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.
What are the most common sequalae seen in survivors of congenital CMV infection?
Sensorineural hearing loss is detected in ~70%of newborns with symptomatic congenital CMV infection and in ~15% with asymptomatic infection. This hearing loss almost always is progressive, eventually producing severe to profound hearing loss in the affected ear(s).
In intrauterine fetal death, how soon can maceration be seen?
Maceration may be seen at delivery in as early as 6 hours and almost always by 12 hours.
What ages does SIDS affect?
Although the definition includes infants up to 1 year of age, one should be hesitant to certify a death as due to SIDS before 1 month of age or after 6 months of age.
Is SIDS heritable?
SIDS is a sporadic, nonheritable syndrome. A prior SIDS death in the same family should raise the suspicion of a genetic disorder (such as metabolic disease) or homicide.
What are risk factors for development of hepatoblastoma?
Extreme prematurity, very low birth weight, Beckwith-Weidemann syndrome, family history of APC gene mutations, and congenital hepatic fibrosis associated with autosomal recessive poly cystic kidney disease.
What are risk factors for development of HCC in children?
GSD type 1a, hereditary tyrosinemia, HBV infection, and chronic cholestasis disorders including biliary atresia, progressive familial hepatic cholestasis type 2 (ABCB11 disease), and Alagille syndrome.
What are the 3 types of pleuropulmonary blastoma?
Type I (cystic). Type II (cystic and solid). Type III (solid).
What are the 5 types of congenital pulmonary airway malformation in the Stocker classification?
Type 0 CPAM to type 4 CPAM. Type 4 is now thought to represent a regressed or undersampled form of type I (cystic) pleuropulmonary blastoma.
What is fetal lung interstitial tumor?
FLIT is a congenital pulmonary mass typically identified prenatally or within the first 3 months of life. Histologically, the tumor has immature airspace structures separated by widened cellular septa giving the tumor a microcystic appearance. The spaces are lined by flat to cuboidal non-ciliated epithelium with clear cytoplasm. The septa contain a monotonous population of immature, round to ovoid mesenchymal cells in the interstitium. The interstitial cells are PAS positive diastase sensitive, positive for vimentin, and there is variable positivity for SMA and desmin in cases with myofibroblastic morphology.
Low grade fibromyxoid sarcoma is seen in what ages and locations?
LGFMS are often seen in young adult males with a median age in the third decade. But they are not uncommon in children, with up to a third of cases in those <18. LGFMS is typically a slow growing, painless deep soft tissue tumor of the extremities and trunk, superficial and visceral lesions can also be seen.
What are fetiform teratoma and fetus in fetu, and how can they be distinguished?
FT is a highly developed and organized mature teratoma resembling a malformed fetus. FIF is a parasitic monozygotic twin usually found inside the body of a neonate or infant (essentially, a form of monozygotic monochorionic diamnionic twin gestation in which the parasitic twin grows inside the body of its partner). Classically, the distinguishing feature of FIF has been the presence of an axial skeleton, but this is now controversial, and it is thought that FT and FIF lie along a continuum.
Can mesenchymal hamartoma of liver and infantile hemangioendothelioma cause elevated AFP levels?
Yes.
What feature of the cysts in mesenchymal hamartoma of liver distinguishes it from choledochal cysts and Caroli disease?
The cysts in MHL do not communicate with the biliary tree, whereas the latter 2 entities by definition do communicate with the biliary tree.
What is the relationship between mesenchymal hamartoma of the liver and undifferentiated embryonal sarcoma?
Rarely, UES has arisen either in a preexisting MHL or following incomplete excision of MHL.
What genetic abnormalities have been identified in mesenchymal hamartoma of liver?
Aneuploidy in some, as well as balanced translocation involving a common breakpoint on the long arm of chromosome 19 (band 19q13.4) with alternative partners on chromosomes 11 and 15.
Achondroplasia is an autosomal dominant disorder. It is due to mutation in what gene? What % are caused by sporadic new mutations?
Fibroblast growth factor receptor 3, encoded by the FGFR3 gene on chromosome 4p16.3. 75% of cases are caused by sporadic new mutations.
What is the most common form of skeletal dysplasia, and what is the most common lethal form of skeletal dysplasia?
Most common form of skeletal dysplasia: achondroplasia (1 per 10-30,000 live births). Most common lethal form of skeletal dysplasia: thanatophoric dysplasia (1 per 35-50,000 births).
