Peds Flashcards
What are the average diameters for a normal glomerulus in newborns and adults?
Newborn, 100 um. Adult, 200-250 um. Glomeruli reach normal adult size by ~8 years of age.
Biliary atresia. Epidemiology and classification.
Biliary atresia is an inflammatory cholangiopathy of infancy that results in progressive fibrosis and obliteration of extrahepatic and intrahepatic bile ducts and represents the main indication for liver transplant in young children. The portoenterostomy/Kasai procedure is the only form of therapy that can be offered to these patients besides liver transplant. The reported incidence of biliary atresia shows some regional variability, being higher in Asia and the Pacific region. Biliary atresia is broadly classified into 2 main forms. The first form is the embryonic/fetal, “early,” or syndromic form (10-20% of cases), which is associated with a high frequency of additional congenital malformations (including asplenia, polysplenia, cardiovascular defects, situs inversus, intestinal malrotation, small-intestinal atresia, anomalous choledochopancreatic ductal junction, and various positional abnormalities of the portal vein and hepatic artery), and is referred to as biliary atresia-splenic malformation (BASM) syndrome. Cystic dilatation of biliary remnants may be seen in a small minority of cases of fetal-type biliary atresia (5-10% of cases) and these cases are referred to as cystic biliary atresia. The second form is the perinatal/postnatal, “late,” or nonsyndromic form (80-90% of cases), generally occuring as an isolated abnormality.
What is the etiology of biliary atresia?
Biliary atresia is though to represent the end result of intrauterine or perinatal injury to bile ducts, leading to fibrous obliteration of these structures and severe cholestatic liver disease in the neonatal period. Various parts of the extrahepatic biliary system are initially affected, but intrahepatic bile ducts are subsequently involved in a significant proportion of patients, even in those who undergo an initially successful portoenterostomy/Kasai procedure. Histologic examination of bile duct remnants supports the contention that, in most cases, the observed fibro-obliterative cholangiopathy in biliary atresia results from destruction of a presumably well-formed biliary system rather than from primary failure of normal embryologic development of these structures. To date, however, no single agent or abnormality has consistently been implicated as a cause of biliary atresia in humans. Instead, multiple etiologic factors (including immunologic, viral, genetic/metabolic, vascular insult, and environmental/miscellaneous categories) have been postulated to be part of the pathogenesis of this complex disease.
Mesenchymal hamartoma of liver.
MH is an uncommon tumor that occurs almost exclusively in children; most cases are diagnosed in the first two years of life. It is the third most common liver tumor in this age group, following hepatoblastoma and infantile hemangioma. In most cases, serum AFP is normal or mildly elevated. MH may be solid or cystic, the latter being formed as a result of degeneration of the loose mesenchymal tissue. Extramedullary hematopoiesis is a frequent finding. The stroma tends to be more fibrotic in the rare adult cases. In some cases the mesenchymal component may dominate, with sparse ductal elements. The ductal elements express CK7 and lack CK20. The stromal cells are positive for SMA and vimentin.
Plasmacytic differentiation is seen in what % of MALT lymphoma cases?
Plasmacytic differentiation in MALT lymphoma is fairly common, seen to some extent in ~1/3 of MALT lymphoma cases. Occasionally, plasma cells are the predominant cell type, potentially leading to confusion with other hematolymphoid neoplasms, such as plasmacytoma and lymphoplasmacytic lymphoma. Thus, MALT lymphoma with plasmacytic differentiation should be considered in the differential diagnosis of any plasmacytic lesion, particularly in the setting of a disease site or clinical senario that would be unusual for a plasmacytoma, such as a very young patient.
What are the first, second, and third most common tumors of the liver seen in children under 3 years of age?
First: Hepatoblastoma. Second: Infantile hemangioma. Third: Mesenchymal hamartoma.
Hepatoblastoma is the most common malignant liver tumor in children and comprises ~__% of the pediatric malignant neoplasms. Nearly 90% of cases occur between __ months and __ years of age. The two morphologic subtypes of HB are __ (55%) and __ (45%).
Hepatoblastoma is the most common malignant liver tumor in children and comprises ~1% of the pediatric malignant neoplasms. Nearly 90% of cases occur between 6 months and 5 years of age. The two morphologic subtypes of HB are epithelial (55%) and epithelial-mesenchymal (45%).
What is the leading cause of neonatal jaundice?
Physiological jaundice due to hepatic enzymes not being up to full capacity; the infant’s liver is not able fully to conjugate bilirubin for excretion. This can be exacerbated by peripartum hemolysis, which leads to an increased bilirubin load, or breast milk jaundice, since breast milk contains inhibitors of bilirubin conjugation.
What signs indicate that an infant may not have just physiological jaundice?
Jaundice within 24 hours of birth, rising bilirubin after 1 week, persistence past 10 days, a total bilirubin >12 mg/dL, a single day increase in bilirubin >5 mg/dL, or a direct bilirubin >2 mg/dL.
What is a gangliorhabdomyosarcoma?
Embryonal rhabdomyosarcoma is a primitive soft tissue sarcoma with small blue cells resembling embryonic skeletal muscle. It is the most common rhabdomyosarcoma (RMS) subtype (65% of RMS cases), and usually occurs in children ages 3-10 years in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Gangliorhabdomyosarcoma is a rare variant of embryonal rhabdomyosarcoma which also has cells exhibiting neuronal differentiation. A related entity is malignant ectomesenchymoma, composed of a malignant mesenchymal component (often but not exclusively rhabdomyosarcoma) and a neuroectodermal component (often ganglion cells or neuroblasts). The differential diagnosis includes Triton tumor (rhabdomyosarcoma plus MPNST), Wilms tumor, and teratoma. Optimal treatment is not well defined for this rare tumor, but most authors recommend a combination of surgery, radiotherapy, and a chemotherapeutic protocol based on the RMS component.
Why does a normal placenta show heterogeneous maturation?
A normal placenta shows heterogeneous maturation because better-oxygenated centers of cotyledons (placentones) are less mature (larger chorionic villi with less syncytial knots) than are their peripheral parts, where the less-oxygenized blood returns toward the uterus. The accelerated heterogeneous hypermaturity is a sensitive feature of uteroplacental malperfusion. Homogeneous placental maturation is always abnormal, the placentas being either hypomature or hypermature.
