Alan D. Irvine1 and Jemima E. Mellerio2
1Our Lady's Children's Hospital, Crumlin; St James's Hospital, Dublin; and Trinity College, Dublin, Ireland
2St John's Institute of Dermatology, Guy's and St Thomas’ NHS Foundation Trust, London; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Chromosomal disorders may be due to abnormalities of chromosome number or structure and may involve autosomes or sex chromosomes. Somatic cells are diploid, with a complement of 46 chromosomes, whereas gametes (ova and sperm) are haploid, with only 23 chromosomes following reduction division in meiosis. Numerical abnormalities that involve the gain or loss of one or more chromosomes are known as aneuploidies. Structural chromosome rearrangements result from chromosome breakage with subsequent reunion in a different configuration. They may be balanced or unbalanced, depending on whether or not gain (or loss) of genetic material occurs. Approximately 7.5% of all conceptions have a chromosomal disorder, but most of these are spontaneously aborted, so the birth frequency is 0.6%. Among early spontaneous abortions, the frequency of chromosomal disorders is 60%, whereas in late spontaneous abortions and stillbirths the frequency is 5%. Chromosomal abnormalities generally cause multiple congenital malformations. Children with more than one physical abnormality, particularly if developmentally delayed, should undergo chromosomal analysis as part of their investigation. Chromosomal disorders are incurable but can be reliably detected by prenatal diagnostic techniques. Amniocentesis or chorionic villous sampling should be offered to women whose pregnancies are at increased risk, namely women over the age of 35 years and couples with an affected child.
While the traditional approach to studying chromosomal anomalies has involved karyotype or fluorescence in situ hybridization (FISH) analysis, in recent years array comparative genomic hybridization (array CGH or ‘microarray’, also known as chromosomal microarray analysis (CMA)) has been developed and is becoming the primary genetic tool in examining chromosomes for abnormalities of chromosome number (aneuploidy) and structure (deletions/duplications/inversions).
Down [1] described this syndrome in 1866. In 1959, it became the first recognized chromosomal anomaly [4]. It is the most common autosomal abnormality, with a frequency of about 1/700 live births [5].
Most cases (95%) result from trisomy of chromosome 21, in which the extra chromosome is derived by non-disjunction at meiosis, usually from the mother; the incidence of this type rises with maternal age. Less common, and clinically indistinguishable, is the type that shows no relation to maternal age and is sometimes familial. The affected child has the normal number of 46 chromosomes but one of the clinically normal parents carries a translocation of part of chromosome 21. A few patients are themselves mosaics and tend to have less marked physical stigmata and higher intelligence [6].
Congenital heart defects are common and the brain is small with flat convolutions. Renal tract anomalies are less common.
Immunological defects are frequent. Autoimmune disease is common in Down syndrome, T-cell function is impaired and the atopic state is often associated [7]. There is an increased risk of developing acute leukaemia, usually under the age of 5 years.
The lichenified patches of skin show no distinctive pattern on histology, with hyperkeratosis, acanthosis and a dermal inflammatory infiltrate.
The facial appearance often permits a clinical diagnosis. The head is small, the face flat, the nose short and squat and the ears small and misshapen. The eyes are usually conspicuously almond shaped, with slanting palpebral fissures. The eyelids are thickened and the eyelashes short and sparse. Epicanthic folds are frequent in early childhood but tend to become less noticeable with age. The iris tends to be hypoplastic and may show light areas in its outer third (Brushfield's spots). The limbs are stumpy and the joint ligaments lax. The fingers are short and cone shaped and are sometimes webbed. The little finger is often curved. The presence of these features varies in affected individuals, and a diagnostic index has been proposed [9].
Intellectual disability is a serious complication: the IQ is usually less than 50, and if it is not mosaicism should be suspected. Congenital heart malformations, especially endocardial cushion defects, are present in 40%, and duodenal atresia may occur. Other complications include cataracts (2%), epilepsy (10%), hypothyroidism (3%), leukaemia (1%), atlantoaxial instability (2–3%) and recurrent respiratory infections. Down syndrome accounts for about one-third of all moderate and severe mental disability in children of school age. Puberty is often delayed and incomplete, with adult height at about 150 cm. Presenile dementia commonly supervenes after 40 years of age.
