In the neonatal period, disorders may sometimes present with hyperkeratosis and desquamation of the skin. The differential diagnosis for hyperkeratosis and desquamation in the neonatal period is broad and includes infectious, genetic, inflammatory, immunodeficiency, and metabolic causes. Rarely, these disorders may also present with erythroderma, or generalized skin erythema affecting at least 90% of the body surface.1 Scaling is a commonly associated symptom of erythroderma. Although the frequency of hyperkeratotic and desquamating disorders in the newborn period is unknown, the incidence of neonatal erythroderma has been estimated2 to be 0.11%.
These skin changes are nonspecific and do not indicate any particular diagnosis; thus, this constellation of findings may prove to be challenging both diagnostically and therapeutically. Clinical clues and diagnostic testing can be of great importance in reaching a diagnosis. Management can be extremely challenging, as often these neonates are quite ill. Both general management principles and treatments aimed at the specific disorder are vital to the care of these babies. Despite advanced care, the mortality rate3 in these patients, particularly those with erythroderma, can approach 15%. Factors contributing to this high mortality rate are large ratio of surface area to body mass with subsequent increased transepidermal fluid loss and increased susceptibility to infection.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS), which has also been called pemphigus neonatorum, is a toxin-mediated blistering condition of the skin that primarily affects infants and young children. Neonatal SSSS and outbreaks in neonatal intensive care units are also known to occur.4 The more localized form of the disease is called bullous impetigo; the more widespread counterpart with generalized involvement is called SSSS.
The initiating staphylococcal infection may start with impetigo that is localized, most commonly in the nares, eyes, or umbilicus in neonates. Toxins produced by the Staphylococcus aureus bacteria, exfoliative toxins A and B, are released by the bacteria. These toxins target desmoglein 1, which is a protein vital in epidermal cell-to-cell adhesion.5 Infants and young children are most susceptible because of a lack of protective antibodies and immature renal clearance of these toxins. Clinical manifestations are that of initial facial and perioral erythema followed by superficial blisters that may progress rapidly to generalized erythroderma and the appearance of “wrinkled” skin. This is often more noticeable around the mouth and in skin folds.4 Affected infants are usually fussy.
Other disorders that may be considered in the differential diagnosis are few, although it may be mistaken for Kawasaki disease, viral exanthema, drug eruption, or toxic epidermal necrolysis. Many of these do not usually occur in the neonatal period.
Often, SSSS is a clinical diagnosis. Any cultures taken from the bullae are expected to be sterile as blisters are directly caused by the toxin and not the bacteria itself. Biopsy can be performed but is rarely required. Histopathology will show an intraepidermal split above or below the granular layer with minimal inflammation.5
Management of SSSS is with antistaphylococcal intravenous antibiotics. Supportive care for pain control, careful handling of the patient’s skin, and prevention of secondary infection is often required. Bland emollients such as Aquaphor or white petrolatum should be used to areas of denuded skin. Close attention to fluid balance and body temperature is critical, particularly in the neonatal period.
Overall prognosis for SSSS is quite good. The most common complications are rare and include cellulitis, sepsis, and pneumonia, with a 3% mortality rate.5 The skin will usually heal rapidly within 2–3 weeks without scarring. Desquamation of the palms and soles can continue for an additional 2–3 weeks after the initial disease. Long-term follow-up is usually not needed.
Congenital Cutaneous Candidiasis
Congenital cutaneous candidiasis is a rare condition. Less than 100 cases have been reported in the literature.6 Although 20%–25% of pregnancies are complicated by vaginal candidiasis, less than 1% of these will proceed to ascending infections involving the placenta and amnion.6 Preterm infants are more susceptible to the presence of the disease, with increased risk of disease severity, in large part because of immature keratinization of the skin.
When congenital candidal infection occurs, small erythematous macules, papules, and pustules erupt within the first week of life. These may then become confluent and progress to exfoliative erythroderma.7 Nail dystrophy may be present.8 The oral cavity and diaper area can be spared. There can be severe systemic involvement, especially in premature or small-for-gestational-age neonates.
