Cutaneous features

Collodion babies are encased at birth in thickened, shiny, variably erythematous skin that resembles cellophane (Fig. 19.1). The collodion baby (Figs 19.1, 19.2) is the phenotype at birth of several ichthyotic disorders, but variable severities of autosomal recessive congenital ichthyoses (ARCI, non-syndromic) are the eventual phenotype in most patients.² Others (syndromic forms) include Sjögren–Larsson syndrome, Conradi–Hünermann syndrome, trichothiodystrophy, and neonatal Gaucher disease.³ In 5–6% of collodion babies, normal-appearing skin replaces the collodion membrane, and these babies have the mildest form of ARCI, termed spontaneously healing, self-healing, or self-improving collodion baby.⁴

Extracutaneous features

Despite the thickening of the stratum corneum, the collodion membrane is actually a poor barrier, which can result in excessive transcutaneous fluid and electrolyte loss with resultant hypernatremic dehydration,^5,6 increased metabolic requirements, and temperature instability owing to increased evaporative cooling. Collodion babies are often premature, and the combined skin disorder and prematurity further increase the risk of complications. In addition, numerous cutaneous fissures may be present which, together with the poor skin barrier, increase the risk of the skin being a site of entry for bacteria and subsequent sepsis. Infection may also be difficult to diagnose owing to the intrinsic temperature instability and fluid imbalances associated with the underlying skin condition. Aspiration of squamous material in the amniotic fluid may lead to neonatal pneumonia.⁷ In addition, the thickening of the skin may restrict movement, making sucking, eye closure, and rarely respiration, difficult.

Etiology and pathogenesis

The underlying basis for collodion babies is varied, reflecting the different forms of ichthyosis that present as collodion babies, and these are discussed below. The most common cause is mutations in transglutaminase 1 (TGM1). The self-healing collodion baby phenotype was first shown to be due to mutations in TGM1.⁸ In two affected siblings, increased hydrostatic pressure significantly reduced the activity of the mutant enzyme, suggesting that this pressure both traps water molecules and locks the mutated enzyme in an inactive trans conformation in utero. After birth, these water molecules are removed and the enzyme is predicted to isomerize back to a partially active cis form, explaining the dramatic improvement of this skin condition.⁸

Subsequent publications have shown that the ‘self-healing’ variant can reflect underlying mutations in ALOX12B or ALOXE3, in addition to TGM1.⁹

Differential diagnosis

Several conditions can result in the collodion baby phenotype (Box 19.2). Occasionally, severe cases can be confused with harlequin ichthyosis.

Treatment and care

Collodion babies should be placed in high-humidity environments to increase hydration, and bland emollients should be applied (see Box 19.1). Electrolytes should be monitored,⁵ as should fluid intake and output. The membrane usually sloughs during the first month of life (Fig. 19.2). The use of topical keratolytic agents should be avoided in view of the increased potential for toxicity resulting from absorption through the compromised permeability barrier.⁵

Cutaneous features

Ichthyosis vulgaris is one of the most common genetic disorders of skin, occurring in approximately 1 in 250 individuals, based on a survey of healthy English schoolchildren.¹⁰ In contrast to other forms of ichthyosis, ichthyosis vulgaris does not manifest during the neonatal period. The condition usually appears after 3 months of age as fine, light-colored scales that are larger and coarser on the lower extremities. Palmoplantar markings are accentuated (hyperlinearity).

Extracutaneous features

There is an association in some cases with atopic asthma and rhinitis in later life, and ichthyosis vulgaris is associated with a strong risk for atopic dermatitis.

Differential diagnosis

In affected boys, ichthyosis vulgaris in the young infant may need to be distinguished from X-linked recessive ichthyosis (see below).

Treatment and care

In the neonatal period no specific care is necessary. Good skin care with regular emollients and the avoidance of irritants such as detergents is advisable, as these infants tend to have lifelong dry skin and a high incidence of atopic dermatitis.¹⁰

Cutaneous features

Recessive X-linked ichthyosis (RXLI) is a disorder that affects 1 : 6000–1 : 2000 males. The ichthyosis manifests by 3 months of age in 84% of patients, although only 17% show evidence of exaggerated neonatal desquamation and peeling at birth. Extensor surfaces, the preauricular areas, and the sides of the neck are most severely affected by the large, dark, adherent scales (Fig. 19.3).

