David Chiu, M.D.

• Assistant Professor of Neurology
• Baylor College of Medicine
• The Methodist Hospital
• Houston, TX

There has been a steady rise in the incidence of melanoma in fair-skinned populations over recent decades treatment under eye bags buy epitol without prescription, with the highest figures in Australasia art of medicine purchase cheapest epitol. Primary prevention and early detection are essential medicine 1900s spruce cough balsam fir cheap epitol 100 mg on line, as therapy for advanced and metastatic disease remains unsatisfactory symptoms gallbladder buy generic epitol online. This can persist for years in patch and plaque stages treatment multiple sclerosis order epitol 100mg online, often resembling eczema or psoriasis medications used to treat anxiety epitol 100mg overnight delivery. B-cell lymphomas, on the other hand, usually present as nodules or plaque-like tumours. The diagnosis of cutaneous T-cell lymphoma requires a high index of suspicion, particularly in patients thought to have unusual recalcitrant forms of eczema or psoriasis. Once lesions have moved beyond plaque stage, localised radiotherapy, electron beam ks f ok s fre Cutaneous lymphomas Melanoma can occur at any age and site and in either sex, but typically affects the leg in females and back in males. Early lesions may be in situ and pre-invasive before becoming invasive melanoma with metastatic potential. Any change in naevi or development of new lesions should be assessed to exclude malignancy and, for this, the dermatoscope is invaluable. Real-time non-invasive imaging techniques are being investigated as tools to assist in diagnosis but are largely experimental. Given the low risk of malignant transformation, the option of no active treatment may also be appropriate for some elderly frail patients. It usually presents as a slowly enlarging, macular, pigmented lesion, with increasing irregularity in shape and pigment; this superficial, radial growth phase can last for co. This shows an intra-epidermal carcinoma with no invasion through the basement membrane. The type of sunlight exposure is under debate but intermittent exposure, such as recreational time in the sun, sunburn and sunbed use, is implicated. Patients with multiple atypical naevi (dysplastic naevus syndrome) and fair-skinned people, often with variant alleles in the melanocortin-1 gene, are at increased risk of melanoma. A family history of melanoma increases the risk but a strong family history is unusual. Several other susceptibility genes and potential genetic targets for therapeutic intervention in advanced disease have also been identified. The lower radiation, the synthetic retinoid bexarotene, interferon-alpha, extracorporeal photopheresis and systemic anti-lymphoma chemotherapy regimens may be needed. Management of advanced disease invariably requires a multidisciplinary team approach, with collaboration between dermatologists, pathologists and haematological oncologists. The initial biopsy should include a 2 mm margin, followed up where possible by wider excision if the diagnosis is confirmed. Occasionally, radiotherapy or imiquimod may be used for lentigo maligna, if surgery is not feasible. It occurs as a very slowly expanding, pigmented, macular lesion, usually on photo-exposed head and neck sites of elderly patients; histology shows in situ changes only. This phase may last for several years before a nodule of invasive melanoma develops in a proportion of cases (lentigo maligna melanoma). This may account in part for the increased mortality rates from melanoma in men, as these are tumours with greater metastatic risk. Nodular melanomas may be heavily pigmented, or relatively amelanotic and erythematous, and be confused with benign vascular lesions. Subsequently, the lesion may become palpable and this is indicative of a vertical growth phase, with dermal invasion; when this occurs, the tumour has the potential to invade lymphatics and vessels and to become metastatic. The mitotic rate and the presence or absence of any evidence of lymphovascular or perineural involvement should also be ascertained. The clinical staging of melanoma extent is essential, in order to establish whether disease is primary and localised, or if there is nodal or metastatic spread. Wide excision of melanoma with a low risk of metastasis (stage 1 disease, Breslow thickness < 1 mm) with a 1 cm clear margin is accepted practice. For tumours with a Breslow thickness of 1 mm or more, a sentinel lymph node biopsy should be considered. This procedure provides additional prognostic information but there is no evidence that it improves survival. Local recurrence of disease and palpable local node involvement should be treated surgically. Localised cutaneous metastases or in transit disease may be amenable to palliation with electrochemotherapy if there is no evidence of widespread metastatic disease. Despite the major advances in treatment options for advanced melanoma, the prognosis for metastatic disease remains poor and treatment options are palliative. Genetic developments have facilitated the introduction of tumour-targeted treatments for advanced, unresectable and/or metastatic disease, such as the B-Raf and c-Kit kinase inhibitors for patients expressing these gene mutations, notably dabrafenib and vemurafenib, with demonstrable clinical responses. Standard chemotherapy may also be used in some cases of metastatic disease, although outcomes are poor. It is important for patients with advanced melanoma to be managed through a multidisciplinary team in order to optimise care and facilitate their inclusion in clinical trials. All patients should be advised regarding ongoing photoprotection, with sensible behaviour in the sun, covering up, wearing hats and high-factor sunscreen use. However, evidence has shown that despite patients with melanoma being advised to photoprotect, many follow this advice only for the first year following diagnosis, thus emphasising the need for ongoing reinforcement of guidance with regard to photoprotection. It is also prudent to advise patients who are photoprotecting to optimise oral vitamin D through diet and/or supplements. Survival rates fall to less than 10% for those with advanced nodal or metastatic disease. It is thought to be associated with chronic sun exposure and most commonly occurs on the central face. The classical appearance is of an isolated dome-shaped nodule often of 5 cm or more in diameter, with a central