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. Others (syndromic forms) include Sjögren–Larsson syndrome, Conradi–Hünermann syndrome, trichothiodystrophy, and neonatal Gaucher disease. 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.

Shiny collodion membrane of a 1-day-old collodion baby. Note the eclabion and tightened skin of the hands.

One week after birth, this collodion baby with congenital ichthyosiform erythroderma is showing desquamation of scale. Despite the severity of the early phenotype, this infant had very mild congenital ichthyosiform erythroderma at 6 months of age.

(From Paller AS. Ichthyosis in the neonate. In: Dyall-Smith D, Marks R, eds. Dermatology at the millennium: Overview of past achievements, current knowledge and future trends. London: Parthenon Publishing Group; 1998, with permission.)

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, 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. 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 . 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.

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

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, 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.

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. 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.

Etiology and pathogenesis

Mutations in the filaggrin gene ( FLG ) have now clearly been shown to underlie ichthyosis vulgaris, leading to decreased to absent expression of filaggrin. These mutations are semi­dominant; heterozygotes exhibit a very mild phenotype with incomplete penetrance, whereas homozygotes or compound heterozygotes show much more severe disease. The mutations show a combined allele frequency of ~4% in Caucasian populations, explaining the high incidence of ichthyosis vulgaris. FLG gene mutations are now well established as the highest genetic 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.

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 ).

Diffuse scaling of the trunk and extremities is seen in this 2-week-old infant with X-linked ichthyosis.

Extracutaneous features

RXLI is regarded as syndromic when accompanied by associated manifestations and non-syndromic when ichthyosis is isolated. 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 .

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.

Cutaneous features

Patients are born with thickening of the skin, including the palms and soles, with generalized prominent follicular keratoses and mild erythema. The clinical findings have been described as a ‘nutmeg grater’. The scalp is hairless, and severe photophobia is noted from birth. The nails may be dystrophic, and follicular pustules may be present. Biopsies show a hyperkeratotic stratum corneum with a thinned dermis. The hair follicles are atrophic and shortened, with abnormal localization of the bulbs to the deep portion of the dermis, rather than a subcutaneous location. There are no normal hair shafts, and sebaceous glands are absent. It is possible that at least two other forms exist in addition to this classic form.

Extracutaneous features

Some patients have had short stature, psychomotor delay, and/or seizures. Ocular changes including corneal ulceration, greatly reduced visual acuity, and cataract have been reported.

Etiology and pathogenesis

IFAP syndrome is an X-linked disorder caused by functional deficiency of membrane-bound transcription factor protease, site 2 (MBTPS2). This results in disturbed differentiation of epidermal structures evoking the triad of ichthyosis follicularis, atrichia and photophobia. Female carriers may have linear involvement. An autosomal recessive form has also been described.

Differential diagnosis

The constellation of clinical signs should make the diagnosis apparent.

Treatment and care

Systemic retinoids have been used in children as young as 3 years, with reported improvement.

Cutaneous features

Most cases of chondrodysplasia punctata are the X-linked dominant Conradi–Hünermann–Happle form. Affected neonates are usually female, because the disorder is considered lethal to male fetuses. However, Conradi syndrome has been described in a few male patients with and without Klinefelter syndrome. At birth, patients most commonly have patterned erythroderma with overlying thin to thick psoriasiform scale ( Fig. 19.4 ). In severe cases, generalized ichthyosiform erythroderma with thick scale is seen at birth, and later shows typical patterning along Blaschko’s lines with scale desquamation. Involvement may be predominantly unilateral. With advancing age the ichthyosiform erythroderma and stippling improve, leaving finer scaling without underlying erythema and follicular atrophoderma. Cicatricial alopecia occurs as scalp scaling resolves. Psychotropism may be seen (see ‘ CHILD syndrome ’, below).

Conradi–Hünermann syndrome.

(A) Thick, psoriasiform scaling overlying erythema in a 1-month-old girl with the syndrome and chondrodysplasia punctata. As the scaling desquamated, the underlying erythema along Blaschko’s lines became more apparent. (B) The pattern of scale along Blaschko’s lines is more evident in this neonate with Conradi–Hünermann syndrome.

(From Paller AS. Ichthyosis in the neonate. In: Dyall-Smith D, Marks R, eds. Dermatology at the millennium: Overview of past achievements, current knowledge and future trends. London: Parthenon Publishing Group; 1998, with permission.)

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.

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

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). 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.

Differential diagnosis

The differential diagnosis usually includes two other forms of chondrodysplasia punctata: autosomal recessive rhizomelic chondrodysplasia punctata, and X-linked recessive chondrodysplasia punctata with steroid sulfatase deficiency. 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.

Cutaneous features

The term ‘CHILD syndrome’ is an acronym for ‘congenital hemidysplasia with ichthyosiform nevus and limb defects’. The condition occurs almost exclusively in girls, and is presumed to be lethal in affected males. The only case in a boy is thought to represent early postzygotic mosaicism. The inflammatory ichthyosiform skin lesion of CHILD syndrome may be present at birth or develop during the first few months of life. It is characterized by yellow, waxy scaling and is strikingly unilateral, generally with a sharp demarcation at the ventral and dorsal midline regions ( Fig. 19.5 ). Streaks of inflammation and scaling can also follow Blaschko’s lines, with involvement of the apparently unaffected side of the body. Similarly, streaks of normal skin may be interspersed within the area of the CHILD nevus. With increasing age, the skin lesions may improve or clear spontaneously, but thickened erythematous plaques in intertriginous areas tend to persist and be the most severely affected sites (psychotropism). The skin lesions of CHILD syndrome nevus can occur without any other abnormalities, but the occurrence of all features of CHILD syndrome in a sibling of a patient with only the CHILD nevus suggests variable expressivity within the spectrum of CHILD syndrome.

CHILD syndrome.

Sharply demarcated, erythematous ichthyosiform lesions with mostly unilateral distribution and hemidysplasia are characteristic findings. Thickened, yellow-brown scale in a whorled pattern is seen within areas of the CHILD nevus.

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.

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.

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. 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.

Cutaneous features

Netherton syndrome should be suspected in the neonate with generalized scaling erythroderma, especially if there is failure to thrive ( Fig. 19.6 ). Affected infants are often born prematurely and develop the typical ichthyosiform erythroderma in utero or during the first weeks of life. A collodion baby phenotype is not associated. The classic hair shaft abnormality, trichorrhexis invaginata (‘bamboo hairs’, ‘ball-and-socket deformity’), is thought to result from a defect in keratinization of the internal root sheath. Multiple hairs from different areas should be examined, as only 20–50% of hairs may be affected. Although trichorrhexis invaginata may be present in the neonatal period, delayed and sparse hair growth at this time, as well as the easy breakage of these hairs, makes demonstration of the hair defect in the neonatal period difficult. Ichthyosis linearis circumflexa, the characteristic skin change associated with Netherton syndrome, is usually not seen before 2 years of age, but occurs eventually in 70% of patients. It manifests episodically, often lasting for a few weeks and then clearing for weeks or months. The ichthyosiform erythroderma, however, frequently improves with age. The atopic diathesis becomes problematic in two-thirds of patients, with the development of pruritic atopic dermatitis, multiple food allergies, and often accompanying urticaria, angioedema, asthma, and/or anaphylaxis.

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