Genetic Disorders

Genetic Disorders

Many references have been made already to the importance of the family history which may indicate an inherited liability to the common disorders of the skin such as psoriasis and atopic eczema. A large number of less common skin conditions are also caused by genetic defects which involve enzyme processes either in the skin or in the metabolism of other systems which then influence the skin. Some of the skin abnormalities are unimportant trivial defects, but others produce severe disability or disfigurement, or indicate systemic metabolic disorders. It is not necessary to acquire a knowledge of all the ‘rare stamp’ syndromes but an awareness of their existence and possible modes of inheritance can be elicited in the history. The inherited pattern of disorders with a simple dominant trait can be discovered easily since affected members will occur in every generation, and approximately 50 per cent of the offspring of an affected individual will show the disease; those not involved will not transmit the complaint. In some instances a smaller proportion than 50 per cent is affected and a generation may be skipped. This is termed incomplete penetrance.

Genetic Disorders

In recessive inheritance affected children are born to apparently normal parents and the possibility of a genetic disorder may be suspected only if two siblings are abnormal. Because recessive disorders are due to marriage of individuals both carrying a rare trait, consanguinity increases the risk. Some conditions can be inherited both as a dominant and a recessive trait and as a generalisation the recessive disease has the more severe manifestations. The possibility of a fresh mutation should be considered where no family history of a disorder usually inherited as a dominant can be obtained. Apart from autosomal transmission there is today an increased knowledge of chromosomal aberration, which is associated with a number of eponymous syndromes in which the skin may be affected. It is important to appreciate that many genetic disorders are not visible at birth but appear in childhood, at puberty, or even in middle age. It is not practicable to list the numerous genetic disorders but mention will be made of several which are either seen frequently or which illustrate some noteworthy feature.


The disorders of keratin formation in which there is also reduction of sweat and sebaceous secretion are common genetic malformations of the skin. When inherited as an autosomal dominant the skin change ichthyosis vulgaris is not noticed until after the first three months of life and is often associated with atopic eczema. The extensor surfaces of the limbs are covered with dry scales which resemble fish or lizard skin (hence the name) and characteristically the axillae and elbow flexures are usually unaffected. On the outer aspects of the arm and thighs the dry hyperkeratosis may affect especially the follicles giving the impression of a nutmeg grater. There is usually some improvement in the condition at puberty but it becomes more troublesome again in old age and painful cracks occur over the joints in cold weather. The sex-linked recessive variety which affects males only can be differentiated from ichthyosis vulgaris on clinical grounds as it starts soon after birth, affects all parts of the body and the scales are noticeably large and dark.

The autosomal recessive varieties in common with many other skin disorders are more severe than the dominant type and may be lethal to the foetus. When the new-born infant is affected erythema is present in addition to scaling and the child may appear to be enveloped in a coating of collodion or parchment and this condition is called lamellar ichthyosis. The erythema persists until later life and as a result is termed ichthyosiform erythroderma.

Treatment. There is no curative treatment and neither vitamin A nor thyroid extract, which have been advocated on the basis that deficiency of either makes the skin dry, are of value. Hydration of the keratin by bathing followed by an emollient cream such as aqueous ointment or Boots E. 45 are palliative and can be made even more effective by occlusive polythene at night but the condition recurs immediately treatment is stopped. Salt water bathing is sometimes a help and in recent years it has been appreciated that 10 per cent urea in Ung. Emulsificans or a similar proprietary remedy calmurid are more effective than a simple emollient. Retinoic acid, a very unstable compound related to vitamin A does temporarily improve patients with ichthyosiform erythroderma and sex-linked ichthyosis when used in a concentration of 0-1 per cent in soft paraffin.

Palmar and plantar keratosis (Tylosis)

Localised thickening of the skin on the palms and soles is another comparatively common disorder inherited as a dominant. Such thickening may be present soon after birth or it may appear only in adult life; in the mildest examples only if manual work is done. Various patterns of keratosis, diffuse, linear or punctate have been described. The most severely affected patients are considerably disabled and again no curative treatment exists.

Epidermolysis bullosa

This is an uncommon disease characterised by the formation of blisters after friction or minor trauma, due to defective adherence of epidermis and dermis. As in ichthyosis, there are a number of clinical varieties which can be inherited either in dominant or recessive forms. The mildest type consists of blister formation on the feet in hot weather and the onset may be delayed until adult life. Simple epidermolysis bullosa may be noticed soon after birth when blisters form on skin exposed to the trauma of deliver or, more often, blisters occur when the child starts to crawl. Scarring is minimal and the liability to blister formation lessens with age. Blisters in the more severe dystrophic forms are deeper in the dermis and form extensive scars which contain milia (epidermal cysts). Mucous membrane lesions also leave scars which can give rise to strictures of the pharynx and oesophagus. Treatment consists of protection against trauma and the control of pyogenic infection on the ulcerated areas. The control of blister formation by systemic corticosteroids may be necessary in the severe dystrophic varieties as a life saving measure.

The close association between the epidermis and the nervous system is reflected in the number of genetic disorders which affect both. It may well be that the recognition of the skin lesion will aid in the diagnosis of the neurological condition.