keratin plug. They are most common on sun-exposed sites in fair-skinned individuals, particularly children and those with red hair, and on the face. It is thought that they may arise as the result of abnormalities in the normal migration of melanocytes during development. Most melanocytic naevi appear in childhood and early adult life, or during pregnancy or oestrogen therapy. They occur in both sexes and with increasing age, and are most common on the face and trunk. If there is no doubt about the diagnosis, they can be left alone or treated by cryotherapy or curettage if they are cosmetically troublesome. If there is a suspicion of melanoma, excision or diagnostic biopsy should be undertaken. Benign melanocytic naevi and basal cell papillomas, in particular, can often be mistaken for melanoma, even by dermatologists. They can sometimes be difficult to distinguish from melanocytic lesions, particularly if they are thrombosed or occur on particular sites, such as the lip or genitalia. Lipoma Lipomas are benign tumours of adipocytes that are characteristically soft and lie more deeply in the skin than epidermal tumours; they are usually diagnosed easily on clinical grounds. Treatment is not required unless there is diagnostic doubt or they are symptomatic or cosmetically troublesome, in which case a diagnostic biopsy or surgical excision may be required. Compound and intradermal naevi are nodules because of the dermal component, and may be hair-bearing. Such naevi are known to occur in some rare families with an inherited melanoma predisposition. However, the significance of such changes in non-familial cases is unclear and there is no consensus on management and follow-up. Although approximately 50% of melanomas arise in pre-existing naevi, most naevi do not become malignant; although a changing naevus must be taken seriously, most will not be melanomas. Malignant change is most likely in large congenital melanocytic naevi (risk may correlate with the size of the lesion) and possibly in families who have been diagnosed as showing large numbers of atypical naevi with a history of melanoma. Treatment is not required unless there is diagnostic doubt or they are causing symptoms, such as irritation, or for cosmetic reasons. Melanocytic naevi are normal and do not require excision, unless malignancy is suspected or they become repeatedly inflamed or traumatised. Advice on photoprotection is important for fair-skinned individuals with multiple naevi. There are two main presentations: bullous impetigo, caused by a staphylococcal epidermolytic toxin, and non-bullous impetigo. All ages can be affected but non-bullous disease particularly affects young children, often in late summer. Its aetiology is unclear, although a reactive process secondary to insect bites or trauma is one hypothesis. There is frequently a ring of pigment around the lesion and dimpling when the skin is pinched, reflecting epidermal tethering. They may be difficult to distinguish from nodular melanoma and are therefore often excised. It is caused by staphylococcal toxins and early cases were thought to arise with tampon use. Staphylococcal folliculitis is most common in children and often occurs on the scalp or limbs. The focus of infection may be minor skin trauma, the umbilicus, urinary tract or nasopharynx. Systemic antibiotics and intensive supportive measures should be commenced immediately. Bacterial swabs from nostrils, axillae and groins should be taken from family members to exclude staphylococcal carriage. Predisposing factors include poor hygiene, malnutrition and underlying skin disease, such as scabies. It is commonly seen in drug abusers, and minor trauma can predispose to lesion development. B the condition was rapidly diagnosed by examination of a frozen section of skin snip. Predisposing factors are minor skin abrasions and the existence of other skin conditions, such as infestations or eczema. In non-bullous impetigo, a thin-walled vesicle develops; it rapidly ruptures and is rarely seen intact. The face, scalp and limbs are commonly affected but other sites can also be involved, particularly if there are predisposing factors such as eczema. A bacterial swab should be taken from blister fluid or an active lesion before treatment commences. Around one-third of the population is a nasal carrier of Staphylococcus, so swabs from the nostrils should also be obtained. In mild, localised disease, topical treatment with mupirocin or fusidic acid is usually effective and limits the spread of infection. The use of topical antiseptics and soap and water to remove infected crusts is also helpful. Staphylococcal carriage should be treated, with mupirocin topically to the nostrils, if swabs are positive. In severe cases, an oral antibiotic, such as flucloxacillin or clarithromycin, is indicated. If nephritogenic streptococci are isolated then systemic antibiotics should be considered to reduce the risk of streptococcal glomerulonephritis (p. Underlying disease, such as infestations, must be treated and cross-infection minimised. In contrast, erysipelas is bacterial infection of the dermis and upper subcutaneous tissue. These conditions are most commonly caused by group A streptococci but culture of swabs from affected sites is often negative. There is frequently a source of organism entry, such as an ear infection, varicose eczema/ulcer or tinea pedis, and swabs should also be taken from these sites. Initially, an inflammatory follicular nodule develops and becomes pustular, fluctuant and tender. Lesions rupture over days to weeks, discharge pus, become necrotic and leave a scar. This usually occurs in middle-aged men, often with predisposing conditions such as diabetes or immunosuppression. A carbuncle is an exquisitely tender nodule, usually on the neck, shoulders or hips, associated with severe constitutional symptoms. Bacterial swabs must be taken and treatment is with anti-staphylococcal antibiotics. The face (erysipelas) and legs (cellulitis) are most often affected and the site is hot, painful, erythematous and oedematous. Erysipelas typically has a well-defined edge due to its more superficial level of involvement, whereas cellulitis is typically ill defined. Treatment is usually with intravenous flucloxacillin, with clarithromycin, clindomycin and vancomycin as alternatives for penicillin-allergic patients. If cases are untreated, sequelae include lymphoedema, cavernous sinus thrombosis, sepsis and glomerulonephritis.

