Neurofibromatosis
Neurofibromatosis type 1 (NF1) is a hereditary condition. Depending on where the fibromas develop, the disease has many different signs and symptoms. The skin, nervous system and skeleton are primarily affected.
Occurrence
NF1 occurs in 1 in every 3,000–4,000 newborns and affects boys and girls equally.
Cause
NF1 is caused by a defect in a hereditary unit (gene) on the long arm of chromosome 17. This gene controls the production of a protein called neurofibromin, which prevents uncontrolled tissue growth. The NF1 gene is large, and various changes in this gene can lead to NF1.
Inheritance
About half of people with NF1 have inherited the condition. The mode of inheritance is autosomal dominant. In the other half, NF1 arises as the result of a mutation (a new change in the genetic material).
Symptoms, course of the disease and complications
The symptoms and their severity vary greatly, even within the same family.
Light brown, flat spots (café-au-lait spots) are present from birth or appear in the first years of life and grow with the child. Freckling in areas of skin not exposed to light is also common.
Fibromas (lumps of varying size in the skin) appear or increase during puberty and may grow in size and number during pregnancy or the menopause.
Dermal neurofibromas are soft, jelly-like lumps under the skin, ranging in diameter from one or two millimetres to several centimetres.
Nodular fibromas lie deeper in the tissue and are firmer in consistency. They may cause pain, fatigue and tingling in the area supplied by the nerve concerned.
Plexiform neurinomas are soft swellings under the skin with no clear border with the surrounding tissue. They may cause no symptoms, but they can also be troublesome, especially in areas exposed to pressure.
Fibromas are benign to begin with, but plexiform neurinomas can become malignant. In such cases they grow and cause increasing pain.
Lisch nodules (small nodules in the iris of the eye) are seen in many patients by the age of six or seven, and in almost all patients in adulthood.
Before the age of seven, about 15% of patients have a particular tumour of the optic nerve (optic glioma), but it causes symptoms in only one in five of these patients.
Brain MRI scans also show characteristic bright lesions known as UBOs (unidentified bright objects). These are benign and require no special follow-up.
More than half of patients have skeletal abnormalities, primarily scoliosis, but also false joint formation (pseudarthrosis), especially in the ankle region. These conditions may be congenital or may develop during childhood. Dental problems, a large head circumference and increased fatigue are common.
Many have learning difficulties, but neuropsychological studies do not reveal any specific profile. Some may have difficulty learning mathematics, while others may have dyslexia. In childhood, 40–50% of patients have attention deficit and hyperactivity/impulsivity. Only a small number of patients have a functional disability, and this is mainly mild.
Children with NF1 show gross and fine motor clumsiness, manifesting as poor balance and a slow working pace. In adulthood, many find it difficult to organise daily activities because of a short working memory and poor planning ability. The education they receive does not always match their difficulties; many have poor self-confidence and burn out at an early age. Many also experience the distress of having children with the same disease and problems.
Not knowing what the future will bring can be a great burden and source of anxiety for patients. In addition, because NF1 can be a hidden or semi-hidden functional disability, patients may worry that they will not be understood by doctors or support services.
Diagnosis
In many cases the diagnosis is easy to make if at least two of the following criteria are present: at least 5–6 café-au-lait spots, at least two neurofibromas or one plexiform neurofibroma, freckles in the groin or armpit, close relatives with NF1, false joints or absence of the wing of the sphenoid bone, Lisch nodules and optic gliomas.
Treatment
To date, there is no medical treatment for NF1 that targets its cause. Changes in the skeleton can, where possible, be treated surgically. False joints require careful orthopaedic follow-up.
If fibromas press on the optic nerve, chemotherapy, radiotherapy or surgery may be considered. Plastic surgery may be considered for painful or disfiguring skin changes, but such changes tend to recur. It is advisable to monitor children’s vision annually, paying particular attention to squint and narrowing of the visual field.
Computer-assisted teaching is important both for specific learning difficulties and for helping with attention difficulties and poor fine motor skills. Many patients need to be followed up by physiotherapists and to rest during the day. Treatment of ADHD symptoms may be considered.
Adults should be followed up by a designated doctor, including from a social medicine perspective. Blood pressure should be checked annually because of the increased occurrence of adrenal cortex tumours and high blood pressure due to neurofibromas in the circulatory system. Symptoms arising in the stomach/intestinal system may be caused by tumours in the bowel wall. Plexiform neurinomas should be monitored in view of the possibility of malignancy. Families with more than one member with NF1 should be given coordinated support, such as from a joint team of responsible professionals.
Tuberous Sclerosis
Tuberous sclerosis is a familial multisystem disease characterised mainly by the triad of intellectual disability, epilepsy and adenoma sebaceum.
