The skin and systemic disease Genetics and skin disease
In ancient times changes in the skin were taken to indicate that the whole body was diseased and although arguments continue about what the Old Testament writers understood by “leprous”, there was clearly an appreciation of the connection between the skin and systemic illness.
Clinical signs in the skin may give valuable diagnostic clues to underlying disease.
The cutaneous signs of systemic disease is a very large subject; and what follows is only an outline of the more common skin changes that may be associated with systemic illness.
A disease affecting internal organs may produce the same changes in both the skin and other organs as in the connective tissue diseases.
However, underlying conditions may be associated with skin changes brought about by quite different processes, as in acanthosis nigricans or dermatomyositis in which there is an underlying neoplasm with characteristic skin signs.
Sometimes severe skin disease itself may be the cause of generalised illness.
The skin is also a common site for allergic reactions to drugs, with a rash being the first clinical sign.
The florid skin lesions of AIDS illustrate the results of infections when the immune response is impaired.
Conditions affecting both the skin and the internal organs
Immune reactions
Allergic reactions to drugs such as penicillin can occur. In this case the penicillin molecule attaches to serum protein.
This compound acts as an antigen and may form a complex with IgG antibody.
It is this complex which attaches to blood vessel walls to produce an inflammatory reaction.
This presents as a rash developing a few days to two weeks after treatment on the skin, but if it occurs in the kidneys the resulting tissue damage can have serious consequences.
This is an example of Type III allergy with antigen–antibody complexes being deposited in the small blood vessels.
Sometimes a much more acute anaphylactic reaction develops A fixed drug eruption is characterised by a localised patch of erythema that flares up whenever the drug is taken.
Erythema multiforme can occur in drug reactions.
Connective tissue diseases involve complex immunological processes that affect both internal organs and the skin.
This means that it is particularly important to realise the significance of any associated skin changes. Lupus erythematosus
This condition has been described as “a disease with a thousand faces” because of the wide range of organs involved and the numerous ways in which it can present. In three quarters of the patients the skin is involved.
There are four main types, with numerous variations.
In systemic lupus erythematosus (SLE) the commonest skin change is an acute erythematous eruption occurring bilaterally on the malar area of the face in a “butterfly” distribution.
There may also be photosensitivity, hair loss, and areas of vasculitis in the skin. There is often intolerance of sunlight.
It is more common in females with a female:male ratio of 8:1.
The systemic changes include fever, arthritis and renal involvement, but there may be involvement of a wide range of organs.
The criteria for diagnosing the condition include at least four of the features in the box on the right.
Subacute lupus erythematosus is a variant in about 10% of patients with lupus erythematosus that presents with non-scarring erythematosus plaques mainly on the face, hands and arms.
Papulo squamous lesions also occur.
They may be annular.
Systemic involvement is less common and severe than in SLE.
It is associated with a high incidence of neonatal lupus erythematosus in children born to mothers with the condition.
The antinuclear factor test is positive in 60% and anticytoplasmic antibodies are present in 80% of patients.
Discoid lupus erythematosus (DLE) is a condition in which circulating antinuclear antibodies are very rare.
There are quite well defined photosensitive inflammatory lesions, with some degree of atrophy and hyperkeratosis of the follicles, giving a “nutmeg grater” feel.
It occurs predominantly on the face or areas exposed to the sun, becoming worse in the summer months.
Scarring is common causing hair loss in lesions on the scalp.
Treatment of SLE with the threatened or actual involvement of other organs is important.
Prednisolone is usually required and sometimes immunosuppressant drugs such as azathioprine as well.
Treatment of DLE is generally with topical steroids.
Hydroxychloroquine by mouth is also used, generally in a dose of 200 mg daily.
This drug can diminish visual acuity in higher doses and this should be checked every few months.
A simple chart, the Amsler Chart, is available for patients to use, consisting of a central dot with a grid which becomes blurred when held at arm’s length when there is any impairment of acutity.
Dermatomyositis
This condition is associated in adults with underlying carcinoma commonly of the breasts, lung, ovary, or gastrointestinal tract.
It is characterised by localised erythema with a purple hue (heliotrope), predominantly on the eyelids, cheeks, and forehead.
There may be similar changes on the dorsal surface of the fingers, often with dilated nail fold capillaries.