Extracutaneous features

RXLI is regarded as syndromic when accompanied by associated manifestations and non-syndromic when ichthyosis is isolated.¹ The absence of steroid sulfatase activity during fetal life also leads to increased fetal production of DHEAS (dehydroepiandrosterone sulfate) and decreased placental estrogen production, which may delay the progression of parturition. Rarely, affected boys have hypogonadism with undescended testes, hypoplasia of the penis and scrotum, and/or failure of normal sexual maturation. The development of testicular cancer has been described in one patient without undescended testes. Approximately 10% of affected boys have a contiguous gene deletion syndrome, a larger deletion which encompasses genes that are contiguous with the steroid sulfatase gene on the terminal short arm of the X chromosome. Deletion of surrounding genes results in mental retardation, hypogonadism, and anosmia (Kallmann syndrome), or a bone dysplasia characterized radiographically by stippled epiphyses (X-linked recessive chondrodysplasia punctata).

Etiology and pathogenesis

X-linked ichthyosis results from mutations of the STS gene encoding steroid sulfatase (arylsulfatase C), particularly deletions (90% of patients). In a study assessing the clinical and molecular features in 28 patients with Kallmann syndrome 1, submicroscopic deletions were found at Xp22.3 in four contiguous genes, VCXA, STS, KAL1, and OA1.¹²

Differential diagnosis

Recessive X-linked ichthyosis (RXLI) in the neonate is not associated with collodion membrane and is therefore distinguishable from other ichthyotic disorders associated with collodion membranes and early skin thickening. Ichthyosis vulgaris is an important differential diagnosis in older male infants and can be distinguished by fluorescent in situ hybridization (FISH) and other genetic analyses. Patients with RXLI, who additionally have a concomitant FLG mutation, have a more severe manifestation of their RXLI. Babies with the rare autosomal recessive disorder, multiple sulfatase deficiency, show scaling typical of RXLI and decreased steroid sulfatase due to a global deficiency of sulfatases. Affected patients also show neurologic abnormalities characteristic of metachromatic leukodystrophy, and features of storage diseases because of the deficiency of several additional sulfatases.

Treatment and care

In the neonatal period, no specific care is necessary, but patients will generally need lifelong skin care advice and appropriate emollients. RXLI may be detected prenatally. The most common scenario for this is in pregnancies not known to be at risk with an abnormal ‘triple screen’ test that detects decreased maternal estriol levels. RXLI may then be confirmed by FISH, STS (steroid sulfatase), and DHEAS for deletions and/or the demonstration of decreased placental sulfatase activity in amniotic fluid cells and increased DHEAS levels in amniotic fluid.

Extracutaneous features

Extracutaneous features include limb reduction, typically asymmetric, and facies with frontal bossing, saddle nose, and malar hypoplasia. Asymmetric, focal stippled calcifications of the epiphyseal regions are common in childhood but typically disappear in adulthood. Bone defects normally begin soon after birth and during childhood as punctate calcifications, as a result of abnormal calcium deposition during endochondral bone formation. They typically appear in the epiphyses of the long bones, but may also develop in the scapulae, clavicles, sternum, ribs, and spinal column. These lesions usually disappear during adulthood.²⁵

Cataracts usually develop later during childhood, but may be present at birth.²³

Etiology and pathogenesis

The underlying molecular basis is mutations in emopamil binding protein (3β-hydroxysteroid-Δ8, Δ7-isomerase), which is involved in cholesterol synthesis (see below).²⁶ Chondrodysplasia punctata can be inherited in both autosomal and X-linked fashion, and may also be the result of an environmental insult, particularly fetal exposure to warfarin.²⁴

Differential diagnosis

The differential diagnosis usually includes two other forms of chondrodysplasia punctata: autosomal recessive rhizomelic chondrodysplasia punctata,²⁴ and X-linked recessive chondrodysplasia punctata with steroid sulfatase deficiency.²⁷ The rhizomelic form is also associated with multiple peroxisomal defects. The ichthyosis occurs in approximately one-third of patients and is poorly described. Affected patients have developmental retardation and tend to die as infants. The X-linked recessive form of chondrodysplasia punctata occurs as a contiguous gene deletion syndrome of Xp, not at the site of Conradi syndrome. The ichthyosis is consistent with recessive X-linked ichthyosis, but stippled epiphyses are associated. Affected infants are deficient in steroid sulfatase activity, and have no peroxisome defects.