Lipoblastoma is a tumor of infancy and early childhood composed of lobules of mature adipocytes and lipoblasts in different stages of development within peripheral zones of myxoid stroma. M:F = 2:1. Genetic abnormality?
Lipoblastomas are characterized by rearrangements of 8q11-13 involving the PLAG1 gene.
What are the most common genotypes for complete and partial moles?
The most common genotype of complete moles is 46,XX; a small number are 46,XY. Triploid and tetraploid complete moles are much less common. Triploid conceptions which have duplication of paternal chromosomes are partial moles, typically with a 69,XXX or 69,XXY genotype. Triploid conception resulting from a duplication of maternal chromosomal material (also 69,XXX or 69,XXY genotype) represent non-molar triploidy and lack the trophoblastic proliferation which is the hallmark of a molar pregnancy.
Both partial hydatidiform mole and non-molar triploid conceptions can have 69,XXX or 69,XXY genotypes. What differentiates them?
Triploid conceptions which have duplication of paternal chromosomes are partial moles, typically with a 69,XXX or 69,XXY genotype. Triploid conception resulting from a duplication of maternal chromosomal material (also 69,XXX or 69,XXY genotype) represent non-molar triploidy and lack the trophoblastic proliferation which is the hallmark of a molar pregnancy.
p57 IHC is useful for distinguishing complete hydatidiform mole from hydropic abortus and partial hydatidiform mole (HA and PHM have nuclear staining of villous cytotrophoblast and stromal cells, while CHM does not). What IHC stain distinguishes HA from PHM?
IHC cannot distinguish HA (biparental diploidy) from PHM (diandric triploidy). Short tandem repeat genotyping, which determines the parental source of polymorphic alleles, is useful.
Placental mesenchymal dysplasia is an unusual placental condition where stem villi are hydropically enlarged. MD is typically seen in the second to third trimester. Is it associated with normal or abnormal pregnancies?
Both. It is seen in association with normal pregnancy or Beckwith-Wiedemann syndrome.
What are renal metanephric stromal tumors?
MSTs are a group of benign tumors of the kidney, distinct from congenital mesoblastic nephroma with which they were previously grouped. They are now thought to be related more closely to Wilms tumor rather than mesenchymal tumors of the kidney. They were first recognized and referred to as nephrogenic adenofibroma, but were subsequently renamed as MST. They are considered to be part of the spectrum of metanephric tumors ranging from metanephric adenoma to metanephric adenofibroma to MST, all considered to represent the benign end of Wilms tumor.
Histologic appearance of metanephric stromal tumor?
Loose spindle cell proliferation with uniform hyperchromatic nuclei and thin indistinct cytoplasm. No capsule. Subtle infiltration into adjacent renal parenchyma. The spindle cells surround entrapped renal tubules and show condensation around them with a myxoid background giving it a characteristic “onion skin” pattern. There may be areas of prominent cellularity or epithelioid morphology. Prominent vascularity with changes of angiodysplasia. Another feature is the presence of heterologous elements, usually glial or cartilaginous.
What 2 entities are in the main DDx for metanephric stromal tumor, and how can they be differentiated?
Congenital mesoblastic nephroma and clear cell sarcoma of kidney. CMN: Unencapsulated like MST but more infiltrative. Entraps tubules only at the periphery and usually does not have mesenchymal collars like MST. Cellular CMN have the classic cytogenetic abnormality t(12;15). CMN lacks the heterologous elements and angiodysplasia as seen in MST. Are frequently desmin and/or actin positive, reflecting their myofibroblastic nature. CCSK: Is extremely cellular, although some may be composed of large areas of bland spindle cells mimicking MST. Lacks onion-skinning around tubules or heterologous elements. Has a characteristic branching vascular pattern not seen in MST.
What are the 3 most common intramedullary spinal cord lesions in the pediatric population?
Astrocytomas (40-60%, with low grade fibrillary astrocytomas (WHO grade II) being more common than pilocytic astrocytomas (WHO grade I)). Ependymomas (20-30%). Gangliogliomas (15-27%).
Clear cell sarcoma of the kidney metastasizes frequently to ___.
Clear cell sarcoma of the kidney metastasizes frequently to bone (which is unlike Wilms tumor). Bony mets often precede mets to organs, and affected children may be hypercalcemic at presentation. In fact, CCSK was initially referred to as “bone matastasizing renal tumor of childhood”.
What is the classic histologic appearance of clear cell sarcoma of the kidney?