There are more than 50 types of keratin and their expression varies by body site treatment without admission is known as cheap 100 mg epitol with amex, site within the epidermis and disease state symptoms 2 days after ovulation discount epitol 100mg overnight delivery. As keratinocytes migrate from the basal layer symptoms uti buy discount epitol 100mg line, they differentiate treatment 5th metatarsal avulsion fracture cheap 100mg epitol visa, producing a variety of protein and lipid products treatment jellyfish sting order on line epitol. Keratinocytes undergo apoptosis in the granular layer before losing their nuclei and becoming the flattened corneocytes of the stratum corneum (keratin layer) medicine just for cough 100mg epitol amex. Terminal differentiation of keratinocytes relies on the keratin filaments being aggregated and this is, in part, mediated by filaggrin. Mutations of the filaggrin gene are found in icthyosis vulgaris and in some patients with atopic eczema (p. Cell-to-cell attachments must be able to transmit and dissipate stress, a function performed by desmosomes. They occur throughout the skin, with the exception of palms, soles and parts of the genitalia (glabrous skin). By contrast, scalp hair becomes terminal hair, which is thicker with a central medulla, is usually pigmented and grows longer. At puberty, vellus hairs in hormonally sensitive regions, such as the axillary and genital areas, become terminal hairs. Human hairs grow in a cycle with three phases: anagen (active hair growth), catagen (transitional phase) and telogen (resting phase). On the scalp, anagen lasts several years, catagen a few days and re ks fre ks f ok s fre. Hair follicles co Epidermal appendages m the dermis is vascular and supports the epidermis structurally and nutritionally. It varies in thickness from just over 1 mm on the inner forearm to 4 mm on the back. Fibroblasts are the predominant cells but others include mast cells, mononuclear phagocytes, T lymphocytes, dendritic cells, neurons and endothelial cells. The outer layer is the epidermis, a stratified squamous epithelium consisting mainly of keratinocytes. The epidermis is attached to , but separated from, the underlying dermis by the basement membrane. The dermis is less cellular and supports blood vessels, nerves and epidermal-derived appendages (hair follicles and sweat glands). The cell membrane of the epidermal basal cell is attached to the basement membrane via hemi-desmosomes. The lamina lucida lies immediately below the basal cell membrane and is composed predominantly of laminin. Anchoring filaments extend through the lamina lucida to attach to the lamina densa. This may be exacerbated by the fact that people with skin disease can suffer the effects of stigma, often brought about by the ill-informed understanding of others with respect to skin diseases, particularly as regards visually disfiguring skin changes or the belief that they are contagious. Skin diseases affect all ages and there are more than 2000 different types and presentations. Assessment of the skin is valuable in the management of anyone presenting with a medical problem and, conversely, assessment of the other body systems is important when managing primary skin diseases. This chapter concentrates on common skin diseases and those that are important components of general medical conditions. They synthesise the pigment melanin from tyrosine, package it in melanosomes and transfer it to surrounding keratinocytes via their dendritic processes. The cells of the sebaceous gland (sebocytes) produce a range of lipids, discharging the contents into the duct around the hair follicle. Sebum excretion is under hormonal control, with androgens increasing it (as do progesterones, to a lesser degree) and Eccrine sweat glands develop in the second trimester and are also epidermal invaginations found all over the body. They play a major role in thermoregulation and, unusually, are innervated by cholinergic fibres of the sympathetic nervous system. In animals, sebum is important for hair waterproofing but its role in humans is unclear. What makes dermatoscopy unique is the fact that it allows visualisation through contact of a glass plate on the instrument with a liquid film applied to the skin, or through special optics to allow non-contact dermatoscopy, enabling deeper structures to be seen without interference from reflection and refraction of light in the epidermis. In the most common scenario, a skin biopsy is undertaken in order to obtain tissue on which to perform standard histopathology. However, tissue may also be subjected to a variety of staining and culture techniques, including immunostaining. In hypopigmentation, such as in vitiligo, it can help in appreciating the extent of disease. Hormonal Steroidogenesis, testosterone synthesis and conversion to other androgenic steroids Conversion of thyroxine (T4) to triiodothyronine (T3) Conversion of 7-dehydrocholesterol to vitamin D oo k oo oo Hair follicles, sebaceous glands ks Magnifying glass fre Protection, and fine manipulation of small objects re e Investigation of skin disease Nails. Metabolism Detoxification of xenobiotics, retinoid metabolism, isomerisation of urocanic acid Predominantly keratinocytes m Functions of the skin eb Human skin has a plentiful blood supply, arranged in superficial and deep plexuses consisting of arterioles, arterial and venous capillaries, and venules. The upper plexus in the papillary dermis communicates with the lower plexus at the junction between the dermis and the subcutis. Capillary loops arise from terminal arterioles in the horizontal papillary plexus. Blood vessels are supplied by sympathetic and parasympathetic nerves, with the relative contributions of the pathways differing by site. Sympathetic signals are important in mediating autonomic-induced vasoconstriction. The blood supply of skin is far greater than that required for normal skin physiology and reflects the importance of skin in thermoregulation. Apocrine sweat glands are restricted to the axillae and the mammary and genital areas, are connected to hair follicles and are not involved in thermoregulation. After 48 hours the patches are removed and patch-test readings are undertaken at time points of up to 7 days after patch-test application, with the most typical time Although most patients presenting with a skin problem do not need blood tests as part of their investigations, there are many systemic diseases that can present with skin features and, indeed, blood tests may also be indicated in the investigation of primary skin disease. If potassium hydroxide and a simple light microscope are available, this can be performed in any outpatient clinic. Microbiology laboratories will also routinely undertake microscopy and culture for fungi and yeasts. However, organisms identified from the skin surface may not be the cause of the skin disease but instead may simply reflect colonisation of skin that has already been damaged by a primary skin disease. When a dermatologist or pathologist with dermatopathology expertise is involved, it can also assist in the diagnosis of inflammatory skin diseases. It is rare for histopathology of a previously undiagnosed inflammatory skin disease to provide a diagnosis on its own; clinico-pathological correlation is critical. Most biopsies are stained with haematoxylin and eosin but other stains may be useful in special situations, such as for fungal hyphae, iron or mucin. Direct immunofluorescence can also be undertaken on a fresh skin biopsy, allowing antigen visualisation using fluorescein-labelled antibodies; this is especially important in the diagnosis of autoimmune bullous disorders or connective tissue disease, such as cutaneous lupus. This is the dose required to cause just perceptible skin reddening and is compared with values for the normal population. Thus, monochromator phototesting can be used to determine whether a patient is abnormally photosensitive, which wavebands are involved and how sensitive the patient is (p. Provocation testing to a variety of light sources, including artificial compact fluorescent lamps, may also be indicated, the latter being