Anaemia is defined as a low Hb concentration in blood, or less often, as a low haematocrit, the percentage of blood volume that consists of red blood cells. The Hb and Ht range for assessing iron deficiency are: Hb (g/dL)Ht (%) Children 6 months - 5 years1133 Children 5 - 11 years11,534 Children 12 - 13 years12,036
Normal levels of RBCs at birth range from 5.1 to 5.3 million/mm3 for term newborns and 4.6 to 5.3 million/mm3 for premature neonates. Because of active in uteroerythropoiesis, the reticulocyte count at birth is 3 to 7% in full-term babies and 8 to 10% in premature babies. This declines to 0 to 1% by the first week of age, reflecting diminished erythropoiesis. The life span of adult erythrocytes is 120 days. RBCs in term neonate will survive between 60 and 90 days. Erythrocytes from premature neonates have considerably shorter life spans, ranging from 35 to 50 days
Mean Cell Volume. Early embryonic RBCs are large; diameters range from 20 to 25 µm with a mean cell volume (MCV) of 180 femtoliters (fl) or µm3. Cell size decreases gradually during development reaching 130 fl at midgestation and 115 fl at term. MCV at 1 year of age is 82 fl. The mean corpuscular hemoglobin concentration (MCHC) is fairly constant from birth through adulthood.It averages 34 pg in full-term cord blood, 35 pg on the first day of life, and 33 picograms (pg) at 1 week of age. Premature neonates, however, have higher MCHCs; values range from 40 pg at 28 weeks to 38 pg at 34 weeks
RBC and Hemoglobin Physiology RBCs, erythrocytes, play role in the support of tissue metabolism. They contain hemoglobin, which transports oxygen to and removes carbon dioxide from tissues. RBC production involves a series of maturational steps, beginning with a pluripotent cell that differentiates into erythroid As the cells undergo maturational changes, they lose their nuclei and acquire hemoglobin. Once RBCs have achieved their normal life span, usually about 120 days, they become sequestered and destroyed in the spleen. Liberated iron is then recycled for use by the marrow in further RBC production
.Hemoglobinis a molecule composed of two globulin chains and four heme groups. It has been described as the respiratory protein of the RBC, related to its important role in the transport of oxygen and carbon dioxide. • Hemoglobin is able to bind reversibly with oxygen, which allows it to be released to the tissues when needed. Carbon dioxide is then picked up by unbound hemoglobin for transport to the lungs and excretion. The fetus is able to produce a unique type of hemoglobin, fetalhemoglobin (HgF), which more efficiently binds and releases oxygen within the relatively hypoxic intrauterine environment.
Anemia refers to RBC mass, amount of hemoglobin, and/or volume of packed RBCs less than normal. Clinically, this is determined either as a hematocrit (% of RBCs per spun whole blood sample) or hemoglobin (directly measured concentration) greater than 2 standard deviations below the normal mean for age. For children between 6 months and 2 years of age, this represents a hemoglobin <11 grams/dl or hematocrit < 33%. Hemoglobin is considered a more sensitive indicator of anemia than hematocrit, as it is not affected by variations in RBC size within the specimen; however, both are commonly utilized in clinical practice.
WHO data show that 40% of the world's population suffer from anaemia. The World Health Organization calls iron deficiency the most common anemia (Centers for Disease Control) as it is estimated to affect approximately 2 billion people worldwide. The groups with the highest prevalence in pediatric age are: infants and children of 0-2 years, 48%; school children, 40%; adolescents, 30-55%; and preschool children, 25%. Anaemia occurs at a late stage of iron deficiency, after stores are depleted. The prevalence of iron deficiency, which is usually detected by low serum ferritin concentrations, is estimated to be from 2.0 to 2.5 times the prevalence of anaemia.