How can decreased extracellular matrix of chorionic villi be distinguished from villous edema?
The extracellular matrix of chorionic villi can be decreased and the villous cores as pale as the intervillous space. Such a finding has to be distinguished from villous edema, where, in addition, a split artifact between the trophoblastic shell and the villous core is, at least focally, present. An increased extracellular matrix of chorionic villi, produced in excess by villous fibroblasts in response to intravillous hypoxia associated with intervillous hyperoxemia, manifests as intense eosinophilia of villous cores.
In what clinical situations are preuterine hypoxic, uterine hypoxic, and postuterine hypoxic patterns of chronic hypoxic placental injury seen, and what are the histologic features?
Preuterine hypoxic pattern is seen in maternal anemia, pregnancy at high altitudes, air pollution, maternal smoking, and multifetal pregnancy. Histologic features are: Homogeneously, diffusely hypomature villi. Diffusely increased (including diffuse or incipient chorangiosis) villous vascularity. Increased (b/c of tangential cutting) nonapoptotic, syncytial knotting; increased villous cytotrophoblasts and Hofbauer cells; and extracellular matrix of chorionic villi are diffusely present. Uterine hypoxic pattern is seen in late onset fetal growth restriction and preeclampsia. Heterogeneously hypermature villi. Same additional histologic patterns as in preuterine hypoxic pattern, but only focally present; lesions associated with increased extravillous trophoblasts; decidual arteriolopathy. Postuterine hypoxic pattern is seen with retained stillbirth and early onset fetal growth restriction and preeclampsia. Homogeneously hypermature villi. Diffusely increased apoptotic (smudgy) syncytial knotting; decreased villous cytotrophoblasts and Hofbauer cells; increased extracellular matrix of chorionic villi (terminal villous hypoplasia).
What is the histologic evolution of villous infarction in the placenta?
Agglutination of villi –> vascular congestion –> intravillous hemorrhage –> coagulative necrosis –> acute inflammatory response –> fibrin deposition, fibrosis, calcification. Villous infarction is the most frequently (or readily) diagnosed placental lesion; it starts to develop 2-4 hours to 4 days after an aucte hypoxic event. Once intravillous stromal hemorrhage (red infarction) occurs, the sequence is irreversible. The time frame of these sequential changes in humans has not been determined. Villous infarctions have diagnostic limitations b/c they occur not infrequently in otherwise uncomplicated pregnancies, indicating a substantial placental reserve. Only infarctions in a central/paracentral location and occupying >5-20% of the placental parenchyma are regarded as diagnostically significant.
What is the most common primary malignant tumor of the kidney in children?
Described by Max Wilms in 1899, Wilms tumor (nephroblastoma) is the most common primary malignant tumor of the kidney in children. While it rarely occurs in adults, the peak incidence is in young children (average age, 3-4 years). Approximately 500 cases are diagnosed annually in the United States.
Wilms tumor typically has a triphasic morphology. Describe.
Typically, Wilms tumors has a classic triphasic morphology: blastema, stroma, and epithelium, although in some cases only one or two of these components are present, for example in the “blastema-predominant” variant composed only of the primitive small round cell component, or in the “epithelial-predominant” variant mimicking metanephric adenoma. The epithelial component is typically formed by hyperchromatic primitive-appearing tubules and less commonly, small glomeruloid structures. Mesenchymal differentiation within Wilms tumors is prominent in some cases, particularly smooth muscle or skeletal muscle elements. Fat, cartilage, osteoid, squamous or glandular epithelium, and glial elements are also reported.
What are the unfavorable and favorable histologies of Wilms tumor?
Histologic classification of Wilms tumor is generally divided into two types: Unfavorable histology (tumors with focal or diffuse anaplasia) and Favorable histology (tumors with no anaplasia). Anaplasia is defined as presence of markedly enlarged hyperchromatic nuclei (3x greater in size than other tumor nuclei) and presence of atypical multipolar mitoses, both of which are changes typically seen at screening magnification. Diffuse anaplasia is defined as presence of anaplastic cells in multiple different fields of the primary tumor or in a metastatic site, whereas focal anaplasia refers to presence of anaplastic cells in one or only a few discretely localized foci. This distinction between focal and diffuse anaplasia warrants documentation or “mapping” of the site of sampling of tissue blocks in order to determine proximity of anaplastic fields submitted in separate blocks.
What are the variants of Wilms tumor?
Variants of Wilms tumor include the rhabdomyoblastic , blastemal-predominant, epithelial-predominant, teratoid, cystic variant, and cystic, partially differentiated nephroblastoma (CPDN). CPDN is characterized by microscopic foci of Wilms tumor within fibrous septations in a grossly cystic tumor. Gross identification of solid nodules within a cystic neoplasm warrants a diagnosis of cystic Wilms tumor rather than CPDN.
Approximately 90% of Wilms tumors are sporadic, while a minority are associated with syndromes and/or mutations in the tumor suppressor genes ___ or ___.
Approximately 90% of Wilms tumors are sporadic, while a minority are associated with syndromes and/or mutations in the tumor suppressor genes WT1 (chromosome 11p13) or WT2 (chromosome 11p15).
What are syndromes associated with Wilms tumor?
Syndromes associated with Wilms tumor include WAGR (Wilms tumor-Aniridia-Growth Retardation), Denys-Drash syndrome (Wilms tumor, mesangial sclerosis, gonadal dysgenesis), Beckwith-Wiedemann syndrome (Wilms tumor predilection, organomegaly, hemihypertrophy of extremities, omphalocele, and other anomalies), Simpson-Golabi-Behmel syndrome (Wilms tumor predilection, facial overgrowth, congenital anomalies), and isolated hemihypertrophy.
What are nephrogenic rests within Wilms tumors?
Nephrogenic rests are benign pre-neoplastic lesions associated with Wilms tumor in some cases. Detection of nephrogenic rests typically prompts screening and follow-up of the contralateral kidney due to the risk of multifocality and/or metachronous tumor formation. Hyperplastic nephrogenic rests are typically wedge-shaped and interdigitate microscopically with adjacent renal tubules, whereas incipient Wilms tumor nodules are typically spherical and have a capsule separating the tumor from the surrounding kidney. The difficulty in distinguishing a hyperplastic “adenomatous” nephrogenic rest from a small epithelial-predominant Wilms tumor is well-recognized. Accurate distinction requires examination of the edge of the lesion, and cannot be accurately distinguished by needle biopsy.