It was first described in 1862 by Von Recklinghausen from the autopsy findings of an infant, with sclerotic areas in the brain and a tumour in the heart. In 1880 Bourneville used the term tuberous sclerosis, defining the disease for the first time as a separate syndrome. Although these early descriptions remain accurate, the term tuberous sclerosis complex (TSC) is now preferred because of the widespread involvement of body systems.
TSC is a hamartomatosis that mainly affects the central nervous system, skin, retina, kidneys and heart. The lungs, gastrointestinal system, spleen, lymph nodes, gonads, endocrine glands (thyroid, parathyroid, adrenal glands) and bone may be affected to a lesser extent. This disease is inherited in an autosomal dominant manner, yet in three quarters of cases there may be no family history.
For the antemortem diagnosis of TSC, certain criteria have been established based on clinical and neuroradiological findings related to these system involvements. According to these criteria, the diagnosis of TSC requires: 1) the presence of at least two characteristic lesions (such as two hamartomas of the brain, skin or retina), 2) the presence of at least one characteristic hamartoma in two different organs, or 3) involvement of a single organ when a first-degree relative has definite disease. The most common neurological finding in TSC is seizures. Seizures have been reported as the first presenting symptom in 75% of patients.
Sebaceous Adenoma
Sebaceous adenoma is also commonly known as an epidermal or epidermoid cyst (because it arises from the epidermis) and a pilar cyst or trichilemmal cyst (because it arises from the hair follicle). By definition, however, neither epidermoid cysts nor pilar cysts are sebaceous cysts, because the oily, white, cheese-like material inside these cysts is keratin rather than sebum. In addition, no sebaceous glands are found in epidermoid and/or pilar cysts when examined under the microscope. In practice, all three terms are generally used interchangeably.
What causes sebaceous adenomas to form?
Blockage of the sebaceous gland, infection and inflammation of the hair follicle, and high testosterone levels lead to the formation of sebaceous cysts and adenomas. In some hereditary diseases genetic factors may also be responsible, for example Gardner’s syndrome and basal cell naevus syndrome.
Where do sebaceous adenomas or cysts occur?
They are usually seen on the scalp, ears, back of the neck, face and arms. In fact, sebaceous adenomas can occur on any part of the body except the palms and the soles of the feet. In men they are seen particularly on the chest and scrotum. In general, sebaceous adenomas and cysts are more common in areas with dense hair.
Hypopigmented Macules
Hypopigmentation or depigmentation may develop as a result of a reduction or loss of melanin pigmentation of the skin. This may be present at birth or appear at any stage of life under the influence of hereditary factors. Under the influence of various environmental factors, the number of melanocytes or the amount of melanin decreases or disappears, and hypo- or depigmentation develops in the skin. Lightening of skin colour is also seen as a result of a decrease in haemoglobin pigment, hyperkeratosis or an increase in collagen fibres.
Disorders arise with a complete or partial absence of epidermal and/or follicular melanocytes and a reduced number of melanocytes. In addition, disorders with reduced melanin pigment are seen as a result of problems in the removal of melanin pigment.
Clinically, hypopigmented or depigmented areas may be found among normal skin. They can be distinguished from one another by features such as size, shape, colour and pattern. Confetti-like macules or macules of one to two millimetres may be seen in vitiligo, chemical leukoderma and tuberous sclerosis. The lesions of pityriasis alba and post-inflammatory leukoderma are larger, but they lack the sharp borders seen in idiopathic guttate hypomelanosis and tinea
versicolor. Scalloped or convex borders may be seen in vitiligo and chemical leukoderma. An ash-leaf (lance-ovate) shape is typical of the lesions of tuberous sclerosis.
While a few scattered lesions are usually seen in naevus depigmentosus and tuberous sclerosis, numerous macules are seen in vitiligo, tinea versicolor and chemical leukoderma. A dermatomal, segmental distribution is shared by vitiligo, naevus depigmentosus, tuberous sclerosis (usually together with separate macules) and hypomelanosis of Ito. Symmetrical involvement is frequently observed in piebaldism,
vitiligo, Waardenburg syndrome and chemical leukoderma. In piebaldism the central forehead, the legs and the middle of the arms are involved, whereas vitiligo typically involves the extensor surfaces, periorificial areas, flexural folds and the lower back.
Shagreen Patches
These are connective tissue naevi of the skin located on the trunk, particularly on the lower back; they are soft, skin-coloured, slightly raised above the skin, with an uneven, orange-peel-like surface. These lesions, which may be skin-coloured or slightly yellow, are seen in a quarter to a fifth of patients. They can sometimes also occur on the gums and inside the mouth.