Sources of iron The sources of iron are:Birth - 6 months Breast milk alone Iron-fortified formula from birth 6 months to 1 year Infant formulas based on cow's milk contain 1.0 to 1.5 mg of iron per litre; soy-based formula and iron-fortified formula based on cow's milk contain 12 to 13 mg of iron per litre. The availability of iron from soy-based formulas appears to be lower than that from milk-based products. Iron-fortified formula ( supplementing with formula or if no breastfeeding) The iron source of fortified formulas is ferrous sulfate, which is significantly more available than the iron used in infant cereals. Iron-fortified infant cereals Iron-enriched breakfast cereals and breads Meats (poultry ) , yolk egg Fish
One litre of human milk contains only 0.3 to 0.5 mg of iron. About 50% of the iron is absorbed, in contrast to a much smaller proportion from other foods. Term infants who are breast-fed exclusively for the first 6 months may not be at risk for iron depletion or for the development of iron deficiency. However, if solid foods are given they may compromise the bioavailability of iron from human milk. Although some term infants who are exclusively breast-fed may remain iron-sufficient until 9 months of age, a source of dietary iron is recommended starting at 6 months (or earlier if solid foods are introduced into the diet) to reduce the risk of iron deficiency.
Etiology • Low iron diet • Inadequate absorption of dietary iron • Growth spurt • Blood loss
At high risk for iron deficiency are preterm infants and infants from a low socioeconomic background, low birth weight, perinatal bleeding, a low hemoglobin concentration at birth, chronic hypoxia, • frequent infections, early intake of cow's milk or solid food, or both, excessive tea intake, low vitamin C or meat intake, breast-feeding for more than 6 months without supplemental iron, intake of infant formula not fortified with iron for more than 4 months without other foods.
Premature infants have a lower level of body iron at birth, approximately 64 mg in infants weighting 1 kg • The rapid rate of postnatal growth lead to a higher requirement for dietary iron than in term infants of 2.0 to 2.5 mg/kg daily to prevent late anemia. • 10% of the iron in a mixed diet is absorbed • the recommended iron intake is approximately 7 mg/d for term infants aged 5 to 12 months, 6 mg/d for toddlers aged 1 to 3 years and 8 mg/d for children aged 4 to 12 years.
There are some factors that interfere absorbtion of iron: • High Gastric pH: hemigastrectomy, vagotomy, pernicious anemia , histamine H2 receptor blockers, calcium-based antacids • Disruption of Intestinal Structure: hemigastrectomy, segments of bowel which are sometimes removed surgically, disrupting iron absorption, volvulus or intusseception, vagotomy, pernicious anemia, • Inhibitors:phylates, tannins, soil clay, laundry starch, iron overload, cobalt, lead, strontium • Some factors are facilitating iron absorbtion: bioavailability(heme > Fe2+> Fe3+ ),ascorbate, citrate, amino acids, iron deficiency
As regarding growth spurt iron need for infants is1.0 mg/1,000 kcal of dietary energy; for adolescent girls, 0.8 (half of their iron requirement is needed to replace iron losses in menstruation ); adolescent boys need 0.6 mg/1,000 kcal. Some absorbtion problems can interfere iron. A major cause of anaemia is infection with malaria or other parasites. Plasmodium falciparumis the primary cause of severe malaria in regions of the world where malaria is endemic Sprue, both of the tropical and non-tropical variety (celiac disease), can also interfere with iron absorption. Degeneration of the intestinal lining cells along with chronic inflammation causes profound malabsorption.
Blood loss DIGESTIVE Meckel'sdiverticulum (persistent omphalomesenteric duct) Colonic arteriovenous malformations Arteriovenous malformations (the Osler-Weber-Rendu syndrome.) Ulcer disease are associated with Helicobacter pylori infection Gastric hiatal hernia Erosive esophogitis Milk-induced enteropathy (whole cow's milk contains proteins that often irritate the lining of the gastrointestinal tract in infants ) Parasites :the world's leading cause of gastrointestinal blood loss is parasitic infestation. Hookworm infection is caused primarily by Necatoramericanus or Ancylostoma duodenal Trichuristrichiura. Growth retardation, in addition to iron deficiency, occurs with heavy infestations.