Other infectious skin diseases may present similarly, including SSSS, herpes simplex virus infection, varicella zoster virus infection, and syphilis. Neonatal blistering skin conditions such as epidermolysis bullosa, congenital ichthyosiform erythroderma (CIE), and incontinentia pigmenti may also be considered. Additional benign considerations include neonatal pustular melanosis and miliaria. However, neonatal candidiasis is usually acquired from the birth canal, develops after the first week of life, and tends to involve the intertriginous areas, including the diaper area. Erythroderma is not typical of neonatal candidiasis.
Diagnosis of congenital cutaneous candidiasis can be made at the bedside by demonstrating spores and pseudohyphae on skin scraping of a pustule. Biopsy of the skin may also be performed, demonstrating fungal elements in the stratum corneum, but is often unnecessary.9
Any neonate who has signs of systemic candidiasis should be pan cultured. Full-term infants without systemic disease can usually be treated successfully with topical antifungal therapy. Neonates who are preterm and those who are systemically ill will require parenteral antifungal therapy.
Neonates with congenital candidiasis limited to the skin and without systemic symptoms do well with quick resolution of skin findings without sequelae. Neonates with systemic infection have a much more guarded prognosis, particularly those who are less than 1 kg. These infants have a high mortality rate6 of up to 40%. Otherwise, follow-up is not necessary after the infection is cleared and the skin normalizes.
The ichthyoses (Table 66-1) are a heterogeneous group of disorders of abnormal cornification that results in scaly skin. Many of these disorders present in the neonatal period or early childhood. The nonsyndromic ichthyoses are diseases that are primarily limited to the skin and do not have significant systemic involvement.
Table 66-1Ichthyoses ||Download (.pdf) Table 66-1Ichthyoses
| ||Harlequin Ichthyosis (HI) ||Collodion Membrane (Self-Healing) ||Congenital Ichthyosiform Erythroderma (CIE) ||Lamellar Ichthyosis (LI) ||Epidermolytic Ichthyosis (EI) ||X-Linked Ichthyosis (XLI) |
|Inheritance ||Autosomal recessive ||Unknown ||Autosomal dominant ||Autosomal recessive ||Autosomal dominant ||X-linked recessive |
|Genetics ||ABCA12 || |
|TGM1 || |
|Incidence ||1 in 1 million ||Rare; < 300 reported ||1 in 300,000 ||1 in 300,000 to 500,000 ||1 in 100,000 to 300,000 ||1 in 6000 |
|Examination findings ||Polygonal hyperkeratotic plaques with fissuring forming an armor-like casing || |
|Erythroderma with fine white scales || |
Ichthyosis with plate-like scales
Later develops hyperkeratotic scales
Dark brown, tightly adherent scales
|Location ||Diffuse ||Diffuse ||Generalized ||Spares central face and flexural areas || |
Flexures and joints typically involved
|Diagnosis ||Clinical || |
|Clinical || |
|Clinical course ||Guarded prognosis || |
Eventual normal skin
|Normal life expectancy || |
Persists throughout life
Risk for heat intolerance and heat exhaustion
Lifelong and debilitating
Risk for significant odor
Skin may improve with age
Increased risk for testicular cancer
|Treatment || |
Bland emollient use
|Supportive care ||Frequent use of skin emollient || |
Frequent use of skin emollient
|Gentle, supportive skin care with bland emollient use || |
Frequent use of skin emollient
Self-Healing Collodion Membrane
Rarely, a neonate may be born with a collodion membrane. The condition generally cannot be detected in utero, and diagnosis is therefore usually made at birth. A collodion baby has a “membrane” covering the entire body that is smooth and taut with a shiny surface. The skin is thick and inelastic with frequent contractures of the joints and eversion of the mouth and eyelids. This sign can signify the presence of a significant underlying skin disorder but may also be seen in a neonate who will not go on to develop a skin disorder, thus termed a “self-healing” collodion baby. The presence of a collodion membrane is rare, with approximately 300 cases reported in the literature (Figure 66-1). Approximately 10%–20% of these babies end up with clear skin.10
Self-healing collodion membrane baby. On presentation, collodion membrane is seen with eventual skin desquamation.
The pathogenesis of the self-healing collodion baby has yet to be fully understood. Several genes, including the transglutaminase 1 (TGM1) gene and ALOX12B, have been implicated but not definitively linked.
The differential diagnosis for the underlying cause of a collodion baby also includes the various types of congenital ichthyoses, namely, CIE, lamellar ichthyosis (LI), epidermolytic hyperkeratosis (EHK), and Sjogren-Larsson syndrome (SLS).