Treatment and care

There is no specific care for the neonate with Conradi syndrome.

Extracutaneous features

A variable degree of ipsilateral skeletal hypoplasia is an important feature of CHILD syndrome. As with the skin changes, unilaterality is not absolute and slight changes may be present on the contralateral side. Punctate epiphyseal calcifications may be demonstrable by X-ray, but tend to disappear after the first few years of life. Cardiovascular and renal abnormalities are the major visceral problems in CHILD syndrome, although anomalies of other viscera have been described.²⁹

Etiology and pathogenesis

Biopsy of skin lesions shows epidermal acanthosis with marked parakeratosis alternating with orthokeratosis. Basophilic ghost cells of the granular layer are common. The papillary dermis is often filled with histiocytes showing foamy cytoplasm, resulting in the characteristic histopathologic pattern of verrucous xanthoma. Patients with CHILD syndrome have mutations in 3β-hydroxysteroid dehydrogenase, an enzyme in the cholesterol biosynthetic pathway.³²

Differential diagnosis

The nevus of CHILD syndrome needs to be distinguished from inflammatory linear verrucous epidermal nevus and linear psoriasis by the histopathologic features and the constellation of other clinical manifestations, if present. CHILD syndrome shares features with Conradi–Hünermann syndrome (see above), a disorder that results from mutation in another gene within the cholesterol biosynthetic pathway; shared characteristics include the prevalence in girls with a presumed X-linked dominant inheritance pattern, ichthyosiform erythroderma, limb reduction defects, stippled epiphyses, and peroxisomal defects. The unilateral nature of the nevus and limb deformities helps to distinguish these conditions.

Treatment and care

Patients with CHILD syndrome tend to tolerate topical medications poorly, other than bland emollients. However, dramatic improvement has been demonstrated in adults with twice daily application of compounded 2% lovastatin and 2% cholesterol.³³ Orthopedic involvement may be needed to manage the limb hypoplasia, including with a prosthesis or even partial amputation. Multisystem care may include cardiology and renal evaluation as needed.

Extracutaneous features

Congenital paucity of the bile ducts may be a primary feature leading to hepatomegaly, cholestasis and hepatic fibrosis, without fatty infiltration.⁴² Hepatic involvement varies from transient cholestasis to liver failure. Mild psychomotor delay and bilateral anterior uveal synechiae have been described along with oligodontia, hypodontia and dysplastic enamel.^42,43

Etiology and pathogenesis

This is a rare autosomal recessive disorder caused by homozygous mutations affecting the CLDN1 gene coding for the tight junction component claudin-1, leading to lack of expression of CLDN1 in skin and liver.⁴⁴

Differential diagnosis

Consider this syndrome in any child born with collodion membrane, alopecia and neonatal cholestasis.

Treatment and care

Treatment should follow recommendations for collodion babies. In addition, the hepatic manifestations should be evaluated and managed by specialists.

Extracutaneous features

Several other clinical features may be associated, including low birthweight, nail dystrophy, increased susceptibility to infection, neutropenia, hypothyroidism, nystagmus, optic atrophy, cataracts, and hypertonia.⁴⁶ Not uncommonly, patients die of sepsis during childhood.

Etiology and pathogenesis

Cells from patients with PIBIDS show decreased DNA repair levels similar to those of patients with xeroderma pigmentosum (XP), but the development of skin cancer has not been described. The variable and multiple clinical features of PIBIDS may be due in part to the many genes that can result in this phenotype. TTD syndromes have been shown to be due to phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes,⁴⁷ so that the brittle hair of PIBIDS syndrome may result from decreased transcription of the genes that encode the sulfur-rich matrix of hair and nails. TFIIH is a complex factor that includes the XPD and XPB gene products.⁴⁸ Recently, a 75 amino-acid protein, designated p8 or GTF2H5, was identified as the tenth protein in this complex. This peptide appears to be critical in maintaining TFIIH base levels, which are known to be diminished in TTD-A, where there is an isolated congenital hair defect.⁴⁹ Inactivating mutations in this gene have been shown to cause TTD-A.⁵⁰

Differential diagnosis

In the neonatal period, other causes of collodion membrane need to be excluded. The development of extracutaneous features facilitates the diagnosis.