URINARY Berger's disease, which produces relapsing episodes of gross or microscopic hematuria occurs most commonly in older children and young adults. Diffuse mesangial proliferation or focal and segmental glomerulonephritis with mesangial deposits of IgAis the most common renal pathology related to iron deficiency. Sickle cell trait occasionally develop gross hematuria. Hemoglobinuria classically is ascribed to paroxysmal nocturnal hemoglobinuria. PULMONARY Hemoptysis, chronic pulmonary infection with bronchiectasis,idiopathic pulmonary hemosiderosis, a condition characterized by recurrent pulmonary hemorrhage along with pulmonary fibrosis and right heart strain.
Clinical symptoms • Palor of skin and mucosa • The microcytic, hypochromicanemia impairs tissue oxygen delivery, producing weakness, loss of apetite, fatigue, palpitations, and light-headedness. • Iron deficiency include poor weight gain, anorexia, blood in stools, malabsorption, irritability, decreased attention span, exercise intolerance and decreased physical activity. • Regarding the psychomotor development when iron deficiency progresses to anemia, performance on developmental tests is adversely affected for up to at least 3 months despite correction of the anemia with iron therapy. Among infants with severe or chronic iron deficiency, some of these abnormalities may persist indefinitely despite adequate iron therapy. The relation between iron deficiency and behavioural development is nowadays well known.
Iron deficiency produces significant gastrointestinal tract abnormalities. Some patients develop angular stomatitis and glossitis with painful swelling of the tongue. The flattened, atrophic lingual papillae makes the tongue smooth and shiny. A rare complication of iron deficiency is the Plummer-Vinson syndrome with the formation of a postcrycoid oesophageal web. Long-standing, severe iron deficiency affects the cells that generate the finger nails producing koilonychia. The "spoon-shaped" changes featured in many text books are rare.
Pica occurs variably in patients with iron deficiency. The precise pathophysiology of the syndrome is unknown. Patients consume unusuallylaundry starch, ice, and soil clay, have abnormalities including massive hepato-splenomegaly, poor wound-healing, and a bleeding diathesis; initially had simple iron deficiency associated with pica, including geophagia. The soil contained compounds that bound both iron and zinc. The secondary zinc deficiency caused the hepatomegaly.Both clay and starch can bind iron in the gastrointestinal tract, exacerbating the deficiency. Impaired immune function is reported in subjects who are iron deficient, and there are reports that these patients are prone to infection Splenomegaly may occur with severe, persistent, untreated iron deficiency anemia and is evident in up to 15% of affected children. A systolic murmur can be heard because of the low blood viscosity and increased circulation speed of the blood
Laboratory tests • Iron deficiency anemia lowers the number of circulating red cells (a feature of all anemias). • Hb is low, the red cells are microcytic(usually less than 80 fl in size) and hypochromic. Iron deficiency alters red cell size uneven.( anyzocytosis). • Mean red cell volume or mean corpuscular volume (MCV) is reduced.The range of variation in red cell size expressed as the RDW or red cell distribution width is high. • membranes of iron deficient red cells are abnormally rigid. This rigidity could contribute to poikilocyticchanges, seen particularly with severe iron deficiency. These small, stiff, misshapen cells are cleared by the reticuloendothelial system, contributing to the low-grade hemolysis that often accompanies iron deficiency.reticulocyte count can be under 1% or normal ( 2%-4% ). • Unexplained thrombocytosisoccurs frequently with platelet counts in the range of 500,000 to 700,000 cells /fl.
In bone marrow aspiratesideroblasts are under 10%, and iron stores are low, there is an absence of stainable iron. The quantity of the iron-carrying protein, transferrin, in the circulation increases over baseline by 50% to 100%. The quantity of iron on transferrin can fall by as much as 90%. Consequently the transferrin saturation frequently declines from its usual 30% to under 10%. Ferritin is the cellular storage protein for iron and is low. The plasma ferritin value often falls to under 10% of its baseline level with significant iron deficiency. Total iron-binding capacity (TIBC) is raised. Free erythrocyte protoporphyrin (FEP) has concentrations elevate when serum iron is insufficient for RBC production. Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia. To detect blood loss, the patient can be placed on a strict vegetarian diet for 3-5 days and the stool can be tested for hemoglobin using a benzidine method.
