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Genetic skin disorders
Semin Neonatol 2000; 5: 311–320 doi:10.1053/siny.2000.0020, available online at http://www.idealibrary.com on
Genetic skin disorders Celia Moss Consultant Dermatologist, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK
Key words: blister, collodion baby, harlequin, ichthyosis, pigment, Blaschko lines, mosaicism
Neonatologists do not require a detailed knowledge of all genetic skin disorders but need to recognize one if they see it. The unique accessibility of the skin makes it possible to observe the physical signs and deduce the child’s immediate needs from first principles. The morphological classification given here will help the nondermatologist establish a clinical diagnosis. Tremendous advances over the last 10 years in understanding the molecular basis of skin disease make it possible, in many cases, to confirm the diagnosis and to counsel the family accurately. 2000 Harcourt Publishers Ltd
The neonatologist cannot be expected to remember all possible genetic skin disorders, and rarely needs a precise diagnosis to manage a baby with congenitally abnormal skin. Most of the urgent considerations are apparent on clinical examination. However, in order to predict complications, course and recurrence risk a diagnosis is essential (Table 1). The best approach is to make a careful inspection of the skin to define the physical abnormality. What are the characteristic features of the abnormal skin? What is its texture, colour and distribution? If there are raw areas, has skin been lost (blisters) or was it never there (aplasia cutis)? If the skin appears shiny and tight, is it normal but stretched over underlying swelling (e.g. hydrops) or is it abnormally thickened? Is the thickening superficial (collodion membrane) or deep (stiff skin syndrome)? If there are pale patches are they lacking pinkness (vascularity) or brownness (pigment)? Table 2 should help the neonatologist interpret the physical signs in order to reach the correct diagnostic category. The unique accessibility of the skin compared with other organs facilitates diagnostic precision. It has also, in recent years, enabled scientists to define the molecular basis of many genetic conditions particularly of the epidermis [1]. Once the clinical Correspondence to: Dr Celia Moss, Consultant Dermatologist, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NL, UK. Tel.: +44 (0) 121 333 8230; Fax: +44 (0) 121 333 8231; E-mail: [email protected]
1084–2756/00/040311+10 $35.00/0
Table 1. Factors affecting management of genetic skin disorder in a neonate Apparent on clinical examination Skin fragility Involvement of mucosal surfaces Impairment of skin barrier function fluid loss protein loss heat loss infection Restriction of movement feeding breathing Pain Maternal rejection May require knowledge of the diagnosis Association with abnormalities in other systems nervous system GI tract heart skeleton blood Likely course Recurrence risk in subsequent pregnancies
diagnosis has been made, the next steps are often confirmation on a molecular level and sometimes mutation analysis. In the following account, emphasis is placed on the conditions and physical signs which can be detected at birth. © 2000 Harcourt Publishers Ltd
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Table 2. Morphological classification of genetic skin disease in the neonate Physical sign
Diagnostic group
colour may be normal, pink, or yellow due to underlying fat. Dermal hypoplasia is found in the following situations: Brauer (AD) and Setleis (AR) syndromes, which may be the same thing [3], are characterized by focal round lesions on the temples, either isolated or associated with facial dysmorphism. The lesions are often mistakenly attributed to instrumental delivery. Goltz focal dermal hypoplasia (X-linked) occurs in girls and is characterized by focal dermal hypoplasia following Blaschko lines which reflect random X-inactivation [4]. In addition, there may be fat herniation through the hypoplastic dermis, skeletal abnormalities particularly affecting the digits, and ocular defects such as coloboma.
Unformed skin Thin skin
Aplasia cutis Dermal hypoplasia Collagen disorders Blisters/erosions Fragile skin Other bullous disorders Thick/scaly skin Ichthyoses (collodion, Harlequin) Stiff skin syndrome White skin/hair Pigment deficient disorders Palpable brown patches Syndromes with melanocytic naevi Flat brown patches Syndromes with cafe-au-lait macules Syndromes with lentigines Red (vascular) patches Syndromes with port-wine stains Red (vascular) lumps Syndromes with haemangiomas Blaschko lines Mosaic disorders Deficient hair/nails/sweat Ectodermal dysplasias Syndromes with abnormal hair Erythroderma Immunological disorders
Aplasia cutis congenita (Table 3) [2] A red, glistening patch through which blood vessels are easily visible indicates absence of epidermis and at least superficial dermis. There may be an underlying bony defect. Aplasia cutis (failure of the skin to develop) can be distinguished from antenatal skin loss by looking for remnants of detached skin at the edges of the lesion, or evidence elsewhere of skin fragility. A prominent ‘step’ between lesional and non-lesional skin is usually seen in aplasia cutis, but can also occur after intrauterine loss of epidermis and does not distinguish these two conditions. After birth a crust or scab usually forms over an area of aplasia cutis congenita, and may be mistaken for birth trauma. Eventually it leaves a scar which may be depressed or raised. The different genetic types of aplasia cutis congenita are summarized in Table 3.
Dermal hypoplasia A discrete depression in skin which is of normal texture usually indicates dermal hypoplasia. The
Collagen disorders Thin skin due to a deficiency of dermal collagen occurs in various forms of Ehlers-Danlos syndrome, particularly EDS type IV due to abnormal collagen type III. However, it is rarely necessary or possible to diagnose this at birth.
Bullous disorders Defective skin adhesion can present neonatally either as blisters or as erosions, depending on the age of the blisters. Bisters that have occurred in utero may resemble aplasia cutis at birth (see above), this presentation being known as Bart’s syndrome. Prenatal blisters may have healed leaving milia. Once blisters have been observed it is essential, for management as well as diagnosis, to examine their distribution and the state of the non-blistered skin (Table 4). Localization at sites of friction indicates generalized skin fragility, and the most likely diagnosis is epidermolysis bullosa [5] (see Chapter 7). If they are linear on the limbs, trauma may initially be suspected, but in the absence of skin fragility this distribution in a girl is characteristic of incontinentia pigmenti [6], the pattern being determined by Blaschko lines (see below). Blisters occurring in an inflamed and ichthyotic skin are characteristic of bullous ichthyosiform erythroderma [7]. Blisters related to cutaneous plaques and urticaria may represent cutaneous mastocytosis: the trauma of delivery may provoke
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Table 3. Classification of major types of aplasia cutis congenita (ACC) Type of ACC
Associated features
Diagnosis
Scalp, with no associated features
None
Scalp, with associated features
Distal limb reductions Dysmorphism, deafness Polydactyly, clefting Dysmorphism, clefting None (sometimes amniotic band) Skin tags, ocular defects GI atresia
ACC of vertex Catlin marks (ACC on either side of saggital sinus) Adams Oliver syndrome Johanson-Blizzard syndrome Trisomy 13 Wolf-Hirschorn syndrome ACC with fetus papyraceus Delleman–Orthuys syndrome Carmi syndrome
Trunk/limbs with no associated features Trunk/limbs with associated features
Inheritance AD AD AD AR AD AD Sporadic AD AR
Table 4. Genetic causes of neonatal blisters and erosions Condition
Distribution
Rest of skin
Gene
Epidermolysis bullosa Incontinentia pigmenti Bullous ichthyosiform erythroderma Pachyonychia congenita
Friction sites Linear Friction sites Acral
Normal or milia Normal Ichthyotic Normal
Keratins, laminin, collagen collagen VII etc. NEMO X-linked gene Keratins 1 and 10 Keratins 16, 17, 6a, 7a
histamine release from the mastocytomas, causing dramatic blistering. In a neonate with acral blisters and natal teeth, the keratin gene disorder pachyonychia congenita should be considered.