most relevant in patients with severe photosensitivity. The skin is pricked with commercially available stylets through a dilution of the appropriate antigen solution (p. Alternatively, specific immunoglobulin E (IgE) levels to antigens can be measured in serum. If challenge tests are undertaken for patients with suspected allergy, these must be performed under controlled conditions due to the potential risk of triggering a severe reaction (p. When interpreting patch test readings, it is important to determine the clinical relevance of any allergic reactions before giving avoidance advice. The scalp, face, upper limbs and back in men, and face, hands and lower legs in women, are the most chronically sunexposed sites. Stretching the skin and using a magnifying lens can be helpful, such as for detecting the raised, pearled edge of a basal cell carcinoma. Diagnosis can often be made on clinical grounds, although a biopsy may be required. If there are concerns about the diagnosis or malignancy is suspected on clinical grounds, then skin biopsy in order to obtain a tissue diagnosis is the usual approach. An incisional biopsy may be indicated, although if the lesion is small, excision may be most appropriate. If significant concern exists about the possibility of malignant melanoma, initial excision with a 2 mm margin would usually be undertaken prior to more definitive management once histology was confirmed. Further management of a changed lesion would, of course, depend on the histology of the diagnostic biopsy. Conversely, normal skin markings and fine hairs dispersed evenly over a lesion are reassuring but do not exclude melanoma. Detail of the underlying disorders is mostly provided in the disease-specific sections further on in the chapter. Listen to the patient and pay attention to subtle changes, as people know their skin well. A suspicious naevus in a patient with a first-degree relative with melanoma probably warrants excision. These diverse examples emphasise the importance of considering an underlying systemic disease when assessing a patient with a dermatological presentation. B Dermatoscopy highlights the abnormal pigment network and other features suggestive of melanoma. Excision biopsy confirmed the diagnosis of superficial spreading malignant melanoma (Breslow thickness 0. D Dermatoscopy highlights the vascular lacunae of this benign angioma and the patient was reassured. Atopic eczema often starts in early childhood and psoriasis between 15 and 40 years, and both may be chronic. Infective or druginduced rashes are more likely to be of short duration and the latter to occur in relation to drug ingestion. Flexural sites are more typically involved in atopic eczema, and extensor surfaces and scalp in psoriasis. Symmetry is often indicative of an endogenous disease, such as psoriasis, whereas asymmetry is more common with exogenous causes, such as contact dermatitis or infections like herpes zoster. Guttate psoriasis may be precipitated by a -haemolytic streptococcal throat infection; almost all patients with infectious mononucleosis (p. For example, in psoriasis, no investigations may be needed and initial management with patient counselling and topical therapies may suffice. If the diagnosis is unclear, then a diagnostic skin biopsy and other targeted investigations based on the clinical picture may be required. For example, in a child presenting with a rash that has features suggestive of impetigo, skin and nasal swabs should be performed and, once these have been taken, topical or systemic antibiotics should be introduced, depending on clinical extent of disease, and management should be adjusted accordingly, dependent on investigation findings and clinical course. In contrast, if a patient presents with a maculopapular rash shortly after introduction of a new drug, then drug withdrawal, diagnostic biopsy, full blood count, including eosinophil count, and liver and renal function tests, in parallel with topical emollients and glucocorticoids, may be indicated. Blistering occurs due to loss of cell adhesion within the epidermis or subepidermal region. The clinical presentation depends on the site or level of blistering within the skin, which in turn reflects the underlying cause (p. For example, an initial approach may include directed investigations, such as incisional diagnostic skin biopsy for histology and direct immunofluorescence, indirect immunofluorescence and other targeted blood tests or skin swabs. Management should be based on the likely diagnosis and begin in parallel with investigations, until the diagnosis is confirmed. A history of onset, progression, mucosal involvement, drugs and systemic symptoms should be sought. Clinical assessment of the distribution, extent and morphology of the rash should be made. The Nikolsky sign is useful: sliding lateral pressure from a finger on normal-looking epidermis can dislodge and detach the epidermis in conditions with intra-epidermal defects, such as pemphigus and toxic epidermal necrolysis. This requires a thorough history and examination, sometimes with investigations, to exclude systemic disease. If itch is not connected with primary skin disease, other causes should be considered (Box 29. These include liver diseases (mainly cholestatic diseases, such as primary biliary cirrhosis), malignancies (generalised itch may be the presenting feature. Itch can arise from primary cutaneous disease or be secondary to systemic disease, which may cause itch by central or peripheral mechanisms. Even when the mechanism is peripheral, there are not always signs of primary skin disease. The nerve endings that signal itch are in the epidermis or near the dermo-epidermal junction. Transmission is by unmyelinated slow-conducting C fibres through the spinothalamic tract to the thalamus and then the cortex. The itch of kidney disease, for example, may be mediated by circulating endogenous opioids. The clinical observation that peritoneal dialysis helps reduce itch more frequently than haemodialysis is consistent with this, with smaller molecules generally being dialysed more readily if the peritoneal membrane is used rather than a dialysis machine membrane. If there are no signs of primary skin disease, investigations should be undertaken to exclude systemic disease or iatrogenic causes. There are no consistently effective therapies to suppress itch, and so establishing the underlying cause is critical. If a clear-cut diagnosis cannot be made, non-specific approaches can be used for symptom relief.

Because the DiGeorge/ velocardiofacial syndrome occurs with typical conotruncal cardiac defects in up to 90 percent of cases medicine to stop runny nose cheap 100mg epitol amex, exclusion of these diagnoses by fluorescence in situ hybridization studies is necessary before claims can be credible treatment quadriceps pain generic 100mg epitol otc. Almost all anencephalics reaching the third trimester are ultimately stillborn or die within hours or days of birth treatment plan goals and objectives purchase cheap epitol line. Intellectual disability was noted in 22 (19 percent) symptoms 0f kidney stones order epitol overnight delivery, 146 Genetic Disorders and the Fetus Table 3 medications 5113 order epitol pills in toronto. In a further follow up of these patients between 32 and 38 years medicine 95a order epitol 100 mg fast delivery, 54 percent had died. The range of complications seen in the first study is, as expected, reflected in the later study, with some notable improvement in the degree of morbidity. Residual fecal incontinence at 25 years (between 8 and 16 percent) and the urinary incontinence (albeit well managed by self-catheterization in most) remained troublesome problems. Being wheelchair bound, mentally handicapped, and requiring lifelong continuous care have remained serious issues. On the positive side, 49 percent achieved university entrance and 45 percent were employed. Thirty-two percent required surgery for a tethered cord and 32 percent developed latex allergy, six of the 23 affected patients experiencing severe, life-threatening anaphylactic reactions. Among those who survived beyond 5 years, 75 percent