Positive diagnosis • The diagnosis of iron deficiency is often prompted by historical features and aided by specific clinical and laboratory data.
Differential diagnosis • Chronic inflammation ( ex in rheumatoid arthritis ), perturb the plasma values of iron, transferrin, and ferritin. Body iron stores revealed by serum ferritin level are elevated • Lead poisoning : chronic lead poisoning may produce a mild microcytosis, persons live in old houses, lead concentration is high in blood and urines. • Thalasemia: in peripherial smear anemia target cells usually are present, and anisocytosis and poikilocytosis are marked, there are intraerythrocytic crystals ,bilirubin is raised, family history and clinical aspect of the child is particular in beta thalassemia. Hemoglobin electrophoresis should also be considered to rule out the presence of inherited hemoglobinopathies. • Sideroblasticanemia
Treatment • The profilaxy of infant’s iron deficiency begins in mother’s pregnancy. The WHO recommends that all pregnant women be supplemented with 60 mg iron daily, in a pill that also usually contains 400 mg folic acid. • For low born weight infants the global recommendation is to supply them with supplemental iron drops starting at 2 months of age. For developing countries the recommendation is to provide 12.5 mg of elemental iron plus 50 mg folic acid per day from age 6 months to age 12 months in regions where the anaemia prevalence is <40%, and from age 6 to 24 months where the prevalence of anaemia is > 40%. • Supplements are provided for school children. Together with iron, vitamin B6, folic acid, vitamin C and vitamin A supplements are provided.
When Hb is under the value of 7gm/dl, a transfusion with red packed cells is necessary. Whole blood is a less used alternative, because of anafilactic reactions of plasma proteins, immunological antigens of lymphocytes and risk of infections.RED PACKED CELLS Treatment with iron salts Dose of elemental iron is 6-8 mg/kg/day divided in 3-4 or once daily dose before meals. Therapy is continued until fully Hb normalization; than 6-8 weeks of additional iron therapy is necessary to complete body iron stores. Although ferrous sulphate is often recommended to treat iron deficiency, frequent problems with the drug including gastrointestinal discomfortappear.Ferrous gluconate, produces fewer problems, and is preferable as the initial treatment of iron deficiency. Ascorbic acid supplementation enhances iron absorption. Polysaccharide-iron complex, is a good replacement form of iron that differs from the iron salts. Most patients tolerate this form of iron better than the iron salts, even though the 150 mg of elemental iron per tablet is substantially greater than that provided by iron salts (50 to 70 mg per tablet) Parenteral iron is available either as iron dextran or iron saccharide (commonly ferric polymaltose). There can be side effects as anaphylaxis.
Parenteral, im or iv is indicated when oral iron is poorly tolerated or gastrointestinal iron absorption is compromised Intramuscular injection of iron-dextran can be painful, and leakage into the subcutaneous tissue produces long-standing skin discoloration hages. • Can also cause fever, artralgia,dyspnea, myalgia.
Peak reticulocytosis occurs after about 7-10 days,Hb is restored together with red blood cell number and hematocrit, and complete correction of the anemia can take 3 to 4 weeks, The hematocrit rises sufficiently in a week or two to provide symptomatic relief for most patients, serum iron, transferrinrecoveres and at the end ferritin reaches normality. Human erythropoietin was one of the first agents used to correct the anemia of end-stage renal disease this hormone has provided new insight into the kinetic relationship between iron and erythropoietin in red cell production. The shifting states of storage iron contribute to the inconsistency with which erythropoietin corrects the anemia of renal failureand premature newborn anemia.
Follow up The hematocrit or hemoglobin should be re-evaluated in 1 month. Approximately 6 months following therapy, the hemoglobin or hematocrit should be assessed to document success of treatment and replenishment of iron stores. Severe anemia (hemoglobin < 8 g/dl) and anemia that fails to respond to adequate iron supplementation will require more intensive investigation to confirm the diagnosis and offer appropriate management.