Ichthyoses [7] These scaly disorders are due to defective desquamation of the superficial epidermis (stratum corneum). Usually ichthyosis is an isolated skin disorder, but some rare types also affect the nervous system or the skeleton. Ichthyoses differ in their pattern of scaling, as well as in their associated features. Some ichthyoses have an inflammatory component (the ichthyosiform erythrodermas), appearing red as well as scaly. In one type the structural disturbance within the epidermis produces blistering as well as ichthyosis (bullous ichthyosiform erythroderma). The distribution may be striking, for example the midline demarcation between affected and unaffected skin in CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects) (see linear disorders). Linear ichthyosis in a girl may be due to the X-linked dominant form of chondrodysplasia
punctata (Happle syndrome), in which the abnormality follows Blaschko lines (see below). Table 5 summarizes the clinical features of the ichthyoses and what we know about their genetic basis. Ichthyosis may present to the neonatologist as a collodion baby, or as the much more severe harlequin fetus. A collodion baby has a tight, shiny epidermis which cracks across the flexures as the infant uncurls from the fetal position. Mucous membranes are unaffected and consequently stretched outwards by the adjacent tight skin, creating the characteristic ectropion and eclabion. The skin may be so tight that the baby cannot close its mouth to suck, nor expand its chest to breathe. Barrier function is compromised, risking hypothermia, hypovolaemia and septicaemia. Important emergency measures include coating the baby in a greasy emollient such as 50/50 liquid paraffin/soft white paraffin and nursing in high humidity. Once the raw areas have epithelialized and fluid balance is stable, a water miscible cream or ointment (emulsifying ointment or aqueous cream) more effectively softens the hard scales. Within a few weeks the thick epidermis peels off. A collodion membrane is a physical sign not a diagnosis: it is the presenting feature of several different ichthyoses. Severity at birth is no index of
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Table 5. Classification of the ichthyoses (a) no extracutaneous features Diagnosis
Inheritance
Neonatal appearance
Ichthyosis vulgaris Steroid sulphatase deficient Bullous ichthyosiform erythroderma Non-bullous ichthyosiform erythroderma Lamellar ichthyosis Harlequin ichthyosis
AD XR AD AR AR AR
Normal Normal Collodion Collodion Collodion Harlequin
Gene ? STS KRT1/KRT10 ? TGK ?
(b) with neurological or other associated abnormality Diagnosis Sjogren–Larsson syndrome Refsum syndrome Pollitt syndrome Dorfman–Chanarin syndrome Multiple sulphatase deficiency Chondrodysplasia punctata Chondrodysplasia punctata
Inheritance AR AR AR AR AR AR, AD, XR XD
Neonatal appearance Collodion Normal Normal Normal Normal Ichthyotic Linear ichthyosis
severity of the underlying ichthyosis. Some collodion babies end up with a normal skin [8], while some children with ichthyosis (notably the X-linked type) have a normal skin at birth. Biopsy of the collodion membrane is unhelpful, and the diagnosis of an ichthyosis is usually made on the basis of clinical appearance at a few weeks of age. Harlequin ichthyosis [9] is a very severe and usually fatal neonatal condition. The name refers to the diamond-shaped thick plates of scale separated by deep fissures, resembling the pattern on a harlequin’s costume. In general, the neonatal management issues are the same as for a collodion baby. In addition, there may be ischaemic necrosis of digits owing to the tight skin, and ectropion requiring surgical correction. The horrific appearance may lead to parental rejection. The use of a retinoid drug, acetretin, may have improved the outcome in some non-fatal cases, but survivors are left with a very severe non-bullous ichthyosiform erythroderma.
Stiff-skin syndrome [10] Infantile restrictive dermopathy is a rare recessive disorder which presents at birth and is usually
Associated features
Gene
Delay and spasticity Neuropathy and retinitis pigmentosa Brittle hair Hepatospenomegaly Retardation Dwarfism Asymmetric limb reduction
SLS PAHX ERCC ? ? ? EBP
lethal within days. It is probably a disorder of dermal collagen, although histologically the epidermis is also abnormal. The thick, shiny skin is so tight that all joints are fixed in flexion, unlike a collodion baby in which the more superficial tightness is soon overcome by the baby’s movements. The small round mouth of restrictive dermopathy is quite distinct from the eclabion of a collodion baby. Other dysmorphic features include micrognathia, small nose, low-set ears and wide cranial sutures. Death is usually due to restricted chest movements.
Pigment-deficient disorders [11] The development of normal skin pigment is a multistage process. Melanoblasts originate in the neural crest, migrate outwards along Blaschko lines (see below), and settle in the lower epidermis as melanocytes. Melanin pigment is synthesized within subcellular organelles called melanosomes, production being regulated quantitatively by the enzyme tyrosinase, and qualitatively by several factors which divert the production of simple eumelanin to other pigments. Melanin is passed along the dendrites of the melanocyte and released
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Table 6. Genetic causes of congenital hypopigmentation Pattern of lesions
Condition
Associated features
Generalized
Oculo-cutaneous albinism
Nystagmus
Generalized Generalized Generalized Ash leaf macules White forelock White forelock, belly and limbs Linear Linear
Chediak–Higashi syndrome Hermansky–Pudlak syndrome Phenylketonuria Tuberous sclerosis Waardenburg syndrome Piebaldism Naevus depigmentosus Hypomelanosis of Ito
Immunodeficiency Bleeding diathesis Developmental delay Epilepsy etc Hyperteleorism None None Neurological and skeletal
into adjacent keratinocytes. The process is controlled by dozens of genes, and accordingly there is a wide range of genetic disorders of pigmentation some of which we now understand (Table 6).
Generalized reduction of pigment Oculocutaneous albinism [12,13] It is sometimes difficult to decide whether a very fair baby is albino, especially if the parents are blond. Pathologically fair skin becomes more obvious with age and sun exposure. Pink eyes and nystagmus clinically confirm a diagnosis of oculo-cutaneous albinism, but nystagmus does not usually appear until 2–3 months of age. Type 1 (tyrosinase negative) oculocutaneous albinism is an autosomal recessive disorder caused by mutations in the tyrosinase gene at 11q14-21. Type 2 (tyrosinase positive) oculocutaneous albinism is a heterogeneous group, in which melanin is reduced but not absent, and the eyes are light blue rather than pink. Some type 2 patients are homozygous for a mutation in the ‘p’ gene at 15q11-13, which probably controls the transfer of tyrosine across melanosome membranes. This is also the locus for Prader–Willi syndrome,which may thus be associated with type 2 oculo-cutaneous albinism [14]. No particular skin care is required for the albino neonate apart from sun-protection. Chediak–Higashi and Hermansky Pudlak syndromes are autosomal recessive disorders in which pigment is diluted rather than absent, and albinism may not be apparent at birth. In Chediak–Higashi syndrome [15] there is a generalized disorder of cytoplasmic granules, involving lysosomes as well
Gene TYR (OCA1) P-gene (OCA2) CHS HPS PAH TSC1 and TSC2 PAX3, EDNRB, MITF C-KIT Unknown Mosaicism at several loci
as melanosomes. Patients are, consequently, susceptible to infection and unable to transfer melanin to keratinocytes. In Hermansky Pudlak syndrome [16] there is a bleeding diathesis due to a platelet abnormality, pulmonary fibrosis and granulomatous colitis. The gene, which maps to 10q, produces a transmembrane protein of unknown function. Phenylketonuria is normally diagnosed in the neonate on biochemical screening rather than on the clinical appearance. The fair skin and hair are directly due to deficient phenylalanine hydroxylase, which, like tyrosinase, is involved in melanin synthesis.