Nests or cords of cells separated by regularly spaced, arborizing fibrovascular septa. Regularly spaced small blood vessels give a “chicken wire” pattern. Slightly variable ovoid nuclei with finely granular chromatin. Frequent empty nuclei. Mitoses are uncommon.
What is Alexander disease?
AKA fibrinoid leukodystrophy, is a rare leukodystrophy with 3 clinical phenotypes: infantile (63%), juvenile (24%), and adult (13%). The majority of infantile and juvenile types are caused by a heterozygous (dominant) gain of function mutation in the gene encoding GFAP, located on chromosome 17q21.
What is the histologic appearance of Alexander disease AKA fibrinoid leukodystrophy?
The disease is characterized by dysmyelination and widespread accumulation of Rosenthal fibers in a subpial, subependymal, and perivascular distribution. Early in the disease process, Rosenthal fibers are noted in astrocyte cell bodies, but later accumulate in the astrocyte processes and end-feet in the subpial and perivascular locations. These findings are accompanied by gliosis and myelin disintegration, but no macrophages, as in multiple sclerosis or subacute infarcts. The areas of Rosenthal fiber accumulation do not correlate necessarily with areas of dysmyelination.
What are Rosenthal fibers?
Rosenthal fibers are eosinophilic intracellular rod, beaded, or corkscrew-shaped inclusions. Measurements range from 0.5-25 μm in width and 30 μm in length, to 10–40 μm in width and 100 μm in length. By EM, the fibers correspond to intracellular non-membrane bound protein deposits associated with groups of intermediate filaments including GFAP, associated with chaperone proteins. They have been described in reactive tissue (such as the highly gliotic tissue surrounding cysts and vascular malformations), in neoplasms (such as juvenile pilocytic astrocytomas), and in Alexander disease.
What is the mutation seen in Alexander disease AKA fibrinoid leukodystrophy?
Alexander disease has 3 clinical phenotypes: infantile (63%), juvenile (24%), and adult (13%). The majority of infantile and juvenile types are caused by a heterozygous (dominant) gain of function mutation in the gene encoding GFAP, located on chromosome 17q21. These mutations are typically sporadic and de novo. In Alexander disease, a heterozygous missense mutation in the GFAP gene appears to interfere with polymerization of the protein, and results in abnormal protein folding with overexpression and accumulation of the abnormal GFAP protein within Rosenthal fibers.
There are >20 known human diseases of intermediate filaments involving the keratins, desmin, lamin A/C, neurofilament, phakinin, and GFAP. Which disease differs from all other known intermediate filament disorders in that there is a gain of function mutation, rather than a loss of function mutation?
Alexander disease AKA fibrinoid leukodystrophy.
What is Alagille syndrome (AGS) AKA syndromic paucity of interlobular bile ducts AKA arteriohepatic dysplasia?
AGS is a multisystem disorder with AD inheritance and variable penetrance and expressivity. The traditional diagnostic criteria have consisted of paucity of the interlobular bile ducts in association with 3 of 5 major findings, including chronic cholestasis, cardiac disease (most frequently peripheral pulmonary artery stenosis), skeletal manifestations (short stature, butterfly vertebrae), ocular abnormalities (most commonly posterior embryotoxon, a circular opacity of the posterior peripheral cornea), and characteristic facial features (triangular face with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip). Mutations are in the JAGGED1 (JAG1) gene.
What is the mutation in Alagille syndrome?
Mutations are in the JAGGED1 (JAG1) gene, which encodes a cell surface protein that functions as a ligand in the Notch signaling pathway regulating cell proliferation and differentiation. The precise mechanisms by which JAG1 mutations cause AGS is still incompletely understood. JAG1 mutations have been identified in >90% of clinically diagnosed probands; additionally, NOTCH2 mutations have been detected in the small minority of AGS patients lacking JAG1 mutations.
In Alagille syndrome, abnormalities in which organ system causes the most mortality?
Hepatic complications do contribute significantly to the morbidity of AGS but it is the cardiovascular sequelae that are most directly responsible for the early mortality. Specifically, intracardiac anomalies, which affect ~25% of AGS patients (most commonly tetralogy of Fallot).
What brain tumors are associated with the following syndromes? Turcot syndrome/APC gene mutations. Tuberous sclerosis. Von Hippel Lindau disease. Li-Fraumeni syndrome. NF type 1. NF type 2. Gorlin syndrome.