Tuberous sclerosis (Epiloia)

This is an association of fibrous tumours in the cerebral cortex which cause epilepsy and mental deficiency and both epidermal and dermal skin tumours. The disease is transmitted as an irregular dominant but ‘forme frustc’ are common and only part of the syndrome may occur in any one individual. Ninety per cent of affected babies show depigmented patches in the shape of a mountain ash leaf and these can be detected most easily by examination of the baby under filtered ultraviolet light (Woods light). The skin tumours on the face known as adenoma sebaceum appear in childhood, as a cluster around the nose. The colour of the papules vary from faintly pink to red with obvious telangiectases which form a network over and around the papules. Another useful diagnostic aid is the occurrence of fibrous outgrowths from the nail folds and beneath the nails on fingers and toes. Fibrous collagen plaques are frequently present in the lumbar region and these irregular thickenings of the dermis must be sought by palpation. The discovery of any one of these in a patient with epilepsy or mental deficiency should raise the suspicion of tuberous sclerosis.


Another better known example of a genetic disorder of skin and nervous system is von Recklinghausen’s disease. The most frequent signs are multiple pale fawn patches of pigmentation and these may be present alone in several members of a family. It is considered that over four cafe au lait patches indicate neurofibromatosis but a better clinical guide is a freckled pigmentation present in the axillae. At puberty, skin tumours arise from the Schwann cells of the cutaneous nerves. The tumours start as pea sized, soft, faintly pink or bluish elevations. Some continue to grow and become pedunculated, others atrophy, giving rise to curious flaccid sacs. Of much greater significance is the growth of neurofibromata on cranial nerves or in the spinal canal and a possible later sarcomatous change in the tumours.

Many of the inherited defects of the skin are caused by deficiencies of enzymes essential to the normal metabolic process of the body and skin changes may be the cardinal signs which lead to recognition of such a disorder.


The inheritance of a number of inborn errors of porphyrin metabolism is associated with a variety of skin lesions. Erythropoetic protoporphyria in which protoporphyrins are present in excess in the red blood cells, plasma and faeces is inherited as a dominant. Exposure to sunlight is followed by burning and tingling and an urticarial swelling of the hands and face may occur. The signs quickly fade and the diagnosis may have to be suspected from the history. Confirmation of the diagnosis can be made by the demonstration of fluorescence in red cells when they are examined under a lamp emitting 400 nm.

Hepatic porphyria is also an inherited defect which may remain latent until the patient is exposed to hepatotoxic chemicals the commonest being alcohol. The skin lesions consist of blisters, scars and milia on the light-exposed areas very similar to those seen in epidermolysis bullosa. In fact trauma as well as sunlight may produce blistering. Pigmentation and overgrowth of lanugo hair is often present on the face. Porphyrin excretion in the faeces is usually excessive but the presence of porphyrins in the urine is intermittent. The usual test, the finding of red fluorescence under Wood’s light therefore may not be positive. Repeated examination of faecal levels of coproporphyrin may be necessary to establish the presence of excessive amounts and to confirm the diagnosis. It is important for patients with porphyria to be warned not to take drugs such as barbiturates, sulphonamides, griseofulvin and the contraceptive pill. Successful amelioration of symptoms can be achieved if the excessive body iron stores can be removed by frequent bleeding or by chelating agents.


Though rare, this condition is worthy of mention since it illustrates well a clear cut enzyme deficiency inherited as a recessive trail and occurring most frequently in cousin marriages. The metabolic defect is an inability to convert the amino-acid phenylalanine to tyrosine with the effect that a large amount of phenylalanine accumulates in the blood and it is excreted in the urine as phenylpyruvic acid. Untreated there is progressive mental deterioration. The clinical picture is of an infant with blond hair, pale skin and an eczematous eruption indistinguishable from infantile eczema which appears soon after birth. From the practical point of view this clinical condition should disappear since all infants should have their blood tested for phenylalanine levels the 6th day after birth. If abnormal amounts are discovered then treatment with a diet low in phenylalanine does offer some hope of success if started then.

The hyperlipoproteinaemias

The occurrence of xanthomata, deposits of lipid material in the skin may indicate a disorder of lipoproteins. The most common of these fatty lesions are the soft chamois leather like plaques on the eyelids (xanthelasma) but fortunately less than half the patients with xanthelasma have any evidence of metabolic disorder. The purely cosmetic problem can be solved by the removal of the fatty tissue by excision or diathermy. Far more ominous are the true tumour-like nodules over the bony prominences of the knees, elbows and fingers. Xanthomata also occur in tendon sheaths where they appear as hard nodules, and streaks of yellow material can be observed in the palmar creases and another association is the formation of a premature arcus senilis of the cornea. Though harmless in themselves, the xanthomata indicate either an inherited disorder which may be, associated with an increased risk of ischaemic heart disease or they may arise as a secondary phenomenon in the course of systemic disease such as biliary cirrhosis, the nephrotic syndrome or diabetes.

The inherited abnormalities of lipoproteins have recently been classified into five different types on the basis of their electrophoretic patterns though they also differ genetically. Prognosis and treatment varies with the correct diagnosis of the disorder, thus full investigation of a patient with xanthomata is essential. It is certainly possible, by the use of diet plus cholestyramine or clofibrate, dependent on the variety of the disorder, to control the hereditary hyperlipoproteinaemia and cause resolution of the xanthomata. Whether early treatment can prevent or arrest the vascular disease remains unknow unknown.

Genetic counselling

The greater knowledge of the genetics of skin diseases has enabled a more accurate genetic prognosis to be given to parents if a correct clinical diagnosis has been made and the disorder is known to obey Mendelian rules.

In recent years it has also become feasible to examine amniotic fluid or fetal cells obtained by amniocentesis. By the study of this material it may be possible to establish that the fetus has a serious inherited disorder and termination of the pregnancy can then be carried out. In this way the number of sufferers gravely handicapped by inherited skin conditions may be lessened.