These changes may precede the discovery of an underlying tumour and may also fade away once it is removed.
There is a variable association with muscle discomfort and weakness, mainly in the upper limb girdle.
The finding of muscle weakness together with specific electromyographic changes and an inflammatory infiltrate in the muscle means there is almost certainly an underlying malignancy, so suitable investigation is indicated.
Systemic sclerosis
As the name implies, there is extensive sclerosis of the connective tissue of the lungs, gastrointestinal tract, kidneys, and heart.
Endothelial cell damage in the capillaries results in fibrosis and sclerosis of the organs concerned.
The skin becomes tethered to the subcutaneous tissues and immobile, leading to fixed claw like hands, constricted mouth with furrowed lips, and beak-like nose.
There are vascular changes producing Raynaud’s phenomenon and telangiectasia around the mouth and on the fingers.
There are also flat “mat-like” telangiectasia on the face.
Workers manufacturing polyvinyl chloride can develop skin changes similar to systemic sclerosis with erosions of the bones, hepatic and pulmonary lesions.
Pesticides and epoxy resin can also produce scleroderma-like changes.
It is associated with antinuclear antibodies (speckled or nucleolar), and in about 50% of cases, circulating immune complexes may be present.
A variant is the CREST syndrome. In this type of scleroderma there is Calcinosis with calcium deposits below the skin on the fingers and toes, Raynaud’s phenomenon with poor peripheral circulation, immobility of the oEsophagus, dermal Sclerosis of the fingers and toes, and Telangiectasia of the face and lips and adjacent to the toe and finger nails.
It has a better prognosis than systemic sclerosis.
Antinuclear antibodies at the centromere are frequently present.
Morphoea is a benign form of localised systemic sclerosis in which there is localised sclerosis with very slight inflammation.
There is atrophy of the overlying epidermis.
The early changes often consist of a dusky appearance to the skin.
Lichen sclerosus
The full name is lichen sclerosis et atrophicus or LSA.
This is a relatively uncommon condition seen mainly in women in whom well defined patches of superficial atrophy of the epidermis occur with a white colour.
There is fibrosis of the underlying tissues. It frequently occurs in the vulva and perineum and may also appear on the penis as balanitis xerotica obliterans.
Extragenital lesions may occur anywhere on the skin.
It may occur in a more acute form in children where it tends to resolve, but in adults it is a very chronic condition. There is an increased incidence of squamous cell carcinoma.
Treatment is with topical steroids and excision of any areas that appear to be developing tumours.
The cause of the hyalinized collagen and epidermal atrophy is unknown, but in early lesions there is an infiltrate of lymphocytes with CD3, CD4, CD8, and CD68 markers.
There is also an increase in
Langerhans cells, so there may well be an immunological basis for these changes.
Vascular changes
Vascular lesions are associated with a wide range of conditions including infections, neoplasia, and allergic reactions.
Hormones, particularly oestrogen, may affect the small blood vessels of the skin to produce telangiectasia and small angiomas, such as spider naevi.
Vasculitis and purpura, described in chapter 7, may be associated with disease of the kidneys and other organs.
“Splinter haemorrhages” under the nails are usually the result of minor trauma but may be associated with a wide range of conditions, including subacute bacterial endocarditis and rheumatoid arthritis.
Livedo reticularis is a cyanotic, net-like discoloration of the skin over the legs.
It may be idiopathic or associated with arteritis or changes in blood viscosity.
Erythrocyanosis is a dusky, red, cyanotic change in the skin over the legs and thighs, where there is a deep layer of underlying fat.
The condition becomes worse in the winter months.
It is most common in young women and usually resolves over the years. Lupus erythematosus, sarcoidosis, and tuberculous infection may localise in affected areas.
Telangiectasia and clubbing may be features of scleroderma in the CREST syndrome described above.
In carcinoid and phaeochromocytoma vasoactive substances cause episodes of flushing and telangiectasia.
In hereditary haemorrhagic telangiectasia thin walled ectatic blood vessels develop in the mucous membranes and the skin generally on the upper half of the body and the nail beds.
Erythemas
Erythema is macular redness of the skin due to congestion in the capillaries.
It occurs as part of immunological reactions in the skin as in drug allergies and specific patterns of viral infections, such as measles.
There are other types that show a specific pattern but are associated with a wide range of underlying conditions, such as erythema multiforme.