The skin is normal at birth and in early childhood is soft and velvety [8, 10]. Between the ages of 5 and 10 years it becomes increasingly dry and less elastic, and, by the age of 15, over 70% show generalized xerosis of mild to moderate degree with evidence of accelerated skin ageing [11]. Patchy lichenification is present in some 30% under 10 years and more than 80% over 20 years of age. The patches resemble lichen simplex and most commonly occur on the upper arm, wrists, the fronts of the thighs, the back of the ankle and the back of the neck, and are probably correctly regarded as manifestations of atopic eczema, the incidence of which some authorities [10] have considered to be low.
A chronic follicular papular eruption of the presternal and interscapular regions is frequently present, consistent with Malassezia folliculitis. In a clinical trial, oral itraconazole produced a significant clinical improvement accompanied by a decrease in the skin Malassezia count, but relapse occurred when therapy was discontinued and was accompanied by a return of the Malassezia yeasts [12].
The hair may be normal but is often fine and may be hypopigmented. The prevalence of alopecia areata is high and it tends to be extensive and persistent [7, 13]. The teeth are hypoplastic and late to erupt. Fissuring and thickening of the lips are frequent and increase in prevalence and severity with age [14]. The tongue is scrotal in almost all cases. Elastosis perforans serpiginosa [15, 16] and syringomas, especially in adult females with Down syndrome [17, 18], occur more often than in normal subjects.
Skin infections, angular cheilitis, chronic blepharitis and a purulent nasal discharge are common. There is a high prevalence of onychomycosis [7, 19]. The cheeks are often red. The peripheral circulation is poor, acrocyanosis is frequent and livedo reticularis is often conspicuous throughout the year, on the thighs, buttocks and trunk.
Dermatoglyphic features include a single flexion crease on the fifth finger, the simian palmar crease and an increased incidence of ulnar loops on the fingers.
There is no evidence that the prevalence of other dermatoses is significantly different in individuals with Down syndrome compared with individuals with intellectual disability from other causes. Psoriasis runs its normal course, although an unusual hyperkeratotic form has been described [20]. Acral lentiginous melanoma has been described in association with Down syndrome [21]. There is some evidence that seborrhoeic dermatitis is commoner [22, 23] and also premature greying.
This is the second most common multiple malformation syndrome. It occurs in about 1/3000 live births; 95% of affected fetuses abort spontaneously. Parental non-disjunction at either the first or second meiotic division results in the extra copy of chromosome 18. Rarely, a parental translocation is responsible. Occasionally, mosaicism is seen with a milder phenotype and can give rise to pigmentary skin changes, as seen in hypomelanosis of Ito [4, 5]. The syndrome comprises severe intellectual disability, a characteristic skull shape with a small chin and prominent occiput, low-set malformed ears, clenched hands with overlapping index and fifth fingers, single palmar crease, ‘rocker-bottom’ feet and a short sternum. Malformations of the heart, kidneys and other organs are frequent. Cutaneous features include cutis laxa of the neck, hypertrichosis of the forehead and back, and capillary haemangiomas. Fingerprints show a distinctive low-arch dermal ridge pattern. Death within a month occurs in 30%. Only 10% survive beyond the first year and these infants show profound developmental delay.
The incidence of trisomy 13 is 1/5000 live births. Non-disjunction at either the first or second meiotic division in either parent may cause trisomy 13. In about 20% of cases, one parent is a translocation carrier. In about 5% of patients, mosaicism is present, which may be associated with prolonged survival [5]. The characteristic features of the syndrome are intellectual disability, sloping forehead reflecting underlying holoprosencephaly (a developmental defect of the forebrain), eye defects including microphthalmia or anophthalmia, cleft palate and cleft lip, low-set ears, rocker-bottom feet, cardiac defects and a variety of other visceral abnormalities. Survival for more than 6 months is unusual. Cutaneous features include vascular anomalies, especially of the forehead, hyperconvex nails and localized defects of the scalp. Cutis laxa of the neck has also been reported. The palm print shows a distal palmar axial triradius.