had a disability, 56 percent being severely disabled; 51 percent had mobility limitations, 59 percent were incontinent, 42 percent had hydrocephalus, and 17 percent had intellectual disability. In Glasgow, Scotland, 71 percent survived to 5 years, whereas in the Atlanta region, cumulative survival was calculated to reach 84 percent. A Canadian report of 85 patients showed 41 (48 percent) with normal development, nine (11 percent) with mild delay, 14 (16 percent) with moderate delay, and 21 (25 percent) with severe delay. Hydrocephalus, epilepsy, microcephaly, other brain abnormalities and the presence of brain tissue (in the encephalocele) were associated with poor outcome. Survival rates to 16 years of age prior to and after 1975 were 54 percent and 85 percent, respectively. At age 16, survival with or without a shunt for hydrocephalus was not significantly different. However, at 34 years, those without shunts849 had a survival probability of 94 percent compared with 75 percent with shunts. The moral, ethical, and medicolegal aspects of care of the defective newborn have been thoroughly debated. Although other studies have drawn similar conclusions concerning marital disharmony, not unexpectedly, some have noted little or no negative effect of having severely affected children in these families. Intra-amniotic pressure is not affected by amniocentesis between 13 and 18 weeks of gestation. The exchange of water and electrolytes in the mechanism of amniotic fluid formation and the relationship to hydramnios. The role of the fetus in the water exchange of the amniotic fluid of normal and hydramniotic patients. Transfer of water from maternal blood to amniotic fluid of live and dead fetuses in health and in some pathological conditions of the mother. Ultra-structure of human amnion and its possible relation to the circulation of amniotic fluid. Prenatal diagnosis of congenital cytomegalovirus infection by virus isolation from amniotic fluid. Reappraisal of normal amniotic fluid index in an Asian population: analysis of 27,088 records. 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Significance in neonatal myasthenia gravis of inhibitory effect of amniotic fluid on binding of antibodies to acetylcholine receptor. Adrenomedullin concentrations in early 2nd-trimester amniotic fluid: relation to preterm delivery and fetal growth at birth. Protein and enzyme patterns in the fluid cavities of the first trimester gestational sac: relevance to the absorptive role of secondary yolk sac. Alkaline phosphatase activity in amniotic fluid in pregnancies with fetal disorders. Prenatal diagnosis of argininosuccinic aciduria by assay of argininosuccinate in amniotic fluid at the 12th week of gestation. Mid-trimester amniotic fluid angiogenin, lactate dehydrogenase and fibronectin in the prediction of preterm delivery. Prenatal diagnosis of some metabolic diseases using early amniotic fluid samples: report of a 15 years, experience. Atrial natriuretic factor in amniotic fluid and in maternal venous blood of pregnancies with fetal cardiac malformations and chromosomal abnormalities. Amniotic fluid biochemistry in second-trimester trisomic pregnancies: relationships to fetal organ maturation and dysfunction. Detection of proteins in human amniotic fluid using two-dimensional gel electrophoresis. Direct determination e of calcium, copper, iron, magnesium, manganese and zinc in amniotic fluid samples using inductively coupled plasma-atomic emission spectrometry. An increase in catecholamines and metabolites in the amniotic fluid compartment from middle to late gestation. Expression of cytokines and chemokines in cervical and amniotic fluid: relationship to histological chorioamnionitis.

Incidence and outcome of chromosomal mosaicism found at the time of chorionic villus sampling medicine 6 year buy epitol discount. Limb anomalies following chorionic villus sampling: a registry based case control study medicine 029 buy epitol 100mg with mastercard. Genetic diagnosis by chorionic villus sampling before 8 gestational weeks: efficiency treatment for hemorrhoids buy epitol visa, reliability symptoms als epitol 100 mg online, and risks on 317 completed pregnancies treatment alternatives boca raton cheap 100mg epitol with mastercard. Fetal blood sampling in investigation of chromosome mosaicism in amniotic fluid culture medications management purchase epitol once a day. Rapid chromosome analysis using spontaneously dividing cells from umbilical cord blood (fetal and neonatal). Cordocentesis for the diagnosis and treatment of human fetal parvovirus infection. Percutaneous ultrasound-guided fetal blood sampling: experience in the first 100 cases. Intravenous pancuronium bromide for fetal neuromuscular blockade during intrauterine transfusion for red cell alloimmunization. Intrauterine treatment of fetal goitrous hypothyroidism controlled by determination of thyroid-stimulating hormone in fetal serum. Detection of fetomaternal hemorrhage associated with cordocentesis using serum alpha-fetoprotein and the Kleihauer technique. Fetomaternal hemorrhage after cordocentesis at Maharaj Nakorn Chiang Mai Hospital. Safety of fetal blood sampling by cordocentesis in fetuses with single umbilical arteries. First trimester embryofetoscopic and ultrasound-guided fetal blood sampling for ex vivo viral transduction of cultured human fetal mesenchymal stem cells. Biochemical and molecular components may also reflect fetal disease and maturity and, on occasion, maternal disease or environmental exposures. Amniotic fluid Formation and circulation Fluid exchange between the fetus and the mother occurs via several routes and through different mechanisms, and varies throughout pregnancy. Large volumes of fluid are transferred across the fetal membranes, which are made up of five layers of amnion and four layers of chorion. Amniotic fluid turnover continues even after fetal death, but it is reduced by about 50 percent,18 implying that membranes may be responsible for about half of the water exchange. This suggests that the membranes play a larger role in water disposal than in production. Indeed, electron microscopic studies19 correlate with an absorptive function of the membranes. Ultrasonic assessment of fetal kidney function in normal and complicated pregnancies revealed that the fetal urinary production rate was 2. Comparable results have been reported using dilution techniques, radioactive materials, or various dyes or chemicals. Weeks of gestation 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 5th 134. These extreme cases are frequently associated with amnion nodosum, fetal defects or placental problems. For this reason, they cautioned against attempts at prenatal genetic diagnosis by examination of serum proteins or by linkage analysis using serum protein polymorphisms. Brace16 suggested that the fetus may have a substantial volume of fluid of salivary origin. They suggested that nondialyzable collagenous polypeptides may be the products of the proteolytic conversion of procollagen into the monomeric form of this protein. Those observations underline the significant difference in composition between the two embryonic fluids. Proteins of fetal origin probably derive from skin, amnion, chorion, umbilical cord, urine, and bronchial, buccal, and gastrointestinal secretions, and may be cellular, free organelles or in solution. There is striking variability in the total protein concentration during pregnancy, increasing from a mean of about 3. The highest concentrations of albumin, 1 -antitrypsin, Gc, and transferrin have been noted between 20 and 30 weeks of gestation. The S100B protein is a product of nervous system glia77 and the amnion,78 can be elevated in pre-eclampsia, intrauterine restriction,78 and fetal death. The phospholipids measured included lysophosphatidylcholine, sphingomyelin, phosphatidylcholine, inositol, serine, ethanolamine, phosphatidic acid, and cardiolipin. Biezenski also established values for total fatty acids, including palmitic acid, palmitoleic acid, stearic acid, oleic acid, and linoleic acid. However, in paired samples from individual patients, these two values did not correlate