease-specific treatments that show promise are becoming available. A landmark study demonstrated that keratinocyte stem cells from an adult patient with JEB-nH were genetically corrected and successfully transplanted back to affected areas of the legs, resulting in normal, robust skin during the 1-year follow-up period.⁷⁶ This technique is being investigated as a treatment for RDEB.⁷⁷ Bone marrow transplant has been shown to increase expression of collagen VII at the basement membrane zone and reduces the severity of disease, although there is significant risk with this approach.⁷⁸ Replacement of collagen VII,^79,80 either locally or systemically, is another therapy that is hoped will be available for RDEB on an experimental basis soon.

Linear IgA disease

Linear IgA disease (LAD, also known as linear IgA bullous dermatosis, chronic bullous disease of childhood) is the most common AIBD of childhood, typically occurring between 6 months and 5 years of age. Disease onset in the neonatal period has been reported, albeit infrequently, and case reports suggest that neonatal onset can be associated with significant morbidity due to mucosal involvement.^91–93 As the name suggests, the diagnosis relies on immunopathological findings: the exclusive or predominant presence of linear deposits of IgA along the BMZ.⁹⁴ Disease onset is typically abrupt, and may be associated with pyrexia, malaise or other prodromal symptoms.⁹⁵ The mean disease duration is 3–5 years, after which the majority of patients achieve complete remission, and disease rarely persists or recurs in adulthood.^96,97

Clinically, LAD is characterized by the presence of clear or hemorrhagic vesicles, bullae or erosions that vary in size, arising from normal skin or urticarial plaques (Fig. 11.15). New lesions tend to occur at the periphery of older ones forming rosettes or clusters.⁹⁸ Bullae are usually tense, and may mimic lesions of bullous pemphigoid (Fig. 11.16). Lesions are predominantly localized to the lower abdomen, neck and perineal areas, with prominent anogenital involvement. Mucosal involvement is more common in the pediatric setting, affecting up to 76% of children, and may be associated with significant morbidity.^99,100 Oral lesions usually present as erosions and ulcerations, and predominantly affect the hard and soft palate, buccal mucosa and gingiva, with relative sparing of the lips. Ocular involvement is also common in the pediatric setting and occurs in up to 65% of patients, with scarring occurring in 43% of patients who report symptoms.¹⁰¹ It may appear as isolated conjunctival injection and can result in scarring with subconjunctival fibrosis and symblepharon formation.^101,102 Other mucosal membranes may be involved, and are also at risk of scarring, including the larynx, pharynx, trachea, esophagus, bronchial tree, and vaginal mucosae.

Fresh blisters on routine histopathology may be suggestive, but not diagnostic, showing subepidermal blistering with an inflammatory infiltrate consisting of neutrophils and eosinophils. Skin biopsy of perilesional unaffected skin for direct IF is mandatory to establish the diagnosis. IF shows a linear deposit of IgA antibodies at the BMZ. C3, IgG or IgM may be seen as well, but the predominance of IgA is needed to establish the diagnosis.⁹⁸ The multiplicity and complexity of target antigens is likely due to epitope spreading. Circulating IgA antibodies, although usually present in low titers, are detectable in 80% of children, a higher proportion than occurs in adults.^100,103

Therapeutic options include potent topical steroids for mild cases or mucosal lesions which are often resistant to systemic therapies. Systemic therapy is required until patients enter complete clinical remission, followed by maintenance therapy until the disease remits. Prednisolone (0.5–2 mg/kg per day) is often used first to attain disease control, but should be combined with other therapies and tapered as tolerated in order to minimize adverse effects. Dapsone (0.5–3 mg/kg per day) is considered the treatment of choice beyond the neonatal period. Other options include erythromycin (50 mg/kg per day), IVIG (400–2000 mg/kg per cycle), and tacrolimus 0.03% topically BD. Mycophenolate mofetil (300–600 mg/m²), and cyclosporine (2.5–5 mg/kg per day) have shown good efficacy in older children refractory to other therapies.^104,105

Bullous pemphigoid

Childhood bullous pemphigoid (BP) is an IgG-mediated subepidermal bullous disorder. It is rare in childhood, with peak prevalence in the 1st and 8th years of life.^106–109 Some 50% of cases present under 12 months of age, with the earliest reported cases occurring at 2 months of age.^108,110 Mucous membrane involvement, acral distribution, and facial involvement appear to occur more frequently in childhood BP, and lesions tend to involve the palms and soles of infants of less than 1 year (Fig. 11.17).¹⁰⁸ Lesions of BP may begin as urticarial, irregularly bordered plaques reminiscent of erythema multiforme, evolving into widespread, tense blisters on erythematous or clinically unaffected skin, frequently located on the trunk and flexural areas (Fig. 11.18).¹⁰⁹ Pruritus is often prominent. A limited vulvar variant is recognized and can be mistaken for sexual abuse.¹¹¹ The course of childhood BP is usually indolent, and once appropriate treatment is instigated, remissions typically occur within 1 year.^112,113

The target autoantibodies in BP are the 180 kD or 230 kD bullous pemphigoid antigens (BP180 or BP 230).¹⁰⁶ Lesional histology shows subepidermal blister formation with an intact epidermis and a predominantly eosinophilic infiltrate. Direct IF is characterized by linear deposition of IgG and C3, however IgM and IgA may be found.^114,115 Indirect IF can show circulating autoantibodies directed against the epidermal side of 1.0M sodium chloride (NaCl) split skin.