What entities are in the differential diagnosis of Wilms tumor?
The differential diagnosis of Wilms tumor includes other primary renal tumors of childhood, including malignant rhabdoid tumor, congenital mesoblastic nephroma (classic and cellular variants), clear cell sarcoma of the kidney, and renal cell carcinoma. Other diagnostic considerations include other small cell tumors of the kidney (synovial sarcoma, primitive neuroectodermal tumor of the kidney, desmoplastic small round cell tumor, neuroblastoma, lymphoma) and a variety of benign tumors (cystic nephroma, infantile ossifying tumor of the kidney, oncocytoma, and others).
What histologic changes are seen for stress reactions in the thymus at 0-12 hours, 12-48 hours, 48-72 hours, 3-7 days, 7-14 days, and >14 days?
0-12 hours: Parenchymal hemorrhages. 12-48 hours: “Macrophages” (refers to the “starry sky” appearance in the cortex) in cortex. 48-72 hours: “Macrophages” with “mulberries” (refers to small clusters of lymphocytes) in cortex, cellularity of cortex begins to diminish. 3-7 days: Corticomedullary distinction lost with increasing prominence of Hassall corpuscles. 7-14 days: Involution begins whereby lymphocytes appear in increasing numbers in the medulla. >14 days: Advanced involution whereby there is overall relative depletion of lymphocytes and they mainly occupy the medulla.
What is a gingival granular cell tumor of infancy?
AKA Neumann tumor AKA congenital epulis of the newborn. A rare, benign congenital growth on alveolar mucosa in neonates. M:F = 1:8-10. Maxilla:mandible = 3:1. Can be histologically indistinguishable from granular cell tumor, but unlike GCT, develops in newborns to infants only and is S100 negative. Also, while ~50% of GCTs of the oral cavity have pseudoepitheliomatous hyperplasia, congenital epulis never has it. Not to be confused with “nonneural granular cell tumor,” which is a tumor in adults that is S100 negative.
Primary ciliary dyskinesia AKA immotile cilia syndrome is associated in ~50% of patients with ___ syndrome.
Primary ciliary dyskinesia AKA immotile cilia syndrome is associated in ~50% of patients with Kartagener syndrome AKA situs inversus totalis. Chronic bronchitis, recurrent pneumonia, and atelectasis is virtually pathognomonic for Kartagener syndrome, and in this situation, cilia evaluation is not required for diagnosis.
What is herpangina?
Herpangina is a common viral infection of young children associated with blisters of soft palate or tonsillar pillars. It is caused by viruses belonging to the Enterovirus group (coxsackievirus, poliovirus, echovirus). Coxsackie A16 virus is the most common cause. Transmission is direct contact, usually oral-fecal route.
What virus is the most common cause of herpangina?
Herpangina is a common viral infection of young children associated with blisters of soft palate or tonsillar pillars. It is caused by viruses belonging to the Enterovirus group (coxsackievirus, poliovirus, echovirus). Coxsackie A16 virus is the most common cause, but other coxsackie viruses usually associated include A1 to A6, A8, A10, or A22.
What is hand, foot, and mouth disease?
A common viral illness of infants and children, which causes fever and blister eruptions of mouth and/or skin. Caused by virus belonging to Enterovirus group. Transmission is by direct contact. Virus is found in secretions, including saliva, nose and throat secretions, blister fluid, and stools.
What is Heck disease?
AKA focal epithelial hyperplasia AKA multifocal epithelial hyperplasia. A benign, virus-induced epithelial proliferation of oral mucosa associated with HPV types 13 and 32. Majority of cases are in children. Micro: Prominent acanthosis and elongated broad rete ridges (since the thickened epithelium extends upward, elongated rete are at same depth as adjacent normal rete ridges). May see papillary surface. Mitosoid cells (represents ballooning and nuclear degeneration; represents an altered nucleus resembling a mitosis in an otherwise normal stratified squamous epithelium; can be seen throughout epithelium); do not misinterpret mitosoid cells as atypia. Koilocytic change in superficial keratinocytes can be seen. No dyskeratosis and/or atypia. DDx: Papilloma. Condyloma acuminatum. Oral verruca vulgaris.
What HPV types cause Heck disease (focal epithelial hyperplasia/multifocal epithelial hyperplasia)?
HPV types 13 and 32.
What is Riga-Fede disease?
AKA traumatic ulcer, traumatic ulcer with stromal eosinophilia, eosinophilic granuloma of tongue, traumatic granuloma, atypical histiocytic granuloma. It is a chronic traumatic ulceration of oral mucosa with unique histopathologic features. Riga-Fede disease specifically refers to trauma to the soft tissue (ventral tongue or inner lower lip) in newborns or infants from natal or neonatal teeth. In children, traumatic ulcer is often due to thermal or electrical burns or parafunctional habits. In adults, traumatic ulcer is often due to fractured and/or malposed teeth or parafunctional habits. Micro: Ulcer bed composed of granulation tissue with mixed inflammatory cell infiltrate of lymphocytes, histiocytes, neutrophils, and occasionally plasma cells. Inflammation including scattered eosinophils extends into underlying muscle.
What is an epignathus?
A teratoma that arises in the oral cavity. Most common sites are palate and tongue.
Teratomas of the oral cavity.
AKA epignathus. Rare; 1 in 4000 live births have teratoma, and 1-2% of those involve head and neck. Most common sites of teratoma of the oral cavity are palate and tongue. Prenatally, can have polyhydramnios due to impaired fetal swallowing, and AFP concentrations are increased. At birth, can have significant respiratory distress. Top DDx: dermoid cyst or encephalocele.
What is the most common type of rhabdomyosarcoma?
Embryonal rhabdomyosarcoma is the most common type (65% of RMS cases) and usually occurs in children ages 3-10 in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Subtypes of embryonal rhabdomyosarcoma include embryonal NOS, anaplastic, botryoid, and spindle cell, with embryonal NOS being the most common subtype (75%).
