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The skin in systemic disease

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					Section 9: The skin and internal disease

Chapter 45: The skin in systemic disease
Endocrine disorders                                 Cushing's syndrome
Hypopituitarism                                           Chronic glucocorticoid excess may occur
      Excessive secretion of growth hormone         due to increased secretion of ACTH, usually
(GH) stimulates synthesis of collagen and           from a pituitary adenoma (Cushing's disease)
glycosaminoglycans in the skin and skeleton,        leading     to     adrenal   hyperplasia      and
leading to hypertrophy of skin, subcutaneous        glucocorticoid excess, or from an ectopic
tissues and viscera, and to periosteal bone         ACTH secreting lung carcinoma or carcinoid,
growth. This causes acromegaly in adults and        from ACTH-independent cortisol producing
gigantism in children. The usual cause is a         adrenocortical adenomas or carcinomas, or
benign tumor or hyperplasia of eosinophilic         due to exogenous iatrogenic long-term
cells of the anterior pituitary, producing          administration of systemic glucocorticoids.
excess GH and prolactin. Clinical features          The glucocorticoid hormones, among other
include general features (macroglossia, heart       effects, impair synthesis of collagen and
failure, hypertension, visual field defects and     mucopolysaccharides and thus lead to atrophy
headache due to the tumor), characteristic          and vascular fragility of the skin. Skin features
                                                    include truncal obesity with slender limbs,
facies (prognathism, frontal bossing, widely
                                                    buffalo hump (fat deposits over the back of
spaced teeth), acral hypertrophy (which
                                                    neck), moon facies (facial fullness and
causes elongated, blunt and thickened
                                                    plethora), skin atrophy and fragility, poor
fingers), and skin features (a protruding,
                                                    healing, telangiectasia, bruising, striae
thickened lower lip, oedematous thick
                                                    (typically wide and red),              hirsutism,
eyelids, a large furrowed tongue, triangular        hypertrichosis over the checks, acneiform
large     ears,     numerous      skin     tags,    lesions, and Addisonian-like pigmentation.
hyperpigmentation due to increased MSH,             Clitoral     hypertrophy    and     male-pattern
coarse scalp hair which later becomes fine,         baldness may occur in women. Plasma cortisol
loss of secondary sexual hair, the nails are flat   and 24 h urinary cortisol are increased. Trans-
and wide and grow fast). Diagnosis is by            sphenoidal selective adenomectomy is the
raised serum levels of GH and prolactin and         treatment of choice for Cushing's disease in
MRI for the tumor. Neurosurgical removal of         adults, with radiotherapy as second choice.
the tumor is the preferred treatment.               Radiotherapy is more effective in children.
Hypopituitarism                                     Bilateral adrenalectomy is the third-choice and
     Insufficiency of the anterior pituitary        is the treatment of choice when the disease is
may involve individual or multiple hormones         caused by bilateral adrenal hypersecretion.
and is usually due to pituitary cell destruction    Lifelong       replacement      therapy      with
(tumors, infections, trauma, vascular causes).      glucocorticoids and mineralocorticoids is
The skin        shows    pallor     (generalized    required.
hypopigmentation due to decreased MSH               Adrenal insufficiency
secretion), loss of axillary and pubic hair              Primary adrenal insufficiency (Addison's
(decreased gonadotropins), reduced activity         disease) is most commonly due to
of sebaceous and sweat glands, fine wrinkling       autoimmune adrenalitis and less commonly
and dryness (skin simulates advanced age),          due to tuberculosis. Secondary adrenal
face appears expressionless (due to                 insufficiency is due to pituitary disease
diminution of facial skin folds), and the nails     leading to deficient secretion of ACTH and is
may show onycholysis, longitudinal ridging          characterized by absence of pigmentary
and brownish discoloration. Diagnosis is by         changes and the mineralocorticoid production
the serum level of anterior pituitary               is maintained. General features include
hormones. Treatment is of the primary cause,        wasting, fatigue, orthostatic hypotension,
together with hormone replacement.                  dizziness, anorexia, abdominal pain and



                                                -491-
amenorrhoea. The cardinal skin feature is            radioactive iodine or antithyroid drugs
hyperpigmentation, due to increased secretion        (propylthiouracil or carbimazole).
of pituitary MSH and ACTH as a response to                 Pretibial myxoedema occurs in 1% of
low adrenal corticosteroid levels in Addison's       patients with hyperthyroidism as localized,
disease. The hyperpigmentation is most               pink or skin-colored plaques on the legs and
pronounced on light-exposed areas, areas             feet, with prominent hair follicles giving a
subject to friction (elbows, knees), areas of        'peau d'orange' appearance. Their surface may
high     pigmentation       normally   (genital,     show hypertrichosis or hyperhidrosis. The
perineum, axillae, areolae, umbilicus), palmer       pathology shows that the dermis is thickened
creases, tongue and mucous membranes (spots          by      extensive      deposits      of      acid
or patches), scars, and nails (longitudinal          mucopolysaccharides, which may cause
melanonychia). Anaemia,          lymphocytosis,      separation of the collagen fibers, and stellate,
hyponatraemia,         hyperkalaemia        and      mucin-producing       fibroblasts    may       be
hypoglycemia are expected. In primary                prominent.      Topical     and     intralesional
adrenal insufficiency ACTH levels are raised         corticosteroids may be useful. Other used
and a synacthen test shows impaired cortisol         therapies include intralesional octreotide,
secretion in response to exogenous ACTH.             plasmapheresis, PUVA and intravenous
Primary adrenal failure requires glucocorticoid      immunoglobulin.
and mineralocorticoid replacement while                    Thyroid acropachy occurs in 1% of
cortisol only is required for secondary              patients with Graves' disease as clubbing of
pituitary cases. During stress, such as when         the fingers and toes, associated with soft-tissue
undergoing major surgery and in severe               swelling of the hands and feet and with
systemic infections, the need for cortisol is        periosteal new bone formation, and is usually
increased. The hyperpigmentation takes weeks         associated with pretibial myxoedema and
to months to fully resolve.                          exophthalmos (Diamond's triad).
Hyperthyroidism                                      Hypothyroidism
      This is usually due to Graves' disease               The most common cause is primary
(diffuse toxic goitre). Secondary hyper-             hypothyroidism which is an autoimmune
thyroidism may occur due to production of            disease. Secondary hypothyroidism due to
TSH or TRH. Graves’ disease is an                    deficient TSH production is uncommon.
autoimmune disorder in which there is a high         Tertiary hypothyroidism is due to hypo-
incidence of antithyroid antibodies and of           thalamic failure of TRH production.
other autoimmune disorders. Specific clinical        Congenital     hypothyroidism        (cretinism),
features include pretibial myxoedema, thyroid        usually due to absence of the thyroid, is rare.
acropatchy and exophthalmos, collectively            The most prominent manifestation of
known as Diamond's triad. Non-specific               hypothyroidism (myxoedema) is related to
features include increased sympathetic               dermal accumulation of mucopolysaccharides,
nervous        system       activity       causing   which bind water in the tissue and lead to
vasodilatation, leading to warm skin, facial         puffiness of the skin. The skin is pale, ivory-
flushing, palmar erythema and increased              yellow, cold, wrinkled, scaly, with xerosis,
sweating especially of palms and soles. Hair is      asteatotic eczema, itch and palmoplanter
fine, with diffuse alopecia. Nails may be thin,      keratoderma, absence of sweating, puffy
with koilonychia, onycholysis and fast nail          oedema of the hands, face and eyelids, purpura
growth. Hyperpigmentation similar to that of         and ecchymoses, punctate telangiectases on
Addison's disease, but sparing the buccal            arms and fingertips, delayed wound healing,
mucosa, may occur due to increased ACTH.             and xanthomatosis (secondary to hyper-
Hyperpigmented eyelids (Jellinek's sign) may         lipidaemia). Nails are slow in growth, brittle
occur. Pruritus and chronic urticaria may            and striated. Scalp hair is coarse and sparse,
occur. Diagnosis is by elevated T3 or T4 levels,     with loss of pubic, axillary and facial hair, and
with serum TSH suppressed in Graves' disease         loss of lateral eyebrows. In cretinism,
and increased in secondary hyperthyroidism.          coarseness of features, lethargy, periorbital
Beta-blockers are used to suppress the               puffiness, swelling of hands and feet,
increased       sympathetic      activity.    The    macroglossia, cold and dry skin with livedo,
hyperthyroid state can be reversed by surgery,       umbilical hernia and poor muscle tone are