well. A marked increase in the production of lecithin occurs at about 35 weeks of gestation. Conditions that affect fetal lung maturation, including maternal hypertension, placental insufficiency, and diabetes mellitus, render the L/S ratio less valuable. The disappearance of -glucosidase during the second trimester129 may indicate that the fetal liver has assumed a major role in glucose homeostasis. For example, the mean activities of -galactosidase and N-acetyl-d-glucosaminidase reported by one group136 differed by a factor of two from the mean activities observed by another group. The concentration of eight amino acids decreased toward the end of the pregnancy, whereas 13 amino acids showed no significant change between 10 and 40 weeks, and 10 were present in trace amounts. Variation in lysine values between 10 and 20 weeks did not permit fetal age correlation studies. A dilution factor could explain a general decrease in total amino acid concentration toward term, and the increase in urea and creatinine could come from the maturation of the urinary system. However, a change in fetal metabolism may explain the higher concentration of some amino acids during the end of pregnancy. The concentrations of amino acids were measured in samples of celomic fluid obtained from normal pregnancies between 7 and 12 weeks of gestation. They found a significant positive relation between maternal serum and placental tissue for 10 amino acids, indicating that active amino acid transport and accumulation by the human syncytiotrophoblast occurs as early as 7 weeks. A fetomaternal plasma concentration gradient was observed for 21 amino acids, indicating that the fetomaternal amino acid gradient across the placenta is established from very early in pregnancy. The concentration of Gln increased slightly, whereas the other amino acids did not change significantly during this period. Statistically significant positive correlations, at all gestational ages, were observed among Val, Leu, and Ile. These branched-chain amino acids also correlated positively with Phe, Lys, Asp, Thr, Ser, Glu, Pro, Gly, Ala, and Tyr, and the amino acids within this group correlated with each other. In addition, strong positive correlations were observed between Phe and Tyr and between Gly and Ser. Amniotic fluid amino acid levels are not influenced by normal variations in maternal amino acid concentrations. Tyrosinemia type I and propionic acidemia have been diagnosed at the end of 106 Genetic Disorders and the Fetus the first trimester via amniocentesis. The intestinal mucosa contains disaccharidases able to hydrolyze a variety of substrates. Amniotic fluid microvilli contain typical enzymes of intestinal microvilli, including maltase, sucrase, trehalase, alkaline phosphatase, and -glutamyl transferase, and their morphology detected by electron microscopy resembles that of vesiculated intestinal microvilli. Prenatal detection of genetic diseases due to a deficiency of a protein expressed in these membranes or associated with abnormal morphology of microvilli seems feasible, although such diagnoses have not been described for many years. Transport system activities expressed in these membranes can also be assayed by measuring the uptake of radioactive substrates. There is evidence that trehalase activity also could originate from the fetal kidney, at least in pathologic situations. Several fetuses with proven intestinal obstructions had normal trehalase activity, despite the fact that the other disaccharidases were almost completely deficient. Given the intestinal origin of microvillar enzymes, efforts have been made to establish a diagnosis of intestinal obstruction,176, 177 megacystis-microcolonintestinal hypoperistalsis syndrome178, 179 and even fetal anal incontinence in spina bifida. The drop of disaccharidase activities at around 22 weeks is due to increasing fetal swallowing with age and accumulation of large quantities of meconium in the fetal intestine. These fetuses seem to be unable to release their intestinal content normally into the amniotic cavity. Autosomal recessive villus atrophy syndrome is characterized by an atrophy of intestinal villi and reduced disaccharidase activities in the intestinal mucosa. Thirteen major polypeptides, of which five had not been identified previously, were revealed by two different techniques. Maternal serum relaxin during pregnancy maintains the myometrial quiescence and facilitates uterine stroma remodeling during uterine growth. Relaxin may be derived from the decidualized endometrium rather than the maternal Table 3. Amniotic fluid copper and zinc are among the trace elements that have stable levels during the second and third trimesters. However, zinc deficiency is thought to potentiate the teratogenic effect of alcohol in the fetal alcohol syndrome. Copper, zinc, bromine, lead, and rubidium assays show no significant differences among groups of normal, hypotrophic, and trisomic fetuses. Nevertheless, results obtained for those trace elements are of the same order of magnitude as in previously published reports. Amniotic fluid folate, zinc, copper, and iron concentrations were significantly lower than plasma levels; this relationship was reversed for vitamin B12. Mercury is one of the components of dental amalgam that can pass into the organs and biologic fluids. Cotinine and Cd were much higher in women with oligohydramnios who were also heavy smokers. The simultaneous assessment of the three parameters correlates well with fetal maturity in normal pregnancy. However, in the very cases of abnormal pregnancy states (including diabetes, Rh isoimmunization, hypertensive disorders, intrauterine growth restriction, and hydramnios) in which guidance would be invaluable, these estimations, both singly and together, remain insufficient (see above). Because of their molecular weights (about 300,000), the soluble blood group substrates do not easily cross fetal membranes. Myotonic dystrophy is now accurately diagnosed by trinucleotide repeat analysis (see Chapters 1 and 9). This immunologic test does not apply to all families at risk, and has been replaced by molecular analysis (see Chapter 9). Whereas IgG, IgD, and IgA levels increase from 11 to 25 weeks and then decrease until term, IgM levels tend to remain constant until 35 weeks and then increase until term. There was no correlation between the IgG and IgA titers, suggesting a fetal origin for IgA, which would offer a functional advantage over maternally transmitted IgG. Normal bacteriolytic activities have been found in pregnancies in which respiratory distress syndrome developed in the infants. Several findings suggest that 2 microglobulin exhibits strong antibacterial activity and is upregulated in amniotic cells during bacterial infection. Bacterial proteases and lipases could play a role in weakening fetal membranes and a genetic predisposition may have a role. When performing prenatal diagnosis amniocentesis on patients who have had a cerclage in the preceding weeks, prophylactic antibiotic therapy may 114 Genetic Disorders and the Fetus be indicated to prevent infectious complications. They suggested that the transferrin content is a factor in the growth-inhibiting activity. The presence of specific IgM in fetal serum is not de facto evidence of fetal demise, nor is the recovery of rubella virus from placental tissue331, 404 evidence of fetal infection. However, an apparently unequivocal test for diagnosis of fetal rubella virus is provided by the polymerase chain reaction (see also Chapter 26). To evaluate the risk of embryofetopathy in maternal varicella occurring before 20 weeks of gestation, Dufour et al. The bacterium was a slow-growing, gram-negative anaerobic coccobacillus belonging to the genus Leptotrichia. Studies have been made on the half-life and distribution of several antibiotics, particularly cephalosporins, in fetal tissues. Celomic fluid contains high concentrations of progesterone, 17-estradiol and 17-hydroxyprogesterone, which may be synthesized locally. Free diffusion of steroids across the amnion is limited, which may protect the embryo from unwanted exposure to biologically active steroids.