Treatment and care

Management of the ichthyosis is as usual (see Box 19.1). Prenatal diagnosis of PIBIDS has been performed by DNA repair measurements in amniotic fluid cells, with confirmation by polarizing microscopic analysis of fetal hair.⁵¹

Extracutaneous features

Extracutaneous features of type II Gaucher disease include enlargement of the abdomen due to hepatosplenomegaly, and neurologic signs such as retroflexion of the head, strabismus, dysphagia, choking spells, and hypertonicity. Death usually occurs before the age of 1 year. Although patients with type II typically have acute neurologic progression and those with type III have slow progression, some children have been reported with an intermediate phenotype of delayed age of onset, rapid progression of neurologic disease with refractory seizures, and oculomotor abnormalities.⁶³

Etiology and pathogenesis

Gaucher disease type II is caused by mutation in the gene encoding acid β-glucosidase (GBA). Mutations in this gene also cause Gaucher disease type I and type IIII. Type II is the least common form.⁶⁴

Treatment and care

Management of Gaucher disease type II is palliative, as most children die in the first year.⁶⁵ Knowledge of genotype–phenotype correlation and assessment of biomarkers⁶⁶ may be helpful in delineating severity and counseling parents.

Extracutaneous features

The hearing loss is sensorineural, congenital, and can be progressive. It can be detected in the neonate by brainstem-evoked auditory potential testing. Unlike the auditory changes, ophthalmologic features are progressive and most commonly develop in childhood or early adolescence, although photophobia from birth has been described. The keratoconjunctivitis sicca with corneal vascularization leads to pannus formation and markedly decreased visual acuity.⁶⁸ Approximately 45% of patients have recurrent infections, especially bacterial and candidal infections of the skin, auditory canals, and eyes. Some patients have shown evidence of immunodeficiency, with moderate increases in IgE levels, defective chemotaxis, and absent lymphocyte proliferative responses to Candida albicans.⁶⁹ Death from infection during infancy or early childhood has been reported.⁷⁰

Etiology and pathogenesis

Mutations in the GJB2 gene encoding the gap junction protein connexin 26 are now known to be the cause of KID syndrome in a majority of cases.⁷¹ There does appear to be genetic heterogeneity, however, with mutations also identified in GJB6, which encodes connexin 30.⁷² Connexins are the major proteins of gap junctions, which facilitate efficient cell–cell communication between all cells in multicellular organisms. This system facilitates a synchronized cellular response to a variety of intercellular signals by regulating the direct passage of low-molecular-weight metabolites (<1 kDa) and ions between the cytoplasm of adjacent cells.⁷³ The skin and inner ear have a high number of gap junctions, and in the skin they appear to have a role in the coordination of keratinocyte growth and differentiation.⁷⁴ Mutations in these connexins underlie epidermal disease, sensorineural hearing loss, and peripheral neuropathy.^75,76

Differential diagnosis

Distinction from Clouston syndrome, another connexin 30 gene disorder (see below), can be difficult.⁷² In both conditions the associated keratoderma has a characteristic ‘stippled’ quality that is quite distinctive. Detection of deafness is indicative of KID syndrome. Molecular diagnosis is now relatively straightforward, as connexin genes are small and easily screened for mutations.

Treatment and care

Therapy is supportive, but corneal and cochlear implants⁷⁷ have been successfully performed to treat corneal vascularization and the hearing loss, respectively. Oral fluconazole therapy of recalcitrant fungating candidiasis can result in complete resolution and remission for at least a year.⁷⁸

Extracutaneous features

Hepatomegaly occurs in 46% of patients, although fatty liver may be universal. Liver levels of transaminases are often elevated.^80,81 Almost 70% of patients have either elevated serum creatine kinase activity or muscle weakness, or both, usually mild and first symptomatic in adulthood. Other features may include ataxia, mental retardation, sensorineural hearing loss, and cataracts.

Etiology and pathogenesis

Sections of skin show accumulation of neutral lipids and these non-membrane-bound cytosolic triacylglycerol droplets are also found in liver, muscle, intestinal mucosa, and neutrophils. Vacuolated neutrophils are considered the most consistent marker for neutral lipid storage disease. Mutations in the CGI-58 gene have been found in several families.⁸² The gene product belongs to a large series of proteins most of which are enzymes in the esterase/lipase/thioesterase subfamily. It is widely expressed in skin, lymphocytes, liver, skeletal muscle, and brain.