                                                 -492-
pathognomonic. Diagnosis of hypothyroidism           hypogonadotropic     hypogonadism     (45%),
is by low levels of T3 and T4, raised TSH level      diabetes mellitus, and thyroid antibodies or
in primary and reduced level in secondary            overt thyroid dysfunction. Alopecia areata
hypothyroidism.                                      (25%) and vitiligo (10%) may occur. Nail
      There are associations between either the      dystrophy and tooth enamel defects may
presence of antithyroid antibodies, or of overt      occur.     Patients     with     autoimmune
thyroid dysfunction and some skin diseases,          polyglandular syndrome types 2 and 3 more
notably     chronic     urticaria,    dermatitis     commonly have diabetes, but less commonly
herpetiformis, vitiligo and alopecia areata.         have alopecia or vitiligo, and do not have
Chronic urticaria has resolved after treatment       chronic mucocutaneous candidiasis.
of associated thyrotoxicosis. It has also been
recommended that T4 treatment should be              Cutaneous markers of internal
considered in euthyroid patients with chronic        malignancy
urticaria if they have evidence of thyroid                These can be classified into several broad
autoimmunity.                                        categories including direct tumor spread, skin
Parathyroid disease                                  metastases from internal tumors, cancer-
      Subcutaneous calcification may occur in        associated     genodermatoses       and      the
hyperparathyroidism secondary to renal               paraneoplastic syndromes.
failure. Pruritus may be related to                  Direct tumor spread
hyperparathyroidism.        Hyperparathyroidism           The skin may be involved by spread from
may cause dry, scaly skin, with sparse, coarse       an adjacent organ as occurs in cancer breast,
hair. Nails are brittle and ridged, with cracking    carcinoma of the oral cavity, Paget's disease of
at the free margins. Cloasma or pellagra-like        the nipple and extra-mammary Paget's disease
pigmentation is less common. Chronic                 occurring in apocrine gland-bearing areas such
mucocutaneous candidiasis, especially of the         as anogenital and axillary sites.
nails and oral mucosa may occur in
conjunction with hypoparathyroidism when             Skin metastases of internal tumors
this occurs as a part of the polyglandular                 The skin is a relatively uncommon site
autoimmune syndrome, or in association with          for distant metastatic deposits (4% of patients
immunological defects such as Di George's            with internal cancer), compared with organs
syndrome, but is not a feature of                    such as the liver, lung and bone. The most
postthyroidectomy,                      iatrogenic   common sources of skin metastases are breast,
hypoparathyroidism.                 Subcutaneous     lung, colon, stomach, upper GIT, uterus and
ossification is a feature of Albright's hereditary   kidney. Skin metastases generally present as
osteodystrophy          which        encompasses     nodules: single or multiple, firm, painless,
pseudohypoparathyroidism         and      somatic    skin-colored, blue-brown or reddish-purple, on
features (obesity, short stature, short              the head, neck, upper trunk and umbilicus, and
metacarpals).                                        may be mistaken for cysts or inflammatory
                                                     lesions. A morphoea-like sclerotic pattern may
Multiple endocrinopathy syndrome                     occur. Metastases to the skin occur as a result
       This is the coexistence of autoimmune         of lymphatic or haematogenous dissemination
conditions with endocrine disease. Examples          of tumor. In general, the tumor cells resemble
are the polyglandular autoimmune syndrome,           the cells of the primary tumor. Skin metastases
vitiligo and alopecia areata. There are 3 types      are usually indicative of disseminated disease
of autoimmune polyglandular syndrome and             and correspondingly a poor prognosis and
the most important dermatologically is type 1.       survival is only about 3 months.
It is also termed mucocutaneous candidiasis-
endocrinopathy syndrome. It is defined by the        Cancer-associated genodermatoses
presence of 2 or more of 3 major features,           Gardner's syndrome : This is an autosomal
which are chronic mucocutaneous candidiasis          dominant condition of multiple cutaneous
(usually by age of 5 years, present in 80%),         epidermoid      cysts,   fibromas     and
chronic hypoparathyroidism (by age of 10             pilomatricomas associated with a high
years, present in 90%) and autoimmune                incidence of early malignant change in
adrenal insufficiency (by age of 15 years,           intestinal  adenomatous     polyposis  to
present in 70%). Other features are                  adenocarcinoma.

                                                 -493-
Peutz-Jeghers syndrome: This autosomal             commonest (1 in 4000 while NF2 is 1 in
dominant condition comprises mucocutaneous         200000). NF1 is characterized by presence of
pigmentation, particularly in the peri-and         flexural freckling and Lisch nodules
intraoral regions and gastrointestinal polyposis   (pigmented iris hamartomas) while NF2 is
with increase in cancer frequency.                 characterized by fewer skin lesions and
Palmoplanter keratoderma (Howel-Evans              occurrence of cataracts. CNS tumors include
syndrome): This is an autosomal dominant           meningiomas       and       astrocytomas.       The
keratoderma of the palms and soles (tylosis)       commonest neoplasia developing in patients
with the eventual development of oesophageal       with     neurofibromatosis        is     malignant
carcinoma.                                         neurofibrosarcoma.
Basal cell naevus syndrome: In this autosomal      Tuberous sclerosis complex (Bourneville's
dominant condition there are multiple basal        disease): An autosomal dominant condition of
cell carcinomas, mandibular keratocysts,           angiokeratomas,       epilepsy,      and    mental
skeletal anomalies, abnormal calcification and     retardation that may be associated with
dyskeratotic pits of palms and soles, and may      internal malignancy (CNS, kidney, heart,
be associated with medulloblastoma or ovarian      lung).
tumors.                                            Multiple endocrine neoplasia syndrome
Familial melanoma syndrome (dysplastic             (MEN): MEN type 1 (Wermer syndrome) is an
naevus syndrome):         In this condition with   autosomal      dominant       cancer     syndrome
polygenic inheritance there are large multiple     characterized by skin lesions (multiple facial
and irregular naevi with an early onset of         angiofibromas and collagenomas, café-au-lait
melanoma and there may be internal                 macules and lipomas) and endocrine tumors of
malignancies also (pancreas, lungs, breast,        the parathyroid, pancreatic islet cell (e.g.
GIT, larynx).                                      insulinoma, glucagonoma), anterior pituitary
Xeroderma pigmentosum: In this autosomal           (prolactinomas causing acromegaly or
recessive condition there is early onset of        Cushing's syndrome), and foregut carcinoid.
photoageing in infants followed by sun-            MEN type 2 includes subtypes 2 A and 2 B
induced dysplasias (BCC, SCC, malignant            and both are autosomal dominant. MEN type
melanoma) and increased incidence of internal      2A is characterized by pruritus and café-au-lait
malignancy (CNS, sarcomas, leukaemia, lung         spots     and     a     high       incidence     of
and gastric cancer). Inactivation of tumor         phaeochromocytoma. Type 2B is characterized
suppressors and activation of oncogens due to      by multiple mucosal neuromas in the lips
mutations causing XP results in development        (causing blubbery protuberant lips), buccal
of multiple tumors.                                and gingival mucosa, marfanoid appearance
Werner's syndrome (adult progeria):       An       and high incidence of phaeochromocytoma
autosomal recessive condition of premature         and thyroid medullary carcinoma.
ageing, with onset in the second or third          Carney's complex (LAMB syndrome):            It
decade of life. Neoplasms develop in 10% of        consists of lentigines, atrial myxomas,
cases, although the commonest cause of death       mucocutaneous myxomas and blue naevi.
is arteriosclerosis. Sarcomas, meningiomas,        Cardiac myxomas are potentially life-
melanomas and leukaemia may occur.                 threatening. Often there are tumors of the
Werner's syndrome is a chromosome-                 adrenal cortex, thyroid and pituitary glands
instability syndrome and, as with XP, ataxia-      and gonads.
telangiectasia,    Bloom's     syndrome     and    Multiple Hamartoma and neoplasia syndrome
Fanconi's anaemia, is likely to be associated      (Cowden's disease):        In this autosomal
with a high incidence of neoplasia.                dominant       disorder       with      incomplete
Von-Hippel-Lindau syndrome: This                   penetrance, there are multiple hamartomas of
autosomal dominant condition is characterized      ectodermal, mesodermal and endodermal
by skin haemangiomas and café-au-lait spots        origin associated with a predisposition to
and benign and malignant tumors of the CNS,        neoplasia which can involve nearly all internal
kidney, pancreas and phaeochromocytoma.            malignancies, but particularly the breast, colon
Neurofibromatosis types 1 and 2: Both types        and thyroid. Cancer breast is the most
are autosomal dominant and characterized by        important association and occurs in 50% of
multiple peripheral neurofibromas, CNS             women. Benign internal anomalies include
tumors and café –au-lait macules. NF1 is the       goitres, gastrointestinal polyposis and cysts of