Erythema multiforme is associated with herpes and other viral infections or streptococcal and various bacterial infections, but also with many other conditions, particularly connective tissue disease, sarcoidosis, and reactions to drugs such as sulphonamides.
The lesions consist of erythematous macules becoming raised and typically developing into “target lesions” in which there is a dusky red or purpuric centre with a pale indurated zone surrounded by an outer ring of erythema.
The lesions may be few or multiple and diffuse, often involving the hands, feet, elbows, and knees.
Blisters may develop.
In the more severe forms there may be dermal changes and blister formation with involvement of the mucous membranes (Stevens–Johnson syndrome).
There is often pyrexia with gastrointestinal and renal lesions.
It can progress to toxic epidermal necrolysis, which some consider a form of erythema multiforme.
Erythema annulare is a specific pattern in the skin with a large number of reported associations, ranging from fungal and viral infections to sarcoidosis and carcinoma. It consists of a small erythematous macule that enlarges to form an expanding ring, usually on the trunk.
Erythema chronicum migrans is associated with Borrelia infection and Lyme disease it is described on page 106.
There are many other types of “figurate erythemas”.
Erythema gyratum repens is associated with underlying carcinoma and erythema marginatum, which is now rare, with rheumatic fever.
Angiomas
Spider naevi, which show a central blood vessel with radiating branches, are frequently seen in women (especially during pregnancy) and children.
If they occur in large numbers, particularly in men, they may indicate liver failure.
Palmar erythema and yellow nails may also be present.
Congenital angiomas
Eruptive angiomas may be associated with systemic angiomas of the liver, lung, and brain.
Port wine stain due to abnormality of the dermal capillaries commonly develops on the head and neck.
It may be associated with congenital vascular abnormalities of the meningies and epilepsy.
Vascular abnormalities of the eye, and also glaucoma, occur with lesions on the face.
Erythema of the nailbeds
This may be associated with connective tissue disease, such as lupus erythematosus, scleroderma, and dermatomyositis.
Changes in pigmentation
Hypopigmentation
Hormonal
A widespread partial loss of melanocyte functions with loss of skin colour is seen in hypopituitarism and is caused by an absence of melanocyte stimulating hormone.
Genetic
In albinism, an autorecessive condition, there is little or no production of melanin with loss of pigment from the skin, hair, and eyes. Other genetic conditions with loss of skin pigment include piebaldism, phenylketonuria, and tuberous sclerosis.
Localised depigmentation is most commonly seen in vitiligo, in which a family history of the condition is found in one third of the patients.
In the sharply demarcated, symmetrical macular lesions there is loss of melanocytes and melanin.
There is an increased incidence of organ specific antibodies and their associated diseases.
Other causes of hypopigmented macules include: postinflammatory conditions after psoriasis, eczema, lichen planus, and lupus erythematosus; infections, for example, tinea versicolor and leprosy; chemicals, such as hydroquinones, hydroxychloroquine, and arsenicals, reactions to pigmented naevi, seen in halo naevus; and genetic diseases, such as tuberous sclerosis (“ash leaf” macules).
Hyperpigmentation
There is wide variation in the pattern of normal pigmentation as a result of heredity and exposure to the sun.
Darkening of the skin may be due to an increase in the normal pigment melanin or to the deposition of bile salts in liver disease, iron salts (haemochromatosis), drugs, or metallic salts from ingestion.
In agyria ingested silver salts are deposited in the skin.
Causes of hyperpigmentation include the following factors.
Hormonal
An increase in circulating hormones that have melanocyte stimulating activity occurs in hyperthyroidism,
Addison’s disease, and acromegaly.
In women who are pregnant or taking oral contraceptives there may be an increase in melanocytic pigmentation of the face.
This is known as melasma (or chloasma) and occurs mainly on the forehead and cheeks.
It may fade slowly. Sometimes a premenstrual darkening of the face occurs. Increased deposition of haemosiderin is generalised in haemochromatosis.
Localised red-brown discoloration of the legs is seen with longstanding varicose veins.
It also occurs in a specific localised pattern in Schamberg’s disease, when there is a “cayenne pepper” appearance of the legs and thighs.
Neoplasia
Lymphomas may be associated with increased pigmentation.