Turcot syndrome/APC gene mutations: medulloblastoma, rarely ependymoma. Tuberous sclerosis: subependymal giant cell astrocytoma. Von Hippel Lindau disease: hemangioblastoma. Li-Fraumeni syndrome (with germline TP53 mutations): medulloblastoma, astrocytic tumors, meningioma, schwannoma, choroid plexus tumors, and central PNET. NF type 1: optic glioma, astrocytoma, glioblastoma multiforme. NF type 2: multiple meningiomas, bilateral vestibular schwannomas, spinal ependymomas. Gorlin syndrome: desmoplastic/nodular variant of medulloblastoma.
What is nuchal fibroma, and how is it associated with FAP/Gardner syndrome?
Uncommon fibrocollagenous lesion classically arising in cervicodorsal region. However, it is not restricted to the nuchal region so the term nuchal-type fibroma can be used. Some cases are linked to FAP/Gardner syndrome. The sporadic lesions are often nuchal, seen in 3rd-5th decades, and have striking male predominance. The Gardner-associated cases mostly involve trunk, head and neck, and extremities, are seen in infants to adolescents, and have no gender predominance.
What is inclusion body fibromatosis AKA infantile digital fibromatosis AKA digital fibrous tumor of childhood AKA Reye tumor?
Rare fibroblastic/myofibroblastic neoplasm consisting of a benign proliferation of fibroblasts and myofibroblasts containing scattered eosinophilic inclusion bodies that occur on the digits of children.
What is fibrolipomatous hamartoma AKA fibrolipomatous hamartoma of nerve AKA lipofibromatous hamartoma of nerve AKA neural lipofibroma AKA neurolipomatosis AKA lipomatosis of nerve?
Increased fibrofatty tissue infiltrating and surrounding nerves. Seen predominantly in children. Affects palmar surface of hand, wrist, or forearm, with median nerve and branches most commonly affected. Histologic appearance: Adipose tissue and fibrous tissue infiltrating around and between nerve branches and along perineurium. Epineurial and perineurial fibrous thickening. Perineurium can become hyperplastic (concentric layers, “onion bulb” intraneural hyperplasia). Nerve bundles become separated, atrophic in longstanding cases. DDx: Lipoma of nerve (circumscribed and confined within nerve). Neurofibroma (proliferation of neural elements with no fatty component). Neuroma (increased number of nerve bundles with no fatty component). Lipomatosis (usually affects skin and subcutis and spares nerves).
Peutz-Jeghers syndrome is an autosomal dominant condition caused by inactivating mutations in the serine-threonine protein kinase 11 (STK11) gene, also called LKB1, on chromosome 19p13.3. Mutations in STK11 are found in ~__% of familial cases and ~__% of sporadic cases.
Peutz-Jeghers syndrome is an autosomal dominant condition caused by inactivating mutations in the serine-threonine protein kinase 11 (STK11) gene, also called LKB1, on chromosome 19p13.3. Mutations in STK11 are found in ~70% of familial cases and ~30-70% of sporadic cases.
In Peutz-Jeghers syndrome, hamartomatous intestinal polyps can be present throughout the GI tract, but the most common site is ___. Median age for development of polyps is __ yo. The lifetime risk of small intestinal polyps in PJS is __%, and the risk of intussusception in PJS is __%. Colon polyps occur in __%, stomach polyps in __%, and rectal polyps in __%.
In Peutz-Jeghers syndrome, hamartomatous intestinal polyps can be present throughout the GI tract, but the most common site is small intestine (jejunum > ileum > duodenum). Median age for development of polyps is 11-13 yo. The lifetime risk of small intestinal polyps in PJS is 90%, and the risk of intussusception in PJS is 50%. Colon polyps occur in 53%, stomach polyps in 49%, and rectal polyps in 32%.
How is Peutz-Jeghers syndrome diagnosed?
PJS is diagnosed clinically by the presence of 2 or more of the following three criteria: 2 or more PJS-type hamartomatous polyps. Mucocutaneous pigmentation. Familial history of PJS.
Peutz-Jeghers syndrome patients are at increased risk of cancer (__% of patients by age 70), including GI cancer (__x relative risk), pancreatic cancer, lung cancer, and breast cancer (__x relative risk, affecting 8% of patients by age 40, and 31% of patients by age 60).
Peutz-Jeghers syndrome patients are at increased risk of cancer (85-93% of patients by age 70), including GI cancer (50x relative risk), pancreatic cancer, lung cancer, and breast cancer (20x relative risk, affecting 8% of patients by age 40, and 31% of patients by age 60).
List syndromes in which intestinal polyps may be seen in children.