What is the most common subtype of embryonal rhabdomyosarcoma?
Embryonal rhabdomyosarcoma is the most common type of rhabdomyosarcoma (65% of RMS cases) and usually occurs in children ages 3-10 in the head and neck (nasal and oral cavities, orbit, ear), prostate or paratesticular regions. Subtypes of embryonal rhabdomyosarcoma include embryonal NOS, anaplastic, botryoid, and spindle cell, with embryonal NOS being the most common subtype (75%).
Polycystic disease of the parotid.
AKA dysgenetic polycystic parotid gland disease. Marked dilation and cystic change within intercalated ducts of parotid gland; striated and excretory ducts unaffected. Rare developmental anomaly not associated with polycystic disease of other organ systems. Typically becomes evident in childhood. F»>M. No malignant transformation.
Hemangiomas in salivary gland.
All histologic variants of hemangioma occur in salivary glands, but capillary (juvenile) hemangioma is most common. Hemangiomas account for 90% of parotid gland tumors in infants <1 yo are hemangioma. Capillary (juvenile) hemangiomas have M:F = 1:3, while cavernous hemangiomas tends to be seen more frequently in older males. Parotid gland involved in 90%, and up to 25% are bilateral. Pediatric tumors initially grow rapidly, but 75-95% spontaneously involute before 7 yo, and many earlier. Pharmacological therapy (corticosteroids and interferon) yields a response in up to 98% of cases. IHC: Endothelial cells pos for CD31, CD34, FVIIIRAg. Residual salivary ducts are keratin pos. GLUT1 pos in juvenile hemangiomas.
Mucoepidermoid carcinoma in salivary gland. Epidemiology. Prognosis.
A malignant epithelial tumor with variable components of mucous, epidermoid, and intermediate cells. Environmental exposure: ioning radiation (latent period varies, and long-term f/u is required). Most common malignant salivary gland tumor, ~16% of all salivary gland tumors, most common salivary gland tumor to arise in gnathic bones. Wide age range. Most common malignant salivary gland tumor in children. M<F. Parotid gland most common location. Central (primary intraosseous) type has predilection for mandible. Prognosis: LG tumors rarely met and only 2.5% result in death; for HG tumors, 55-80% met or result in death. Mets go to lung, bone, brain. Sites of aggressive tumors regardless of grade: submandibular gland, tongue, floor of mouth. Primary intraosseous rarely met.
Xp11.2 translocation renal cell carcinoma is a subtype of renal cancer defined by a breakpoint at Xp11.2 with gene fusions between the transcription factor E3 (TFE3) gene and 6 other genes. The most common fusion partners are ___.
Xp11.2 translocation renal cell carcinoma is a subtype of renal cancer defined by a breakpoint at Xp11.2 with gene fusions between the transcription factor E3 (TFE3) gene and 6 other genes. The most common fusion partners are the papillary renal cell carcinoma (PRCC, 1q21) gene and alveolar soft part sarcoma chromosome region, candidate 1 (ASPSCR1, 17q25) gene. The same ASPSCR1-TFE3 gene fusion is seen in alveolar soft part sarcoma, a rare pediatric tumor. Another renal translocation carcinoma exhibits the t(6;11)(p21;q12) translocation with a gene fusion between the alpha gene and the transcription factor EB (TFEB) gene. Both TFEB and TFE3 are members of the MiTF/TFE family of transcription factors.
The only known predisposing risk factor for developing translocation RCC is ___.
The only known predisposing risk factor is cytotoxic chemotherapy treatment during childhood, which was found in about 15% of patients. The chemotherapeutic agents are thought to cause DNA damage, which then induces repair mechanisms that foster a translocation.
How does patient age affect lab test values in the pediatric population (specifically, for Hb, bilirubin, glucose, alk phos, Cr, uric acid)?
Age of the patient has an effect on serum constituents. In the newborn, much of the Hb is Hb F, not Hb A, as seen in the adult. Bilirubin concentration rises after birth and peaks at about 5 days. In cases of hemolytic disease of the fetus and newborn (HDFN), bilirubin levels continue to rise. This often causes difficulty in distinguishing between physiologic jaundice and HDFN. Infants have a lower glucose level than adults because of their low glycogen reserve. With skeletal growth and muscle development, serum alkaline phosphatase and creatinine levels, respectively, also increase. The high uric acid level seen in a newborn decreases for the first 10 years of life, then increases, especially in boys, until the age of 16.
Brief overview of spindle cell rhabdomyosarcoma.
Spindle cell rhabdomyosarcoma is a rare variant of embryonal rhabdomyosarcoma that has a predilection for young males and most commonly involves the paratesticular region followed by head and neck. Histopathology demonstrates elongated spindle cells with fusiform to cigar-shaped nuclei and indistinct eosinophilic cytoplasm arranged in fascicles or whorls. Although the tumor demonstrates increased cellularity and moderate atypia, the microscopic and architectural patterns can allow this tumor to be confused with multiple entities, such as leiomyosarcoma, spindle cell carcinoma, desmoplastic melanoma, or fibrosarcoma, with important therapeutic implications. IHC workup demonstrates sarcomeric differentiation with reactivity for desmin, myogenin, and MyoD1 markers. Compared with other subtypes, the spindle cell variant in children is associated with a favorable outcome; however, in the adult population there does not appear to be any prognostic advantage.
Micro for spindle cell rhabdomyosarcoma.
Histopathology is dominated by a uniform cellular proliferation of elongated, spindle cells arrayed in fascicles or whorls demonstrating a herringbone growth pattern reminiscent of leiomyosarcoma. The cells have centrally located nuclei with blunted or fusiform ends, small to inconspicuous or prominent nucleoli, and eosinophilic fibrillar cytoplasm. Mitotic figures are easily appreciated, including atypical forms. Admixed with this population can be a second cell type of immature rhabdomyoblasts, usually comprising a small percentage of the total tumor. These cells exhibit eccentric nuclei and bright cytoplasmic eosinophilia; on occasion, cytoplasmic cross-striations can be observed. The presence of these cells should be an intimation of the diagnosis. Collagen fibers are frequently intermingled between the spindle cells; however, the degree is highly variable. The extent of collagen production has led some authors to subclassify SC-RMS into collagen-rich and collagen-poor forms. The subclassification does not appear to affect clinical outcome.