Although the syndromes to which these autosomal abnormalities give rise include distinctive craniofacial malformations, they do not exhibit constant or frequent dermatological features, apart from abnormal dermatoglyphics. Other chromosomal disorders are reviewed elsewhere [1, 2].
These children have microcephaly, intellectual disability, hypospadias and multiple malformations, such as cleft lip and/or palate, low-set ears and pre-auricular pits. There are scalp defects in some cases.
This is a clinically heterogeneous syndrome. The patients have severe intellectual delay and microcephaly with a cat-like cry. In some cases a pre-auricular skin tag accompanies low-set malformed ears. There may be premature greying of the hair.
Hypoplasia of the mid-face gives these children deep-set eyes. The antihelix is very prominent and there are multiple skeletal and ocular abnormalities. Eczema has been reported to occur in 25% of cases.
Turner syndrome is defined as a gonadal dysgenesis due to a missing or structurally defective X chromosome. In 1938, Turner described this syndrome in seven girls [1].
The frequency of Turner syndrome is 1/2500 female births [3]. In some 80% of cases, there are 45 chromosomes with an XO sex chromosome complement. Such cases are chromatin negative in buccal smears. More recent data have suggested that all viable 45,X cases are in fact cryptic mosaics, implying an origin by mitotic loss [4]. The incidence of 45,X was reported to be increased in the offspring of teenage mothers [5], but in a study from Denmark there was no significant relation between the mother's age and the risk of Turner syndrome [6].
Most of the remaining 20% of cases are chromatin positive. Some have 46 chromosomes but with partial deletion of one X chromosome [7]. Such individuals may not differ significantly in their phenotype from the common XO but they may be less severely affected [8]. Other cases have shown mosaicism of various types (XX/XO or XXX/XO) [9].
In place of the normal gonads, ovarian streaks are present that are composed of stroma-like cells and quiescent germinal epithelium without follicular activity or germ cells. However, both follicles and germ cells have occasionally been present.
Lymphangiographic studies have shown hypoplasia of cutaneous and subcutaneous lymphatics [10].
A lack of feedback inhibition by hormones from the defective ovaries produces elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the serum by 5 days of age [11].
Turner syndrome results in early spontaneous loss of the fetus in over 95% of cases. Severely affected fetuses who survive to the second trimester can be detected by ultrasonography, which shows cystic hygroma, chylothorax, ascites and hydrops.
Growth failure is a consistent finding at birth in infants with Turner syndrome, which begins in early gestation and is well established by mid-pregnancy [16]. The diagnosis may be suggested in the newborn by redundant neck skin and peripheral oedema. However, the diagnosis is usually made later as a result of investigation for short stature and primary amenorrhoea.
The characteristic clinical features of Turner syndrome include: small stature; a broad shield-shaped chest with widely spaced nipples; a wide carrying angle of the arms; a webbed neck (pterygium colli); low, misshapen ears; high, arched palate; short fourth, and sometimes fifth, metacarpals and metatarsals; hypoplastic nails; and a tendency to keloidal scar formation. Skeletal abnormalities are a common feature [7], but are also very variable. Among the most frequent are cubitus valgus, kyphoscoliosis and epiphyseal defects and pathological fractures. Cardiovascular abnormalities [17] are present in some 25% of cases, especially coarctation of the aorta. Ocular defects, squints or ptosis, are also a feature of some cases. Intelligence is usually normal. Some girls with Turner syndrome experience a range of social difficulties that can cause significant distress. Progress has been made in identifying foundational deficits in attention and executive function that could explain visuospatial and arithmetical impairments [18].