                                               -494-
the female genitourinary system. The disease        premature ageing and predisposition to
is most readily recognized by its characteristic    osteosarcoma.
mucocutaneous appearance          consisting of     Dyskeratosis congenita: An X-linked recessive
warty 'cobblestone' hyperplasia of the mucosal      condition characterized by atrophy and
surfaces of the tongue and buccal mucosa,           pigmentation of the skin, nail dystrophy,
periorificial facial papules, acral warty           mucosal leukokeratosis which is prone to
keratoses and palmo-planter semitranslucent         develop carcinoma, defect in cell-mediated
punctate keratoses. The lesions, which are          immunity involving suppressor T cells, and a
grouped especially around the mouth, nose           high incidence of pancreatic adenocarcinoma
and ears, have a hyperkeratotic, flat-topped,       and leukaemia
wart-like appearance and they consist of
benign trichilemmomas.                              Paraneoplastic syndromes
Sebaceous tumors, keratoacanthomas and                    Some skin diseases are associated with
visceral malignancy (Muir-Torre syndrome):          internal malignancy, but are not themselves
         This autosomal dominant condition          malignant. A paraneoplastic syndrome is
includes     sebaceous     tumors     (adenoma,     characterized by starting at the same time of
carcinoma), keratoacanthomas and internal           the tumour and follows a parallel course.
malignancy (colorectal and urogenital cancer).      These      include    malignant       acanthosis
Wiskott-Aldrich syndrome: A sex-linked              nigricans       (GIT      especially      gastric
recessive condition of immunodeficiency,            adenocarcinoma),       acanthosis       Palmaris
associated with        the development         of   (bronchial carcinoma), dermatomyositis in
malignancy (lymphoma, leukaemia).                   adults (lung carcinoma in men, breast and
Chediak-Higashi syndrome: A fatal autosomal         gynecological tumors in women), painful
recessive illness, with features of partial         digital ischaemia (polycythemia             vera,
albinism,       photophobia,        neurological    leukaemias), vasculitis (myeloproliferative
abnormalities and severe, recurrent bacterial       disorders), migratory erythemas, including 3
infections. It may be associated with               variants (erythema gyratum repens, associated
lymphoma. In the terminal phase, patients           with lung cancer; necrolytic migratory
develop fever, jaundice, hepatosplenomegaly,        erythema, associated with an α-cell tumor of
lymphadenopathy,      pancytopenia       and a      the pancreas; and erythema annulare
deterioration of neurological changes. Death        centrifugum            associated           with
may result        from bleeding due to              myeloproliferative disorders), multicentric
thrombocytopenia, or from infection.                reticulohistiocytosis (breast, ovary, cervix),
Ataxia-telangiectasia syndrome (Louis-Bar           paraneoplastic        acrokeratosis       (upper
syndrome):       An      autosomal      recessive   respiratory and GIT), acquired icthyosis
condition characterized by cerebellar ataxia,       (lymphoreticular tumors), pruritus (mycosis
oculocutaneous telangiectasia, and immune           fungoides, Sézary syndrome, Hodgkin's
deficiency of both cell-mediated and humoural       disease, polycythemia rubra vera; any of the
immunity which results in frequent infections       visceral carcinomas may cause pruritus; brain
and high incidence of neoplasia. The majority       tumors), bullous pemphigoid (breast, lung,
of tumors are lymphoproliferative or                thyroid, larynx, skin, stomach, colon, prostate,
leukaemic and breast cancer occurs in females.      cervix, uterus, kidney, bladder), pemphigoid
Bloom's syndrome: An autosomal recessive            gestationis (choriocarcinoma), paraneoplastic
condition characterized by small stature and        pemphigus (B-cell lymphoma, thymoma,
slight build, a sun-sensitive telangiectatic rash   Hodgkin's disease, chronic lymphocytic
and café-au-lait macules. Levels of IgA and         leukaemia), linear IgA disease (lympho-
IgM are low and bacterial infections are            proliferative      malignancy),        dermatitis
frequent. The occurrence of lympho-                 herpetiformis (lymphoma), porphyria cutanea
proliferative neoplasia and gastrointestinal        tarda, acute intermittent and variegate
cancer is high.                                     porphyria       (hepatocellular      carcinoma),
Rothmund-Thomson syndrome (poikiloderma             erythema       multiforme       (myelomonocytic
congenitale): An         autosomal      recessive   leukaemia),      migratory     thrombophlebitis
condition characterized by photosensitivity,        (pancreas,     stomach,     lung),     pyoderma
poikiloderma, small stature, juvenile cataracts,    gangrenosum (myeloproliferative diseases


                                                -495-
including acute and chronic myeloid                 of iron deficiency, such as koilonychia,
leukaemia, acute lymphocytic leukaemia,             smooth tongue and angular cheilitis. Iron
multiple      myeloma,        lymphoma        and   deficiency is associated with dysphagia and
myelofibrosis),      erythroderma        (mycosis   development of a postcricoid web (Plummer-
fungoides, Sézary syndrome), Leser-Trélat           Vinson syndrome). Paraneoplastic skin
sign (GIT, breast), seed-like keratoses of the      eruptions occur in Howell-Evans syndrome,
palms and soles (carcinoma of the bladder and       Bazex's syndrome and malignancy-associated
bronchus), flushing (carcinoid syndrome),           acanthosis nigricans. Bullous diseases may
acquired        hypertrichosis        lanuginosa    affect the pharynx, esophagus, or stomach.
(colorectal in both sexes, lung and breast in       Dystrophic EB may cause esophageal scarring
women), hyperhidrosis (phaeochromocytoma),          with a risk of SCC. Junctional EB may cause
SLE (non-Hodgkin’s lymphoma), relapsing             pyloric atresia. Cicatricial pemphigoid may
polychondritis (haematological malignancies),       cause esophageal scarring and stenosis.
Sweet’s syndrome (haematological and                Lichen planus may also occur in the
myelodysplastic       disorders),    Sarcoidosis    esophagus. CREST syndrome (calcinosis,
                                                    Raynaud's        phenomenon,        esophagus
(lymphomas), erythromelalgia (polycythemia
                                                    involvement, sclerodactyly, telangiectasia)
rubra vera, essential thrombocythaemia),
                                                    causes decreased and distorted esophageal
chilblain-like lesions (leukaemias, myelo-
                                                    peristalsis. Sjögren's syndrome may cause
proliferative disorders), and epidermolysis
                                                    dysphagia, and also dermatomyositis if it
bullosa acquisita (myeloma, lymphoma).              affects the pharyngeal musculature.
      Malignancy-associated            acanthosis
nigricans is much less common than the non-         Inflammatory bowel disease
malignancy-associated       types. Acanthosis             IBD includes 2 diseases: Crohn's disease
Palmaris consists of thickened palms and/or         (regional ileitis) and ulcerative colitis. Skin
soles with an enhanced dermatoglyphic               lesions are frequently seen in IBD and include
change, which give rise to a velvety or             contiguous spread from the bowel (common
honeycombed        pattern     of   the     hand.   in Crohn's disease and rare in ulcerative
Paraneoplastic       acrokeratosis       (Bazex's   colitis), metastatic spread to the skin (occurs
syndrome) is much more common in males              in Crohn's disease), reactive skin lesions
than females and the skin changes develop           (common in ulcerative colitis and rare in
gradually in several phases, initially with         Crohn's disease), skin lesions due to
violaceous erythema and scaling on the              malabsorption, skin complications of stomas,
peripheries, especially ears, nose, hands and       and association with other dermatoses. In
feet. The eruption then becomes more                Crohn's disease, direct skin involvement
hyperkeratotic, with a keratoderma on hands         occurs at sites in continuity with the bowel
and feet. Subsequently, the eruption may            such as the lip, stoma sites or, commonly, the
become more generalized. Nail dystrophy and         perianal skin. Perineal abscesses and multiple
paronychia are often present. Changes on the        fissures and fistulae occur in 25% of patients.
face may appear more eczematous or LE-like,         Anal tags are common. Oral Crohn's disease is
whereas acral changes are often psoriasiform.       manifest as thickened, corrugated appearance
Acquired icthyosis similar to icthyosis             of the oral mucosa and lips.
vulgaris and starting in adult life is associated         Lesions of metastatic Crohn's disease
with internal malignancy or systemic                may be solitary or multiple, intact or eroded
disorders, including nutritional deficiencies,      plaques and nodules or sinus formation,
leprosy, sarcoidosis, hypothyroidism, LE and        occurring on the lower legs (50%), abdomen,
drug reactions. Leser-Trélat sign is the sudden     groins, inframammary flexures, face and
appearance      of     numerous       seborrhoeic   genitalia. There is a granulomatous histology
keratoses, in an eruptive fashion with or           in the dermis and subcutis. Treatment of both
without pruritus and associated with internal       contiguous and metastatic Crohn's disease
malignancy.                                         include topical and intralesional steroids and
                                                    agents used to treat the bowel disease (oral
The gastrointestinal tract                          steroids, immunosuppressives, sulfasalazine,
Esophagus and stomach                               metronidazole,      hyperbaric oxygen and
    Bleeding from the esophagus or stomach          antitumor      necrosis     factor-α-monoclonal
may be associated with skin and nail changes        antibodies).