An autoantibody with anti-___ specificity is seen in patients with paroxysmal cold hemoglobinuria, a clinical syndrome that may occur in children following viral infection.
An autoantibody with anti-P specificity is seen in patients with paroxysmal cold hemoglobinuria, a clinical syndrome that may occur in children following viral infection.
In the P blood group system, what is auto-anti-P?
An autoantibody with anti-P specificity is seen in patients with paroxysmal cold hemoglobinuria, a clinical syndrome that may occur in children following viral infection. In PCH, autoanti-P is an IgG, biphasic hemolysin capable of binding RBCs at colder temperatures, followed by intravascular hemolysis at body temperature. This characteristic can be demonstrated in vitro in the Donath-Landsteiner test.
What can cause lack of expected reactivity on forward typing of blood?
Malignancy. Transplantation/transfusion (including intrauterine fetal transfusion). Neonates. Excessive soluble blood group substances.
What can cause a mixed field appearance on forward typing of blood?
Chimera (transplantation chimera; genetic chimera (twin); transfusion chimera). Fetomaternal hemorrhage. Some subgroups of A (e.g. A3 and Aend).
What can cause lack of expected reactivity on reverse typing of blood?
Neonates. Elderly. Severe immunosuppression. Transplantation. Hypogammaglobulinemia. Subgroup of a major blood type.
What is the clinical presentation of HDFN due to materal anti-Kell antibodies?
HDFN secondary to maternal anti-Kell antibodies is often characterized by reticulocytopenia, with little or no bilirubinemia. It is now known that maternal anti-Kell (anti-KEL1 or K1) directly suppresses erythroid progenitors, leading to a severe reticulocytopenic anemia in the fetus with up to 30% of affected infants presenting with fetal hydrops. Anti-K1 is present in approximately 1% of pregnancies, with HDFN affecting 40% of K1-positive infants.
In what ages/races is the Le (a+b+) phenotype seen?
The Le (a+b+) phenotype is only rarely observed, usually on RBCs of very young children and some individuals of Polynesian, Japanese, or Taiwanese ancestry.
In what ages/races is the Le (a-b-) phenotype seen?
The Le (a-b-) phenotype is 5 times more common in blacks than whites. The Le (a−b−) phenotype is also increased in neonates owing to developmentally delayed expression of the Lewis and Secretor genes. By 5 years of age, most children will express adult levels of Lewis antigens on their RBCs.
The Le (a−b−) phenotype is increased in neonates owing to developmentally delayed expression of the Lewis and Secretor genes. By __ years of age, most children will express adult levels of Lewis antigens on their RBCs.
The Le (a−b−) phenotype is increased in neonates owing to developmentally delayed expression of the Lewis and Secretor genes. By 5 years of age, most children will express adult levels of Lewis antigens on their RBCs.
Are anti-Lewis antibodies associtated with HDFN or hemolytic transfusion reactions?
They are not associated with HDFN and are only rarely associated with hemolytic transfusion reactions. For transfusion, patients with anti-Lewis antibodies reactive only at room temperature may be safely transfused with crossmatch–compatible RBCs.
Are antibodies against the Duffy antigens clinically significant?
Antibodies against Fya, Fyb, and other Duffy antigens are clinically significant. They are associated with HDFN and both immediate and delayed hemolytic transfusion reactions. They are usually of IgG isotype, reactive at 37° C, and are detected only in the IAT.
Are anti-Xg^a antibodies associated with hemolytic transfusion reactions or HDFN?
Anti-Xga is not associated with hemolytic transfusion reactions or HDFN. Anti-Xga may be immune stimulated or naturally occurring. Most examples are of IgG isotype, including some capable of activating complement.
Infectious meningitis is divided into acute, subacute, and chronic clinical syndromes, based on duration of symptoms. What are probable pathogens based on these categories?
Acute (onset/duration of <24 hours): Pyogenic bacteria. Subacute (onset/duration of 1-7 days): Enteroviruses, pyogenic bacteria. Chronic (persisting at least 4 weeks): M. tuberculosis, T. pallidum, Brucella sp., L. interrogans, B. burgdorferi, C. neoformans, C. immitis, H. capsulatum.
What are common bacterial causes of acute meningitis by age, for neonates-3 months, 4 months-6 years, 6-45 years, and >45 years?
Neonates-3 months: Group B streptococcus, E. coli, L. monocytogenes (Listeria can cause meningitis in immunocompromised individuals in all age groups). 4 months-6 years (Incidence of meningitis due to HIB in the US has declined dramatically due to vaccination): S. pneumoniae. 6-45 years: N. meningitidis. >45 years: S. pneumoniae, L. monocytogenes, Group B streptococcus.
Do anti-Jk antibodies cause HDFN?
Although uncommon, anti-Jk can cause a mild HDFN.
Are anti-Dombrock antibodies clinically significant?
Anti-Dombrock antibodies can be clinically significant, although many examples are benign. Anti-Dombrock antibodies are capable of causing shortened RBC survival and acute and delayed hemolytic transfusion reactions. Anti-Dombrock is not associated with HDFN. Antibodies against Dombrock antigens are usually of IgG isotype, arising from immune stimulation by transfusion or pregnancy.
Are anti-Colton antibodies clinically significant?
Anti-Colton antibodies can be clinically significant: They can be associated with shortened RBC survival, hemolytic transfusion reactions, and HDFN. Antibodies to Coa and Cob are usually of the IgG isotype, resulting from immune stimulation by transfusion or pregnancy. Some examples of anti-Coa and anti-Cob are reported to bind complement.
Are antibodies to the LW blood group system clinically significant?
Clinically benign, anti-LW antibodies are rarely a cause of hemolytic transfusion reactions or HDFN. They usually are of IgG isotype and are detected in the IAT.
Are antibodies against the Chido/Rodgers blood group system antigens clinically significant?
Antibodies against Ch/Rg antigens do not cause hemolytic transfusion reactions or HDFN. Rare reports have described anaphylaxis following transfusion of plasma and platelets. Anti-Ch/Rg antibodies are of IgG isotype and are usually detected with AHG.
By what physiologic mechanisms does hydrops fetalis occur?