Pachydermoperiostosis
Pachydermoperiostosis (PDP) is a rare syndrome characterised by clubbing of the fingers, thickening and coarsening of the facial skin and scalp, cortical thickening of the long bones, and excessive activity of the sebaceous glands. It was first described in 1868 and was thought to be inherited in an autosomal dominant manner. It is more common in men than in women. Clinically it usually begins in adolescence and completes its progression within about ten years. When first described it was thought to be a form of acromegaly, but it was later shown to be a distinct entity.
Goltz Syndrome
Goltz syndrome is a rare disease that affects all three germ layers – ectoderm, mesoderm and endoderm – during embryonic development and differentiation.
It is inherited in an X-linked dominant manner and results in death before birth in males. In mosaicism, it is thought to arise from the destruction of cells that escape X inactivation through lyonisation and carry the mutant allele. For this reason, in women it appears as lesions along the Blaschko lines owing to lyonisation.
Atrophic patches of red, hypopigmented or depigmented skin in a linear or grouped distribution are often present at birth. Telangiectasias are frequently found between the atrophic plaques. At birth the lesions may begin as vesicles or bullae and turn into atrophic scars. Fat herniations, characterised by soft, pinkish-brown nodules appearing on thin, atrophic skin, are another important finding. Raspberry-like papillomas are most often seen on the lips and in the vulval and perianal regions.
The skeletal, ocular and dental systems are most commonly affected. Skeletal findings are mostly seen in the hands and feet. Involvement may be asymmetrical. The lobster-claw deformity is characteristic. Osteopathia striata is also a common skeletal finding. Polydactyly, syndactyly, claw deformity, hypoplasia or aplasia of the fingers, microcephaly and scoliosis may be seen.
Eye findings are seen in 40% of patients and may include asymmetrical placement of the eyes, microphthalmia, strabismus, coloboma and epiphora. Dental findings are present in half of patients and may include enamel defects, recurrent caries, anodontia, delayed tooth development, malocclusion and notched incisors. Gastrointestinal, renal, neurological and other system involvement may occur. The main conditions in the differential diagnosis are MIDAS syndrome (microphthalmia, dermal aplasia, sclerocornea), incontinentia pigmenti and Rothmund-Thomson syndrome. Treatment of Goltz syndrome is planned with a multidisciplinary approach. Pulsed dye laser (PDL) can be used for skin lesions. Cryotherapy or cauterisation can be used for papillomas, but they may recur.
Xeroderma Pigmentosum
Xeroderma pigmentosum is a rare, autosomal recessive disease characterised by extreme sensitivity of the skin to ultraviolet (UV) light, skin cancers appearing at an early age and eye abnormalities. Its prevalence in the population is around 1 in 100,000. Neurological complications are also seen in about 20% of cases.
The underlying defect is the inability to repair the damage caused to cellular DNA by ultraviolet light with a wavelength of 280–310 nm. In xeroderma pigmentosum, the failure to repair damaged DNA impairs cell function, ultimately leading to skin cancers through mutations, cell degeneration and premature cell death. This repair defect may also occur in cells of the immune system, especially lymphocytes, as well as in skin cells. For this reason the frequency of cancers outside the skin is also increased. The hereditary defect is thought to involve not a single gene but several genes, resulting in different clinical pictures.
The skin is normal at birth. It usually begins within the first year with sensitivity to ultraviolet light in exposed areas. The first sign resembles severe sunburn. Freckle-like hyperpigmented macules, thickening of the skin and hyperkeratosis appear. Vesiculobullous lesions are occasionally seen. In addition, with the development of atrophic areas of thinned skin and telangiectasia, a picture of poikiloderma develops.
Atrophy and skin contractures are prominent around the nose and mouth, giving a beak-like nose. Actinic keratoses are frequently present. In childhood the face takes on the appearance of an old face.
Early eye findings are photophobia and increased tearing. Skin lesions around the eyes heal with scarring, and inward turning of the eyelid (entropion) and outward turning of the eyelid (ectropion) are seen. Dryness of the conjunctiva, telangiectasia, hyperpigmented macules and corneal opacities may occur. Neurological findings include intellectual disability, microcephaly, cerebellar ataxia, epilepsy and sensorineural deafness. Keratoacanthoma is the most common tumour. Among cutaneous malignancies, squamous cell carcinoma and basal cell epithelioma are seen in about half of cases. In general, the average age at onset of non-melanoma skin cancers is eight.
Malignant melanoma is seen in about 5% of cases. Fibrosarcoma or angiosarcoma may rarely be seen. In the differential diagnosis, sunburn and acute eczema should be considered for early lesions, and freckles for early pigmented lesions.
Prevention and education are important in treatment. Patients must be protected from sunlight. Beta-carotene and oral retinoids can be used prophylactically. These patients should be checked at frequent intervals, and premalignant or malignant lesions should be treated early. Topical 5-fluorouracil can be applied to premalignant lesions. The treatment of malignant lesions is surgical. Radiotherapy is contraindicated.