                                                -496-
Table 45.1 skin lesions associated with GIT bleeding.
             Disease                          GIT lesion                           Skin lesions
Vascular defects
Osler-Weber-Rindu disease           Telangiectasia                    Telangiectasia
Blue rubber bleb naevus             Haemangiomas                      Haemangiomas
Pseudoxanthoma elasticum            Involvement of visceral           Yellowish papules and plaques
                                    arteries
Ehlers-Danlos syndrome              Fragility of visceral arteries    Hyperelasticity of skin and joints
Polyposis
Neurofibromatosis                   Neurofibromas                     Café-au-lait spots, neurofibromas
Cronkhite-Canada syndrome           GIT polyposis                     Diffuse hyper-pigmentation, alopecia,
                                                                      nail defects
Gardner's syndrome                   Polyposis of colon (cancer)      Lipomas, epidermoid cysts
Peutz-Jeghers syndrome               Polyposis, especially small      Lentigines on lips, intraoral, perioral,
                                     intestine                        finger tips
Cowden's disease                     GIT polyposis                    Papules, lipomas, angiomas
Inflammatory bowel disease           Inflammatory changes of          Erythema nodosum, oral aphthae,
                                     intestinal wall                  erythema multiforme, pyoderma
                                                                      gangrenosum
Vasculitis and systemic disease
Henoch-Schönlein purpura and         Mesenteric vasculitis, gastric   Purpura, livedo nodules, necrosis
other vasculitides                   ulcers
Cholesterol emboli                   Intestinal arterial occlusion    Vasculitis, necrosis, livedo
Degos' disease                       Intestinal perforation           White atrophic lesions
Amyloidosis                          Vascular fragility               Purpuric lesions
Neoplasia
Primary GIT cancer                   Neoplasm                         Metastases, paraneoplastic eruptions
Kaposi's sarcoma                     Kaposi's sarcoma of bowel        Kaposi's sarcoma of skin
      Reactive skin lesions include a variety of           Crohn's disease. Patients with ulcerative colitis
non-specific eruptions that may occur with                 have significant coagulation defects that may
ulcerative colitis or Crohn's disease, usually             lead to microvascular thrombosis of the skin
paralleling the activity of IBD. These include             which may result in skin gangrene. Treatment
erythema nodosum, oral aphthae, erythema                   is with anticoagulant therapy.
multiforme, urticaria and angio-oedema,                           Crohn's disease may be associated with
neutrophilic       dermatoses          (pyoderma           other skin disorders e.g. epidermolysis bullosa
gangrenosum, pyodermatitis- pyostomatitis                  acquisita, polyarteritis nodosa, psoriasis and
vegetans, Sweet's syndrome), and vasculitis                hidradenitis suppurativa. Ulcerative colitis
and intravascular coagulation disorders.                   may be associated with linear IgA disease,
      Pyodermatitis-pyostomatitis        vegetans          finger clubbing and acne fulminans.
shows oral lesions consisting of multiple                         Skin complications of stomas include
pustules, plaques and erosions, which may                  those related to the function of the stoma
have a 'snail's track' appearance, and skin                (irritant dermatitis from faecal leakage,
lesions which are crusted papules and plaques,             infections, contact dermatitis), Koebner
which coalesce into annular lesions, mainly                reaction of existing or new dermatoses
affecting the major flexures and the scalp.                (psoriasis, lichen sclerosus) and disorders
There are similarities to pemphigus vegetans               related to bowel disease (peristomal pyoderma
but direct IF is negative. The pathology shows             gangrenosum, cutaneous Crohn's disease).
intraepidermal     and     superficial     dermal          Parastomal fistulae and ulcers are particularly
microabscesses containing neutrophil and                   associated with ileostomy for Crohn's disease.
eosinophil polymorphs, and a more mixed
                                                           Bowel-associated dermatosis-arthritis
deeper     dermal     inflammatory infiltrate.
                                                           syndrome
Acanthosis,            acantholysis           and
                                                           See chapter 33.
pseudoepitheliomatous hyperplasia occur.
Treatment is difficult and includes high-dose              Whipple's disease
systemic steroids, dapsone and azathioprine.                    This disorder is a cause of malabsorption
      Vasculitis and purpura (leukocytoclastic)            and diarrhoea, which may be accompanied by
may occur in either ulcerative colitis or                  skin manifestations. Diffuse pigmentation is