Patchy reduction of pigment White patches on the skin are not always due to lack of pigment. A naevus anaemicus, which can be considered the reverse of a port-wine stain, is easily mistaken for a hypomelanotic patch in a fair-skinned baby. Warming or rubbing a naevus anaemicus makes it more obvious, as the surrounding vasodilatation contrasts clearly with the vasospastic area. Conversely the edge can be obscured by pressing on it with a spectacle lens, thus compressing the normal surrounding vessels. A hypomelanotic macule is unaffected by these manoeuvres. The shape and distribution of white patches is an important clue to their cause: leaf-shaped and proximal in tuberous sclerosis, triangular or diamond-shaped and on the forehead in Waardenburg syndrome, segmental and asymmetrical in hypomelanosis of Ito. Waardenburg syndrome [17] presents as a triangular white patch with white overlying hair on the central forehead, and facial
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dysmorphism. It is associated with deafness. There are several subtypes, resulting from dominant mutations in various genes responsible for embryonic migration of neural crest derivatives, particularly PAX3. Some neonates present with colonic obstruction due to Hirschsprung disease. Piebaldism [18], like Waardenburg syndrome, is an autosomal dominant disorder characterized by patchy hypopigmentation usually including a white forelock. However, it is not associated with any other abnormalities, and the problem is entirely cosmetic. It is due to mutations in C-KIT, an oncogene responsible for normal melanoblast migration. In affected individuals white patches occur on the belly, limbs and brow, but not the back, perhaps reflecting distance from the neural crest. The edges of the white patches tend to be at right angles to dermatomal boundaries and Blaschko lines (see below). Thus, the patch on the belly is often diamond-shaped, and those on the limbs have a horizontal cut-off. Within the white patches are irregular islands of aberrant melanocytes. It is common for affected dark-haired adults to dye the white forelock, so the dominant inheritance may not be apparent on first meeting the parents.
Tuberous sclerosis Tuberous sclerosis (TS) is an autosomal-dominant neurocutaneous disorder. The cutaneous signs include the hypomelanotic patch, periungual fibroma, facial angio fibroma, forehead fibrous plaque and shagreen patch, but only the first of these is normally apparent at birth. Hypomelanotic patches are easily seen in a racially pigmented baby, but may not be visible at birth in a white child. Wood’s light examination increases the contrast between light and dark skin and may reveal patches invisible in daylight. The typical hypomelanotic macule of TS is ash-leaf shaped (a long, narrow oval) but round, segmental and confetti-like lesions also occur. A useful sign of TS in a hairy neonate is that the long axis of the patch corresponds to the direction of hair growth, particularly on the back.
Naevus depigmentosus and hypomelanosis of Ito Congenital hypopigmentation in a linear or segmental distribution is termed naevus depigmen-
C. Moss
tosus. Naevus depigmentosus is usually an isolated cutaneous anomaly [19], but may be associated with neurological deficit and other abnormalities, when it is termed hypomelanosis of Ito (HI). HI is not a single condition, but a phenotype associated with chromosomal mosaicism [20]. The associated features are variable, depending on the particular chromosome affected. Vitiligo can also occur in a segmental pattern but is rarely congenital.
Syndromes with melanocytic naevi Multiple melanocytic naevi (moles) occur in relatives of patients with giant congenital melanocytic naevi, and probably also as an isolated autosomal dominant trait. They are also seen in Turner syndrome. A birth they may be sparse and faint, increasing in number and degree of pigmentation with time.
Lentigines Lentigines are flat, dark-brown lesions which occur in isolation and in several syndromes such as Peutz–Jegher and LEOPARD. However, they may not be apparent in the neonate.
Syndromes with cafe´ -au-lait macules Cafe´ -au-lait macules are very faint in neonatal Caucasian skin, becoming darker and more apparent with time. They occur most commonly in neurofibromatosis type 1, but are also seen in Fanconi pancytopenia, Bloom syndrome, Russell– Silver syndrome, and adrenoleucodystophy. They can also occur as an isolated anomaly, dominantly inherited. Segmental cafe´ -au-lait pigmentation is usually an isolated birth mark. Sometimes it looks like a negative image of hypomelanosis of Ito, when it is termed linear and whorled hypermelanosis, and this may be a manifestation of cutaneous mosaicism (see below). Segmental or linear cafe´ -au-lait pigmentation is also seen in McCune–Albright syndrome, owing to activating mutations in the protein which stimulates hormone-sensitive adenylate cyclase [21]: the
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Figure 1. Diagram to show Blaschko lines [22].
linear pattern probably represents mosaicism for this dominant mutation.
Syndromes with port-wine stains Flat red birth marks are called salmon patches if they are pink and port-wine stains (PWS) if they are red. The association of facial PWS with ocular and cerebral vascular anomalies is described in Chapter 8. A mid-forehead PWS is an occasional and rather non-specific finding in many different genetic disorders including Beckwith–Wiedemann, Pallister–Hall, trisomy 13 and Rubinstein–Taybi syndromes. Multiple PWS can be inherited as an
isolated autosomal dominant trait. In Proteus syndrome they are associated with other hamartomas and localized overgrowth. In Klippel–Trenaunay syndrome they accompany limb hypertrophy. A mid-forehead salmon patch (Unna’s naevus), often accompanying a similar lesion at the nape of the neck (‘stork mark’) is an isolated anomaly: the forehead lesion resolves spontaneously, while the posterior element tends to persist.
Syndromes with haemangiomas Strawberry naevi may be single or multiple. Usually the abnormality is confined to the skin, but
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Table 7. Morphological classification of skin disorders following Blaschko lines Morpholog
Condition
Type of mosaicism
Thin skin Blisters Thick/scaly skin Epidermolytic hyperkeratosis CHILD syndrome ILVEN Comedone naevus Other epidermal naevus
Goltz focal dermal hypoplasia Incontinentia pigmenti Chondrodysplasia punctata Non-lethal dominant mutation Mutation Lethal dominant mutation Lethal dominant mutation Non-lethal dominant mutation
White skin
Naevus depigmentosus Hypomelanosis of Ito Pallister syndrome Linear and whorled Hypermelanosis McCune-Albright syndrome Segmental neurofibromatosis segmental pigmentary Anomalies Ectodermal dysplasia carrier
Brown skin
Deficient sweating
in disseminated haemangiomatosis internal organs are involved (see Chapter 8). Strawberry naevi accompany macrocephaly and lipomas in the Bannayan–Zonana syndrome.