MEGALOBLASTIC ANEMIA Definition • The term megaloblastic anemia (MA) is used to describe a macrocytic anemia that is associated with a characteristic change-the megaloblastic change in the erythroid precursors in the bone marrow.
Causes of megaloblasticanemia • There are manycauses of megaloblastic anemia, but themostcommonsource in childrenoccursfrom a vitamindeficiency of folic acid or vitamin B-12. Othersources of megaloblastic anemia include thefollowing: • Digestive diseasesThese include celiac disease, chronicinfectiousenteritis, andenteroentericfistulas. Pernicious anemia is a type of megaloblastic anemia causedby an inabilityto absorb Vitamin B-12 dueto a lack of intrinsic factor in gastric (stomach) secretions. which factor enablestheabsorption of Vitamin B-12. • malabsorptionInherited congenital folatemalabsorption, a genetic disease; conditionrequiresearly intensive treatmenttopreventlongtermproblemssuch as mental retardation. • Infection (intestinal parasites, bacterial overgrowth) • Medication-induced folic acid deficiencyCertainmedications, specificallyonesthatpreventseizures, such as phenytoin, primidone, andphenobarbital, canimpairtheabsorption of folic acid. The deficiencycanusuallybetreatedwith a dietarysupplement.
Folic acid is a B vitaminrequired for theproduction of normal redbloodcells. Folic acid ispresent in foodssuch as greenvegetables, liver, andyeast. It isalsoproducedsyntheticallyandaddedtomanyfooditems. • Foods that are rich in folic acid include thefollowing: • orange juice • oranges • romainelettuce • spinach • liver • rice • barley • sprouts • wheatgerm • soybeans • green, leafyvegetables • beans • peanuts • broccoli • asparagus • peas • lentils • wheatgerm • chickpeas (garbanzobeans) • Foods that are rich in folic acid andvitamin B12 include thefollowing: • eggs • meat • poultry • milk • shellfish • fortifiedcereals
Nutritionalmegaloblastic anemia in childrenoccurscommonlyamongunder-nourished or malnourishedsocieties of tropical and subtropical countries. The commonestageis 3-18 monthswith maximum number of casesbeing in 9-12 months(1). Thesechildren are generallyexclusivelybreast-fedbymotherswhoareundernourishedandhavepoorbloodlevels of folateandcobalamin Intrinsic factor is a protein the body uses to absorb vitamin B12. When gastric secretions do not have enough intrinsic factor, vitamin B12 is not adequately absorbed, resulting in pernicious anemia.Absence of intrinsic factor itself is the most common cause of Vitamin B12 deficiency. Intrinsic factor is produced by cells within the stomach
Clinics • The onset of the disease is slow and may span decades. • pallor • Developmental retardation or regressionis an important finding. These children are normally apathetic, not interested in surroundings and havehypotomia. • Hyperpigmentation of knukles, terminal phalanges, dorsum of hand etc is seen. • Tremorsare described in 5-15% cases-the infantile tremor syndrome of megaloblasticanemia, hypotonia, developmental regression and tremors. Some of the cases of MA may clinically mimic cases of acute leukemia and aplasticanemia as hepatosplenomegaly (due to extramedullaryhemopoiesis) of varying severity and cutaneous and other bleeding manifestations are described in 25-30% cases.abnormal paleness or lack of color of theskin • decreasedappetite • irritability • lack of energy or tiringeasily (fatigue) • diarrhea • difficultywalking • numbness or tingling in handsandfeet • smoothand tender tongue • weakmuscles
Laboratory tests • Diagnosis of MA is suggested by presence of macrocytosis. Presence of hypersegmentedneutrophils also supports the diagnosis. Some cases may have circulating red cell precursors showing megaloblastic changes. Reticulocyte count is usually decreased. MCV is found to be increased (>90 fl.) What is more striking on peripheral blood examination is presence of • thrombocytopenia, leucopenia and neutropenia.Thrombocytopenia is described in 50-80% cases with many of them having precariously low platelet counts. Neutropenia has been reported in 20-50% cases. Thus many cases (upto 50% in some cases) of MA may have pancytopenia - a finding which might lead to misdiagnosis of aplasticanemia (or acute leukemia if hepatosplenomegaly is also present). In some series on pancytopenia it has been observed that MA is more frequent etiological diagnosis than aplasticanemia or leukemia. The diagnosis of MA is confirmed on bone marrow examination that shows trilineal hyperplasia with megaloblastic change typically in the erythroid precursors. • Reduced serum levels of B12 and folate will make the etiological diagnosis. It has been shown that serum and urinary methylmalonic acid (MMA) are increased in B12 deficiency and not in folate deficiency states.