Polyposis syndromes include Peutz-Jeghers syndrome, juvenile polyposis, PTEN hamartoma syndromes (Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome), and familial adenomatous polyposis. Intestinal polyps may also be seen in MEN type 2B, Gorlin syndrome, and NF type 1.
Although most juvenile polyps in children are sporadic, a subset of these patients develop numerous polyps (juvenile polyposis) due gene to mutations in ___ or ___. In this syndrome, juvenile polyps may develop dysplasia and eventually carcinoma.
Although most juvenile polyps in children are sporadic, a subset of these patients develop numerous polyps (juvenile polyposis) due gene to mutations in SMAD4 or BMPR1A. In this syndrome, juvenile polyps may develop dysplasia and eventually carcinoma.
What are the criteria for diagnosis of juvenile polyposis?
> 5 juvenile polyps in the colorectum OR multiple JP throughout the GI tract OR one or more JP and a positive family history of JP syndrome.
The PTEN hamartoma syndromes include ___ syndrome and ___ syndrome, both resulting from mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) on chromosome 10q23.3. These syndromes are associated with increased risk of breast and thyroid carcinomas.
The PTEN hamartoma syndromes include Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, both resulting from mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) on chromosome 10q23.3. These syndromes are associated with increased risk of breast and thyroid carcinomas.
Loss of what protein/mutation of what gene is seen in atypical teratoid rhabdoid tumor?
ATRTs are highly malignant (WHO grade IV) CNS neoplasms seen in very young children. INI1 is a ubiquitously expressed protein encoded by the hSNF5/INI1 gene on chromosome 22q11.2. Mutations in this gene are seen in ATRT. Cytogenetic studies often show monosomy or deletion of chromosome 22; however, this is not as specific or sensitive as IHC, since other tumors with complex karyotypes may show loss of 22 in addition to other events, and the INI1 gene may be mutated by a mechanism other than deletion (i.e. point mutations) not detectable by FISH or LOH studies. The presence of an hSNF5/INI1 gene mutation or loss of the INI1 protein expression by IHC is sufficient to confer a diagnosis of ATRT.
Most common primary testicular malignancy in infants?
Yolk sac tumor.
In addition to colorectal polyps, ~__% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (__%), congenital hypertrophy of the retinal pigment epithelium (__%), desmoid-type fibromatosis (__%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (__x), duodenal carcinoma (__x), ampullary carcinoma (__x), nasopharyngeal adenofibroma (__x), thyroid carcinoma (__x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (__x), and pancreatic carcinoma (__x).
In addition to colorectal polyps, ~90% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (80%), congenital hypertrophy of the retinal pigment epithelium (70-80%), desmoid-type fibromatosis (15%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (847x), duodenal carcinoma (330x), ampullary carcinoma (123x), nasopharyngeal adenofibroma (25x), thyroid carcinoma (7.6x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (7x), and pancreatic carcinoma (4x).
Many women of reproductive age are parvovirus B19 seronegative and are thus susceptible to a primary infection during pregnancy. The rate of vertical transmission from mother or fetus is ~__%. The risk of fetal demise is greatest in the __ trimester. The most commonly recognized clinical manifestation of severe parvovirus B19 induced anemia is ___.
Many women of reproductive age are parvovirus B19 seronegative and are thus susceptible to a primary infection during pregnancy. The rate of vertical transmission from mother or fetus is ~33%. The risk of fetal demise is greatest in the early second trimester, when fetal immunity is sluggish. The most commonly recognized clinical manifestation of severe parvovirus B19 induced anemia is non-immune hydrops fetalis. Parvovirus is thought to cause ~10% of non-immune fetal hydrops cases.
Which of these glycosphingolipid lysosomal storage diseases cause neurodegeneration? Fabry disease. Gaucher disease type II. GM1 gangliosidosis. GM2 gangliosidosis (Sandhoff disease, Tay-Sachs disease).
All except for Fabry disease.
Which of the following storage diseases have a positive Luxol Fast Blue stain? Gaucher disease type II. Neuronal ceroid lipofuscinosis. GM1 gangliosidosis. GM2 gangliosidosis (Sandhoff disease, Tay-Sachs disease). Niemann-Pick disease.
All except for Gaucher disease type II.
Beta-galactosidase deficiency is seen in what 3 storage disorders?
Beta-galactosidase deficiency is seen in GM1 gangliosidosis (mutation in the GLB1 gene). Morquio disease type B (mutation in the GLB1 gene), and galactosialidosis (partial beta-galactosidase deficiency and neuraminidase deficiency due to a defect in the protective protein/cathepsin A, which stabilizes the beta-galactosidase/neuraminidase complex).