Skin lesions following Blaschko lines (Mosaic disorders) Several skin disorders follow a pattern of lines delineated 100 years ago by Blaschko [22,23] (Fig. 1). We now know that this pattern represents genetic mosaicism in the skin. The pattern is attributed to the lines of migration and proliferation of epidermal cells during early embryogenesis [24]. The bands of abnormal skin represent clones of cells carrying a mutation in an epidermally expressed gene. Table 7 gives a morphological classification of linear skin disorders. In the neonate, the lesions may be faint and easily missed. Mosaicism can arise in the following ways:
Random X-chromosome inactivation (Lyonisation) [23,25]. Clones of skin cells expressing the abnormal X-chromosome contrast with clones expressing the normal chromosome, producing the linear lesions of incontinentia pigmenti, Goltz syndrome and X-linked dominant chondrodysplasia punctata. Defective sweating in a linear
X-inactivation X-inactivation X-inactivation KRT1,KRT1 0 ? ? FGFR2 Mutation Lethal dominant mutation ? Chromosomal mosaicism Mosaic chrom. 12 anomaly Chromosomal mosaicism Lethal dominant mutation Non-lethal dominant Mutation Chimaerism X-inactivation
Gene ? ? EBP
? ? Multiple ? Multiple GNAS NF1 Multiple EDA1
distribution can be demonstrated in female carriers of X-linked hyphidrotic ectodermal dysplasia. Somatic non-dysjunction producing chromosomal mosaicism. This is found in the linear pigmentary disorders hypomelanosis of Ito [20] and linear and whorled hypermelanosis. Somatic mutation for a dominant skin disorder. Mosaicism for mutations causing bullous ichthyosiform erythroderma has been found in linear epidermolytic hyperkeratosis [26]. Recently a mutation in the gene responsible for Apert syndrome (characterized by skeletal abnormalities and severe acne) was found in a linear comedone (blackhead) naevus [27]. The same mechanism is postulated for segmental neurofibromatosis. Somatic mutation for a lethal dominant gene. This is the presumed explanation for linear disorders not recognizable as localized forms of a generalized condition: the lethal gene is ‘rescued’ by mosaicism. Linear lesions in this category include McCune–Albright syndrome [21] and epidermal naevi (other than epidermolytic and comedone naevi). Epidermal naevi may be accompanied by skeletal or neurological features in Proteus syndrome and epidermal naevus syndrome, reflecting the potentially serious nature of these mutations even in the mosaic form. CHILD syndrome (congenital hemidysplasia with ichthyosiform
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erythroderma and limb defects) may represent a more extensive form of ILVEN (inflammatory linear verrucous epidermal naevus) [28]. Chimerism. A chimera is composed of two genetically different cell lines resulting from fusion of two zygotes or fertilization of an ovum by two sperms. This is extremely rare, and usually only detected by chance on blood grouping. Affected individuals may have segmental patches of light and dark pigmentation [29].
Ectodermal dysplasias This is a heterogeneous group of more than a hundred conditions characterized by any or all of the following: deficient hair, nails, teeth, sweating. They may be associated with other features such as deafness, clefting and skeletal abnormalities. The best known is X-linked hypohidrotic ectodermal dysplasia (see Chapter 4). Ectodermal dysplasia is rarely diagnosed in the immediate newborn period since hair and teeth are normally absent or sparse at this time. A good head of hair at birth does not exclude the diagnosis, since this is often shed and may not re-grow.
Syndromes with abnormal hair Hair is so variable at birth that it is difficult to say if it is abnormal. Fair, tightly curled hair in a male suggests Menkes’ kinky hair syndrome.
Immunological disorders Infection due to immunodeficiency may present later than the neonatal period. However, onset in the first week or so of scaly erythroderma may suggest severe combined immunodeficiency. Previously known as Leiner’s syndrome, this group has now been separated immunologically into specific entities including Omenn syndrome [30] and Netherton syndrome [31]. Clinically, it may be difficult to differentiate these disorders from severe seborrhoeic dermatitis which can be accompanied by marked lymphadenopathy and failure to thrive. References 1 Moss C, Savin J. Dermatology and the new genetics. Oxford: Blackwell Science, 1995.
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2 Evers MEJW, Steijlen PM, Hamel BCJ. Aplasia cutis congenita and associated disorders: an update. Clin Genet 1995; 47: 295–301. 3 Ward KA, Moss C. Evidence for genetic homogeneity of Setleis’ syndrome and focal facial dysplasia. Brit J Dermatol 1994; 130: 645–649. 4 Temple IK, MacDowall P, Baraitser M, et al. Focal dermal dysplasia (Goltz syndrome). J Med Genet 1990; 27: 180– 187. 5 Moss C. Hereditary bullous disorders. Current Paediatrics 1995; 5: 252–257. 6 Landy SJ, Donnai D. Incontinentia pigmenti (BlochSulzberger syndrome). J Med Genet 1993; 30: 53–59. 7 Shwayder T. Ichthyosis in a nutshell. Pediatric Rev 1999; 20: 5–12. 8 Frenk E, Techtermann F. Self-healing collodion baby: evidence for autosomal recessive inheritance. Pediatr Dermatol 1992; 9: 95–97. 9 Akiyama M, Suzumori K, Shimizu H. Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks’ estimated gestational age. Prenat Diag 1999; 19: 167–171. 10 Paige DG, Lake BD, Bailey AJ, et al. Restrictive dermopathy: a disorder of fibroblasts. Brit J Dermatol 1992; 127: 630–634. 11 Biswas S, Lloyd IC. Oculocutaneous albinism. Arch Dis Child 1999; 80: 565–569. 12 Hearing VJ. Unraveling the melanocyte. Am J Hum Genet 1993; 52: 1–7. 13 Oetting WS, King RA. Molecular basis of oculocutaneous albinism. J Invest Dermatol 1994; 103: 131S–136S. 14 Lee S-T, Nicholls RD, Bundey S, et al. Mutations of the P-gene in oculo-cutaneous albinism, ocular albinism and the Prader-Willi syndrome plus albinism. N Engl J Med 1994; 330: 529–534. 15 Spritz RA. Multi-organellar disorders of pigmentation: tied up in traffic. Clin Genet 1999; 55: 309–317. 16 Gahl WA, Brantly M, Kaiser-Kupfer MI, et al. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N Engl J Med 1998; 338: 1258–1264. 17 Read AP, Newton VE. Waardenburg syndrome. J Med Genet 1997; 34: 656–665. 18 Spritz RA, Holmes SA, Itin P, et al. Novel mutations of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. J Invest Dermatol 1993; 101: 22–25. 19 Lernia VD. Segmental nevus depigmentosus: analysis of 20 patients. Ped Dermatol 1999; 16: 349–353. 20 Kuster W, Konig A. Hypomelanosis of Ito: no entity but a cutaneous sign of mosaicism. Am J Med Genet 1999; 85: 346–350. 21 Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune–Albright syndrome. Proc Nat Acad Sci USA 1992; 89: 5152–5156. 22 Blaschko A. Die Nervenverteilung in der Haut in ihrer beziehung zu den Erkrankungen der Haut. In Beilage zu den Verhandlungen der Deutschen Dermatologischen Gesellschaft VII Congress, Breslau. Wien: Braumuller, 1901.
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23 Happle R. Lyonization and the lines of Blaschko. Hum Genet 1985; 70: 200–206. 24 Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Gen 1999; 85: 330–333. 25 Traupe H. Functional X-chromosome mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko. Am J Med Genet 1999; 85: 324–329. 26 Moss C, Jones DO, Blight A, Bowden PE. A birthmark due to cutaneous mosaicism for a keratin 10 mutation. Lancet 1995; 345: 596. 27 Munro CS, Wilkie AOM. Acneiform epidermal naevus due to mutation in fibroblast growth factor receptor
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2 (FGFR2). Brit J Dermatol 1998; 139(suppl 51): 77–78. Moss C, Burn J. CHILD+ILVEN=PEN or PENCIL. J Med Genet 1990; 27: 390–391. Findlay GH, Moores PP. Pigment anomalies of the skin in human chimaera: their relation to systematised naevi. Brit J Dermatol 1980; 103: 489–498. Brooks EG, Filipovich AH, Padgett JW, et al. T-cell receptor analysis in Omenn’s syndrome: evidence for defects in gene rearrangement and assembly. Blood 1999; 93: 242–250. Shwayder T, Banerjee S. Netherton syndrome presenting as congenital psoriasis. Pediatr Dermatol 1997; 14: 473–476.