Dermatological features in Turner syndrome are numerous but variable [19]. Apart from a low posterior hairline and cutis laxa, especially on the neck and buttocks, individuals with Turner syndrome have increased numbers of melanocytic naevi and therefore have an increased risk for melanoma [20]. Lymphangiectatic oedema of the hands and feet may be present at birth and clear in the first 2 years. Alopecia areata and psoriasis have been reported in association with Turner syndrome, which may relate to the fact that Turner syndrome patients are prone to develop autoimmune diseases, mainly autoimmune thyroiditis and inflammatory bowel syndrome [21].
Endocrinological investigations reveal an increased output of pituitary gonadotrophins accompanied by low oestrogen levels. Thus there is usually primary amenorrhoea with failure to develop full secondary sexual characteristics [22]. Some patients menstruate and, exceptionally, may be fertile. Adrenal androgens are present, and pubic and axillary hair may be present in the absence of other manifestations of normal pubertal development. A few examples are known [23] in which otherwise typical Turner syndrome (XO chromosome complement) is accompanied by some degree of genital virilization and hirsutism.
Diagnosis may be made prenatally by amniocentesis [5]. The somatic abnormalities may suggest the diagnosis in infancy or childhood, but if they are inconspicuous or absent, the diagnosis may be unsuspected until puberty. Increased urinary excretion of FSH supports the diagnosis, which can be confirmed by examination of buccal smears supplemented by chromosome studies.
Oestrogen replacement will allow the development of secondary sexual characteristics but does not seem to influence stature or infertility. Treatment with human growth hormone may improve the ultimate adult height. Melanocytic naevi may grow more rapidly during growth hormone therapy [24]. Therefore, individuals with Turner syndrome, especially those on growth hormone therapy, should have periodic skin examinations and be advised on the regular use of sunscreens. For a comprehensive recent review of clinical care please see Pinsker et al. [25].
The frequency of Klinefelter syndrome is 1/600 male births [2]. In buccal smears, the nuclei are chromatin positive and indistinguishable from those of the normal female, but in cultures there are seen to be 47 chromosomes with an XXY sex chromosome complement [3]. The differentiation of the developing gonad proceeds along male lines but the testis fails to develop fully, and many seminiferous tubules are replaced by fibrous tissue. Leydig cells are present in normal or increased numbers.
There are no clinical manifestations before puberty, which occurs at the normal age. The testes are small and fail to produce adult levels of testosterone, which leads to poorly developed secondary sexual characteristics and infertility. Hair growth on the trunk, limbs and face tends to be reduced. Psychiatric disorders are common but intellectual disability is not. Some patients retain eunuchoid body proportions. They are tall, obese and may develop gynaecomastia. Associated features include osteoporosis [7] and taurodontism (vertical enlargement of the molar pulp chamber) [8]. Various minor dermatoglyphic changes have been recorded [9].
An association between systemic lupus erythematosus (SLE) and Klinefelter syndrome has been postulated [10], and this is interesting in view of the fact that SLE is more frequent in women than men and that oestrogens may provoke SLE in some patients [11]. In a case report of SLE in a hypogonadal male with Klinefelter syndrome treated with testosterone in doses sufficient to normalize the serum level of this hormone to the adult male range, haematological and serological abnormalities, including elevated levels of anti-DNA antibodies and depressed complement levels, returned to normal within 9 months of increasing the testosterone dose [12]. Men commonly have SLE that is more severe than that found among women, but patients with Klinefelter syndrome seem to have SLE of the same degree of severity as women [13].
The presence of an additional X chromosome in patients with Klinefelter syndrome may protect them against lethality due to X-linked dominant traits, which are usually fatal in males, as demonstrated in cases of male children affected with incontinentia pigmenti [14, 15] and focal dermal hypoplasia (Goltz syndrome) [16].