Oral prednisolone (0.5–2 mg/kg per day) is the mainstay of therapy, but erythromycin, IVIG, and dapsone may be useful alternative or adjunctive therapies.^{108,110,116–119}

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is a rare AIBD characterized by autoantibodies to type VII collagen, the major component of anchoring fibrils. EBA has been reported as early as 3 months of age. It is exceptionally rare; less than 50 cases have been reported in the pediatric literature.^120,121 Two phenotypes of EBA are recognized: the classic presentation with a noninflammatory mechanobullous phenotype, resembling the dystrophic form of inherited EB; and less frequently an inflammatory presentation that mimics other AIBD. Children less than 5 years of age are more likely to present with the inflammatory type, and mucosal involvement is also thought to occur more frequently.¹²¹ Ocular involvement, which may be associated with visual loss, has been reported to occur more commonly in IgA-mediated EBA. The IgA variant, however, accounts for a minority of childhood EBA; the majority are mediated by IgG autoantibodies.^{102,122–124} In contrast to adult EBA, which is often refractory to therapy, children with EBA typically respond well to therapies such as low-dose corticosteroids and dapsone.¹²⁵ Other therapeutic options include colchicine, dapsone, infliximab, and IVIG.^126,127

Bullous systemic lupus erythematosus

The bullous variant of systemic lupus erythematosus (SLE) is rarely seen in children, although an isolated case of neonatal lupus erythematosus presenting with overt blistering has been reported.¹²⁸ Autoantibodies to type VII collagen have been reported as pathogenic in bullous SLE, however autoantibodies to a variety of other molecules involved in dermal–epidermal adhesion have been found, including BP antigen 1, laminin-332, and laminin-331.^129,130 Bullous SLE may be difficult to differentiate from EBA, as the direct IF pattern is similar; patients should fulfill diagnostic criteria for SLE to establish the diagnosis.¹³¹

Non-autoimmune bullous disorders

A range of other disorders may present with blisters and erosions in addition to other changes and must be considered in the differential diagnosis. Toxin-producing strains of Staphylococcus aureus (see Chapter 12) can produce localized flaccid bullae that quickly progress to erosions (bullous impetigo) or the generalized eruption of staphylococcal scalded skin syndrome. Viral infections with herpes simplex virus and varicella zoster virus (see Chapter 13) produce grouped or isolated vesicles on a base of erythematous skin. In any ill-appearing child with the abrupt onset of blisters, toxic epidermal necrosis (TEN) and Stevens–Johnson syndrome (SJS) (see Chapter 20) must be excluded. Wells syndrome, a rare disorder characterized by pruritic, erythematous plaques mimicking cellulitis, can also sometimes be bullous (see Chapter 20).

Mastocytosis (see Chapter 28) is a disorder of clonal mast cell proliferation that commonly affects the skin. Three cutaneous variants are recognized: mastocytomas (discrete plaques or nodules), maculopapular (often called urticaria pigmentosa) and diffuse cutaneous mastocytosis (DCM). All cutaneous variants can manifest with cutaneous blistering,^132–136 although DCM is most likely to be problematic. In DCM, there is widespread erythroderma and blistering which usually presents in the first year of life, with a congenital presentation in 25% of cases.¹³⁷ The clinical presentation is broadly divided into two phenotypes; patients presenting with blistering on a background of erythema and urticarial plaques, or presentation with indurated leathery skin and minimal blistering. Sudden release of mast cell mediators results in pruritus, flushing, urticaria, blistering, tachycardia, hypotension, wheeze, diarrhea, abdominal pain, melena, and shock.¹³³ Mortality in the neonatal period has been reported as high as 23% of cases, due to overwhelming mast cell degranulation, sepsis or mast cell leukemia.¹³⁸

Blistering in mastocytosis usually resolves by 1–3 years; skin lesions improved in 71% in one series by 1 year of life, and 90% are symptom-free by puberty.¹³⁹ Therapeutic strategies aim to control symptoms of mast cell degranulation and to block their proliferation. The key to management is avoidance of agents that trigger histamine release, including heat, friction, polymyxin B sulfate, narcotics and NSAIDs. Symptomatic approaches include non-sedating H1 and H2 antihistamines, topical and systemic corticosteroids, oral sodium cromoglycate for intestinal complaints, ketotifen, PUVA, and antiseptic measures because of high risk of sepsis.

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