Genetic skin disorders Celia Moss Consultant Dermatologist, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK
Key words: blister, collodion baby, harlequin, ichthyosis, pigment, Blaschko lines, mosaicism
Neonatologists do not require a detailed knowledge of all genetic skin disorders but need to recognize one if they see it. The unique accessibility of the skin makes it possible to observe the physical signs and deduce the child’s immediate needs from first principles. The morphological classification given here will help the nondermatologist establish a clinical diagnosis. Tremendous advances over the last 10 years in understanding the molecular basis of skin disease make it possible, in many cases, to confirm the diagnosis and to counsel the family accurately. 2000 Harcourt Publishers Ltd
The neonatologist cannot be expected to remember all possible genetic skin disorders, and rarely needs a precise diagnosis to manage a baby with congenitally abnormal skin. Most of the urgent considerations are apparent on clinical examination. However, in order to predict complications, course and recurrence risk a diagnosis is essential (Table 1). The best approach is to make a careful inspection of the skin to define the physical abnormality. What are the characteristic features of the abnormal skin? What is its texture, colour and distribution? If there are raw areas, has skin been lost (blisters) or was it never there (aplasia cutis)? If the skin appears shiny and tight, is it normal but stretched over underlying swelling (e.g. hydrops) or is it abnormally thickened? Is the thickening superficial (collodion membrane) or deep (stiff skin syndrome)? If there are pale patches are they lacking pinkness (vascularity) or brownness (pigment)? Table 2 should help the neonatologist interpret the physical signs in order to reach the correct diagnostic category. The unique accessibility of the skin compared with other organs facilitates diagnostic precision. It has also, in recent years, enabled scientists to define the molecular basis of many genetic conditions particularly of the epidermis [1]. Once the clinical Correspondence to: Dr Celia Moss, Consultant Dermatologist, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham B4 6NL, UK. Tel.: +44 (0) 121 333 8230; Fax: +44 (0) 121 333 8231; E-mail: [email protected]
1084–2756/00/040311+10 $35.00/0
Table 1. Factors affecting management of genetic skin disorder in a neonate Apparent on clinical examination Skin fragility Involvement of mucosal surfaces Impairment of skin barrier function fluid loss protein loss heat loss infection Restriction of movement feeding breathing Pain Maternal rejection May require knowledge of the diagnosis Association with abnormalities in other systems nervous system GI tract heart skeleton blood Likely course Recurrence risk in subsequent pregnancies
diagnosis has been made, the next steps are often confirmation on a molecular level and sometimes mutation analysis. In the following account, emphasis is placed on the conditions and physical signs which can be detected at birth. © 2000 Harcourt Publishers Ltd
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Table 2. Morphological classification of genetic skin disease in the neonate Physical sign
Diagnostic group
colour may be normal, pink, or yellow due to underlying fat. Dermal hypoplasia is found in the following situations: Brauer (AD) and Setleis (AR) syndromes, which may be the same thing [3], are characterized by focal round lesions on the temples, either isolated or associated with facial dysmorphism. The lesions are often mistakenly attributed to instrumental delivery. Goltz focal dermal hypoplasia (X-linked) occurs in girls and is characterized by focal dermal hypoplasia following Blaschko lines which reflect random X-inactivation [4]. In addition, there may be fat herniation through the hypoplastic dermis, skeletal abnormalities particularly affecting the digits, and ocular defects such as coloboma.
Unformed skin Thin skin
Aplasia cutis Dermal hypoplasia Collagen disorders Blisters/erosions Fragile skin Other bullous disorders Thick/scaly skin Ichthyoses (collodion, Harlequin) Stiff skin syndrome White skin/hair Pigment deficient disorders Palpable brown patches Syndromes with melanocytic naevi Flat brown patches Syndromes with cafe-au-lait macules Syndromes with lentigines Red (vascular) patches Syndromes with port-wine stains Red (vascular) lumps Syndromes with haemangiomas Blaschko lines Mosaic disorders Deficient hair/nails/sweat Ectodermal dysplasias Syndromes with abnormal hair Erythroderma Immunological disorders
Aplasia cutis congenita (Table 3) [2] A red, glistening patch through which blood vessels are easily visible indicates absence of epidermis and at least superficial dermis. There may be an underlying bony defect. Aplasia cutis (failure of the skin to develop) can be distinguished from antenatal skin loss by looking for remnants of detached skin at the edges of the lesion, or evidence elsewhere of skin fragility. A prominent ‘step’ between lesional and non-lesional skin is usually seen in aplasia cutis, but can also occur after intrauterine loss of epidermis and does not distinguish these two conditions. After birth a crust or scab usually forms over an area of aplasia cutis congenita, and may be mistaken for birth trauma. Eventually it leaves a scar which may be depressed or raised. The different genetic types of aplasia cutis congenita are summarized in Table 3.
Dermal hypoplasia A discrete depression in skin which is of normal texture usually indicates dermal hypoplasia. The
Collagen disorders Thin skin due to a deficiency of dermal collagen occurs in various forms of Ehlers-Danlos syndrome, particularly EDS type IV due to abnormal collagen type III. However, it is rarely necessary or possible to diagnose this at birth.
Bullous disorders Defective skin adhesion can present neonatally either as blisters or as erosions, depending on the age of the blisters. Bisters that have occurred in utero may resemble aplasia cutis at birth (see above), this presentation being known as Bart’s syndrome. Prenatal blisters may have healed leaving milia. Once blisters have been observed it is essential, for management as well as diagnosis, to examine their distribution and the state of the non-blistered skin (Table 4). Localization at sites of friction indicates generalized skin fragility, and the most likely diagnosis is epidermolysis bullosa [5] (see Chapter 7). If they are linear on the limbs, trauma may initially be suspected, but in the absence of skin fragility this distribution in a girl is characteristic of incontinentia pigmenti [6], the pattern being determined by Blaschko lines (see below). Blisters occurring in an inflamed and ichthyotic skin are characteristic of bullous ichthyosiform erythroderma [7]. Blisters related to cutaneous plaques and urticaria may represent cutaneous mastocytosis: the trauma of delivery may provoke
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Table 3. Classification of major types of aplasia cutis congenita (ACC) Type of ACC
Associated features
Diagnosis
Scalp, with no associated features
None
Scalp, with associated features
Distal limb reductions Dysmorphism, deafness Polydactyly, clefting Dysmorphism, clefting None (sometimes amniotic band) Skin tags, ocular defects GI atresia
ACC of vertex Catlin marks (ACC on either side of saggital sinus) Adams Oliver syndrome Johanson-Blizzard syndrome Trisomy 13 Wolf-Hirschorn syndrome ACC with fetus papyraceus Delleman–Orthuys syndrome Carmi syndrome
Trunk/limbs with no associated features Trunk/limbs with associated features
Inheritance AD AD AD AR AD AD Sporadic AD AR
Table 4. Genetic causes of neonatal blisters and erosions Condition
Distribution
Rest of skin
Gene
Epidermolysis bullosa Incontinentia pigmenti Bullous ichthyosiform erythroderma Pachyonychia congenita
Friction sites Linear Friction sites Acral
Normal or milia Normal Ichthyotic Normal
Keratins, laminin, collagen collagen VII etc. NEMO X-linked gene Keratins 1 and 10 Keratins 16, 17, 6a, 7a
histamine release from the mastocytomas, causing dramatic blistering. In a neonate with acral blisters and natal teeth, the keratin gene disorder pachyonychia congenita should be considered.