Skin biopsy can aid with diagnosis of an underlying congenital ichthyosis; however, no diagnostic tests are necessary in diagnosing a self-healing collodion baby. Self-healing collodion baby is a diagnosis that is made with clinical observation.
Collodion babies are at high risk for increased transepidermal water loss, electrolyte imbalance, temperature instability, and infection.5 Supportive care with specific attention to maintaining hydration and fluid and electrolyte balance, controlling temperature, and vigilance for infection is important. Keratolytic agents should never be used. Light emollients and wet compresses can aid in peeling of the membrane skin. Ophthalmologic care should be sought to manage eversion of the eyelids. Oral retinoids can be considered for severe collodion babies whose shedding is delayed beyond 3 weeks.
Self-healing collodion babies have a good prognosis with essentially normal skin after the neonatal period. Shedding of the collodion membrane is usually complete within 3 weeks but can sometimes take longer.11 Follow-up is not necessary after skin normalization.
Congenital Autosomal Recessive Ichthyosis
Autosomal recessive (AR) ichthyosis is an umbrella term that encompasses CIE, LI, and harlequin ichthyosis (HI).12
Congenital Ichthyosiform Erythroderma
Congenital ichthyosiform erythroderma is also a frequent cause of collodion membrane; in fact, nearly 50% of collodion membrane babies go on to develop features consistent with CIE.11 Although the true incidence of CIE is unknown, it is likely underreported as the features can be mild and subtle in some patients.
The most common mutations involved in the development of CIE are in the ALOX12B and ALOXE3 genes. Also involved, but less commonly, are mutations in tissue TGM1 and ABCA12. At times, a genetic mutation cannot be found. If a collodion membrane is present at birth, on shedding of the membrane, erythroderma with fine white scales in a generalized distribution is noted. If there is no collodion membrane, the erythroderma and fine white scales usually develop in the first few weeks of life. Patients’ disease ranges in severity.
Lamellar ichthyosis and other congenital ichthyoses can be considered in the differential diagnosis. Diagnosis is usually made on clinical grounds. Skin biopsy may be minimally helpful as findings are not specific. Genetic testing is usually not indicated but useful.
Hydration of the skin is necessary, with regular bathing followed by a good skin moisturization regimen. Petrolatum-based emollients should be used. There may be increased absorption of ingredients that may be added to moisturizers; thus, caution must be used when selecting an emollient. Referral to the Foundation for Ichthyosis and Related Skin Types (FIRST) can be a helpful resource for families.13
The prognosis for patients with CIE may vary depending on phenotype. Minimally affected patients may be able to live as “normal” children, while more severely affected patients will need intensive care of their skin on a daily basis. Life expectancy is normal. Periodic monitoring by a dermatologist may be necessary depending on the severity of disease.
Lamellar ichthyosis is felt to be on a clinical spectrum with CIE. It has an incidence12 of 1 in 300,000 to 500,000. Approximately 20% of collodion babies have underlying LI.11
Lamellar ichthyosis is most often caused by mutations in TGM1, which encodes an enzyme responsible for the integrity and function of the stratum corneum. Patients with LI have thick plate-like scales covering much of the cutaneous surface, most pronounced on the face and lower legs.5 Blockage of the eccrine glands by hyperkeratosis of the skin leads to subsequent diminished ability to sweat and resulting heat intolerance and hyperthermia. Scalp alopecia and ectropion of the eyelids are common features. Nail dystrophy can be present.
The scaling of X-linked ichthyosis (XLI) may be similar in appearance but it is seen in males and should not have associated features of alopecia, with ichthyosis usually sparing the central face and flexural areas.
The diagnosis of classical LI is primarily clinical. Biopsy results from skin are nonspecific, and genetic testing is usually not necessary.
Hydration and moisturization of the skin are necessary in all patients. Topical retinoids can be helpful in reducing scaling, as can other keratolytics, but these should not be used in the neonatal period. Low-dose oral retinoids may also be used in some patients as oral retinoids have been shown to upregulate TGM1 activity. Careful attention must be paid to the eyes, with continued corneal lubrication and involvement by ophthalmology.5 Counseling should be provided to families to educate and prevent heat exhaustion, particularly those that live in hot and humid climates. Referral to FIRST can be helpful for families.13
Most patients have significant difficulty with the thickness of scale on their skin and are often limited in their physical activity. There are also significant psychosocial implications and morbidity. Close follow-up with a dermatologist should be maintained.