HDFN is the destruction of fetal or newborn RBCs by maternal alloantibodies specific for inherited paternal RBC antigen(s). The maternal IgG is transported across the placenta into the fetal circulation where it binds to the corresponding RBC antigen, targeting the antibody-coated RBCs for destruction by macrophages in the fetal spleen. The fetal marrow initially responds by increasing erythropoiesis and releases many of the newly produced RBCs into the circulation prematurely as nucleated precursors, leading to the term “erythroblastosis fetalis.” With worsening anemia, erythropoiesis expands to the liver and spleen, causing organ enlargement and portal hypertension. A resulting decrease in liver production of albumin leads to reduced plasma colloid osmotic pressure, generalized edema, ascites, and effusions known as “hydrops fetalis.”
Overview of chondromyxoid fibroma.
A rare benign cartilaginous bone tumor arising in young adults aged 15-25 years that often occurs in the metaphysis of long tubular bones or in the small bones of the feet. Grossly: well circumscribed, solid and glistening. It is often lobulated with zonation. Older tumors are more hyalinized. Microscopic: well circumscribed, hypocellular lobules of poorly formed hyaline cartilage composed of chondroblasts with abundant pink cytoplasm, and myxoid tissue with fibrous septae containing spindle cells and osteoclasts. Atypia is common, including large, hyperchromatic nuclei. Scattered calcification and osteoclast-like giant cells are present. At the periphery, the tumor is more cellular and vascular. No/rare mitotic activity. Tumors often have 6q13 rearrangements, with recurrent 6p25 and 6q25 anomalies.
Rosette test. If there is insufficient or no washing before adding the indicator red blood cells, there can be a false (positive/negative) result. If the mother is a weak D phenotype, there can be a false (positive/negative) result. If the fetus is weak D phenotype, there can be a false (positive/negative) result.
Rosette test. If there is insufficient or no washing before adding the indicator red blood cells, there can be a false positive result because excess unbound anti-D reagent is still present. If the mother is a weak D phenotype, there can be a false positive result because she may type as negative even though she is actually positive, and the test needs to have a D- mother and a D+ fetus to work as it should. If the fetus is weak D phenotype, there can be a false negative result because the weak D may not be enough to bind the anti-D reagent. In this last situation, if a baby initially types as D-, weak D testing is done, and if weak D is positive, go straight to a Kleihauer-Betke test instead of doing a rosette test.
The rosette test can detect a fetomaternal hemorrhage of approximately __ mL or more.
The rosette test can detect a fetomaternal hemorrhage of approximately 10 mL or more.
In the Kleihauer-Betke test, what is the formula?
(Fetal cells x Maternal blood volume) / Total cells counted = Fetal hemorrhage in mL. Maternal blood volume is calculated from 70 mL/kg or assumed to be 5000 mL if weight is not known. Total cells counted is always 2000. The result is divided by 30 (b/c one dose of RhIG (30 ug) covers 30 mL of whole blood). The resulting number is then rounded down if the number to the right of the decimal point is less than 5, then 1 is added to give the total vials/doses of RhIG. The resulting number is rounded up if the number to the right of the decimal point is 5 or more, then 1 is added to give the total vials/doses of RhIG.
What are indications for washed blood products?
Prevention of recurrent severe allergic/anaphylactic transfusion reactions. Neonatal alloimmune thrombocytopenia. Large-volume or rapid transfusion into neonates and small children. Irradiated RBC products. Patients with T-activation. Washing of RBC products for patients with paroxysmal nocturnal hemoglobinuria used to be advocated, but is no longer recommended.
Neonatal alloimmune thrombocytopenia (NAIT) is secondary to maternal alloantibodies, usually ___, against the platelet antigen in the fetus or neonate.
Neonatal alloimmune thrombocytopenia (NAIT) is secondary to maternal alloantibodies, usually anti-HPA-1a, against the platelet antigen in the fetus or neonate.
In neonatal alloimmune thrombocytopenia, maternal platelets are serologically compatible and are therefore a potential source of platelets for transfusion to the fetus/neonate. What must be done to the maternal platelets before transfusion?
Prior to transfusion the maternal platelets must be washed to remove the antibody against the fetal/neonatal platelet antigen contained within the maternal plasma, and irradiated to prevent TA-GVHD.
Why are washed RBC products indicated for large volume (>25 mL/kg) or rapid transfusion in neonates and small children?
Washing may be used to remove potassium, anticoagulant-preservative solution (particularly additive solutions) and other substances in the supernatant in RBC products. This decreases the risk of hyperkalemia and cardiac arrhythmias. Volume reduction can achieve the same goal.
Unlike HDFN caused by anti-D, HDFN caused by anti-K uniquely produces suppression of fetal ___, in addition to hemolysis.
Unlike HDFN caused by anti-D, HDFN caused by anti-K uniquely produces suppression of fetal erythropoiesis, in addition to hemolysis.
Which causes more severe HDFN, IgG1 or IgG3?
IgG1 is associated with more severe disease because it is transported across the placenta earlier and in larger amounts than IgG3.
Before the development of color Doppler US, the severity of HDFN was usually monitored by ___.
Before the development of color Doppler US, the severity of HDFN was usually monitored by amniocentesis, typically performed with US guidance, to follow the level of bilirubin in amniotic fluid. The aspirated amniotic fluid is protected from light and tested by a scanning spectrophhotometer for the change in fluid optical density at 450 nm, which is proportional to the bilirubin concentration. The delta OD 450 is then plotted on a graph according to gestational age. The graph is divided into zones that correspond to severity disease.
Amniotic fluid analysis for bilirubin does not correlate well with the degree of fetal anemia in HDFN in mothers with ___ system antibodies. For these patients, middle cerebral artery peak systolic velocity and/or cordocentesis is indicated.
Amniotic fluid analysis for bilirubin does not correlate well with the degree of fetal anemia in HDFN in mothers with Kell system antibodies. For these patients, middle cerebral artery peak systolic velocity and/or cordocentesis is indicated.
Which is the more common cause of HDFN, ABO incompatibility or D incompatibility?
With the widespread use of RhIG, ABO incompatibility has become the most common cause of HDFN. D incompatibility is more severe, though.
In the US, what is the platelet antigen most commonly implicated in fetal and neonatal alloimmune thrombocytopenia (FNAIT)?