Ichthyoses [7] These scaly disorders are due to defective desquamation of the superficial epidermis (stratum corneum). Usually ichthyosis is an isolated skin disorder, but some rare types also affect the nervous system or the skeleton. Ichthyoses differ in their pattern of scaling, as well as in their associated features. Some ichthyoses have an inflammatory component (the ichthyosiform erythrodermas), appearing red as well as scaly. In one type the structural disturbance within the epidermis produces blistering as well as ichthyosis (bullous ichthyosiform erythroderma). The distribution may be striking, for example the midline demarcation between affected and unaffected skin in CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects) (see linear disorders). Linear ichthyosis in a girl may be due to the X-linked dominant form of chondrodysplasia
punctata (Happle syndrome), in which the abnormality follows Blaschko lines (see below). Table 5 summarizes the clinical features of the ichthyoses and what we know about their genetic basis. Ichthyosis may present to the neonatologist as a collodion baby, or as the much more severe harlequin fetus. A collodion baby has a tight, shiny epidermis which cracks across the flexures as the infant uncurls from the fetal position. Mucous membranes are unaffected and consequently stretched outwards by the adjacent tight skin, creating the characteristic ectropion and eclabion. The skin may be so tight that the baby cannot close its mouth to suck, nor expand its chest to breathe. Barrier function is compromised, risking hypothermia, hypovolaemia and septicaemia. Important emergency measures include coating the baby in a greasy emollient such as 50/50 liquid paraffin/soft white paraffin and nursing in high humidity. Once the raw areas have epithelialized and fluid balance is stable, a water miscible cream or ointment (emulsifying ointment or aqueous cream) more effectively softens the hard scales. Within a few weeks the thick epidermis peels off. A collodion membrane is a physical sign not a diagnosis: it is the presenting feature of several different ichthyoses. Severity at birth is no index of
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Table 5. Classification of the ichthyoses (a) no extracutaneous features Diagnosis
Inheritance
Neonatal appearance
Ichthyosis vulgaris Steroid sulphatase deficient Bullous ichthyosiform erythroderma Non-bullous ichthyosiform erythroderma Lamellar ichthyosis Harlequin ichthyosis
AD XR AD AR AR AR
Normal Normal Collodion Collodion Collodion Harlequin
Gene ? STS KRT1/KRT10 ? TGK ?
(b) with neurological or other associated abnormality Diagnosis Sjogren–Larsson syndrome Refsum syndrome Pollitt syndrome Dorfman–Chanarin syndrome Multiple sulphatase deficiency Chondrodysplasia punctata Chondrodysplasia punctata
Inheritance AR AR AR AR AR AR, AD, XR XD
Neonatal appearance Collodion Normal Normal Normal Normal Ichthyotic Linear ichthyosis
severity of the underlying ichthyosis. Some collodion babies end up with a normal skin [8], while some children with ichthyosis (notably the X-linked type) have a normal skin at birth. Biopsy of the collodion membrane is unhelpful, and the diagnosis of an ichthyosis is usually made on the basis of clinical appearance at a few weeks of age. Harlequin ichthyosis [9] is a very severe and usually fatal neonatal condition. The name refers to the diamond-shaped thick plates of scale separated by deep fissures, resembling the pattern on a harlequin’s costume. In general, the neonatal management issues are the same as for a collodion baby. In addition, there may be ischaemic necrosis of digits owing to the tight skin, and ectropion requiring surgical correction. The horrific appearance may lead to parental rejection. The use of a retinoid drug, acetretin, may have improved the outcome in some non-fatal cases, but survivors are left with a very severe non-bullous ichthyosiform erythroderma.
Stiff-skin syndrome [10] Infantile restrictive dermopathy is a rare recessive disorder which presents at birth and is usually
Associated features
Gene
Delay and spasticity Neuropathy and retinitis pigmentosa Brittle hair Hepatospenomegaly Retardation Dwarfism Asymmetric limb reduction
SLS PAHX ERCC ? ? ? EBP
lethal within days. It is probably a disorder of dermal collagen, although histologically the epidermis is also abnormal. The thick, shiny skin is so tight that all joints are fixed in flexion, unlike a collodion baby in which the more superficial tightness is soon overcome by the baby’s movements. The small round mouth of restrictive dermopathy is quite distinct from the eclabion of a collodion baby. Other dysmorphic features include micrognathia, small nose, low-set ears and wide cranial sutures. Death is usually due to restricted chest movements.
Pigment-deficient disorders [11] The development of normal skin pigment is a multistage process. Melanoblasts originate in the neural crest, migrate outwards along Blaschko lines (see below), and settle in the lower epidermis as melanocytes. Melanin pigment is synthesized within subcellular organelles called melanosomes, production being regulated quantitatively by the enzyme tyrosinase, and qualitatively by several factors which divert the production of simple eumelanin to other pigments. Melanin is passed along the dendrites of the melanocyte and released
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Table 6. Genetic causes of congenital hypopigmentation Pattern of lesions
Condition
Associated features
Generalized
Oculo-cutaneous albinism
Nystagmus
Generalized Generalized Generalized Ash leaf macules White forelock White forelock, belly and limbs Linear Linear
Chediak–Higashi syndrome Hermansky–Pudlak syndrome Phenylketonuria Tuberous sclerosis Waardenburg syndrome Piebaldism Naevus depigmentosus Hypomelanosis of Ito
Immunodeficiency Bleeding diathesis Developmental delay Epilepsy etc Hyperteleorism None None Neurological and skeletal
into adjacent keratinocytes. The process is controlled by dozens of genes, and accordingly there is a wide range of genetic disorders of pigmentation some of which we now understand (Table 6).
Generalized reduction of pigment Oculocutaneous albinism [12,13] It is sometimes difficult to decide whether a very fair baby is albino, especially if the parents are blond. Pathologically fair skin becomes more obvious with age and sun exposure. Pink eyes and nystagmus clinically confirm a diagnosis of oculo-cutaneous albinism, but nystagmus does not usually appear until 2–3 months of age. Type 1 (tyrosinase negative) oculocutaneous albinism is an autosomal recessive disorder caused by mutations in the tyrosinase gene at 11q14-21. Type 2 (tyrosinase positive) oculocutaneous albinism is a heterogeneous group, in which melanin is reduced but not absent, and the eyes are light blue rather than pink. Some type 2 patients are homozygous for a mutation in the ‘p’ gene at 15q11-13, which probably controls the transfer of tyrosine across melanosome membranes. This is also the locus for Prader–Willi syndrome,which may thus be associated with type 2 oculo-cutaneous albinism [14]. No particular skin care is required for the albino neonate apart from sun-protection. Chediak–Higashi and Hermansky Pudlak syndromes are autosomal recessive disorders in which pigment is diluted rather than absent, and albinism may not be apparent at birth. In Chediak–Higashi syndrome [15] there is a generalized disorder of cytoplasmic granules, involving lysosomes as well
Gene TYR (OCA1) P-gene (OCA2) CHS HPS PAH TSC1 and TSC2 PAX3, EDNRB, MITF C-KIT Unknown Mosaicism at several loci
as melanosomes. Patients are, consequently, susceptible to infection and unable to transfer melanin to keratinocytes. In Hermansky Pudlak syndrome [16] there is a bleeding diathesis due to a platelet abnormality, pulmonary fibrosis and granulomatous colitis. The gene, which maps to 10q, produces a transmembrane protein of unknown function. Phenylketonuria is normally diagnosed in the neonate on biochemical screening rather than on the clinical appearance. The fair skin and hair are directly due to deficient phenylalanine hydroxylase, which, like tyrosinase, is involved in melanin synthesis.