Differential diagnosis

In the neonate, the ichthyosis may be impossible to distinguish from other CIE phenotypes and possible causes of collodion baby. Diagnosis is usually made by a peripheral blood smear, which shows lipid droplets in granulocytes.⁸³

Treatment and care

Preliminary observations suggest that a low-fat diet, including medium-chain triglycerides, may improve liver function and the skin, especially if begun in early childhood.⁸⁴

Extracutaneous features

Pregnancies are complicated by polyhydramnios, and ultrasound shows opaque amniotic fluid. The birth is premature, and delivery usually takes place at around 30–32 weeks’ gestation. Affected children may suffer from postnatal asphyxia, possibly related to aspiration of amniotic debris.

Etiology and pathogenesis

The pattern on electron microscopy is characterized by membrane aggregations in the upper epidermal cells. Mutations occur in a gene encoding the fatty acid transporter 4 (SLC27A4).⁸⁷ SLC27A4, expressed in the suprabasal layer of the epidermis, encodes a protein, FATP4, that functions as a fatty acid transporter and an acyl coenzyme A synthetase. Reduced function of this protein most likely leads to disturbance of the intercellular lipid layer of the stratum corneum.

Differential diagnosis

The differential diagnosis in the neonatal period includes collodion membrane and harlequin ichthyosis.

Treatment and care

For general neonatal management principles, see Box 19.1.

Extracutaneous features

Affected individuals have a distinctive facies with ocular hypertelorism, brachycephaly, epicanthal folds, macrostomia, and a broadened nasal root. The ear defects can be morphologic, with a cupped appearance and rolled helices, or functional. The colobomas are most commonly retinal, although choroidal colobomas have been described.⁹⁰ Heart defects are common including tetralogy of Fallot, transposition of the great vessels and ventricular septal defect.⁸⁸ Other frequent characteristics include seizures and a wide-based gait. Cleft palate and renal anomalies have been described.

Etiology and pathogenesis

This extremely rare neuroectodermal disorder is thought to be autosomal recessive. Mutations in the PIGL gene have recently been described in five previously reported cases.⁹¹

Differential diagnosis

Other ichthyoses with neurologic manifestations should be considered including Sjögren–Larsson syndrome, Netherton syndrome, Refsum disease, KID syndrome and Tay syndrome. The characteristic ocular, cardiac, ear and dysmorphic features help confirm the diagnosis.

Treatment and care

Affected neonates should have ophthalmology, otorhinolaryngology and cardiology assessments.

Extracutaneous features

There is high neonatal mortality due to respiratory complications, infections through the defective skin barrier, and dehydration.

Differential diagnosis

Severe forms of collodion baby may cause confusion but the diagnosis of harlequin ichthyosis is usually straightforward.

Treatment and care

In general, harlequin babies require vigorous supportive therapy, including a humid environment, the aggressive use of emollients, and careful monitoring of fluid and electrolyte needs. Survival past the neonatal period is uncommon, but reported. Most affected infants have complications, such as systemic infection through fissured skin, difficulties with feeding and respiration, and distal gangrene. Therapy with retinoids may improve the clinical appearance, but the condition at best evolves into a severe generalized ichthyosiform erythroderma phenotype.^94–98 Harlequin ichthyosis is the only ichthyotic condition that may justify the use of systemic retinoid therapy during the newborn period. Treatment with retinoids, first undertaken in 1985, encourages shedding of the grossly thickened skin.^99,100 A recent review of 45 cases reported an overall survival rate of 56%, ages 10 months to 25 years.¹⁰⁰ Death usually occurred in the first three months from sepsis and/or respiratory failure. The administration of systemic retinoids should generally be considered in infants who have survived the first few weeks with intensive nursing support, although a possible exception is in infants with particularly thick areas of plate-like scale causing digital constriction, in which the early use of retinoids may cause faster desquamation, potentially helping to avoid digital gangrene. The parental decision to use retinoids should be made with the knowledge that the resultant ichthyotic condition is severe and associated with a poor quality of life. The recovery of lipid secretion after gene correction of ABCA12 in cultured cells raises hope for future therapeutic approaches.¹⁰¹

Extracutaneous features

Neonates and infants with severe forms of ARCI can face similar problems to those with Harlequin ichthyosis (discussed above). Care needs to be taken to carefully monitor and take corrective action for variations in body temperature, fluid balance and caloric intake. In later childhood, exposure keratitis can result from prolonged ectropion.