                                                    -497-
frequent, and may resemble Addison's disease,      Gianotti-Crosti syndrome. Skin features of
but buccal pigmentation is not a feature.          acute HBV infection include urticaria, non-
Subcutaneous nodules may occur, resembling         specific erythema or a serum-sickness-like
rheumatoid nodules or sarcoidosis. The             picture (malaise, fever and arthralgia in 20%
disorder usually presents with arthralgia,         of     patients). Angio-oedema,         erythema
malaise and abdominal features (pain,              multiforme or erythema nodosum-like lesions
diarrhoea and malabsorption leading to weight      may occur. Circulating immune complexes are
loss). Cardiac, pleural, ophthalmologic or         probably involved. Gianotti-Crosti syndrome
neurological symptoms also occur and there         (papular acrodermatitis of childhood) is
may     be generalized lymphadenopathy.            caused by numerous viral infections including
Diagnosis is by PCR from the causative             HBV infection. Lesions consist of small,
organism Tropheryma whippelii in infected          umbilicated papules, often affecting the knees,
tissue.                                            buttocks, cheeks and extremities and usually
                                                   last 8 weeks. About 10% of patients with
Skin disorders associated with GIT
                                                   polyarteritis nodosa have positive serology to
bleeding
                                                   HBV.
      See table 45.1
                                                         Hepatitis C virus (HCV) infection is
Intestinal polyposis
                                                   usually transmitted parenterally. Acute HCV
     See table 45.1. The pigmented macules
                                                   infection is usually only mildly symptomatic;
of Peutz-Jeghers syndrome appear in early
                                                   chronic hepatitis occurs in 75%, but
childhood and may fade with increasing age,
                                                   progression varies considerably. The skin
although the mucosal lesions persist. The
                                                   features include pruritus, urticaria, erthyma
bowel polyps in Gardner's syndrome are
                                                   multiforme and erythema nodosum. Pruritus
premalignant, and virtually all untreated cases
                                                   may be a presenting symptom and persistent
will eventually develop colonic cancer.
                                                   itch may occur. Necrolytic acral erythema is a
Regular colonoscopy and early colectomy is
                                                   specific skin feature of HCV infection. Mixed
advised to affected individuals. Cronkhite-
                                                   cryoglobulinaemia (usually type II and less
Canada syndrome is characterized by skin
                                                   commonly type III) occurs in HCV infection.
pigmentation, alopecia, nail-plate defects and
                                                   About 70% of type II cryoglobulinaemia is
polyposis of the GIT, from esophagus to anus.
                                                   HCV        associated.     Features     of     the
Affected patients are middle-aged or elderly,
                                                   cryoglobulinaemic vasculitis include small-
with a male to female incidence ratio of 3:2.
                                                   vessel vasculitis (mainly on the legs), livedo
Chronic diarrhoea due to protein-losing
                                                   reticularis,      acrocyanosis,        arthralgia,
enteropathy associated with the intestinal
                                                   glomerulonephritis, peripheral neuropathy,
polyposis is the usual presenting feature,
                                                   hepatosplenomegaly                            and
leading Ito hypoalbuminaemia, hypokalaemia
                                                   hypocomplementaemia.
and hypocalcaemia. There is diffuse macular
                                                         HCV infection has been reported in 30%
pigmentation of the skin (but not intraorally)
                                                   of patients with the cutaneous variant of
with accentuation over the face, neck and
                                                   polyarteritis nodosa. Like alcoholic liver
extremities. The palms are also involved. Total
                                                   disease and hereditary haemochromatosis,
alopecia occurs. All fingernails and toenails
                                                   HCV infection may be a risk factor for
are dystrophic with a peculiar, triangular,
residual nail plate.                               development of porphyria cutanea tarda.
                                                   HCV infection has also been linked to
Liver disease                                      variegate porphyria. There are associations
Acute liver disease (hepatitis)                    between HCV infection and auto-immune
      Acute hepatic damage is most often due       disorders including lichen planus, Behcet's
to viral hepatitis, alcohol or other drugs. Skin   disease, vitiligo and thrombocytopenic
features may be absent or there may be             purpura. Treatment of HCV infection and
jaundice. Hepatitis B virus (HBV) infection is     associated cryoglobulinaemia is with antiviral
transmitted parenterally and sexually and          agents, typically interferon with ribavirin.
vaccination is recommended for all health care           Necrolytic acral erythema is specific to
workers and high-risk groups (HIV-positive         acute HCV infection. Histology shows
individuals and drug abusers). Vaccination         necrolysis and clinically there are keratotic
may cause skin effects including urticaria,        erythrokeratoderma-like lesions on the hands,
lichen planus, granuloma annulare and              feet, forearms, knees and lower legs. Some

                                               -498-
patients have zinc deficiency and improve        gangrenosum may occur. Vasculitis appears
with oral zinc. More commonly, treatment has     as firm reddish papules resembling pityriasis
usually been that of HCV i.e. interferon and     lichenoides    chronica   or   lymphomatoid
ribavirin.                                       papulosis, on the trunk and extremities, and
Chronic liver disease (cirrhosis)                may heal leaving atrophic scars. Erosive
      Skin lesions associated with chronic       lichen planus of mouth may occur with
liver disease include palmar erythema, spider    primary biliary cirrhosis and chronic active
angiomas and telangiectasia (caused by           hepatitis. HCV infection is associated with
hyperestrogenaemia due to decreased hepatic      lichen planus.
metabolism of estrogen), dilated abdominal       Pancreatic disease
and chest veins including caput medusae               Apart from jaundice and panniculitis,
around umbilicus (caused by portal               skin changes associated with pancreatic
hypertension), jaundice (affecting sclerae and   disease are uncommon.
skin and caused by hyperbilirubinaemia),         Acute pancreatitis
hyperpigmentation (muddy-grey, due to                 Jaundice and fat necrosis may both be
hypermelanosis, on sun-exposed areas, may        prominent. Purpura or bruising of the left
be blotchy or diffuse or cloasma-like), thin     flank (Grey Turner sign) or of the
'paper-money' skin (due to diffusely scattered   periumbilical area (Cullen's sign) may occur.
tiny telangiectatic vessels), striae (on
abdomen, thighs and         buttocks), pseudo-   Subcutaneous fat necrosis (enzyme
Cushing's syndrome (altered metabolism of        panniculitis)
corticosteroids    in chronic alcoholism),           See chapter 30.
pruritus (most prominent in primary biliary      Migratory thrombophlebitis (Trousseau's
cirrhosis and disorders causing cholestasis),    sign)
testicular atrophy, gynaecomastia and loss of         See chapter 28.
secondary sexual hair in males (due to
hyperestrogenaemia), purpura (deficiency of      Migratory necrolytic erythema
vitamin C), bruising (deficiency of vitamin            This is a skin reaction that is produced by
K), nail changes (clubbing, diffuse white        hyperglucagonaemia which is usually caused
color with invisible lunula or proximal white    by a glucagonoma, which is an α-cell tumor
color with distal pink color i.e. Terry nails,   in the tail of the pancreas, or uncommonly by
and white bands i.e. Muehrke's bands),           other       causes      including       pancreatic
acquired zinc deficiency (due to increased       insufficiency,      intestinal      causes      of
loss of urinary zinc, appears as cracked and     malabsorption, hepatic cirrhosis, MEN type 1
reticulate eczema on trunk and extensor          syndrome (Wermer's syndrome), and aberrant
limbs, with erosive crusts on perianal and       glucagon-secreting tumors such as bronchial
genital areas, and cheilitis, hair loss and      or    nasopharyngeal        carcinoma.     Hyper-
Beau's lines on the nails).                      glucagonaemia also causes diabetes; the
      Primary biliary cirrhosis, which occurs    diabetico-dermatogenic syndrome occurs in
mainly in middle-aged women as an                60% of patients with glucagonoma. The
autoimmune disease, is characterized also by     pathogenesis of the skin eruption is probably
pruritus, xanthomas due to secondary             due to hypoaminoacidaemia caused by high
hyperlipidaemia       (xanthelasma,     palmar   glucagon levels. There may be a contributory
creases, tuberous, tendinous), and Sjögren's     role of essential fatty acids and zinc
syndrome (in 50% of cases). There are            deficiency.
antimitochondrial     antibodies    in   serum         The typical patient with glucagonoma is
(diagnostic in women with unexplained            a woman 45-65 years. Clinical features
pruritus) and is associated with other           include weight loss (70%), diabetes (60%),
autoimmune conditions (CREST, morphoea,          angular cheilitis and a painful beefy-colored
lichen planus, lichen sclerosus). PCT occurs     tongue (30%), diarrhoea (20%), venous
in alcoholic liver disease and shows bullae,     thrombosis, psychiatric disturbances, and
scarring, hyperpigmentation of sun-exposed       necrolytic migratory erythema (70%). The
skin and hypertrichosis of the face. In          rash is itchy and affects the lower abdomen,
chronic active hepatitis (juvenile cirrhosis,    groins, buttocks and thighs. Perianal and
lupoid hepatitis) vasculitis and pyoderma        perineal lesions are common. The rash is