Patients with Klinefelter syndrome have an increased risk of developing leg ulcers, especially in combination with hyperpigmentation or atrophie blanche [17–19]. Some authors have attributed the cause of leg ulceration to venous insufficiency, others have implicated increased activity of plasminogen activator inhibitor 1 [20]. It seems likely that androgens may protect against the development of leg ulcers, because ulcers are more common in women than men, and it may be relevant that men who do develop leg ulcers tend to be taller, heavier and less fertile than age-matched control subjects [21].
The association of gynaecomastia with small testes and otherwise apparently normal genitalia should suggest the diagnosis, which is supported by finding an increased urinary excretion of gonadotrophin. The diagnosis is confirmed by chromosome studies.
Testosterone replacement therapy will improve secondary sexual characteristics, but infertility is the rule, except in mosaic patients [22].
There are several other syndromes affecting the sex chromosomes. However, they are very rare and the cutaneous features are not so prominent.
These individuals show many of the main features of Klinefelter syndrome, including sparse body hair. Additional features reported are multiple cutaneous angiomas, acrocyanosis and early peripheral vascular disease.
These patients are phenotypic males, often tall and with, perhaps, an increased incidence of severe acne (see Chapter 90). They may have intellectual disability, and have a reputation for aggressive behaviour [3], not accepted by all authorities. There is no evidence of increased secretion of FSH or LH [4].
These patients, of low birth weight, are slow to grow physically and are intellectually impaired. There are multiple skeletal defects, of which limited elbow pronation is the most characteristic. The ears are large, low set and malformed. There is hypogenitalism. No consistent dermatological defects are reported, but some patients have hypotrichosis.
Fragile X syndrome is associated with a folate-sensitive fragile site in band Xq27.3 due to a triplet DNA repeat that is expanded and unstable. Subjects have intellectual disability and mild dysmorphic features, with mild connective tissue abnormality that leads to fine skin, hyperextensible joints and flat feet. Males are more commonly affected than females. The disorder is common, with about 1/2000 children affected.
A working definition of chromosomal mosaicism is the coexistence within an individual of two or more distinct cell lines that are genetically identical except for the chromosomal difference (total number/ploidy, deletions, duplications, other chromosomal abnormalities) between them. Mosaicism results from a post-zygotic event caused by a mitotic error in some cell lines during embryogenesis. Mosiacism results in uneven development and growth of abnormal cells throughout the tissues of the body. The degree of mosaicism (the proportion or percentage of cells that are chromosomally normal as compared to chromosomally abnormal) very roughly correlates to phenotype severity. Low-level mosaicism is more likely to result in a less abnormal phenotype.
Constitutional mosaicism often involves the skin, and this commonly is expressed as patchy pigmentary, vascular, atrophic or hyperkeratotic changes along the lines of Blaschko. Any child with patchy pigmentary abnormalities, especially if asymmetrical or following the lines of Blaschko, should be considered to possibly have chromosomal mosaicism. An awareness of this possibility is important for dermatologists as they will often make or suggest the diagnosis. The possibility of chromosomal mosaicism should be entertained in any child or adult with patchy blaschkoid pigmentation occurring in association with syndromic developmental anomalies. One special type of chromosomal mosaicism is the condition known as hypomelanosis of Ito, which often has an Xp11 breakpoint translocated with an autosomal fragment.
It is relatively easy to confirm mosaicism in the skin if fibroblast lines are affected. Fibroblasts collected via skin biopsy can be cultured and chromosome analysis can take place using either traditional karyotyping or CGH arrays. If keratinocytes are affected in the absence of fibroblast involvement, this cell line will need to be isolated and cultured separately. Sampling the peripheral blood mononuclear cells (PBMCs), the skin and any other organ if possible provides an insight into the degree of mosaicism. Detection of mosaicism using karyotyping is a laborious and expensive process. To exclude 20% mosaicism with 95% confidence limits, 14 cells must be examined; but to exclude 5% mosaicism, 63 cells must be examined, an extremely time-consuming process [1]. Recent work has highlighted the important role that array CGH will play in the detection of mosaicism [2]. Low-level mosaicism for several chromosomal abnormalities has been detected on array CGH in individuals in whom the routine karyotype was normal.