The Schilling test is performed to detect vitamin B12 absorption. In the Schilling test, vitamin B12 levels are measured in the urine after the ingestion of radioactive vitamin B12. With normal absorption, the ileum (portion of the small intestine) absorbs more vitamin B12 than the body needs and excretes the excess into the urine. With impaired absorption, however, little or no vitamin B12 is excreted into the urine.
Treatment • Daily dose of 1mg of folic acid is more than adequate though larger doses are safe. • The dose schedule if B12 therapeutic response can be obtained with a dose of 0.2 µg/kg for 2 days, but usually a 1000 µg dose is recommended which may be continued for the first 7 days. In our experience and other studies, use of this high dose has resulted in hyperexitability and tremors in some patients. Smaller dose i.e. 100-250 µg by initially given daily for a week and then less frequently • reticulocytosis. appear, fall in MCV by 5-10 fl over 1-2 weeks, platelet count and neutrophil count tend to improve quickly, some patients may develop thrombocytosis
ETIOLOGY Inherited Bone Marrow Syndromes Associated with Pancytopenia, Fanconi's Anemia Dyskeratosis Congenita Shwachman-Diamond Syndrome Cartilage-Hair Hypoplasia Pearson's Syndrome Down Syndrome Familial Marrow Dysfunction Inherited Bone Marrow Failure Syndromes Associated with Isolated Cytopenia, Diamond-Blackfan Anemia Congenital Dyserythropoietic Anemia Severe Congenital Neutropenia Inherited Thrombocytopenia Amegakaryocytic Thrombocytopenia, Thrombocytopenia with Absent Radii,
ETIOLOGY • Aquired: * Imune * Nonimune : • radiations • drugs- Chloramphenicol, phenylbutazone, and gold • benzene exposure, chemicals • infectious causes such as hepatitis viruses, Ebstein-Barr virus (EBV), HIV, parvovirus, and mycobacterialinfections • Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare;however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolyticanemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. • In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia. • The antigen that incites disease is unknown in aplasticanemia.