                                             -499-
initially macular, extending to form                vasculitis include anaphylactoid purpura (IgA
superficially eroding areas of erythema that        nephropathy), SLE (albuminuria, haematuria,
progress to fragile vesicle and bullae              casts, membranous lupus nephritis), systemic
formation. Irregular centrifugal extension of       sclerosis (proteinuria, azotaemia, malignant
the annular lesions causes a marginated, often      hypertension),    Wegener's     granulomatosis
crusted, polycyclic or geographical pattern. It     (focal necrotizing glomerulitis), Behcet's
has a prolonged fluctuating course or cyclical      disease (renal failure) and drug-induced toxic
pattern; the central part heals over 7-14 days,     epidermal necrolysis (renal failure). Other
leaving      post-inflammatory    pigmentation,     diseases include linear IgA disease (renal cell
while the erythematous periphery becomes            carcinoma),         partial       lipodystrophy
crusted.                                            (glomerulonephritis with subsequent renal
          The plasma glucagon level is              failure), familial Mediterranean fever with
elevated. Biopsy shows necrolysis of the            urticaria and Muckle-Wells syndrome (renal
outer cell layers in the Malpighian stratum,        failure secondary to amyloidosis), and
with clefts and separation, associated with         sarcoidosis (polyuria,      nocturia,    hyper-
necrotic keratinocytes and cellular debris          calcaemia,          nephrolithiasis         and
surrounding the cleft. The dermis shows a           nephrocalcinosis).
mild perivascular lymphocytic and histiocytic
infiltrate. Older lesions show various degrees      Skin signs of renal failure
of dyskeratosis and acanthosis. Diagnosis is              The skin is dry, with fine scaling, pale
by CT scanning and determination of serum           (anaemia), with purpura (thrombocytopenia),
                                                    hyperpigmentation (muddy brown, due to
levels of glucagon, glucose, zinc and amino
                                                    impaired renal processing of MSH), half-
acids. In the non-tumor cases e.g. due to
                                                    and-half nails (proximal white and distal
malabsorption, correction of the cause is
                                                    brown), generalized pruritus (severe in 30%,
usually effective. Surgical resection of
                                                    unusual in acute renal failure, pathogenesis
glucagonoma is indicated. Chemotherapy
                                                    obscure, treated by UVB or UVA,
may be useful and includes dacarbazine, and         cholestyramine and activated charcoal),
streptozocin with 5-fluorouracil.                   calcifying     panniculitis    (caused     by
Renal disease                                       calciphylaxis, papules or nodules around
Renocutaneous syndromes                             large joints or flexures), perforating
      The skin and renal system may be              collagenosis (hyperpigmented papules up to
affected not uncommonly by the same disease         1 cm with a central keratinous plug, on the
processes. The renocutaneous syndromes              extensor surfaces of limbs, trunk and face),
include hereditary syndromes, metabolic             sensorimotor uraemic neuropathy (in 60% of
disorders, collagen diseases and vasculitis         patients), gynaecomastia (in 40%, while
and other diseases. Hereditary syndromes            receiving dialysis), porphyria cutanea tarda-
include angiokeratoma corporis diffusum             like bullous eruption, and nephrogenic
                                                    fibrosing dermopathy (scleromyxoedema-
(proteinuria, haematuria, lipiduria, renal
                                                    like illness with indurated plaques having
failure      due      to      deposition       of
                                                    finger-like projections and differentiated by
glycosphingolipids),          neurofibromatosis
                                                    absence of associated plasma cell dyscrasia
(obstruction of urinary outflow by a
                                                    and no face involvement). UVB radiation is
neurofibroma, renal artery thrombosis and
                                                    effective in uraemic pruritus and, recently,
subsequent      hypertension,     renal    artery   gabapentin has been demonstrated to be
stenosis, nephroblastoma), tuberous sclerosis       effective.
(renal cysts, malignant tumors especially
angiomyolipoma),       nail-patella     syndrome    Cardiac disease
(chronic     glomerulonephritis     and     renal         There are several diseases in which both
failure), Cowden's disease (renal cell              cardiac and skin involvement may be found
carcinoma), von Hippel-Lindau syndrome              (table 45.2). Common cardiac features include
(cysts and adenocarcinomas).                        coronary artery disease (CAD), congestive
      Metabolic disorders include primary           cardiac failure (CCF), conduction defects and
systemic amyloidosis (renal failure) and            arrhythmias,     hypertension,     pericarditis,
calcinosis cutis. Collagen disease and              cardiomyopathy and valvular disease.


                                                -500-
Table 45.2 Conditions that affect the heart and skin.
Disease                                               Main cardiac feature
Congenital/inherited
Ehlers-Danlos syndrome                                Dilated main vessels, mitral insufficiency
Cutis laxa                                            CAD, aortic aneurysm, mitral prolapse
Marfan syndrome                                       Aortic aneurysm, mitral regurge, aortic regurge
Pseudoxanthoma elasticum                              Arterial calcification, CAD, mitral prolapse
Werner's disease                                      Early CAD
Progeria                                              Early CAD
Fabry's disease                                       Conduction defects, arrhythmias, hypertension
LEOPARD syndrome                                      ECG abnormalities, pulmonary stenosis
Tuberous sclerosis                                    Cardiac rhabdomyomas
Neurofibromatosis                                     Hypertension
Incontinentia pigmenti                                Patent ductus arteriosus, tricuspid insufficiency
Inflammatory disease
SLE                                                   Vegetations, pericarditis, myocarditis, aortic regurge
Neonatal LE                                           Heart block, sepal defects, persistent ductus
                                                      arteriosus
Systemic sclerosis                                    Pericarditis, conduction defects, cor pulmonale
Polyarteritis nodosa                                  CAD, ECG abnormalities, hypertension
Behcet's disease                                      Pericarditis, pulmonary and coronary artery
                                                      aneurysm
Antiphospholipid syndrome                             CAD, vegetations, pericardial effusion
Dego's disease                                        Pericarditis, pericardial effusion
Churg-Strauss disease                                 Pericarditis, cardiac fibrosis, pericardial effusion
Wegener's granulomatosis                              Cardiomyopathy
Cholesterol emboli                                    CAD
Dermatomyositis                                       Conduction defects, CCF, arrhythmias,
                                                      cardiomyopathy
Relapsing polychondritis                              Dissecting aortic aneurysm, CAD, heart block
Subacute bacterial endocarditis                       Vegetations, valvular incompetence.
Rheumatic fever                                       Mitral and aortic valve disease
Kawasaki disease                                      Conduction defects, coronary artery aneurysm
Multicentric reticulohistiocytosis                    CAD, CCF, pericarditis, cardiomegaly
Hypereosinophilic syndrome                            CCF, eosinophilic endomyocarditis
Sarcoidosis                                           CCF, conduction defects, arrhythmias
Reiter's disease                                      Conduction defects, aortic regurge
Metabolic/endocrine disorders
Amyloidosis                                           CCF, conduction defects, cardiomegaly
Haemochromatosis                                      CCF, arrhythmias, cardiomyopathy
Wilson's disease                                      Arrhythmias, cardiomegaly
Scleromyxoedema                                       CCF, cardiomyopathy
LAMB syndrome                                         Atrial myxomas
Hyperlipidaemias                                      CAD
Diabetes mellitus                                     CAD, cardiomyopathy
Hyperthyroidism                                       Tachycardia, atrial fibrillation
Hypothyroidism                                        Bradycardia, CAD, pericardial effusion
Acromegaly                                            CCF, left ventricular hypertrophy
Carcinoid syndrome                                    CCF, tricuspid or pulmonary stenosis
Phaeochromocytoma                                     Variable heart rate, hypertension/ hypotension
Mastocytosis                                          CAD, tachycardia, hypotension, arrhythmias
Homocystinuria                                        Atherosclerosis
Other diseases
Lyme disease                                          Myocarditis, heart block
Varicella                                             Myocarditis
Congenital rubella                                    Patent ductus arteriosus, pulmonary artery stenosis
Erythroderma, any cause                               High output cardiac failure
Clubbing of nails                                     Cyanotic congenital heart defects
Red lunulae                                           Occur in CCF