Comprehension and decision making may be less than adequate given the increased realization of residual behavioral and intellectual deficits medications used to treat migraines order cheapest epitol and epitol. A French study in which the outcome was known for 75 patients noted a prematurity rate of 18 percent and one maternal death during pregnancy medicine 513 buy epitol overnight delivery. The better the control medications japan travel purchase 100mg epitol mastercard, the lower the risk of having a child with congenital defects medicine ball core exercises purchase cheap epitol line. Muscle weakness may increase in about half of pregnant women with limb-girdle muscular dystrophy symptoms 5dp5dt buy generic epitol 100mg, leading to the need for assistance after delivery medicine stone music festival generic 100mg epitol overnight delivery. A World Health Organization multicenter study concluded that the problem appeared predominantly in males in 20 percent of cases, predominantly in females in 38 percent, and in both partners in 27 percent. In the remaining 15 percent of cases, no definitive cause for the infertility was identified. Microarrays performed after routine cytogenetics on products of conception in 2,389 cases revealed significant copy number changes or whole genome uniparental disomy in 1. Such studies may reveal a parent (rarely both) with a chromosomal rearrangement with significant risks for bearing a child with intellectual disability and/or malformations, who could benefit from prenatal diagnosis. Examples of disorders characteristically associated with recurrent pregnancy loss or infertility, include premature ovarian failure in fragile 26 Genetic Disorders and the Fetus X syndrome carriers (see Chapter 7), and the Xlinked disorders, steroid sulfatase deficiency,356 and incontinentia pigmenti. Although the investigation to determine the cause of male or female infertility can be extensive, three observations are pertinent here. Such couples frequently consider epididymal sperm aspiration,367, 368 with pregnancy induced by in vitro fertilization. Precise prenatal and/or preimplantation diagnosis can be achieved only if specific mutations have been recognized. Third, even "balanced" reciprocal translocations in males may be associated with the arrest of spermatogenesis and resultant azoospermia. Rarer disorders may need to be considered in the quest to determine the cause of infertility including, for example, the blepharophimosis, ptosis, epicanthus inversus syndrome, which may respond to treatment. Referral for genetic counseling in these circumstances is appropriate given complex questions relative to risk, prognosis in a future pregnancy and potential pitfalls/reservations concerning prenatal diagnosis (see Chapter 4). In virtually all ethnic groups, particular recessive disorders occur more frequently than in the population at large379 (Table 1. Carrier tests performed simultaneously for a wide range of monogenic disorders have become available381 raising counseling, logistic and ethical issues. Unfortunately initial commercial testing by next generation sequencing of hundreds of different monogenic disorders yielded a high proportion of incorrect "disease mutation" calls. Faulty data analysis, exaggerated clinical claims, fraudulent data, misleading test results, and poor clinical performance signaled a need for major improvements. In contrast to these findings, which could reflect ascertainment bias, are the prior salutary observations of Palomaki et al. Further studies are necessary before formal recommendations can be made for carrier testing in this ethnic group. With or without a family history of the disorder in question, referral to a clinical geneticist would be appropriate for final evaluation of possible implications. Failure to recognize obvious features in a manifesting female may well result in a missed opportunity for prenatal genetic studies and an outcome characterized by a seriously affected male (or occasionally female) offspring. The American Academy of Pediatrics recommended that female carriers be informed of their risks, have a full cardiac evaluation in late adolescence or early adulthood and be re-evaluated at least every 5 years. Women who are known carriers of hemophilia A or B have an increased risk of primary postpartum hemorrhage with 23 percent having that 28 Genetic Disorders and the Fetus Table 1. Difficulties are introduced when neither family nor previous physicians have recognized a genetic disorder within the family. Clinical clues would include individuals in the family with deep-vein thrombosis, sudden death possibly due to a pulmonary embolus, and yet other individuals with recurrent pregnancy loss. Seventeen cancers in different organs in family members may not be recognized as manifestations of the same common mutation. In hereditary nonpolyposis colon/rectal cancer, various family members may suffer from cancers of the uterus, ovary, stomach, small bowel, or ureter. Analysis of the five culprit genes in the proband would enable detection of the mutation, which could then be assayed in other family members at risk. In another example, there may be two or more deceased family members who died from "kidney failure," and another one or two who died from a cerebral aneurysm or a sudden brain hemorrhage. Other disorders in which sudden death due to a conduction defect might have occurred, with or without a family history of cataract or muscle weakness, should raise the suspicion of myotonic muscular dystrophy. Hereditary pancreatitis, although rare, is an autosomal dominant disorder for which several genes are known. Consanguineous couples may opt for the entire gamut of prenatal tests to diminish even their background risks, with special focus on their ethnic-specific risks. Many of these anxieties and frequently real risks could be avoided through preconception care. Public health authorities, vested with the care of the underprivileged in particular, need to focus their scarce resources on preconception and prenatal care and on the necessary public education regarding infectious diseases, immunization, nutrition and genetic disorders. In preconception planning, careful attention to broadly interpreted fetal "toxins" is necessary, and avoidance should be emphasized. Alcohol, smoking, illegal drug use, certain medications, and Xray exposure require discussion. Estimates of the prevalence of the fetal alcohol spectrum disorder approximate 2 per 1,000 livebirths463 in the United States but in certain regions and countries rates reach as high as 10 percent. Preconception advice to avoid heat exposure in early pregnancy is now appropriate. Clinical geneticists will frequently be cautious in these situations, providing potential recurrence risks of Identification of preconception options the time to deal with unwanted risks is not during the second trimester of pregnancy, as is so often 32 Genetic Disorders and the Fetus the case in practice. Genetic counseling as a prelude to prenatal diagnosis Prospective parents should understand their specific indication for prenatal tests and the limitations of such studies. Frequently, one or both members of a couple fail to appreciate how focused the prenatal diagnostic study will be. Either or both may have the idea that all causes of intellectual disability or congenital defects will be