Acanthosis nigricans, characterised by darkening and thickening of the skin of the axillae, neck, nipples, and umbilicus, occurs with internal cancers, usually adenocarcinoma of the stomach.
It is also seen in acromegaly.
There is a benign juvenile type. Pseudoacanthosis nigricans is much more common, consisting of simple darkening of the skin in the flexures of obese individuals; it is not associated with malignancy.
Drugs
Chlorpromazine, other phenothiazines, and minocycline may cause an increased pigmentation in areas exposed to the sun. Phenytoin can cause local hyperpigmentation of the face and neck.
Inflammatory reactions
Postinflammatory pigmentation is common, often after acute eczema, fixed drug eruptions, or lichen planus.
Areas of lichenification from rubbing the skin are usually darkened.
Malabsorption and deficiency states
In malabsorption syndromes, pellagra, and scurvy there is commonly increased skin pigmentation.
Congenital conditions
There is clearly a marked variation in pigmentation and in the number of freckles in normal individuals.
There may be localised well defined pigmented areas in neurofibromatosis with “cafe au lait” patches.
Increased pigmentation with a blue tinge occurs over the lumbosacral region in the condition known as Mongolian blue spot.
Peutz–Jeghers syndrome is described under the section “The gut and the skin”, below.
There are pigmented macules associated with intestinal polyposis in the oral mucosa, lips, and face.
Malignant lesions
Malignant lesions may cause skin changes such as acanthosis nigricans and dermatomyositis or produce secondary deposits.
Lymphomas can arise in or invade the skin.
Pruritus may be associated with Hodgkin’s disease.
Mycosis fungoides is a T cell lymphoma of cutaneous origin.
Initially well demarcated erythematous plaques develop on covered areas with intense itching. In many cases there is a gradual progression to infiltrated lesions, nodules, and ulceration.
In others the tumour may occur de novo or be preceded by generalised erythema.
Poikiloderma, in which there is telangiectasia, reticulate pigmentation, atrophy, and loss of pigment, may precede mycosis fungoides, but it is also seen after radiotherapy and in connective tissue diseases.
Parapsoriasisis a term used for well defined maculopapular erythematous lesions that occur in middle and old age.
Some cases undoubtedly develop into mycosis fungoides and a biopsy specimen should be taken of any such fixed plaques that do not clear with topical steroids.
The gut and the skin
Vasculitis of various kinds, periarteritis nodosa, connective tissue diseases such as scleroderma, and many metabolic diseases produce both cutaneous and gastrointestinal lesions.
There are, however, some specific associations.
Dry skin, asteatosis, and itching, with superficial eczematous changes and a “crazy paving” pattern, occur in malabsorption and cachectic states.
Increased pigmentation, brittle hair and nails may also be associated.
Pyoderma gangrenosum gives rise to an area of non-specific inflammation and pustules break down to form a necrotic ulcer with hypertrophic margins.
There is an underlying vasculitis. There is a strong association with ulcerative colitis and also with Crohn’s disease, rheumatoid arthritis, abnormal gamma globulins, and leukaemia.
Dermatitis herpetiformis, which has already been discussed, is an intensely itching, chronic disorder with erythematous and blistering lesions on the trunk and limbs.
It is more common in men than women.
Most patients have a gluten sensitive enteropathy with some degree of villus atrophy.
There is an associated risk of small bowel lymphoma.
Peutz–Jeghers syndrome is inherited as an autosomal dominant characterised by the appearance in infancy of pigmented macules of the oral mucosal membranes, lips, and face.
Benign intestinal polyps, mainly in the ileum and jejunum, which rarely become malignant, are associated with the condition.
Other conditions include congenital disorders with connective tissue and vascular abnormalities that affect the gut, such as Ehlers–Danlos syndrome and pseudoxanthoma elasticum (arterial gastrointestinal bleeding), purpuric vasculitis (bleeding from gastrointestinal lesions), and neurofibromatosis (intestinal neurofibromas).
In Crohn’s disease (regional ileitis) perianal lesions and sinus formation in the abdominal wall often occur.
Glossitis and thickening of the lips and oral mucosa and vasculitis may be associated.
Liver disease may affect the skin, hair, and nails to a variable degree.
Obstructive jaundice is often associated with itching which is thought to be due to the deposition of bile salts in the skin.