                                                   -501-
Table 45.3 Conditions that affect the skin and respiratory system.
Disease                                                Respiratory tract features
Congenital/inherited
Atopic disease                                         Asthma, hay fever
Cutis lax                                              Emphysema, cor pulmonale
Tuberous sclerosis                                     Rhabdomyomas
Neurofibromatosis                                      Intrathoracic neuromas, lung fibrosis
Ataxia-telangiectasia                                  Pneumonia, bronchiectasis, lung fibrosis
Hereditary haemorrhagic telangiectasia                 Haemoptysis, dyspnoea
α1- antitrypsin deficiency                             Emphysema
Darier's disease                                       Lower lobe fibrosis, larynx involvement
Lipoid proteinosis                                     Larynx involvement
Infections
Tuberculosis                                           Specific lesions
Leprosy                                                Larynx involvement
Dissemination of pulmonary                             Blastomycosis, coccidioidomycosis, cryptococcosis,
fungal infections                                      aspergillosis, histoplasmosis
Varicella                                              Pneumonia
Measles                                                Pneumonia
Chronic MC candidiasis                                 Bronchiectasis
Whipple's disease                                      Pleural effusion, lung infiltrate, hilar
                                                       lymphadenopathy
Metabolic
Langerhans’ cell histiocytosis                         Pulmonary nodules and infiltrations
Amyloidosis                                            Lung infiltration in primary amyloidosis
Carcinoid syndrome                                     Bronchospasm
Hypothyroidism                                         Larynx involvement
Inflammatory
Sarcoidosis                                            Pulmonary fibrosis, hilar lymphadenopathy
Behcet's disease                                       Pleurisy, pulmonary arterial aneurysm
Small-vessel vasculitis                                Asthma, chronic obstructive lung disease
Wegener's granulomatosis                               Necrotizing vasculitis of upper and lower
                                                       respiratory tracts
Churg-Strauss syndrome                                 Rhinitis, asthma, pneumonitis
Systemic sclerosis                                     Interstitial fibrosis, pneumothorax
Sjögren's syndrome                                     Decreased secretions, bronchoalveolitis
SLE                                                    Pleurisy
Mixed CT disease                                       Fibrosing alveolitis
Antiphospholipid syndrome                              Pulmonary embolism, infarction, thrombosis
Dermatomyositis                                        Muscular weakness, pharyngeal dysfunction
Relapsing polychondritis                               Tracheal collapse
Multicentric reticulohistiocytosis                     Lung infiltration, pleural effusion
Bullous diseases (EB, pemphigoid)                      Upper respiratory tract involvement
Pyoderma gangrenosum                                   Neutrophilic nodules in lung, tracheal pyoderma
Familial Mediterranean fever                           Pleuritis
Stevens-Johnson syndrome                               Mycoplasma infection
Lymphomatoid granulomatosis                            Nodules of lower lungs
Craft-versus-host disease                              Restrictive defect, fibrosis
Other diseases
Angio-oedema                                           Upper airway obstruction
Anaphylaxis                                            Bronchospasm
Yellow nail syndrome                                   Pleural effusion, bronchiectasis
Mastocytosis                                           Rhinorrhoea, laryngeal oedema, bronchospasm
Tumors                                                 Metastatic disease

Respiratory system                                     proteinosis, pemphigus vulgaris, relapsing
      There are several diseases in which both         polychondritis (trachea), hypothyroidism,
respiratory and skin involvement may occur             erythema multiforme, sarcoidosis, secondary
(table 45.3). Hoarseness is an important sign          syphilis,    LE,    dermatomyositis     and
of laryngeal or tracheal involvement in lipoid         pachyonychia congenita.


                                                 -502-
Table 45.4 Conditions associated with bone or joint disease.
Disease                                               Bone or joint change
Bone disease
Congenital/inherited
Neurofibromatosis                                     Kyphoscoliosis, vertebral erosions, cystic lesions
Tuberous sclerosis                                    Intracerebral calcification, bone cysts of phalanges
Klippel-trenaunay syndrome                            Bony hypertrophy, macrocephaly, syndactyly
Maffuci's syndrome                                    Enchondromas of hands, chondrosarcoma
Sturge-Weber syndrome                                 Calcification of meningeal vessels, hemiatrophy
Gardner's syndrome                                    Osteomas, exostoses
Ehlers-Danlos syndrome                                Kyphoscoliosis, short clavicles
Marfan syndrome                                       Increased limb length, joint laxity
Focal dermal hypoplasia                               Syndactyly, bony tumors, scoliosis
Rothmund-Thomson syndrome                             Hypoplasia of thumbs, dental abnormalities
Linear epidermal naevus syndrome                      Asymmetry, kyphoscoliosis, bone cysts
Incontinentia pigmenti                                Conical teeth, spina bifida occulta
McCune-Albright syndrome                              Fibrous dysplasia, fractures, osteomas
Lipoid proteinosis                                    Intracranial calcification
Pseudoxanthoma elasticum                              Calcification of soft tissues, flax cerebri
Nail-patella syndrome                                 Absent patellae, iliac horns, absent fibulae
Werner's syndrome                                     Osteoporosis, joint contractures, sarcomas
Progeria                                              Osteolysis, avascular necrosis of hip
Gaucher's disease                                     Bone pains (crises), fractures
Other disorders
Chronic ulcer                                         Underlying osteomyelitis
Syphilis                                              Periostitis, osteitis
Cryptococcosis                                        Osteolytic lesions
Blastomycosis                                         Osteomyelitis
Sarcoidosis                                           Acrosclerosis, honeycomb change and bone cysts
Scleroderma                                           Resorption of terminal phalanges, erosive arthritis
Pyoderma gangrenosum                                  Multifocal osteomyelitis, localized osteitis
Gorlin's syndrome                                     Cysts of jaw, calcification of falx cerebri
Langerhans' cell histiocytosis                        Lytic lesions, defects of skull and mandible
Mastocytosis                                          Diffuse or focal osteoporosis or sclerosis
Becker's naevus                                       Scoliosis, spina bifida
Acromegaly                                            Increased periosteal bone growth
Joint disease
Inflammatory
Connective tissue disorders (any)                     Arthralgia or arthritis (90% in SLE)
Vasculitis (any)                                      Arthralgia or arthritis
Relapsing polychondritis                              Migratory arthritis sparing the hands
Psoriasis, Reiter's syndrome                          Erosive arthritis, sacroiliitis
Multicentric reticulohistiocytosis                    Polyarthritis mutilans of finger joints
SAPHO syndrome                                        Sternoclavicular osteitis, multifocal osteomyelitis
Acne fulminans                                        SAPHO syndrome, arthritis of large joints
Familial Mediterranean fever                          Arthralgia or arthritis
Sweet's syndrome                                      Arthralgia
Metabolic
Fabry's disease                                       Arthritis of distal interphalangeal joints
Gout                                                  Erosive arthritis
Scleromyxoedema                                       Arthritis, carpal tunnel syndrome, acro-osteolysis
Amyloidosis                                           Rheumatoid arthritis
Ochronosis                                            Calcium crystal deposition
Infection
Lyme disease                                          Arthralgia
Whipple's disease                                     Arthralgia
Brucellosis                                           Arthralgia
Bone and joint disease                                   SAPHO is an acronym for synovitis, acne,
      Skin disorders associated with bone or             pustulosis, hyperostosis and osteitis. It
joint involvement are presented in table 45.4.           includes sternoclavicular disease (synovitis,