Rothmund-Thomson Syndrome
An autosomal recessive syndrome, seen particularly in women, characterised by reticulated, atrophic, hyperpigmented, telangiectatic cutaneous plaques, often accompanied by a depressed nasal bridge, congenital bone defects, abnormalities of hair, nail and tooth growth, and hypogonadism. Juvenile cataracts develop in about half of patients. Skeletal dysplasia is an important feature of the syndrome. The increased incidence of squamous cell skin carcinomas and osteogenic sarcomas is the major prognostic factor.
Dyskeratosis Congenita
Dyskeratosis congenita (DC) is a progressive disease characterised by premature ageing of tissues, caused by a defect in telomere activity, and may be accompanied by bone marrow failure, mucocutaneous abnormalities and many other systemic findings.1,2,3,4 It is usually seen in males and, although X-linked recessive inheritance is seen, autosomal dominant inheritance is also known to play a role. Mucocutaneous features include dysplastic fingernails or toenails, lacy reticulated pigmentation of the skin and leukoplakia. In addition, bone marrow aplasia, gastrointestinal findings, and neurological, pulmonary and ocular findings are the main systemic findings of this syndrome.
Incontinentia Pigmenti
Incontinentia pigmenti (IP) is also known as Bloch-Sulzberger syndrome.
IP is a genodermatosis in which lesions following the Blaschko lines are seen, characterised by linear or whorled hyperpigmented, non-raised macules on the trunk, arms and legs. In addition to its characteristic skin findings, it can be associated with various systemic findings.
In IP it is thought that keratinocytes are mainly affected and that cells carrying the mutant X chromosome are destroyed.
This X-linked dominant disease has been found to be caused by a defect in the NEMO gene on chromosome Xq28. Its incidence is 1 in 40,000. It is usually fatal in males, so more than 95% of patients are girls.
The skin signs occur in four stages, although not all stages may be seen.
- Stage 1: This stage begins at birth. It may occur anywhere on the body but most often affects the arms, legs and trunk, with a distribution following the Blaschko lines of the skin. Redness (erythema), vesicles and pustules (91%) are observed in the lesions. At this stage, blood eosinophilia of up to 50% may be seen. The disease regresses spontaneously and enters Stage 2. However, external factors such as sunlight can cause Stage 1 signs to flare up again during the newborn period.
- Stage 2: A few weeks or months after the first stage, the verrucous stage – the second stage – follows, with hyperkeratotic papules and verrucous plaques on the Stage 1 lesions (84%). Stage 1 and 2 lesions regress on average between the 4th and 7th months
- Stage 3: The hyperpigmentation stage (95%); the third stage often appears between the 12th and 26th weeks and is characterised by brown or grey patches following the Blaschko lines
- Stage 4: Hypopigmentation (10%), atrophy and scarring (31%). No hair or sweat glands remain in the skin of these lesions.
IP does not always follow this sequence and may begin directly at Stage 3.
At least 50–80% of IP cases also have involvement outside the skin. Other associated conditions may include dental involvement (40%), central nervous system involvement (30%), musculoskeletal and eye involvement (35%), and ear, auricular, cardiovascular and nail abnormalities (40%). Immunological disorders may also be found.
Nail deformities ranging from mild pitting to onychogryphosis are observed.
The hair may show alopecia, dullness, and a coarse, brush-like appearance.
Central nervous system signs reported include delayed mental development, oligophrenia, hemiplegia, spastic tetraplegia, microcephaly and hydrocephalus.
Eye findings include squint, retinal vascular abnormalities, loss of vision, microphthalmia, cataract and optic atrophy.
Because dental findings persist throughout life, they are of diagnostic value. Dental findings such as hypodontia, delayed tooth development and conical teeth may be seen.
There may be accessory nipples, nipple hypoplasia, or breast hypoplasia or aplasia.
Skeletal abnormalities such as contractures and scoliosis, and ear abnormalities may also be present
There is no specific treatment. The skin should be kept clean to prevent infection, and local wound care should be provided. Topical corticosteroid treatment can be applied. Seizures can be treated with anticonvulsants. Surgery or systemic retinoids may be helpful for nail involvement.
A multidisciplinary approach including a dermatologist, neurologist, ophthalmologist, dentist and orthopaedic surgeon is essential for patients with IP.
Ectodermal Dysplasia
Ectodermal dysplasia is a group of conditions affecting tissues and organs of ectodermal origin. It is a rare condition with the triad of hypotrichosis, anodontia and anhidrosis. A total of 154 different types have been described within eleven clinical subgroups. The most commonly seen form is hypohidrotic or anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome). The features of the syndrome were first described by Darwin, and its genetic, hereditary aspects and clinical features were
described by Christ, Siemens and Touraine. The main features of this rare hereditary disease are abnormalities of the epidermis and its appendages (hair, nails, eccrine and sebaceous glands), together with an absence or, more often, a reduction of sweat glands, leading to a rise in body temperature.