Evidence of this is the fact that drugs which combine with bile salts such as cholestyramine improve pruritus in some patients.
Jaundice is the physical manifestation of bile salts in the skin.
Liver failure is characterised by a number of skin signs, particularly vascular changes causing multiple spider naevi and palmar erythema due to diffuse telangiectasia.
It is not unusual to see spider naevi on the trunk in women but large numbers in men should raise suspicion of underlying hepatic disease.
Porphyria cutanea tarda as a result of chronic liver disease produces bullae, scarring, and hyperpigmentation in sun exposed areas of the skin.
Xanthomas may be associated with primary biliary cirrhosis and in chronic liver disease asteotosis, with dry skin producing a “crazy paving” pattern.
Diabetes and the skin
In diabetes the disturbances of carbohydrate–lipid metabolism, small blood vessel lesions, and neural involvement may be associated with skin lesions.
The more common of these include the following.
Infection
Diabetic patients have an increased susceptibility to staphylococcal, coliform, and pseudomonal infection.
Candida albicans infection is also more common in diabetics.
Vascular lesions
“Diabetic dermopathy”, due to a microangiopathy, consists of erythematous papules which slowly resolve to leave a scaling macule on the limbs.
Atherosclerosis with impaired peripheral circulation is often associated with diabetes.
Ulceration due to neuropathy (trophic ulcers) or impaired blood supply may occur, particularly on the feet.
Specific skin lesions
Necrobiosis lipoidica
Between 40% and 60% of patients with this condition may develop diabetes, but it is not very common in diabetic patients (0·3%).
As the name indicates, there is necrosis of the connective tissue with lymphocytic and granulomatous infiltrate.
There is replacement of degenerating collagen fibres with lipid material.
It usually occurs over the shin but may appear at any site.
Granuloma annulare
This usually presents with localised papular lesions on the hands and feet but may occur elsewhere.
The lesions may be partly or wholly annular and may be single or multiple.
There is some degree of necrobiosis, with histiocytes forming “palisades” as well as giant cells and lymphocytes.
It is seen more commonly in women, usually those aged under 30.
There is an association with insulin dependent diabetes.
In itself it is a harmless and self limiting condition that slowly clears but may recur.
Other diseases
Porphyrias are due to the accumulation of intermediate metabolites in the metabolic pathway of haem synthesis. There are several types.
In hepatic porphyrias there is skin fragility leading to blisters from exposure to the sun or minor trauma.
In erythropoietic and erythrohepatic photoporphyrias there is intense photosensitivity.
They are sometimes associated with sensitivity to long wavelength ultraviolet light that penetrates window glass.
Porphyria cutanea tarda usually occurs in men, with a genetic predisposition, who have liver damage as a result of an excessive intake of alcohol.
There is impaired porphyria metabolism leading to skin fragility and photosensitivity, with blisters and erosions, photosensitivity on the face and the dorsal surface of the hands.
Xanthomas are due to the deposition of fat in connective tissue cells.
They are commonly associated with hyperlipidaemia either primary or secondary to diabetes, the nephrotic syndrome, hypothyroidism, or primary biliary cirrhosis.
Four of the primary types are associated with an increased risk of atherosclerosis; type I is not. Diabetes may be associated with the eruptive type.
Necrotising fasciitis is an area of cellulitis that develops vesicles. Necrosis of the skin may indicate much more extensive, life threatening necrosis of the deeper tissues.
Urgent surgical debridement is indicated.
Amyloid deposits in the skin occur in primary systemic amyloidosis and myeloma.
Pregnancy
Pregnancy may be associated with pruritus, in which the skin appears normal in 15–20% of women (prunigo gestationis).
It is generally more severe in the first trimester.
Polymorphic eruptions also present with pruritis with urticaria papules and plaques (the PUPP syndrome).
It usually occurs on the abdomen in the third trimester and then becomes widespread.
There may be a postpartum flare up.
It can be a distressing condition for the mother but the baby is not affected, and it rarely recurs in subsequent pregnancies.
Topical steroids can be used, but systemic steroids should be avoided.
Pemphigoid gestationis is a rare disorder that may resemble PUPP initially but develops pemphigoid-like vesicles, spreading over the abdomen and thighs: autoantibodies to the basement membrane are present.
Sarcoidosis
Pulmonary and other systemic manifestation of sarcoidosis may occur without involvement of the skin.