Differential diagnosis

Lamellar ichthyosis can be difficult to distinguish from nonbullous congenital ichthyosiform erythroderma in the neonatal period.

Treatment and care

In the neonatal period, general supportive measures are appropriate (see Box 19.1). In older children and adults more potent topical keratolytic preparations and oral retinoids may be appropriate, but these should be avoided in infancy.

Extracutaneous features

Not uncommonly, patients with CIE have associated neurologic abnormalities, and the CIE phenotype may be part of syndromic ichthyosis, such as neutral lipid storage disease (Chanarin–Dorfman syndrome). These patients have failure to thrive and short stature, if severe.

Differential diagnosis

Because of the associated neurological abnormalities and the potential to respond to dietary tailoring, it is important to exclude Chanarin–Dorfman syndrome (see below). However, this is a very uncommon cause of the CIE phenotype.

Treatment and care

See Box 19.1 for general principles of care in the neonatal period.

Cutaneous features

This autosomal dominant disorder manifests in the neonate as widespread areas of denuded skin with only subtle skin thickening and/or scaling (Fig. 19.12). Confusion with other blistering disorders in the neonate is common, particularly epidermolysis bullosa, and secondary cutaneous bacterial infection caused by Staphylococcus aureus often occurs. As patients age, the scaling becomes more verrucous, with large dark scales, particularly at intertriginous sites, and the propensity towards blistering tends to decrease. Annular EI is a subtype characterized by annular polycyclic erythematous plaques over the proximal extremities and trunk.¹¹³

Extracutaneous features

In the neonatal period, infants with EI risk dehydration, electrolyte imbalance, and infection; however, most babies do well and death rarely occurs in neonates.

Etiology and pathogenesis

The gene defects of EI involve abnormalities of keratins 1 or 10,^114,115 the major differentiation-specific keratins of the upper epidermis. These mutations cause the formation of defective keratin filaments, which are functionally responsible for the tonofilament clumping and blistering of this disorder. Prenatal diagnosis has been performed at 20–24 weeks’ gestation by fetal skin biopsy, based on the abnormal clumping of keratin filaments,¹¹⁶ but also by molecular analysis of keratin 10 in an affected family.¹¹⁷

Differential diagnosis

Distinction from epidermolysis bullosa is important in the neonatal period. The principles of care at this stage remain the same, but accurate diagnosis is important in order to properly inform and counsel parents. The histologic appearance of lesional skin confirms the diagnosis, showing vacuolization of the granular and upper spinous layers. Hyperkeratosis, acanthosis, and papillomatosis are variable, but the granular layer is thickened. On electron microscopy the tonofilaments are seen to be clumped in the lower epidermal layers and form perinuclear shells in the granular cell and upper spinous layers.

Treatment and care

The neonate should be managed according to the same broad principles as outlined in Box 19.1, but with additional specific precautions on skin handling of neonates with fragile skin directed by a detailed nursing protocol.

Extracutaneous features

None.

Etiology and pathogenesis

Microscopic examination of skin biopsy specimens shows orthokeratosis, papillomatosis, and acanthosis of the granular and upper spinous layers, with perinuclear vacuolization. Keratinocytes may have two nuclei. Ultrastructural examination shows concentric shells of tonofibrils that encase the nuclei with perinuclear vacuoles, lamellar body abnormalities, and binuclear keratinocytes.¹¹⁸ In two families, the ICM phenotype has been attributed to mutations in keratin 1.^119,120 The condition is genetically heterogeneous; in other families linkage to the keratin gene clusters has been excluded.¹²¹

Differential diagnosis

ICM can be confused with epidermolytic ichthyosis. The lack of erythroderma, blistering, and typical ultrastructural characteristics distinguish these conditions. Epidermal nevi, although they may resemble ICM both clinically and histologically, are distinguishable by their distribution along the lines of Blaschko.

Treatment and care

Neonatal care is outlined in Box 19.1. In older children, keratolytics and oral retinoids may be of value.

Extracutaneous features

There are usually no extracutaneous features, although ataxia has been described.¹²⁴

Etiology and pathogenesis

Mutations in the GJB3 gene which encodes for connexin 31,¹²⁵ and the GJB4 gene which encodes for connexin 30.3,^75,126 have been shown to cause erythrokeratoderma variabilis. There is likely to be further genetic heterogeneity as mutations in these two genes do not account for all cases of EKV.⁷⁵

Differential diagnosis

KID syndrome and Clouston syndrome can cause diagnostic confusion, but palmoplantar keratoderma is not usually a feature of EKV.