Harlequin ichthyosis is the most severe type of AR ichthyosis. It is rare, with an incidence of approximately 1 in 1 million.13 The disorder is inherited in an AR manner and is caused by mutations in the gene encoding adenosine triphosphate binding cassette transporter protein ABCA12.14 Affected neonates present at birth with thick plate-like scales covering the entire body with significant fissuring throughout the cutaneous surface (Figure 66-2). There is frequently associated ectropion and eclabium and sometimes underdevelopment of the nose, ears, and distal limbs.
Harlequin ichthyosis. Severely affected neonate born with extensive fissuring of the cutaneous surface; thick, plate-like scales; ectropion; eclabium; and underdeveloped limbs.
The differential diagnosis is limited. In the mildest forms, it may be confused with a collodion baby. The diagnosis is made on clinical grounds. Genetic testing is not needed but can be obtained for diagnostic confirmation to exclude other conditions, such as self-healing collodion baby.
Oral retinoids can be started on the first day of life and likely improve prognosis. However, initiation of therapy is individualized depending on the neonate’s likelihood for longevity and compatibility with life. A significant amount of supportive care is necessary in the neonatal period, including assistance with ventilation, maintenance of hydration, fluid and electrolyte balance, pain control, and prevention of secondary infection and sepsis. The use of bland emollients is central to skin care. Ophthalmology must be involved closely for management of severe ectropion.
In the past, HI was nearly universally fatal, but with improved supportive care and the use of oral retinoids,14 survival can approach 50%. Prognosis of affected neonates is still poor, and survivors have lifelong difficulty with CIE-like skin, developmental delay, and visual difficulties.14,15 Those patients who survive will need lifelong monitoring by a dermatologist and possibly an ophthalmologist.
Epidermolytic ichthyosis (EI) is an autosomal dominant disorder that was previously known as bullous CIE or EHK. It is a rare disorder and is estimated to have an incidence16,17 of 1 in 100,000 to 1 in 300,000.
Epidermolytic ichthyosis results from mutations in keratin 1 or keratin 10. Although it is autosomal dominant, half of cases can be new or sporadic mutations.18 Seventy-one percent of patients have lesions at birth and present with erythema, blistering, and superficial erosions in the newborn period.16 Beyond the neonatal period, patients develop hyperkeratotic spiny ridges that are easily infected with bacteria. Older patients have a distinct odor.
Ichthyosis bullosa of Siemens is a variant of EHK caused by mutation in keratin 2e. Because keratin 2e is expressed in the upper half of the spinous layer of the epidermis, the blistering is more superficial that seen in EKH. Furthermore, the compensatory hyperkeratosis is less and skin thickening is clinically milder.
Early in the neonatal period, other blistering disorders may also be considered. These include epidermolysis bullosa, SSSS, Omenn syndrome, and toxic epidermal necrolysis.
Epidermolytic ichthyosis is a clinical diagnosis that is usually confirmed by histopathologic analysis. Skin histology is fairly typical and shows hyperkeratosis, separation, and vacuolization in the epidermis. Electron microscopy shows clumping of intermediate filaments within the keratinocytes in the epidermis.
In the neonatal period, children should be handled with care because of skin fragility. The babies should be placed in an isolette with humidified air and temperature control and monitored for dehydration and secondary infection. Skin care should consist of bland with ointment-based moisturizer emollients, nonadherent dressings, and padded wrapping. Referral to support groups such as FIRST should be offered to parents.
Patients with EI may have physical and psychological morbidity because of their skin disease. The odor associated with the hyperkeratotic scale can be significant and debilitating. With diligent wound care, life expectancy may be normal. Patients should be monitored by a dermatologist throughout their lives.
X-linked ichthyosis is inherited in an X-linked recessive manner. It is the second most common ichthyosis after ichthyosis vulgaris and is estimated to have a frequency of 1 in 6000 male births.18 It has rarely been reported to occur in female offspring of affected males or female carriers.19
X-linked ichthyosis is caused by a mutation in the gene encoding steroid sulfatase (STS), also known as arylsulfatase C. Defects in STS result in compromise of the stratum corneum, which then results in excess scaling. Seventy-five percent of infants with XLI will have skin manifestations within the first week of life. This consists of polygonal translucent scales that develop into large, dark brown, tightly adherent scales primarily on the extensor surfaces and trunk.20 These scales have a “dirty” appearance. In infancy, the scalp, preauricular areas, and neck are affected. Patients can also have hypohidrosis, ocular abnormalities, and cryptorchidism.