What is GM1 gangliosidosis?
An AR lysosomal storage disorder caused by deficiency of the beta-galactosidase enzyme due to mutations in the GLB1 gene on chromosome 3p. The function of the enzyme is to hydrolyze the terminal beta-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans. Without the enzyme function, GM1 gangliosides accumulate in lysosomes of various tissues, particularly the CNS. The 3 clinical phenotypes are: type 1 (infantile), type 2 (late infantile or juvenile), and type 3 (adult or chronic).
~__% of MPNSTs arise from neurofibromas. ~__% of MPNSTs arise in the setting of neurofibromatosis type 1.
~66% of MPNSTs arise from neurofibromas, often of the plexiform type. ~25-75% of MPNSTs arise in the setting of neurofibromatosis type 1.
What are the 3 histologic variants of MPNST, and which are associated with NF1?
Epithelioid variant, glandular variant, and malignant triton tumor (MTT)/MPNST with rhabdomyosarcomatous differentiation. The epithelioid variant is rare and not associated with NF1. The glandular variant contains foci of gland-forming epithelium that resembles intestine and may be keratin- and/or CEA-positive, often with intra- or extracellular mucin. Scattered NE cells immunoreactive for chromogranin, somatostatin, and serotonin are also a common finding. ~75% are associated with NF1. The MTT is 3-4x more common than the glandular variant and is often characterized by divergent mesenchymal differentiation with areas of chondrosarcoma, osteosarcoma, or epithelial glands. ~60% are associated with NF1.
What genetic abnormalities are seen in sporadic MPNST and in NF1-associated MPNST?
Both typically have complex karyotypic abnormalities that are both numerical and structural, but no consistent karyotypic pattern has been identified. On a molecular level, homozygous deletions of the CDKN2A gene, which encodes the p16 cell cycle inhibitory molecule, occurs in the progression of neurofibromas to MPNST, being identified in ~50% of MPNST but not in neurofibromas.
What is the correction for ionized calcium level in the setting of hypo/hyperalbuminemia?
The equation used to measure corrected calcium in cases of hypo/hyperalbuminemia is: Corrected (Ca) = Measured total (Ca) + (0.8 x [4.5 - (alb)]). Or, 0.8 mg/dL Ca per 1g/dL protein. While this formula often provides a good estimate of the ionized calcium, its use should be avoided in patients with acid-base disturbances, renal insufficiency, liver disease, and neonates.
Congenital coagulation factor XIII deficiency. Clinical presentation?
Congenital FXIII-A deficiency may be a quantitative defect (type I deficiency) or a qualitative defect (type II deficiency). Untreated, severe congenital FXIII-A deficiency causes critical bleeding events in most cases, with intracranial hemorrhage being the major cause of death. Typically, delayed-type umbilical stump bleeding represents the first classic clinical sign of congenital FXIII-A deficiency. Muscle and subcutaneous soft tissues are also preferred sites of severe bleeding complications. The FXIII-A deficiency is frequently associated with impaired wound healing and leads to abortion. Severe FXIII-B deficiency has been rarely reported.
At what weeks’ gestation do bilirubin levels peak in normal fetuses (unaffected by hemolytic disease of the newborn)?
Bilirubin levels normally peak at 23-25 weeks’ gestation in unaffected fetuses.
What is a Liley curve/chart?
It predicts the severity of hemolytic disease of the newborn based on amniotic fluid bilirubin levels. On semilog paper, absorbances are plotted against wavelength. A straight line is drawn from the point at 350 nm to the point at 550 nm. This line reflects the theoretical plot if there were no pigments in the fluid. The difference between the line and the actual absorbance at 450 nm is the delta OD450, which reflects the bilirubin concentration. The delta OD450 is plotted against the EGA on a Liley chart, and results fall into zones I, II, or III.
What do results in each of the 3 zones on a Liley curve indicate?
A result in Zone I indicates mild or no disease. Fetuses in zone I are usually followed with amniocentesis every 3 weeks. A result in zone II indicates intermediate disease. Fetuses in low Zone II are usually followed by amniocentesis every 1-2 weeks. A result above the middle of Zone II may require transfusion or delivery. Patients with results in zone I or low zone II can be allowed to proceed to term, at which point labor should be induced. In most cases, patients in the middle of zone II can progress to 36-38 weeks of gestation. If results are in zone III or rising in zone II, deliver immediately for EGA >36 wks, and consider intrauterine transfusion otherwise.