Inherited bone marrow failure syndromes (IBMFSs) are genetic disorders characterized by inadequate blood cell production Bone marrow failure usually presents in childhood, with petechiae, bruising, and hemorrhages due to thrombocytopenia; pallor and fatigue from anemia; and infections due to neutropenia
Inherited bone marrow failure syndromes (IBMFS) are genetic disorders characterized by inadequate blood cell production. Bone marrow failure (BMF) may be manifested as an isolated cytopenia (pure red cell aplasia, neutropenia, or thrombocytopenia) or as pancytopenia and the clinical picture of aplastic anemia. • Other organ systems are often affected by these genetic abnormalities and result in birth defects or clinical disease in nonhematopoietic organs. Birth defects and extrahematopoietic manifestations are often characteristic and may be noticed before the onset of BMF. • BMF may be present at birth (congenital BMF) or develop later in life
Fanconi's anemia is an autosomalrecessiveandX-linkeddisordercharacterizedbyprogressive bone marrowfailure, congenital abnormalities, and a predisposition for malignancies. • Cellsfrom FA patientsexhibitspontaneouschromosomalinstabilityand a characteristichypersensitivityto DNA interstrandcross-linkingagents. • The incidence of FA is estimated to be approximately 3 per million with a carrier frequency of 1 in 300. • The clinical manifestations of FA are heterogeneous (variable penetrance and expressivity)
Specific Types of Anomalies in Fanconi's Anemia SKIN • Generalizedhyperpigmentation on thetrunk, neck, andintertriginousareas; café au laitspots; hypopigmentedareas • BODY • Shortstature, delicate features, smallsize, underweight • UPPER LIMBS • Thumbs: absent or hypoplastic; supernumerary, bifid, or duplicated; rudimentary; shorttriphalangeal, tubular, stiff, hyperextensible • Radii: absent or hypoplastic (onlywith abnormal thumbs); absent or weakpulse • Hands: clinodactyly; hypoplasticthenareminence; sixfingers; absent firstmetacarpal; enlarged, abnormal fingers; shortfingers, transverse crease • Ulnae: dysplastic
GONADS • Males: hypogenitalia, undescendedtestes, hypospadias, abnormal genitalia, absent testis, atrophictestes, azoospermia, phimosis, abnormal urethra, micropenis, delayeddevelopment • Females: hypogenitalia; bicornuateuterus; abnormal genitalia; aplasia of theuterusandvagina; atresiaoftheuterus, vagina, andovary OTHER SKELETAL ANOMALIES • Headand face: microcephaly, hydrocephalus, micrognathia, peculiar face, bird-likeface, flathead, frontal bossing, scaphocephaly, slopedforehead, choanalatresia, dentalabnormalities • Neck: Sprengel'sdeformity; short, lowhairline; webbed • Spine: spina bifida (thoracic, lumbar, cervical, occult sacral), scoliosis, abnormal ribs, sacrococcygeal sinus, vertebral anomalies, extra vertebrae EYES • Smalleyes, strabismus, epicanthalfolds, hypertelorism, ptosis, cataracts, astigmatism, blindness,, nystagmus, proptosis, small iris EARS • Deafness (usually conductive); abnormal shape; atresia; dysplasia; low-set, large or small; infections; abnormal middleear; absent drum; canal stenosis
KIDNEYS • Ectopic or pelvic; abnormal, horseshoe, hypoplastic, or dysplastic; absent; hydronephrosis or hydroureter; infections; duplicated; rotated; reflux; hyperplasia; no function; abnormal artery GASTROINTESTINAL SYSTEM • High-arched palate, atresia (esophagus, duodenum, jejunum), imperforate anus, tracheoesophageal fistula, Meckel's diverticulum, umbilical hernia, hypoplastic uvula, abnormal biliary ducts, megacolon, abdominal diastasis, Budd-Chiari syndrome LOWER LIMBS • Feet: toe syndactyly, abnormal toes, flatfeet, short toes, clubfeet, six toes, supernumerary toe • Legs: congenital hip dislocation, Perthes' disease, coxa vara, abnormal femur, thigh osteoma, abnormal legs CARDIOPULMONARY SYSTEM • Patent ductus arteriosus, ventricular septal defect, abnormal heart, peripheral pulmonic stenosis, aortic stenosis, coarctation, absent lung lobes, vascular malformation, aortic atheromas, atrial septal defect, tetralogy of Fallot, pseudotruncus, hypoplastic aorta, abnormal pulmonary drainage, double aortic arch, cardiac myopathy OTHER ANOMALIES • Slow development, hyperreflexia, Bell's palsy, central nervous system arterial malformation, stenosis of the internal carotid artery, small pituitary gland, absent corpus callosum
Hematologic Abnormalities • The first hematologic abnormalities in individuals with FA are detected at a median age of 7 years. The majority of FA patients already have pancytopenia at the time of diagnosis (53%). By the age of 40, the cumulative incidence of hematologic abnormalities is 90% to 98% • In rare cases, thrombocytopenia may be present at birth and progress to pancytopenia in the neonatal period or infancy • Bone marrow examination generally shows reduced cellularity