X-linked ichthyosis may have a presentation similar to atopic dermatitis or other ichthyoses, such as ichthyosis vulgaris and LI.
Family history and birth history are important for the diagnosis of XLI. Affected neonates may have male relatives on the mother’s side with ichthyosis, low-to-absent levels of estriol may be present on triple screen during pregnancy, and there may be a history of prolonged labor.21 The diagnosis of XLI can be confirmed with genetic testing of the STS gene. A skin biopsy is usually not helpful as histopathologic changes are nonspecific.20
The majority of patients with XLI have disease that is limited to the skin. Skin-directed therapy is aimed at hydration of the skin and reduction of scaling. Soaking baths and bland emollients should be used daily. Topical keratolytics such as lactic acid, salicylic acid, and retinoids can be used as well. Patients with extracutaneous complications such as cryptorchidism or deep corneal opacities should be managed by the appropriate subspecialists. Patients are also at increased risk of testicular cancer and thus families should be instructed on regular testicular self-examinations.
X-linked ichthyosis is a lifelong disease, but skin symptoms generally improve with age. Long-term follow-up with a dermatologist is indicated.
The syndromic ichthyoses, as opposed to the nonsyndromic ichthyoses, are disorders with multisystem disease where 1 major manifestation is in the skin. Several of the most common syndromic ichthyoses that may present in the neonatal period are discussed here.
Netherton syndrome is a rare AR disorder. Its estimated frequency is 1 in 50,000 to 1 in 100,000. Eighteen percent of cases with neonatal and infantile erythroderma had Netherton syndrome.3
Netherton syndrome is caused by a mutation in the SPINK5 gene that encodes the serine protease inhibitor LEKTI. This results in a compromised skin barrier. At birth, neonates with Netherton syndrome usually present with an exfoliative erythroderma. Individuals with Netherton syndrome who have exfoliative erythroderma at birth can also have failure to thrive, hypernatremia, hypothermia, and recurrent infections, which may be life-threatening.22 Many infants will go on to develop characteristic polycyclic and erythematous plaques with double-edged scale, also called ichthyosis linearis circumflexa. Asthma, food allergy, and elevated immunoglobulin (Ig) E level are often seen in patients with Netherton syndrome.
When presenting with erythroderma, other disorders that can cause neonatal erythroderma should be considered. These include generalized seborrheic dermatitis, SSSS, metabolic disorders, and congenital psoriasis.22,23
The most specific clinical finding in Netherton syndrome is a hair abnormality called trichorrhexis invaginata. This can be visualized under light microscopy and dermoscopy. This, however, may not be present during the neonatal period, making the diagnosis difficult. Skin biopsy is often nonspecific. Genetic testing for SPINK5 mutations may be done for children suspected to have this disorder.
Extreme caution must be used when applying topical preparations to the skin of patients with Netherton syndrome as transcutaneous absorption is greatly increased. The use of topical tacrolimus is strongly discouraged in these patients because immune-suppressing levels can be reached from topical application alone.
In the neonatal period, intensive medical care, including close attention to hydration, thermoregulation, electrolyte balance, and prevention of infection, is necessary. Regular moisturization is a necessary intervention. Low-dose systemic retinoids may be indicated in some patients. Other systemic symptoms such as infection, growth failure, and allergies must be managed as well. Lifelong follow-up with close attention to the status of the skin barrier is necessary.
Keratitis, Ichthyosis, Deafness Syndrome
Keratitis, ichthyosis, deafness (KID) syndrome is an extremely rare syndrome, with approximately 100 cases reported in the literature. Although it may be inherited in an autosomal dominant manner, most cases are caused by new mutations.