For the diagnosis, the disease must be congenital, diffuse and non-progressive and must involve at least one ectodermal appendage. It is usually X-linked and sometimes autosomal recessive. 90% of affected patients are male. The aim was to review the clinical features, follow-up and treatment of the disease through case presentations. We believe it is noteworthy to present this rare syndrome also with regard to its lower occurrence in girls.
Ataxia Telangiectasia
Ataxia telangiectasia (A-T) (Boder-Sedgwick syndrome or Louis-Bar syndrome) is a rare, neurodegenerative, hereditary disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to dilated blood vessels; both are distinguishing features of the disease. The disease is characterised by hypersensitivity to X-rays and a predisposition to lymphomas. A-T affects the cerebellum (the body’s motor coordination control centre) and, in about 70% of cases, also weakens the immune system, leading to respiratory disorders and an increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as unsteadiness, slurred speech and increased infections. Because all children of this age take time to develop good walking skills, coherent speech and an effective immune system, several years may pass before A-T is correctly diagnosed. A-T is caused by a defect in the ATM gene, which encodes a kinase important for p53, responsible for recognising and correcting errors in DNA copying when cells divide and for destroying cells when the errors cannot be corrected. The protein normally repairs double-stranded DNA when it breaks.
Signs and Symptoms
A-T is characterised by the following:
- Early-onset progressive cerebellar ataxia (difficulty controlling movement)
- Ocular apraxia (difficulty following objects across the visual field)
- Telangiectasia of the eyes and skin
- Immunodeficiency, low immunoglobulin concentrations
- Chromosomal instability
- Hypersensitivity to ionising radiation
- Increased incidence of malignancy (primarily haematological)
- Raised alpha-fetoprotein levels
- Absence of a thymic shadow on X-ray
- Ovarian dysgenesis
At first it can be hard to be sure that anything is wrong, and some children seem to improve between the ages of 3 and 5, but eventually it becomes obvious that balance control is abnormal. Towards the end of the first decade and the beginning of the second, other problems emerge; these can be as disabling as the loss of balance control. Because A-T can have somewhat incomplete penetrance, some patients may have a mild form of the disease with later onset and less severe symptoms. Because of the rarity of the disease, many doctors are not familiar with its symptoms, diagnostic methods or treatment. It may take time for doctors to rule out other possible conditions such as cancer (a high AFP level can mislead doctors) or cerebral palsy.
Ataxia
The first signs of A-T usually appear in the toddler years. These early signs show difficulty in controlling posture and body movement (truncal ataxia). The child may start walking later than normal (after 18 months), may be reluctant to let go of supporting people or objects, may continue to walk unsteadily for longer than normal, may be unable to stand without swaying and may fall frequently.
Walking may require more and more effort and looks awkward; walls and doorways are often used for support. For a while running seems less affected; this is because less balance is needed for fast movements than for slow, graceful ones. At the start of the second decade of life, most people with A-T begin to use a wheelchair.
Coordination of the limbs becomes abnormal later in the disease (peripheral ataxia). In some patients involuntary movements may begin and usually worsen over time. These may include small jerks of the hands and feet that look like fidgeting (chorea), slower writhing movements of the upper body (athetosis), the adoption of stiff and twisted postures (dystonia), occasional uncontrolled jerks (myoclonic jerks) and shaking of a limb (tremors).
Slurred speech (dysarthria) may develop in the first decade, worsens between the ages of 5 and 10 and then remains a static problem. Patients can usually be understood, but conversation can be a slow process. Eye movements may be restricted (vertical and horizontal saccadic apraxia). Reading and following moving objects become difficult.
Telangiectasia
Prominent blood vessels in the whites of the eyes (telangiectasias) usually appear by the age of 5. These are the ocular telangiectasias of the condition and resemble the vessels seen in the eyes of older people. They are occasionally present at birth, but in others they may not develop until the teenage years. Although they are potentially a cosmetic problem, they do not bleed or itch. Their permanent nature – they do not change with time, weather or emotion – distinguishes them from other eye vessels.
Immune Problems
About half of people with A-T have immune problems. These usually take the form of recurrent colds and runny nose (sinopulmonary infections). The immune system is complex and difficult to assess, but a doctor should carry out this assessment if the child is suffering from more than their fair share of infections. Some people with A-T need additional vaccinations (DPT, Hib and Pneumovax), others need ongoing antibiotics to provide ‘background cover’ and some require immunoglobulin injections. Others have no problems. There is an impression that bacterial rather than viral infections cause the most problems. Treatment of infections includes regular IVIg administration. Doses should be determined by a doctor.