Patchy reduction of pigment White patches on the skin are not always due to lack of pigment. A naevus anaemicus, which can be considered the reverse of a port-wine stain, is easily mistaken for a hypomelanotic patch in a fair-skinned baby. Warming or rubbing a naevus anaemicus makes it more obvious, as the surrounding vasodilatation contrasts clearly with the vasospastic area. Conversely the edge can be obscured by pressing on it with a spectacle lens, thus compressing the normal surrounding vessels. A hypomelanotic macule is unaffected by these manoeuvres. The shape and distribution of white patches is an important clue to their cause: leaf-shaped and proximal in tuberous sclerosis, triangular or diamond-shaped and on the forehead in Waardenburg syndrome, segmental and asymmetrical in hypomelanosis of Ito. Waardenburg syndrome [17] presents as a triangular white patch with white overlying hair on the central forehead, and facial
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dysmorphism. It is associated with deafness. There are several subtypes, resulting from dominant mutations in various genes responsible for embryonic migration of neural crest derivatives, particularly PAX3. Some neonates present with colonic obstruction due to Hirschsprung disease. Piebaldism [18], like Waardenburg syndrome, is an autosomal dominant disorder characterized by patchy hypopigmentation usually including a white forelock. However, it is not associated with any other abnormalities, and the problem is entirely cosmetic. It is due to mutations in C-KIT, an oncogene responsible for normal melanoblast migration. In affected individuals white patches occur on the belly, limbs and brow, but not the back, perhaps reflecting distance from the neural crest. The edges of the white patches tend to be at right angles to dermatomal boundaries and Blaschko lines (see below). Thus, the patch on the belly is often diamond-shaped, and those on the limbs have a horizontal cut-off. Within the white patches are irregular islands of aberrant melanocytes. It is common for affected dark-haired adults to dye the white forelock, so the dominant inheritance may not be apparent on first meeting the parents.
Tuberous sclerosis Tuberous sclerosis (TS) is an autosomal-dominant neurocutaneous disorder. The cutaneous signs include the hypomelanotic patch, periungual fibroma, facial angio fibroma, forehead fibrous plaque and shagreen patch, but only the first of these is normally apparent at birth. Hypomelanotic patches are easily seen in a racially pigmented baby, but may not be visible at birth in a white child. Wood’s light examination increases the contrast between light and dark skin and may reveal patches invisible in daylight. The typical hypomelanotic macule of TS is ash-leaf shaped (a long, narrow oval) but round, segmental and confetti-like lesions also occur. A useful sign of TS in a hairy neonate is that the long axis of the patch corresponds to the direction of hair growth, particularly on the back.
Naevus depigmentosus and hypomelanosis of Ito Congenital hypopigmentation in a linear or segmental distribution is termed naevus depigmen-
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tosus. Naevus depigmentosus is usually an isolated cutaneous anomaly [19], but may be associated with neurological deficit and other abnormalities, when it is termed hypomelanosis of Ito (HI). HI is not a single condition, but a phenotype associated with chromosomal mosaicism [20]. The associated features are variable, depending on the particular chromosome affected. Vitiligo can also occur in a segmental pattern but is rarely congenital.
Syndromes with melanocytic naevi Multiple melanocytic naevi (moles) occur in relatives of patients with giant congenital melanocytic naevi, and probably also as an isolated autosomal dominant trait. They are also seen in Turner syndrome. A birth they may be sparse and faint, increasing in number and degree of pigmentation with time.
Lentigines Lentigines are flat, dark-brown lesions which occur in isolation and in several syndromes such as Peutz–Jegher and LEOPARD. However, they may not be apparent in the neonate.
Syndromes with cafe´ -au-lait macules Cafe´ -au-lait macules are very faint in neonatal Caucasian skin, becoming darker and more apparent with time. They occur most commonly in neurofibromatosis type 1, but are also seen in Fanconi pancytopenia, Bloom syndrome, Russell– Silver syndrome, and adrenoleucodystophy. They can also occur as an isolated anomaly, dominantly inherited. Segmental cafe´ -au-lait pigmentation is usually an isolated birth mark. Sometimes it looks like a negative image of hypomelanosis of Ito, when it is termed linear and whorled hypermelanosis, and this may be a manifestation of cutaneous mosaicism (see below). Segmental or linear cafe´ -au-lait pigmentation is also seen in McCune–Albright syndrome, owing to activating mutations in the protein which stimulates hormone-sensitive adenylate cyclase [21]: the
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Figure 1. Diagram to show Blaschko lines [22].
linear pattern probably represents mosaicism for this dominant mutation.
Syndromes with port-wine stains Flat red birth marks are called salmon patches if they are pink and port-wine stains (PWS) if they are red. The association of facial PWS with ocular and cerebral vascular anomalies is described in Chapter 8. A mid-forehead PWS is an occasional and rather non-specific finding in many different genetic disorders including Beckwith–Wiedemann, Pallister–Hall, trisomy 13 and Rubinstein–Taybi syndromes. Multiple PWS can be inherited as an
isolated autosomal dominant trait. In Proteus syndrome they are associated with other hamartomas and localized overgrowth. In Klippel–Trenaunay syndrome they accompany limb hypertrophy. A mid-forehead salmon patch (Unna’s naevus), often accompanying a similar lesion at the nape of the neck (‘stork mark’) is an isolated anomaly: the forehead lesion resolves spontaneously, while the posterior element tends to persist.
Syndromes with haemangiomas Strawberry naevi may be single or multiple. Usually the abnormality is confined to the skin, but
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Table 7. Morphological classification of skin disorders following Blaschko lines Morpholog
Condition
Type of mosaicism
Thin skin Blisters Thick/scaly skin Epidermolytic hyperkeratosis CHILD syndrome ILVEN Comedone naevus Other epidermal naevus
Goltz focal dermal hypoplasia Incontinentia pigmenti Chondrodysplasia punctata Non-lethal dominant mutation Mutation Lethal dominant mutation Lethal dominant mutation Non-lethal dominant mutation
White skin
Naevus depigmentosus Hypomelanosis of Ito Pallister syndrome Linear and whorled Hypermelanosis McCune-Albright syndrome Segmental neurofibromatosis segmental pigmentary Anomalies Ectodermal dysplasia carrier
Brown skin
Deficient sweating
in disseminated haemangiomatosis internal organs are involved (see Chapter 8). Strawberry naevi accompany macrocephaly and lipomas in the Bannayan–Zonana syndrome.