detected or excluded. Major advantages that flow from this arrangement include a clearer perception by the partner regarding risks and limitations, a more accurate insight into his family history, and an opportunity to detect an obvious (although unreported or undiagnosed) genetic disorder of importance. Women making an appointment for genetic counseling should be informed about the importance of having their partner with them for the consultation, avoiding subsequent misunderstanding about risks, options, and limitations. Before prenatal genetic studies are performed, a couple should understand the inherent limitations both of the laboratory studies and, when relevant, of ultrasound. For detection of chromosomal disorders, they should be aware of potential maternal cell admixture and mosaicism (see Chapter 4). When faced with potential X-linked hydrocephalus, microcephaly, or other serious Xlinked disorders, and the realization of less than 100 percent certainty of diagnosis, couples may elect fetal sex determination as the basis for their decision to keep or terminate a pregnancy at risk. The time taken to determine the fetal karyotype or other biochemical parameters should be understood before amniocentesis. The known anxiety of this period can be appreciably aggravated by a long, unexpected wait for a result. The need for a second amniocentesis is rarer nowadays but, in some circumstances, fetal blood sampling remains an additional option that may need discussion. Despite the very unlikely eventuality that no result may be obtained because of failed cell culture or contamination, this issue should be mentioned. The potential possibility for false-positive or false-negative results should be carefully discussed when applicable. Any quandary stemming from the results of prenatal studies is best shared immediately with the couple. The role of the physician in these situations is not to cushion unexpected blows or to protect couples from information that may be difficult to interpret. All information available should be communicated, including the inability to accurately interpret the observations made. This is especially so with the advent of the chromosomal microarray (see Chapter 8). Other key issues to be considered by the genetic counselor and discussed when appropriate with the consultant follow. Focus on the transmission of all results or only actionable results requires the most careful discussion while exome or whole genome sequencing for prenatal diagnosis is very close. The American College of Medical Genetics and Genomics has issued a list of 56 (now 58) monogenic disorders for which communication of results is regarded as medically and ethically appropriate. Although the accuracy rate for prenatal diagnostic studies exceeds 99 percent, it is not 100 percent. From a previous worldwide survey of prenatal diagnosis,475 and two formal amniocentesis studies,478, 479 an error rate between 0. After communication of all the necessary information concerning amniocentesis and prenatal genetic studies pertinent to the couple and especially tailored to their particular situation, an informed consent form should be signed and witnessed. In successful litigation, some plaintiffs have claimed that prenatal diagnostic studies or maternal serum screening were neither discussed nor offered by their physicians. Carrier detection Before any effort to make a prenatal diagnosis of an autosomal recessive or sex-linked biochemical disorder, the carrier state should be documented (see above). A previous birth of an affected child with an autosomal recessive disorder might alert the physician to consanguinity. Recognition of compound heterozygosity in a couple will influence discussions about prognosis and should also initiate tracking of carriers through the respective families. There are at least 1,139 autosomal recessive disorders for which a next-generation sequencing carrier screen has been devised for 448 associated with severe childhood diseases. Further refinement of this approach may well provide a major preconception opportunity for extensive carrier detection for disorders that lead to severe childhood recessive diseases. Commercial directto-consumer genetic testing services have evoked considerable controversy. Presymptomatic or predictive testing Presymptomatic or predictive testing is available for a rapidly increasing number of disorders, especially neuromuscular and neurodegenerative (see Chapter 9). Huntington disease is the prototype and predictive testing using guidelines promulgated by the World Federation of Neurology,259, 481,482 the International Huntington Association, and the European Huntington Disease Network483 are well established. Although the follow up was only 3 years for about half the group, pregnancies followed in 28 percent of noncarriers and only 14 percent of carriers. As others earlier,488 we remain very concerned about the use of a test that can generate a "no hope" result. Even in sophisticated programs offering Huntington disease tests, fewer than expected at-risk individuals requested testing. However, a worldwide assessment of suicide rates, suicide attempts, or psychiatric hospitalizations after predictive testing did not confirm a high rate of suicide. Others have written about the psychologic burden created by knowledge of a disabling fatal disease decades before its onset. Mean distress scores for both carriers and noncarriers were not significantly different but carriers had less positive feelings. On the other hand, an increasing number of examples already exist (see Chapter 9) in which presymptomatic testing is possible and important to either the patient or future offspring or both. Uptake has been high by individuals at risk, especially for various cancer syndromes. The importance of accurate presymptomatic tests for potential atrisk kidney donors has been emphasized. Individuals in whom this mutation was found with greater than 99 percent certainty may choose more frequent colonoscopies and eventually elective colonic resections, thereby saving the lives of the vast majority. The need for involvement of clinical geneticists is especially evident in this and other disorders in which complex results may emerge. However, failure to test because of parental refusal may invite the reporting of child neglect. Mothers have in these circumstances, faced with an affected fetus, elected to terminate the pregnancy, invoking miscarriage as the reason to her unknowing partner. Distressing as it is to contemplate such a marital relationship, textured on the one hand by extreme care and on the other hand by deceit born of sensitivity, consider our report of symptomatic juvenile Huntington disease at 18 months of age and diagnosed at the age of 3 years. Homozygotes for Huntington disease are rare515, 516 and reported in one out of 1,007 patients (0. Counseling a patient homozygous for Huntington disease about the 100 percent probability of transmitting the disorder to each child is equivalent to providing a nonrequested predictive test,517 while failing to inform the patient of the risks would be regarded as the withholding of critical information. Pretest counseling in such cases would take into consideration a family history on both sides and therefore be able to anticipate the rare homozygous eventuality.

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