The most common cause of KID syndrome is a missense mutation in connexin 26. These mutations lead to the main features of the disorder: keratitis, ichthyosis, and deafness. Patients with KID syndrome may present with erythroderma at birth that then fades to erythema with hyperkeratotic plaques within days to weeks.24 There is often alopecia, palmoplantar hyperkeratosis, varying amounts of alopecia, and characteristic facies with deep grooves. Hearing loss is congenital bilateral neurosensory hearing loss; photophobia and vascularizing keratitis usually develop with time. Patients are susceptible to superinfection, particularly with Candida.24
As KID syndrome has fairly unique defining characteristics, the diagnosis is fairly easy to make. In the neonatal period when the only known manifestation may be erythroderma, other causes of neonatal erythroderma as discussed previously should be considered.
The diagnosis is suggested by the constellation of clinical findings. Histopathology on skin biopsy is nonspecific. Confirmation can be obtained by testing for connexin 26 genetic mutation.
Regular moisturization and use of keratolytics is recommended. Systemic retinoids may be helpful in some severely affected patients. Oral fluconazole has also been reported to be successful in the treatment of candidiasis in patients with KID syndrome.
Patients have lifelong disease and require regular surveillance by various specialties. There can be morbidity and mortality from superinfection and poorly controlled patients. A dermatologist will monitor for the possible development of squamous cell carcinoma and other tumors of the skin. Ophthalmology longitudinal follow-up is also necessary because of vascularizing keratitis.
Trichothiodystrophy (TTD) is also known as IBIDS for ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature. PIBIDS is also used, where the P stands for photosensitivity. It is inherited in an AR manner and is present worldwide.18
Genes that are involved in nucleotide excision repair are responsible for the development of TTD. ERCC2 and ERCC3 are most frequently implicated. These mutations lead to the constellation of findings listed, although not all patients have all of the manifestations. Low sulfur content is seen in the hair because of a decrease in sulfur-containing amino acids. Ichthyosiform erythroderma or fine desquamation is noted at birth or in the first few months of life.25 Newborns may have congenital alopecia and collodion membranes. Diffuse alopecia with fragile hair shafts, intermittent hair loss, nail abnormalities, and dental caries may be observed later in life. Patients may also have associated neurologic, ocular, cardiovascular, skeletal, and other findings. Cryptorchidism may be seen in male patients.
The differential diagnosis of TTD includes other genetic disorders associated with photosensitivity. Xeroderma pigmentosa and Cockayne syndrome may both be considered in the differential diagnosis, although characteristic features of both of these entities are usually seen.
Abnormalities of the hair shaft are paramount to the diagnosis of TTD. With light microscopy, transverse fractures of the hair shafts can be seen. With polarizing microscopy, a characteristic “tiger-tail” pattern of alternating light and dark bands is seen. This pattern may not be seen in the neonatal period, thus making diagnosis in that age group difficult.
Photoprotection and moisturization are the mainstay of therapy for the skin.
Prognosis and outcome are dependent on the degree of skin and systemic involvement. Infection may lead to mortality early in life.
Sjogren-Larsson syndrome is a rare disorder that is most common in Sweden, where its prevalence is 0.4 per 100,000 people.26 It is inherited in an AR manner and presents at birth.27
Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene, which results in interference of epidermal permeability and in the biosynthesis of epidermal lipids. This results in erythema and ichthyosis at birth, followed by thickening of the skin with accentuated skin markings particularly in flexural areas. Skin findings are especially noticeable around the umbilicus and in flexural folds. Individuals are extremely pruritic. Older patients will develop neurological symptoms, specifically spastic diplegia, and will develop perifoveal glistening white dots of the eyes.
Before the appearance of neurologic and ocular symptoms, other ichthyoses such as CIE and other AR ichthyoses, can be considered. DNA-based molecular testing is used to diagnose SLS. Skin biopsy findings are nonspecific. Eye examination findings of glistening perifoveal white dots are supportive of the diagnosis.
Management of SLS requires multidisciplinary care from dermatology, ophthalmology, neurology, and orthopedics specialties. Aggressive physical therapy should be implemented early. Leukotriene inhibitors may be beneficial. Patients are debilitated and have increased risk of mortality. Follow-up from the specialists mentioned should be lifelong.
Conradi-Hünermann-Happle (CHH) is a rare X-linked autosomal dominant disease. There are no published data on its frequency, but it has been estimated at 1 in 200,000.