Treatment and care

Treatment with systemic retinoids has resulted in improvement or clearing.

Extracutaneous features

None.

Etiology and pathogenesis

In 1996, Clouston syndrome was linked to chromosome 13q11–q12.1,¹³³ and subsequent studies have shown genetic homogeneity to this locus.^134–138 Recently, mutations in the GJB6 gene encoding the β connexin 30 were identified in all available kindreds. Interestingly, only two mutations in GJB6 (G11R and A88V) accounted for all the families tested.¹³⁹ Mutations in GJB6 had previously been identified in a small family with dominant nonsyndromic hearing loss,¹⁴⁰ emphasizing the complexity and diversity of phenotypes caused by dominant-acting connexin mutations.

Differential diagnosis

Distinction from other connexin disorders such as KID syndrome and EKV is important and not always obvious. Alopecia is most commonly associated with Clouston syndrome. The stippled palmoplantar keratoderma is seen in both KID and Clouston syndromes.

Treatment and care

No specific treatment is needed in the neonatal period. In the older child the nail dystrophy can be severe and require podiatric attention. In some individuals the alopecia is a major issue: psychological support and wigs may be required.

Extracutaneous features

There are usually no extracutaneous features.

Etiology and pathogenesis

Skin biopsies show acanthosis with perinuclear vacuolization of granular cells. Ultrastructural studies show lipid vacuoles in the stratum corneum, and increased numbers of swollen mitochondria in granular cells.¹⁴¹ Mutations in loricrin have been shown in some patients with this condition.^142,143 Patients with these mutations may show features of Vohwinkel syndrome (VS), EPS, or CIE with a collodion baby phenotype at birth.¹⁴⁴ Common clinical features include hyperkeratosis of the palms and soles, with digital constriction. Histologic characteristics common to all of these conditions include parakeratotic hyperkeratosis with hypergranulosis, and nuclear accumulation of mutant loricrin. The term ‘loricrin keratoderma’ has been proposed to encompass all these phenotypes.¹⁴⁵ The molecular basis in individuals with no palmoplantar involvement is not clear.

Differential diagnosis

EKV can be distinguished from EPS by absence of palmoplantar involvement and transient migratory plaques (see Table 19.1).

Treatment and care

The use of oral retinoids has been reported to be effective. Topical keratolytics, retinoids, and glucocorticoids have also been used with more variable effects.¹⁴⁶

Extracutaneous features

There are no extracutaneous features.

Etiology and pathogenesis

Olmsted syndrome is caused by a missense mutation in TRPV3, expressed in skin, hair follicles, brain and spinal cord.¹⁵⁸

Differential diagnosis

Olmsted syndrome is usually easily distinguished from other mutilating keratodermas.

Treatment and care

In the neonatal period no specific care is necessary, and indeed keratolytics are best avoided as they do not tend to be helpful. In the older child, regular paring and sometimes grafting is needed to preserve good hand function and the ability to walk.

Extracutaneous features

The ocular manifestations of the disorder appear soon after birth.¹⁶⁰ Photophobia and bilateral tearing commonly occur within the first 3 months of life, and progress to corneal erosions. Ocular lesions are typically transitory, and are subject to intermittent relapses. The corneal lesions are frequently misdiagnosed as herpetic keratitis, and remissions may be misinterpreted as a response to antiviral therapy. The eye changes occasionally develop after the skin manifestations. Varying degrees of intellectual impairment have been described in less than half of affected patients.

Etiology and pathogenesis

Tyrosinemia type II is caused by a deficiency of hepatic tyrosine aminotransferase (TAT)¹⁶¹ that results in elevated tyrosine levels in the plasma and urine.

Differential diagnosis

Diagnosis is occasionally delayed until adulthood. Early diagnosis is important, as appropriate dietary advice can help diminish the severity of neurological and ocular manifestations. In the neonate the corneal erosions can be mistaken for herpetic infections. The focal PPK that occurs later in life can resemble that associated with keratin 6A, 6B, 16, and 17 mutations, but may be more erosive.

Treatment and care

The treatment of choice is dietary restriction of tyrosine with a low-phenylalanine, low-tyrosine diet.