                                                  -503-
hyperostosis, osteitis) which is also called        Most are cutaneous T-cell lymphomas and
anterior chest wall syndrome, and skin              about one-third are B-cell lymphomas.
lesions (acne conglobata, palmoplanter                    Dermatoses characterized by presence of
pustulosis). Therapy includes NSAIDs,               peripheral     blood      eosinophilia     include
doxycycline, methotrexate, and intra-articular      infestations (scabies, helminthes, insect bites),
corticosteroid injections. Periodic fevers          immunologic disorders (atopic diseases as
include familial Mediterranean fever (FMF),         atopic dermatitis, urticaria, angioedema;
FMF with amyloidosis, TNF receptor-                 immunobullous         diseases     as      bullous
associated periodic syndrome (TRAPS) and            pemphigoid and pemphigoid gestationis;
the hyperimmunoglobulin D and periodic              vasculitis as Churge-Strauss syndrome,
fever syndrome (HIDS). All are characterized        eosinophilic       vasculitis,      drug-induced
by recurrent fever with serositis (peritonitis-     vasculitis), eosinophilic dermatoses with
like abdominal pain, pleurisy, pericarditis),       eosinophils in biopsy (eosinophilic cellulitis,
headache and arthralgia or arthritis. In FMF,       eosinophilic fasciitis, eosinophilic panniculitis,
there may be urticarial lesions, subcutaneous       chronic      GVHD,       eosinophilic     pustular
nodules, purpura, leukocytoclastic vasculitis,      folliculitis of Ofugi, incontinentia pigmenti,
or transient cellulitis- like erythematous          pyoderma          vegetans,        angiolymphoid
plaques. Like the articular symptoms, the           hyperplasia with eosinophilia), and neoplastic
erysipelas-like plaques are predominantly on        disorders      (hypereosinophilic      syndrome,
the lower leg. In HIDS there are                    cutaneous T cell lymphoma, leukaemias,
erythematous macules and nodules. In                systemic mastocytosis).
TRAPS, the skin features include migratory                Purpura may arise from intravascular,
patches, oedematous plaques and periorbital         vascular       or      extravascular       causes.
oedema.                                             Thrombocytopenia is a common cause.
                                                    Thrombocythaemia may cause purpura,
Haematology                                         ecchymoses,            livedo          reticularis,
      The signs of iron deficiency anaemia          erythromelalgia,        recurrent      superficial
include pallor, koilonychia, brittle and ridged     thrombophlebitis, ischaemic limbs and leg
nails, angular cheilitis and atrophic glossitis.    ulcers. Cases of mixed cryoglobulinaemia
Generalized pruritus may occur. Pernicious          often develop palpable purpura on the lower
anaemia shows a deep-red cobblestone                limbs and can also exhibit livedo reticularis,
appearance of the tongue, a lemon tinge of          cold-induced urticaria, and frank ulceration or
jaundice (due to excessive production of            gangrene. The presence of antiphospholipid
unconjugated bilirubin subsequent to defective      antibodies may cause the antiphospholipid
erythropoiesis), premature greying of hair          syndrome with skin features of livedo
(canities), and melanin pigmentation of the         reticularis, leg ulcers, necrotizing purpura,
skin. Sickle cell anaemia may be suggested by       distal       ischemia         and       gangrene,
the occurrence of leg ulcers, particularly when     thrombophlebitis          and       haemorrhage.
occurring at an early age. In dermatitis            Examination for these antibodies is indicated
herpetiformis, anaemia is often due to              in patients with thrombotic cutaneous signs.
dapsone-induced haemolysis.          Classically,   Cold agglutinins may manifest with
polycythemia vera may present with pruritus,        Raynaud's      syndrome,       acrocyanosis     or
especially on cooling of the skin, often after      gangrene. Cold haemolysins may give rise to
bathing. Leukocytosis is common with                cold urticaria or Raynaud's syndrome.
infection and occurs also in erythroderma,          POEMS syndrome is a multisystem disease
pustular psoriasis, pustular miliaria, erythema     caused by plasma cell dysplasia and includes
multiforme, and as a result of corticosteroid       polyneuropathy, organomegaly, endocrine
therapy. A neutrophil leukocytosis usually          disorders, IgM protein, and skin features
occurs in Sweet's syndrome. Sézary cell             (Raynaud's        phenomenon,        scleroderma,
counts may be raised in Sézary syndrome.            angiomas).
Specific cutaneous leukaemic infiltrates can              Skin      diseases      associated      with
occur in all types of leukaemia, but are more       paraproteinaemias                    (monoclonal
common in monocytic forms. After the GIT,           gammopathy) and multiple myeloma include
the skin is the extralymphatic organ most           amyloidosis       AL       type,      type       1
frequently affected by malignant lymphoma.          cryoglobulinaemia, POEMS syndrome, livedo


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reticularis, small vessel vasculitis, neutrophilic   Erythema annulare centrifugum
disorders (pyoderma gangrenosum, SPD,                      Although numerous causes are described
Sweet’s      syndrome,     erythema      elevatum    for this disease, in the majority of cases the
diutinum), mucinoses (scleredema, papular            aetiology remains obscure and it is seldom
mucinosis          and        scleromyxoedema),      possible to discover and eliminate an
xanthomatous          disorders       (necrobiotic   underlying cause. Reported causes include
xanthogranuloma,         normolipaemic       plane   infections (cutaneous tinea, intestinal candida,
xanthoma,         xanthoma         disseminatum),    ingested fungi in cheese, tuberculosis,
immunobullous disorders (IgA pemphigus,              ascariasis), drugs (e.g. ampicillin, penicillin,
linear IgA disease, epidermolysis bullosa            aldactone,     amitriptyline),    haematological
acquisita), acquired cutis laxa, acquired            disorders (leukaemias, lymphomas, myeloma,
icthyosis, acanthosis nigricans, pityriasis          polycythemia, cryoglobulinaemia), neoplasms
rotunda,      calcinosis    cutis,    SLE      and   (e.g. bronchial carcinoma), and other diseases
dermatomyositis.                                     (hyperthyroidism, liver disease, relapsing
                                                     polychondritis, sarcoidosis). The pathology
Annular and figurate reactive                        shows a characteristic perivascular 'sleeve-
erythemas                                            like' lymphohistiocytic infiltrate which may be
Erythema chronicum migrans                           superficial, deep or mixed. In some cases there
     This is the term applied to the skin lesion     are epidermal changes (spongiosis and
of early stage of Lyme borreliosis. The              parakeratosis). Eosinophils are occasionally
primary lesion occurs at the site of a tick bite     present.
as a macule which expands slowly over a                    The disease usually occurs in young and
period of weeks to a median size of about 15         middle-aged adults. A small, pink, firm papule
cm with central clearing making a ring. See          slowly enlarges and forms a ring, as the
chapter 9.                                           central area flattens and fades. The rate of
                                                     extension is usually 2-3 mm/day and the ring
Erythema marginatum (rheumaticum)                    may become several centimeters in diameter.
     This occurs in 25% of patients with             Extension may be irregular to leave arciform
active rheumatic fever as evanescent, pale or        segments. Lesions may be single or, more
dull red rings or segments of rings, in crops,       often, multiple. The edge may be flat or easily
and fades after few hours or days. See chapter       palpable with a superficial cord-like quality,
31.                                                  and lesions may be smooth or show slight
Erythema gyratum repens                              scaling behind the advancing edge. Itching is
      This is a paraneoplastic dermatosis            variable. Any area may be affected but
associated with an internal tumor (most              commonly the buttocks, thighs, and upper
commonly the lung) in 80% of the cases,              arms. Individual lesions may last for a few
while 20% are idiopathic. Pathology shows a          days, weeks or months. Further lesions usually
superficial perivascular lymphocytic infiltrate      occur, and the disease is usually chronic with
associated with acanthosis, spongiosis and           periodic fluctuation over many years.
                                                           The differential diagnosis includes
parakeratosis. Clinically, regular waves of
                                                     granuloma      annulare,     annular    mycosis
erythema spread over the body to produce a
                                                     fungoides, necrolytic migratory erythema,
series of concentric figurate bands in a pattern
                                                     pityriasiform       seborrhoeic       dermatitis,
resembling the grain of wood. Rings, swirls or
                                                     sarcoidosis     and     leprosy.         Several
waves appear within existing lesions to form a       immunobullous diseases have been reported to
concentric pattern of sequential eruptions,          have an erythema annulare centrifugum-like
with day-to-day migration of the leading edge        lesions, especially in the prodromal phase,
by about 1 cm. Scaling and itch are usually          including bullous pemphigoid, pemphigus,
prominent. Hyperkeratosis of palms occurs in         dermatitis herpetiformis and linear IgA
10% of cases. Differential diagnosis includes        disease. Numerous treatments have been used
other     migratory     erythemas:     erythema      but most are relatively unsuccessful.
chronicum migrans, erythema annulare                 Treatments include topical steroids, or
centrifugum, necrolytic migratory erythema           calcipotriol, and oral corticosteroids and
and erythrokeratoderma variabilis.                   immunosuppressives.



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