Other Features
People with A-T have an increased incidence of tumours (probably a 1% risk per year), particularly lymphoma and leukaemia. A small increase in the risk of breast cancer has been reported in the mothers of children with A-T. This finding is currently the subject of considerable debate and research. Mammography is not recommended before the age of 50 unless there is a strong family history of breast cancer.
Although people with A-T have an increased sensitivity to ionising radiation (X-rays and gamma rays), they can normally cope with other forms of radiation, such as tanning from ultraviolet light. Furthermore, the tumours seen in A-T are not thought to be radiation-related. Exposure to X-rays should be strictly limited to medically necessary cases, because exposing an A-T patient to ionising radiation can mutate cells in a way the body cannot repair.
Intellectual disability is not seen in A-T. However, many appear to have a slower speed of thinking. Some children are placed in special schools, while others remain in mainstream schools and even graduate from university. Choreoathetosis, slurred speech, ocular apraxia and cerebellar ataxia develop throughout childhood.
A-T patients are often very thin. This may be due to poor appetite, energy spent on involuntary movements or features inherent in the disorder. Some people with A-T, both male and female, may have delayed puberty. This appears to be more common in those who are thin or prone to infections.
There may be thymic hypoplasia. Hypogonadism (ovarian dysgenesis) and hypersensitivity to ionising radiation are also part of the clinical picture.
Diagnosis
The diagnosis is usually made clinically by examination and detection of both ataxia and oculocutaneous or skin telangiectasia. This is then followed by laboratory tests to measure the serum AFP level, the response of white blood cells to X-rays and the level of ATM protein. Patients may also have a low lymphocyte count and other immunological abnormalities. Cytogenetic and molecular testing may then follow to confirm the diagnosis. MRI and CT scans may show signs of cerebellar atrophy. (MRI is the preferred method, because patients should limit exposure to any diagnostic radiological test that uses ionising radiation.)
Molecular diagnosis of A-T can be carried out by sequencing all 66 exons of the gene or, if there is a significant family history, by linkage. Protein function testing can also be used. However, testing for A-T is usually done cytogenetically, because specific breakpoints and cytogenetic instability are important characteristic features of the disorder. This must be done on lymphocytes. 10% of patients with A-T show balanced translocations, two thirds of which involve the immunoglobulin genes on chromosome 7 and chromosome 14. Some patients show expansion of immunoglobulin genes, which may expand during mitosis, resulting in prolymphocytic leukaemia.
Prenatal diagnosis can be made using linkage and microsatellite markers. However, direct gene analysis between known patients and the foetus is more common.
Treatment
Treatment is symptomatic and supportive. Physiotherapy and occupational therapy can help maintain flexibility. Speech therapy may also be needed. Gammaglobulin injections may be given to help boost a weakened immune system. High-dose vitamin regimens may also be used. Antibiotics are used to treat infections. Some doctors recommend low-dose chemotherapy to reduce the risk of cancer, but this is controversial. Regular monitoring of heterozygous family members for cancers is also recommended. Deferoxamine has recently been shown to increase the stability of A-T cells and may prove to be an effective treatment for the disorder.
People with A-T have an increased incidence of tumours (probably a 1% risk per year), particularly lymphomas and leukaemia, but radiotherapy and chemotherapy are rarely used because of the patients’ hypersensitivity to ionising radiation.
Werner Syndrome
Werner syndrome is a premature ageing disease that in some respects resembles Cockayne syndrome. The disease is named after Otto Werner, who first described the clinical picture in 1905 in four siblings (as familial cataracts and signs of premature ageing). In Werner syndrome, however, the signs of premature ageing appear much later than in Cockayne syndrome, in early adulthood, and patients usually die between the ages of 45 and 50, often from myocardial infarction, cerebrovascular events or complications of cancer.
The only obvious key finding of the disease from childhood onwards is growth retardation and short stature. After adolescence, however, findings such as musculoskeletal disorders (especially muscle atrophy in the upper limbs, osteoporosis and postural problems), greying and early loss of hair, wrinkling and widespread atrophy of the skin, bilateral cataracts forming at around the age of 20, atherosclerosis and type II diabetes, together with their complications, are added to the picture. With these features, although Werner syndrome is a congenital disease, it is almost impossible to diagnose in childhood unless the family consults a genetics specialist.
Werner syndrome is an autosomal recessive genetic disease. In other words, for the disease to appear, both the mother and the father must be carriers, or one must be affected and the other a carrier. For this reason, although the incidence of the disease is known to be higher in consanguineous marriages and isolated communities, Werner syndrome is an extremely rare disease
The molecular genetic mechanism of Werner syndrome has been shown to involve mutations in the WRN gene (also known as RECQL2), located on the short arm of chromosome 8. The WRN gene product is known to be a DNA helicase of the RecQ family that binds to quadruplex G-DNA regions, which are rich in GC sequences and usually located in telomeric DNA regions. However, exactly how mutations in the WRN gene lead to this disease at the cellular level, and what other factors are involved, are still being actively researched.