What are the sensitivities of the following for Down syndrome? Triple screen, quad test, integrated screen (and then the addition of US nuchal fold thickness).
Triple screen - 70%, Quad test - 80%. Integrated screen - 85%. Integrated screen combined with US nuchal fold thickness - >90%.
What are the components of the following prenatal screening panels? Triple screen. Quad test. Integrated screen.
Triple screen: hCG, AFP, unconjugated estriol. Quad test: the components of the triple screen plus dimeric inhibin A. Integrated screen: PAPP-A and hCG are measured in the 1st trimester; AFP, unconjugated estriol, and dimeric inhibin A are measured in the 2nd trimester; then the data are combined.
What is the main reason for better performance of the Quad test over the triple screen for prenatal screening?
The improved performance of the Quad test comes mainly from amelioration of the effects of inaccurate gestational age which plague the triple screen.
Trisomy 18 (Edwards syndrome) usually shows a characteristic pattern on prenatal triple screen. What is it?
All 3 components (uE, hCG, AFP) are decreased.
Trisomy 21 (Down syndrome) shows a characteristic pattern on prenatal triple screen. What is it?
hCG increased, AFP and uE decreased. Also, dimeric inhibin A is increased.
Neural tube defects show a characteristic pattern on prenatal triple screen. What is it?
AFP increased, uE decreased, hCG normal. With increased AFP, if an US confirms gestational age and excludes overt anatomic abnormalities, multiple gestations, or fetal demise, then amniocentesis is performed to obtain amniotic fluid for AFP and AChE.
2-3% of maternal serum AFPs are elevated on prenatal screening; of these, __% are due to an actual NTD. The sensitivity of MSAFP screening is __%.
2-3% of maternal serum AFPs are elevated on prenatal screening; of these, 10% are due to an actual NTD. The sensitivity of MSAFP screening is 90% - the sensitivity is worse for multiple gestations (30%).
AFP is the principal plasma protein in the fetus. It is a fetal specific globulin, synthesized by the fetal yolk sac, gastrointestinal tract, and liver. What factors affect MSAFP level interpretation?
MSAFP rises progressively during the 1st and 2nd trimesters. Adjustments to the MSAFP interpretation are made for maternal weight, race, number of fetuses, and maternal diabetes. Increased maternal weight can have a dilutional effect on the AFP, providing a falsely low value. Levels are much higher in multiple gestations, and much lower in maternal diabetes.
MSAFP is >2.5 MOM in >80% of NTDs. How many MOM are considered abnormal in maternal diabetes, and in twin gestations?
> 2.0 MOM is considered abnormal in maternal diabetes, and >4.5 MOM is considered abnormal in twin gestations.
What conditions are associated with increased MSAFP?
NTDs. Omphalocele and gastroschisis. Renal anomalies. Sacrococcygeal teratoma. Cystic hygroma. Hydrops fetalis. Turner syndrome. Bowel obstruction. Twins. Wrong gestational age. Fetal demise. Fetal-maternal hemorrhage.
Maternal serum hCG is ~__x higher than normal in Down syndrome.
Maternal serum hCG is ~2x higher than normal in Down syndrome.
Unconjugated estriol is weakly sensitive to Down syndrome, but is a very good indicator of what other 3 conditions?
Trisomy 18 (Edward syndrome). Smith-Lemli-Optiz syndrome. Inherited (fetal) deficiencies of steroid sulfatase.
Dimeric inhibin A is a glycoprotein produced by the placenta. In a Down syndrome fetus, DIA is increased to an average of ___ MOM.
Dimeric inhibin A is a glycoprotein produced by the placenta. In a Down syndrome fetus, DIA is increased to an average of 1.9 MOM.
What is fetal fibronectin? Where is it found? How can it be used to determine preterm labor?
Fetal fibronectin is a protein found normally at the placental fetomaternal interface. Cervicovaginal fluid contains fetal fibronectin briefly during early gestation, after which time it is absent until just before labor. The absence of fetal fibronectin has very high NPV and can exclude impending preterm birth. A positive result suggests the onset of preterm labor, but the overall PPV is low.
Mature type II pneumocytes produce a mixture of phospholipids composed predominantly of lecithin. The vast majority of lecithin is ___. Lesser amounts of ___, ___, ___, and ___ also comprise lecithin.