The most common changes are:
• Erythema nodosum, which is often a feature of early pulmonary disease.
• Papules, nodules, and plaques are associated with acute and subacute forms of the disease.
• Scar sarcoidosis, with papules occurring in scars.
• Lupus pernio is characterised by dusky red infiltrated lesions on the nose and fingers.
Thyroid disease
Thyroid disease is associated with changes in the skin, which may sometimes be the first clinical signs.
There may be evidence of the effect of altered concentrations of thyroxine on the skin, with changes in texture and hair growth.
Associated increases in thyroid stimulating hormone concentration may lead to pretibial myxoedema. In autoimmune thyroid disease vitiligo and other autoimmune conditions may be present.
Genetics and skin disease
Though many genetic disorders of the skin are inherited in a classically Mendelian way (single gene disorders), others are genetically more complex.
As a general rule, the common skin disorders that run in families, such as psoriasis, atopic eczema, and acne, tend to belong to the latter group.
Single gene disorders
Recent advances in genetic technology have been relatively easy to apply to these, usually rather uncommon, disorders, most of which had already been classified accurately on clinical grounds.
Several things followed from this:
(1) The next step has often been an improvement in current clinical classifications, which can now be based logically on the underlying molecular abnormalities of the disorders in question.
A good example of this is the modern classification of the inherited mechano-bullous disorders (also known as epidermolysis bullosa).
(2) New skin constituents were quickly recognized, their function being understood after studying the disorders in which they are abnormal.
Soon it was realized that the same molecules could be the targets both for genetic abnormalities and for acquired skin diseases.
One example of this is the way in which autoantibodies directed against one of the constituents of hemidesmosomes (BP180) cause pemphigoid, whereas mutations in the gene responsible for BP180 are the basis of the junctional type of epidermolysis bullosa.
(3) Advances have been made too in our understanding of the structure and function of normal skin and its appendages for example, the finding that melanocortin-1 receptor gene variants are associated with fair skin, red hair, and skin tumours.
(4) Mosaics were soon recognized.
Clinically these are linear abnormalities in the skin, usually present at birth, which often contain cells with the same genetic abnormalities as those of known generalised genodermatoses.
A good example of this is the way the same abnormalities in the genes controlling the production of keratins 1 and 10 can be responsible both for a generalised skin condition (epidermolytic hyperkeratosis) and for warty linear naevi.
The mosaic areas follow Blashko’s lines, a bizarre pattern of lines and whorls, which are not the same as dermatomes.
(5) The prenatal diagnosis of severe genodermatoses has become more accurate, though gene therapy has not yet fulfilled its early promise.
Genetically complex disorders
Psoriasis is a good example.
It clusters in some families but does not follow a classical Mendelian pattern of inheritance.
Environmental triggers are important, as well as genetic factors.
Over the last few years, several wide scans of the genome have been undertaken with the aim of identifying the location of the genes that determine susceptibility to psoriasis.
Five have been confirmed, all on different chromosomes, and now designated as Psors1 to Psors5. A further six loci may have similar effects, but the evidence for them is less strong.
Psors1, on chromosome 6p21.3, is an especially important gene for psoriasis susceptibility in many populations and lies within the area of the major histocompatibility complex (MHC).
However it is not itself an HLA class 1 gene, and may belong to the newly described MHC class 1 chain-related (MIC) gene family.
The possession of one allele (A5.1) of this gene seems to lead to a type of psoriasis that starts especially early, and is more common in familial than in sporadic cases. In atopic eczema, matters are equally complicated.
Environmental factors may well be responsible for the recent rise in its prevalence as the gene pool within the population is not likely to have changed greatly, but a genetic component is obvious too, even though affected children can be born to clinically normal parents.
Within each family, atopic disorders tend to run true to type, so that, in some, most affected members will have eczema, in others, respiratory allergy predominates.
The inheritance of atopic eczema probably involves genes that predispose to the state of atopy, and others that determine whether it is asthma, eczema, or hay fever that develops.
One plausible gene for the inheritance of atopy encodes for the beta subunit of the high affinity IgE receptor, and lies on chromosome 11q13.
However several groups have failed to confirm earlier reports of this linkage, and a gene linked to atopic eczema has recently been found on chromosome 3q21.