HPA-1a, formerly known as P1 A1, accounts for ~80% of cases. HPA-5b accounts for ~10%, HPA-1b accounts for ~4%, HPA-3a accounts for 2%, and 6% is by other antibodies.
Are antibodies to the Cromer blood group system clinically significant?
The clinical significance of anti-Cromer antibodies is variable. In some individuals, anti-Cromer antibodies are associated with decreased RBC survival and HTRs. Cromer antibodies do not cause HDFN owing to adsorption of antibodies by DAF (Cromer antigens are present on DAF (CD55)) on trophoblast epithelium.
How many antigens are in the Indian blood group system? On what glycoprotein are the Indian antigens present? Are antibodies against the Indian antigens clinically significant?
The Indian (IN) blood group contains 2 autosomal codominant antigens: In^a (IN1) and In^b (IN2). Three additional high-incidence antigens are known: IN3, IN4, and AnWj. The Indian antigens are present on CD44, a ubiquitous glycoprotein on many cell membranes. Antibodies against the Indian antigens can be clinically significant, with shortened RBC survival and transfusion reactions. They are not associated with HDFN.
How many antigens are in the JMH blood group system? On what protein is it found? Are anti-JMH antibodies clinically significant?
The JMH (John Milton Hagen) system contains 6 high-incidence antigens and can vary in strength between individuals. JMH is carried on CD108 (SEMA-L), a semaphorin glycoprotein. Anti-JMH antibodies are of IgG isotype and can be naturally occurring. They do not cause HTRs or HDFN.
The I blood group system. What are the antigens and how are they biochemically related? How do the antigen expressions change with age of the person? On what cells/tissues are the antigens present?
The I blood group system contains two biosynthetically related antigens: I and i. The biosynthetic precursor to I antigen, the i antigen, is strongly expressed on cord cells because of developmental delays in the enzyme responsible for I antigen synthesis. By 3 months of age, there is a perceptible decrease in i antigen, accompanied by increased I antigen, with an adult I+i− phenotype by 18–24 months of age. Both I and i antigens are ubiquitously expressed on glycolipids and glycoproteins on red cells and other tissues.
The i antigen from the I blood group system is normally present only in children. In what conditions/situations do adults have increased i antigen?
The iadult phenotype is a rare, autosomal recessive phenotype found in <1/10,000 donors. In Asia, the iadult phenotype can be associated with congenital cataracts. i antigen is also observed on cord RBCs and reticulocytes and in megaloblastic anemia, leukemia, and chronic hemolytic states as a sign of stressed erythropoiesis. Elevated i antigen is also observed in HEMPAS (hereditary erythroblastic multinuclearity with positive acidified-serum test), a congenital dyserythropoietic anemia.
Despite the common occurrence of major maternal-fetal ABO incompatibility, severe HDFN due to ABO incompatibility is rare (0.04%). How is the developmental delay in I antigen synthesis thought to be protective?
It is hypothesized that the developmental delay in I antigen synthesis may play a protective role against HDFN-ABO by minimizing the number of ABH antigens expressed on fetal red cells. This is supported by parallel increases in I and ABH during the first 2 years of life.
The GIL blood group system. How many antigens are in the system? On what protein is the antigen carried? Is anti-GIL clinially significant?
The GIL blood group system contains one high-incidence antigen, GIL (100% donors). GIL is carried by aquaglyceroporin (AQP-3), a member of the major intrinsic protein family of water channels. Anti-GIL is associated with hemolytic transfusion reactions. No reports have described clinical HDFN due to anti-GIL despite a positive DAT. Anti-GIL is usually of IgG isotype, reactive at 37° C and enhanced with AHG.
The presence of ___ and ___ in cord blood is responsible for the nonspecific agglutination that can be seen in cord blood samples contaminated with Wharton’s jelly.
The presence of hyaluronic acid and albumin in cord blood is responsible for the nonspecific agglutination that can be seen in cord blood samples contaminated with Wharton’s jelly.
Isolated lymphopenia is uncommon but may be seen in what conditions (6)?
Isolated lymphopenia is uncommon but may be seen in SLE, HIV, SARS, anti-CD20 (rituxan) therapy, steroid therapy, and certain congenital immunodeficiencies (Bruton, SCID, DiGeorge, CVI).
Pancreatoblastoma. Ages affected?
Pancreatoblastoma has a bimodal distribution, with tumors presenting in both children (mean age 2.4 yrs) and adults (mean age 40 yrs), although the incidence (or perhaps simply its diagnosis) is more common in the young.
Nasal chondromesenchymal hamartoma. Epidemiology? Histologic appearance? DDx?
A rare, often cystic lesion that typically fills the nasal cavity and extends into the ethmoid sinuses. It is considered an upper respiratory tract analogue of chest wall mesenchymal hamartoma. Although benign, it may erode the cribriform plate, and have an intracranial component. It is more common in males (2/3), and typically affects children, with a mean age of 14 months. Histologically, there is well demarcated mature cartilage, myxoid stroma and spindle cells. There may also be focal osteoclast-like giant cells, aneurysmal bone cyst-like formations, and collagen fibers. DDx: aneurysmal bone cyst, chondroblastoma, chondromyxoid fibroma, fibrous dysplasia, osteochondromyxoma.
What are the 4 main sources of alkaline phosphatase in the body?
Bile ducts, bone, placenta, intestine.
Put the 4 alkaline phosphatase isoenzymes into order of anodal mobility on electrophoresis.
Anodal mobility 1 = biliary. Anodal mobility 2 = bone. Anodal mobility 3 = placenta. Anodal mobility 4 = intestinal.
For the 4 alkaline phosphatase isoenzymes, list how strongly each is inhibited by L-phenylalanine and by heat/urea (sensitivity to heating parallels sensitivity to urea incubation, which is why they are grouped).
Biliary: -, +. Bone: -/+++. Placenta: +++/-. Intestinal: +++/+. For sensitivity to heat/urea, think “bone burns, placenta persists.”
What is the Regan isoenzyme?
AKA carcino-placental alkaline phosphatase. Appears to be mostly identical to placental alk phos (same anodal mobility, same degree of inhibition by L-phenylalanine, slightly less degree of heat/urea inhibition). The Regan isoenzyme is observed in ~5% of individuals with carcinoma.