In Werner syndrome, molecular genetic diagnosis is made by direct sequencing of the WRN gene. However, because the disease is extremely rare, mutation screening is an experimental genetic test of academic value. Nevertheless, since it may enable direct mutation analysis for future carriers, it may be advisable in diagnosed families to set up a DNA bank including all reachable first- and second-degree relatives on both the mother’s and the father’s side.
Aplasia Cutis Congenita
Aplasia cutis congenita (ACC) is a genodermatosis characterised by an absence of skin that may be localised or widespread on the body. It may occur through acquired mutations or as part of genetic syndromes. The estimated frequency of the disease has been reported as 3 in 10,000 births. The incidence of familial transmission is higher in the localised form of the disease than in the widespread form.
The cause of aplasia cutis congenita is not fully known, but various theories have been put forward. The theory of incomplete closure of the neural tube during embryonic development can explain midline ACC lesions better, but falls short of explaining those developing on the trunk, arms and legs. The vascular theory proposes that the defects arise in the skin as a result of placental insufficiency, while the amniotic theory holds that amniotic membrane adhering to the skin causes ACC. The teratogenic theory states that various teratogenic drugs and infections to which the foetus is exposed during development may cause ACC. ACC probably results from a combination of many factors such as genetic factors, teratogens, vascular causes and trauma.
In 20–30% of cases with absent skin, depending on the location of the lesion, defects are also observed in the underlying bone or in neural structures such as the dura, the membrane covering the brain. Lesions are usually round or oval and measure 1–4 cm. They heal quickly within 1–2 months, leaving scar tissue and permanent hair loss. They are most often seen on the scalp but may also occur in other areas.
It may be seen together with cutis marmorata telangiectatica congenita and epidermal sebaceous naevus.
Bullous or membranous aplasia cutis congenita is a rare subgroup of ACC. In this type the skin defect appears cystic or bullous at birth, but over time it turns into a flat, atrophic scar covered by a thin epithelium. In some cases an association with an underlying neural tube defect has been reported. Some authors have stated that membranous (bullous) ACC is an incomplete form of a neural tube defect and arises from a similar embryological defect. The fact that the lesion is covered by a thin epithelial structure, as in encephalocele and meningocele, supports this view. Only a few cases of bullous aplasia cutis congenita have been reported in the literature. In some cases a collar of dark black hair, called the “hair collar” sign, is seen around the lesion and may be a strong indicator of an underlying neural tube defect. The “hair collar” sign can be seen in cases of encephalocele, meningocele, heterotopic brain tissue and membranous ACC. This sign is a relatively specific marker of an underlying neural tube closure defect. The pathogenesis of the “hair collar” sign has not been clearly established, but a number of hypotheses have been put forward.
Apart from neural tube defects, ACC may be associated with extensive unilateral linear epidermal naevus, haemangioma and multiple defects. A case of bullous ACC has been reported in an HIV-positive mother and her baby.
Aplasia cutis is seen in Adams-Oliver syndrome (aplasia cutis, heart anomalies, arm and finger defects, cutis marmorata telangiectatica congenita, severe scars), Setleis disease (bilateral forceps-like marks on the head and aplasia cutis), Delleman syndrome (raindrop-shaped aplasia cutis), EEC and Rapp-Hodgkin syndromes, Goltz syndrome, epidermolysis bullosa, Johanson-Blizzard syndrome and the sequelae of amniotic rupture. Patients should be assessed with this in mind.
In the treatment of ACC, a conservative approach with topical silver sulfadiazine or antibiotic ointments is recommended, especially for lesions measuring 4×7 cm or less. Large defects that also involve neural structures require surgery. In addition to skin grafts and local flaps, different surgical options such as autologous dermis grafts, allogeneic dermal grafts and cultured epithelial autografts have been reported in the literature. Genetic counselling is recommended because of the possibility that the disease may recur in children born from subsequent pregnancies.
Oral-facial-digital syndrome
Oral-facial-digital syndrome is a developmental disorder presenting with abnormalities of the oral cavity (cleft palate and tongue, abnormal tooth development, high palate, lobulated tongue, tongue hamartomas), face (frontal bossing, facial asymmetry, hypertelorism, facial milia) and digits (syndactyly, brachydactyly, clinodactyly, polydactyly); 9 different types have been described. Oral-facial-digital syndrome type I (OFDS 1) is the most common type and was first described in 1954 by the French dentists Papillon-Léage and Psaume. OFDS 1 is inherited in an X-linked dominant manner and is lethal in males. OFDS is a rare syndrome, occurring in about 1 in 250,000 live births. About 75% of cases are sporadic. Apart from surgical correction of the dysmorphic features, there is no specific treatment for OFDS.