Extracutaneous features

None.

Etiology and pathogenesis

KLICK syndrome is caused by a single-nucleotide deletion in the proteasome maturation protein (POMP) gene leading to aberrant processing of profilaggrin to filaggrin.¹⁶³ Histopathology reveals an epidermis with acanthosis, hypergranulosis and hyperkeratosis and at electron microscopy numerous keratohyalin granules are found in the keratinocytes of the granular layer.¹⁶²

Differential diagnosis

Differential diagnoses include KID syndrome, Vohwinkel syndrome, Olmsted syndrome and the generalized forms of congenital ichthyosis.¹⁶²

Treatment and care

Treatment with topical keratolytics and oral retinoids results in significant improvement but recurrence is common once treatment is stopped.¹⁶²

Cutaneous features

Neonates with this lethal autosomal recessive condition are born with rigid skin, attributed to fetal akinesia or hypokinesia deformation sequence.^164–166 Polyhydramnios with reduced fetal movements usually results in premature delivery at approximately 31 weeks’ gestational age. Premature rupture of the membranes and an enlarged placenta with a short umbilical cord are often associated. The skin typically is thin, shiny, and red, with prominent vessels. Scaling and erosions are frequently seen (Fig. 19.15).

Extracutaneous features

The facies are characterized by micrognathia, a small open mouth (O-shaped), pinched nares with choanal atresia or stenosis, and flattened or low-set pinnae. The constraint of movement in utero also leads to flexion contractures of the joints, and bony changes such as poor ossification of the clavicle; over-tubulation of the radius, ulna, and distal phalanges; and widened sutures and large fontanelles. Natal teeth have been described in 25–50% of patients with restrictive dermopathy. Most patients die of pulmonary hypoplasia with respiratory insufficiency or sepsis.

Etiology and pathogenesis

Restrictive dermopathy may be caused by dominant de novo LMNA (encoding lamin A) mutations¹⁶⁷ or, more frequently, by recessive null ZMPSTE24 mutations, most of which lie in a mutational hotspot within exon 9.¹⁶⁸ This gene encodes a metalloproteinase specifically involved in the post-translational processing of lamin A. It is likely that many of the dysmorphic features observed in restrictive dermopathy are secondary to restricted fetal movement; this condition has been termed fetal akinesia deformation sequence (FADS).⁹³

Differential diagnosis

Skin biopsy at 20 weeks’ gestational age may be normal,¹⁶⁹ and DNA-based prenatal diagnosis is best if the familial gene defect is known. The onset of intrauterine growth retardation, restricted fetal movement, and polyhydramnios that raise suspicion of the diagnosis may occur late in gestation, precluding prenatal testing. Histopathologic examination of skin biopsy sections shows a thick epidermis, and a thin dermis with a paucity and hypoplasia of cutaneous appendages. Collagen bundles are abnormally arranged, and elastic fibers are almost absent.

Treatment and care

Most patients die during the neonatal period; the longest survivor with restrictive dermopathy died at 4 months of age.

Cutaneous features

Neu–Laxova syndrome is a rare, lethal, autosomal recessive trait characterized by severe intrauterine growth retardation, microcephaly with abnormal brain development, edema, and ichthyosis.^170,171 The ichthyosis is present at birth, but varies from mildly scaling skin to a harlequin fetus appearance. Histologic findings are nonspecific and show the acanthosis and orthokeratosis of lamellar ichthyosis. Excessive subcutaneous adipose tissue and myxomatous connective tissue may contribute to the characteristic edema.

Extracutaneous features

The lack of brain development is characterized by lissencephaly and agenesis of the corpus callosum. Characteristic facial features include a slanted forehead, protuberant eyes, a flattened nose, deformed ears, micrognathia, and a short neck. Microphthalmia and cleft palate are occasionally associated. The limbs, fingers, and toes are abnormal, with syndactyly, hypoplasia, and contractures. Skeletal X-rays often show poor mineralization. The craniofacial and limb abnormalities are related to the reduced intrauterine movement, and are therefore defined as fetal akinesia/hypokinesis sequence, as has been described in other syndromes.

Etiology and pathogenesis

The etiology of this rare and devastating disorder is unknown, but the term is likely to cover a number of heterogeneous disorders.¹⁷²

Differential diagnosis

The constellation of features usually makes the diagnosis clear.

Treatment and care

Treatment is palliative.