Skin lesions following Blaschko lines (Mosaic disorders) Several skin disorders follow a pattern of lines delineated 100 years ago by Blaschko [22,23] (Fig. 1). We now know that this pattern represents genetic mosaicism in the skin. The pattern is attributed to the lines of migration and proliferation of epidermal cells during early embryogenesis [24]. The bands of abnormal skin represent clones of cells carrying a mutation in an epidermally expressed gene. Table 7 gives a morphological classification of linear skin disorders. In the neonate, the lesions may be faint and easily missed. Mosaicism can arise in the following ways:
Random X-chromosome inactivation (Lyonisation) [23,25]. Clones of skin cells expressing the abnormal X-chromosome contrast with clones expressing the normal chromosome, producing the linear lesions of incontinentia pigmenti, Goltz syndrome and X-linked dominant chondrodysplasia punctata. Defective sweating in a linear
X-inactivation X-inactivation X-inactivation KRT1,KRT1 0 ? ? FGFR2 Mutation Lethal dominant mutation ? Chromosomal mosaicism Mosaic chrom. 12 anomaly Chromosomal mosaicism Lethal dominant mutation Non-lethal dominant Mutation Chimaerism X-inactivation
Gene ? ? EBP
? ? Multiple ? Multiple GNAS NF1 Multiple EDA1
distribution can be demonstrated in female carriers of X-linked hyphidrotic ectodermal dysplasia. Somatic non-dysjunction producing chromosomal mosaicism. This is found in the linear pigmentary disorders hypomelanosis of Ito [20] and linear and whorled hypermelanosis. Somatic mutation for a dominant skin disorder. Mosaicism for mutations causing bullous ichthyosiform erythroderma has been found in linear epidermolytic hyperkeratosis [26]. Recently a mutation in the gene responsible for Apert syndrome (characterized by skeletal abnormalities and severe acne) was found in a linear comedone (blackhead) naevus [27]. The same mechanism is postulated for segmental neurofibromatosis. Somatic mutation for a lethal dominant gene. This is the presumed explanation for linear disorders not recognizable as localized forms of a generalized condition: the lethal gene is ‘rescued’ by mosaicism. Linear lesions in this category include McCune–Albright syndrome [21] and epidermal naevi (other than epidermolytic and comedone naevi). Epidermal naevi may be accompanied by skeletal or neurological features in Proteus syndrome and epidermal naevus syndrome, reflecting the potentially serious nature of these mutations even in the mosaic form. CHILD syndrome (congenital hemidysplasia with ichthyosiform
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erythroderma and limb defects) may represent a more extensive form of ILVEN (inflammatory linear verrucous epidermal naevus) [28]. Chimerism. A chimera is composed of two genetically different cell lines resulting from fusion of two zygotes or fertilization of an ovum by two sperms. This is extremely rare, and usually only detected by chance on blood grouping. Affected individuals may have segmental patches of light and dark pigmentation [29].
Ectodermal dysplasias This is a heterogeneous group of more than a hundred conditions characterized by any or all of the following: deficient hair, nails, teeth, sweating. They may be associated with other features such as deafness, clefting and skeletal abnormalities. The best known is X-linked hypohidrotic ectodermal dysplasia (see Chapter 4). Ectodermal dysplasia is rarely diagnosed in the immediate newborn period since hair and teeth are normally absent or sparse at this time. A good head of hair at birth does not exclude the diagnosis, since this is often shed and may not re-grow.
Syndromes with abnormal hair Hair is so variable at birth that it is difficult to say if it is abnormal. Fair, tightly curled hair in a male suggests Menkes’ kinky hair syndrome.
Immunological disorders Infection due to immunodeficiency may present later than the neonatal period. However, onset in the first week or so of scaly erythroderma may suggest severe combined immunodeficiency. Previously known as Leiner’s syndrome, this group has now been separated immunologically into specific entities including Omenn syndrome [30] and Netherton syndrome [31]. Clinically, it may be difficult to differentiate these disorders from severe seborrhoeic dermatitis which can be accompanied by marked lymphadenopathy and failure to thrive. References 1 Moss C, Savin J. Dermatology and the new genetics. Oxford: Blackwell Science, 1995.
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2 Evers MEJW, Steijlen PM, Hamel BCJ. Aplasia cutis congenita and associated disorders: an update. Clin Genet 1995; 47: 295–301. 3 Ward KA, Moss C. Evidence for genetic homogeneity of Setleis’ syndrome and focal facial dysplasia. Brit J Dermatol 1994; 130: 645–649. 4 Temple IK, MacDowall P, Baraitser M, et al. Focal dermal dysplasia (Goltz syndrome). J Med Genet 1990; 27: 180– 187. 5 Moss C. Hereditary bullous disorders. Current Paediatrics 1995; 5: 252–257. 6 Landy SJ, Donnai D. Incontinentia pigmenti (BlochSulzberger syndrome). J Med Genet 1993; 30: 53–59. 7 Shwayder T. Ichthyosis in a nutshell. Pediatric Rev 1999; 20: 5–12. 8 Frenk E, Techtermann F. Self-healing collodion baby: evidence for autosomal recessive inheritance. Pediatr Dermatol 1992; 9: 95–97. 9 Akiyama M, Suzumori K, Shimizu H. Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks’ estimated gestational age. Prenat Diag 1999; 19: 167–171. 10 Paige DG, Lake BD, Bailey AJ, et al. Restrictive dermopathy: a disorder of fibroblasts. Brit J Dermatol 1992; 127: 630–634. 11 Biswas S, Lloyd IC. Oculocutaneous albinism. Arch Dis Child 1999; 80: 565–569. 12 Hearing VJ. Unraveling the melanocyte. Am J Hum Genet 1993; 52: 1–7. 13 Oetting WS, King RA. Molecular basis of oculocutaneous albinism. J Invest Dermatol 1994; 103: 131S–136S. 14 Lee S-T, Nicholls RD, Bundey S, et al. Mutations of the P-gene in oculo-cutaneous albinism, ocular albinism and the Prader-Willi syndrome plus albinism. N Engl J Med 1994; 330: 529–534. 15 Spritz RA. Multi-organellar disorders of pigmentation: tied up in traffic. Clin Genet 1999; 55: 309–317. 16 Gahl WA, Brantly M, Kaiser-Kupfer MI, et al. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N Engl J Med 1998; 338: 1258–1264. 17 Read AP, Newton VE. Waardenburg syndrome. J Med Genet 1997; 34: 656–665. 18 Spritz RA, Holmes SA, Itin P, et al. Novel mutations of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. J Invest Dermatol 1993; 101: 22–25. 19 Lernia VD. Segmental nevus depigmentosus: analysis of 20 patients. Ped Dermatol 1999; 16: 349–353. 20 Kuster W, Konig A. Hypomelanosis of Ito: no entity but a cutaneous sign of mosaicism. Am J Med Genet 1999; 85: 346–350. 21 Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune–Albright syndrome. Proc Nat Acad Sci USA 1992; 89: 5152–5156. 22 Blaschko A. Die Nervenverteilung in der Haut in ihrer beziehung zu den Erkrankungen der Haut. In Beilage zu den Verhandlungen der Deutschen Dermatologischen Gesellschaft VII Congress, Breslau. Wien: Braumuller, 1901.
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23 Happle R. Lyonization and the lines of Blaschko. Hum Genet 1985; 70: 200–206. 24 Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Gen 1999; 85: 330–333. 25 Traupe H. Functional X-chromosome mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko. Am J Med Genet 1999; 85: 324–329. 26 Moss C, Jones DO, Blight A, Bowden PE. A birthmark due to cutaneous mosaicism for a keratin 10 mutation. Lancet 1995; 345: 596. 27 Munro CS, Wilkie AOM. Acneiform epidermal naevus due to mutation in fibroblast growth factor receptor
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2 (FGFR2). Brit J Dermatol 1998; 139(suppl 51): 77–78. Moss C, Burn J. CHILD+ILVEN=PEN or PENCIL. J Med Genet 1990; 27: 390–391. Findlay GH, Moores PP. Pigment anomalies of the skin in human chimaera: their relation to systematised naevi. Brit J Dermatol 1980; 103: 489–498. Brooks EG, Filipovich AH, Padgett JW, et al. T-cell receptor analysis in Omenn’s syndrome: evidence for defects in gene rearrangement and assembly. Blood 1999; 93: 242–250. Shwayder T, Banerjee S. Netherton syndrome presenting as congenital psoriasis. Pediatr Dermatol 1997; 14: 473–476.