Hyperimmunoglobulin E Syndrome
Hyperimmunoglobulin E syndrome (HIES) is a disease characterised by chronic dermatitis, raised serum immunoglobulin E levels and recurrent severe infections. The disease is also known as Job syndrome. This syndrome was first reported in 1966 in two girls who had eczematous dermatitis, recurrent sinopulmonary infections and cold skin abscesses caused by Staphylococcus (Staph.) aureus. In two boys reported in 1972, Buckley and colleagues noted, in addition to the clinical findings above, raised serum immunoglobulin E and a hypersensitivity reaction of the skin to Candida albicans and Staph. aureus.
In this very rare disease, which involves many systems, the immune system, teeth, connective tissue and skeleton may be affected. The clinical features of patients with HIES include recurrent staphylococcal skin and lung infections, pneumatocele formation in the lungs, eczema, fungal infections and eosinophilia. In this disease, whose underlying immunological defect has not been fully established, males and females are equally affected. Its incidence is reported as < 10-6. While most cases are sporadic and present at an early age, autosomal dominant inheritance is also seen. A pattern of autosomal dominant inheritance has been reported in 30 patients with HIES and their relatives, and in some of these families it has been suggested that the disease gene may be linked to chromosome 4. In a recent study, Grimbacher and colleagues reported autosomal recessive inheritance in 13 related patients with HIES. In 2006 Minegishi and colleagues identified a Tyk2 gene mutation in patients with autosomal recessive hyperimmunoglobulin E syndrome. In 2007 the same group demonstrated dominant negative mutations in the STAT3 gene in patients with autosomal dominant HIES. In eight of fifteen unrelated patients with HIES, five different mutations were found in the DNA-binding domain of STAT3. The STAT3 gene is located at 17q21. The in vitro immune responses of these patients’ peripheral blood cells to cytokines such as IL-6 and IL-10 are inadequate. STAT3 is a signal transduction molecule activated in response to many cytokines, growth factors and hormones. This study is important for demonstrating the different roles that the STAT3 molecule plays in the human immune system and for shedding light on HIES, whose underlying genetic pathology had not been established for years. In a large series published in 2007, Holland and colleagues highlighted STAT3 gene mutations in patients with autosomal dominant HIES and also pointed to a correlation between clinical scoring and gene mutation.
Autosomal dominant hyperimmunoglobulin E syndrome
It presents with eczema, recurrent skin abscesses, episodes of pneumonia with pneumatoceles, mucocutaneous candidiasis, high serum IgE levels and eosinophilia.
Types of infection:
These are deep-seated bacterial infections, recurrent skin abscesses, pneumonia, chronic otitis media and sinusitis. Permanent pneumatocele formation and bronchiectasis may develop as sequelae of recurrent pneumonia. Less common types of infection are septic arthritis, cellulitis and osteomyelitis. Although the most common bacterial cause of infection is Staph. aureus, infections caused by Haemophilus influenzae, group A streptococcus, Escherichia coli and Pseudomonas are also encountered. Superinfections caused by Aspergillus fumigatus may occasionally develop on top of bacterial pneumonia. Fungal infections are seen on the skin, and may also involve the mouth, nails and scalp. Candida oesophagitis, meningitis and pneumonia are less common. Cases of cryptococcosis and histoplasmosis also occur in the clinical picture of HIES. Among viral infections, mucosal and skin infections caused by herpes viruses have been reported more often in the autosomal recessive form. It has been shown that early diagnosis of the disease and starting prophylactic anti-staphylococcal treatment can prevent pneumatocele formation and its complications.
Skin findings
Chronic eczema, which is papular and itchy, often results in lichenification. The distribution and characteristics of the skin rash differ from atopic dermatitis. The skin findings of atopic dermatitis begin in early childhood and affect mainly the flexor surfaces of the body; they are papular lesions on an erythematous base. In HIES, by contrast, the face and the extensor surfaces of the body are involved, the lesions are sharply demarcated and there is no underlying erythema.
Nevertheless, it is not easy to distinguish atopic dermatitis from HIES in infancy, because both conditions involve itchy dermatitis, eosinophilia and high serum IgE levels. The clinical clues to look for in the differential diagnosis can be listed as follows. Food allergy, asthma and allergic rhinitis are often found in patients with atopic dermatitis or their family members. In these patients, Staph. aureus skin infections are superficial, whereas in patients with HIES they are deep-seated. Mucocutaneous candidiasis is common in patients with HIES. In atopic dermatitis the lesions begin after 2–4 months, whereas in HIES skin findings are already present during the first two months of life. The high IgE level in HIES is directed against Staph. aureus.