Hyperammonemia is nearly always due to ___.
Hyperammonemia is nearly always due to liver failure. However, particularly in children, it should raise suspicion for an inborn error of metabolism (especially urea cycle enzyme deficiencies).
What are 6 general causes of unconjugated neonatal hyperbilirubinemia?
Physiologic jaundice. Breast milk jaundice. Polycythemia. Hemolysis (HDN, hemoglobinopathies, inherited membrane or enzyme defects). Bowel obstruction (Hirschprung disease, cystic fibrosis, ileal atresia). Inherited disorders of bilirubin metabolism (Gilbert syndrome, Crigler-Najjar syndrome).
What are 6 general causes of conjugated neonatal hyperbilirubinemia?
Biliary obstruction (extrahepatic biliary atresia). Sepsis or TORCH infection. Neonatal hepatitis (idiopathic, Wilson disease, alpha-1 antitrypsin deficiency). Metabolic disorders (galactosemia, hereditary fructose intolerance, glycogen storage disease). Inherited disorders of bilirubin transport (Dubin-Johnson syndrome, Rotor syndrome). Parenteral alimentation.
What areas of the brain specifically are affected in kernicterus?
Bilirubin has a special affinity for the globus pallidus, the hippocampus, and the subthalamic nucleus. Many other structures, including the striatum, thalamus, cranial nerve nuclei, inferior olives and dentate nuclei of the cerebellum are less frequently affected.
Is phototherapy effective for unconjugated or conjugated hyperbilirubinemia?
Unconjugated hyperbilirubinemia. Phototherapy converts unconjugated bilirubin into a molecule that can be excreted without conjugation; phototherapy is not useful for conjugated hyperbilirubinemia.
What are the characteristics of physiologic jaundice in neonates?
Usually noted between days 2-3 of neonatal life and rarely rises at a rate greater than 5 mg/dL/day. Usually peaks by days 4-5 and rarely exceeds 5-6 mg/dL.
In a healthy term infant, phototherapy should be considered when bilirubin exceeds __ mg/dL before 12 hours of age, __ mg/dL before 18 hours of age, and __ mg/dL before 24 hours of age.
In a healthy term infant, phototherapy should be considered when bilirubin exceeds 10 mg/dL before 12 hours of age, 12 mg/dL before 18 hours of age, and 14 mg/dL before 24 hours of age.
In what metabolic disorder is urine black, connective tissue grossly blue-black, and connective tissue microscopically brown or ochre?
Alkaptonuria, an autosomal recessive disorder of amino acid metabolism. Increased homogentisic acid is secreted in urine and polymerized homogentisic acid deposits accumulate in connective tissue. The pigment is Fontana-Masson positive and Prussian blue negative.
Which Legionella species and subgroups cause human disease most frequently in adults and children?
Although more than 70 Legionella serogroups have been identified among 50 species, L pneumophila causes most legionellosis. L pneumophila serogroup 1 alone is responsible for 70-90% of cases in adults. In a pediatric series, L pneumophila serogroup 1 accounted for only 48% of cases, serogroup 6 accounted for 33%, and the remaining cases involved other serotypes and species. Legionella micdadei and L dumoffii are the second and third most common species to cause Legionnaires disease in children, respectively,
What are the peak incidence ages and M:F for the endemic and sporadic forms of Burkitt lymphoma?
Endemic form: peak age 4-7, M:F = 2:1. Sporadic form: peak incidence in children is age 11 and median age in adults is age 30, M:F = 3-4:1.
What are the most common causes of meningitis in neonates?
GBS, GN aerobic bacilli (E. coli, Klebsiellae), L. monocytogenes.
What are the most common causes of meningitis in adults and elderly adults?
In adults, S. pneumoniae, followed by N. meningitidis. In elderly adults, S. pneumoniae, followed by L. monocytogenes, followed by GN aerobic bacilli.
___, the virus that causes exanthem subitum, is a common cause of viral encephalitis in children, and is thought to contribute to many cases of febrile seizures in children.
HHV-6, the virus that causes exanthem subitum, is a common cause of viral encephalitis in children, and is thought to contribute to many cases of febrile seizures in children.
What ages/conditions are risk factors for L. monocytogenes meningitis?
Extremes of age (70 yo), corticosteroid therapy, transplant, DM, HIV, iron overload.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): bacterial (septic) arthritis (monoarticular in children and adults, and polyarticular in young adults).
Monoarticular in children and adults: S. aureus. Polyarticular in young adults: N. gonorrhea.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): croup (acute laryngotracheobronchitis).
Parainfluenza virus, serotypes 1-3.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): viral pneumonia in infants/children and in adults.
Infants/children: RSV. Adults: Influenza A (orthomyxovirus).
For the following clinical syndrome(s), give the causative agent(s) (list most common first): acute epiglottitis.
H. influenzae type B.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): whooping cough.
Bordatella pertussis.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): measles and German measles.
Measles: Rubeola virus. German measles: Rubella virus.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): roseola infantum (exanthem subitum).
HHV-6.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): fifth disease (erythema infectiosum, slapped-cheek disease).
Parvovirus B19.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): scarlet fever.
S. pyogenes (GAS).
What is congenital varicella vs. perinatal varicella?
Congenital varicella is diagnosed when there is evidence of maternal varicella infection during pregnancy, skin lesions on the newborn that have a dermatomal distribution, and serologic evidence of infection in the newborn (either IgM or persistent IgG beyond 7 months). Perinatal varicella arises when maternal infection occurs within a few days of delivery.
The incidence and severity of congenital varicella depend upon the timing of maternal infection. Discuss.
When a woman is infected during pregnancy, the overall incidence of congenital varicella is 1-5%. The incidence is lowest when maternal infection occurs in the 1st trimester and highest in the 3rd. In contrast, the likelihood of perinatal varicella is 50-60%.
What is the most common congenital infection in the US?
CMV. Congenital CMV results from transplacental infection and is most likely to occur when a pregnant woman experiences primary CMV infection during gestation. 30-40% of pregnancies with primary CMV infection result in congenital CMV. In contrast, reactivation infection during pregnancy results in <1% incidence of transplacental transmission.