Most cases of CHH are caused by a mutation in the gene that encodes emopamil-binding protein (EBP). Mutations in EBP cause a severe disturbance in cholesterol biosynthesis, leading to clinical defects. At birth, patients often have significant erythroderma that follows the lines of Blaschko. Within a few months, this usually resolves but leaves behind follicular atrophoderma, pigmentary changes, and scarring alopecia on the scalp. Patients have lifetime ichthyosis on the extremities. Nonskin findings that are also seen include stippled calcification of the bone with various skeletal defects.12 Other causes of neonatal erythroderma may be considered but should not have involvement primarily in the lines of Blaschko.
Histologic features are often nonspecific, but in the neonatal period may show calcification in follicular keratosis, which is indicative of CHH. Electron microscopy may show cytoplasmic vacuoles of keratinocytes in the epidermis.
Management is similar to that for other causes of neonatal erythroderma.
Skin disease usually improves with age. Erythema resolves after the first few months of life, whereas ichthyosis often persists. Partial alopecia is sometimes the only persisting feature into adulthood. Patients should have close orthopedic follow-up.
Primary immunodeficiency syndromes can present with variable skin findings, including erythroderma, in the neonatal period. They account for approximately 30% of all neonatal erythroderma.2
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is a group of heterogeneous immunodeficiency disorders, the most common of which are the X-linked recessive and AR forms. Seventy-five percent of those affected are males.
There are multiple different mutations that cause the clinical phenotype of SCID. Most commonly, mutations in the γ chain of the interleukin 2 receptor are seen, but there are at least 10 other mutations that cause SCID.28 Patients may present with erythroderma or generalized seborrheic dermatitis. Affected infants may also have failure to thrive, diarrhea, and increased susceptibility to infections in the neonatal period.
Patients may also present with graft-vs-host disease (GVHD). Nearly all neonates with GVHD have underlying T-cell immunodeficiency, many of whom will have SCID. GVHD presents as an asymptomatic generalized eruption caused from engraftment of maternal lymphocytes or from lymphocytes from nonirradiated blood products.
The differential diagnosis includes causes of neonatal erythroderma and other immunodeficiency syndromes, such as Ommen syndrome.
The diagnosis of SCID is made by measuring lymphocyte count and the presence of T lymphocytes. Further classification is achieved with fluorescence-activated cell-sorting analysis and with confirmation through genetic testing. The diagnosis of GVHD is usually made on skin biopsy.
Patients with SCID are quite ill. There should be close surveillance for the development of infection. Without intervention, most individuals will die by the age of 2. Stem cell transplantation is the treatment of choice and can lead to significantly improved survival if done early in life. Lifelong close follow-up is necessary.29
Ommen syndrome is a variant of SCID caused by mutations in the RAG1 and RAG2 genes in the majority of cases. It often presents similarly with an exfoliative dermatitis and erythroderma in the setting of eosinophilia and elevated IgE.30 Alopecia and significant lymphadenopathy may also be present. Lymphocyte count can be misleading in Ommen syndrome as they may have normal-to-high lymphocyte count, but humoral immunity is usually depressed while IgE level is quite high.30,31 Treatment is similar to that for patients with SCID.
Although psoriasis occurs commonly in childhood32 with an incidence of 40 per 100,000, congenital presentations are quite rare. However, psoriasis is a fairly common underlying reason for erythroderma.
The pathophysiology of the development of psoriasis is still being elucidated, but there is a complex epidermal and immunologic interplay between T lymphocytes and interleukins. This leads to characteristic well-defined erythematous skin lesions with overlying red scale. In the neonatal period, it most commonly presents as erythroderma, seborrheic dermatitis type of eruption, or diaper dermatitis.33,34
Other causes of neonatal erythroderma as discussed previously should be considered. Seborrheic and atopic dermatitis may be in the differential diagnosis in the neonatal period.
Psoriasis is usually a clinical diagnosis. Skin biopsy is frequently diagnostic and can be helpful, but similar histopathologic changes can be seen in disorders such as Netherton syndrome and immunodeficiencies in the neonatal period.23
Topical corticosteroid medications, vitamin D analogues, and liberal use of emollients are the initial mainstay of therapy for psoriasis in the pediatric population. If erythroderma is present, close attention should be paid to the patient’s hydration and calcium status.
Psoriasis is usually a lifelong condition. Patients who present with neonatal erythroderma tend to have more severe disease and a poorer overall prognosis when compared with other patients with psoriasis.
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