Mature type II pneumocytes produce a mixture of phospholipids composed predominantly of lecithin. The vast majority of lecithin is disaturated phosphatidylcholine (DSPC). Lesser amounts of phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylethanolamine (PE), and sphingomyelin also comprise lecithin.
At what gestational ages is fetal lung maturity a concern?
It is an issue for gestation between 34 to 37 weeks. Prior to 34 weeks, fetal lung maturity is unlikely, and the risk of RDS is very high. After 37 weeks the risk of RDS is exceedingly low, and fetal lung maturity testing is generally not indicated, except in the presence of poorly controlled maternal diabetes.
What are tests that can be done to determine fetal lung maturity?
Lecithin/sphingomyelin ratio. Phosphatidylglycerol concentration. Foam stability. Lamellar body number density. Disaturated phosphatidylcholine concentration. Fluorescence polarization assay.
What is the rationale for determining lecithin/sphingomyelin ratio to evaluate fetal lung maturity?
Lecithin increases with gestational age, while sphingomyelin remains at a relatively constant 2% of total surfactant phospholipid. Until 26 wks, the ratio is 1:1. After that, the L:S ratio increases until 2:1 is reached around 35 wks. This ratio is generally taken to indicate fetal lung maturity. Above 2:1, 2% of premature infants will develop RDS. Below 2:1, nearly 60% will.
What are potential problems in evaluation of lecithin/sphingomyelin ratio to determine fetal lung maturity?
In DM, a ratio of 2:1 does not ensure FLM. The phosphatidylglycerol concentration is more reliable in this senario. The presence of meconium falsely decreases the L:S ratio. The presence of blood normalizes the L:S ratio to ~1.5. The CV of the L:S ratio is high.
What is a better test than L:S ratio to determine FLM in maternal DM?
Phosphatidylglycerol concentration.
How is/when is phosphtidylglycerol concentration used to determine FLM?
PG is first detected around 36 wks and its presence is indicative of FLM. Neither blood nor meconium interfere with PG determinations, making it the test of choice when the only available specimen is a contaminated one. PG can be measured by TLC or agglutination.
How is/when is the foam stability test used to determine FLM?
When pulmonary surfactant is present in amniotic fluid in sufficient concentration, the fluid is able to form a highly stable film that can support the structure of a foam. The amniotic fluid is serially diluted with ethanol, and the highest concentration of ethanol at which a complete ring of bubbles is seen is the foam stability index (FSI). An FSI greater than 0.47 is considered indicative of fetal lung maturity.
How is the lamellar body number density test used to determine FLM?
Surfactant lamellar bodies are about the size of platelets, and the platelet channel of a cell counter can be used to quantify them. An LBND greater than 50,000/mL is predictive of maturity.
How is the disaturated phosphatidylcholine concentration used to determine FLM?
An alternative to the L/S ratio is to determine the DSPC concentration, the major component of lecithin, directly. Since it doesn’t rely on a ratio with sphingomyelin, it is unaffected by meconium and blood contamination.
How is the fluorescence polarization assay used to determine FLM?
This is now the most commonly used method; it is rapid and at least as predictive of FLM as the L/S, with considerably lower CV. A fluorescence polarization value less than 260 is considered mature. Values greater than 290 are considered immature. If these is less than 0.5% blood, results are unaffected. Greater amounts tend to lower high values and raise low values. Even in the presence of blood, values less than 230 are considered mature.
In addition to an increased incidence of IUGR and preterm labor, neonates born to mothers with SLE have a risk of congenital heart block. Why?
Antibodies to SS-A and SS-B (Ro and La) are thought to mediate this complication.
What is a normal LAP score in adults? What conditions cause low or high LAP scores?
Normal adults score in the range of 40-120. Low LAP scores are seen in PNH, some MDSs, congenital hypophosphatasia, CML (LAP score is 0-15), and neonatal septicemia (LAP paradoxically decreased). Elevated levels (>180) are seen in leukemoid reactions, non-CML MPDs, glucocorticoid administration and 3rd trimester of pregnancy.
What are differences in lead absorption and elimination between children and adults?
Lead absorption is inversely proportional to chronologic age. In general, approximately 30-50% of lead ingested by children is absorbed, compared with approximately 10% of that ingested by adults. The elimination half-life of lead in adult human blood has been estimated to be 1 month, whereas in children it may be as high as 10 months.
What renal manifestations occur following long term lead toxicity?
Mitochondrial toxicity leads to reduced ATP available to drive the numerous ATP-dependent channels involved in renal tubular epithelial function. Then end-result is aminoaciduria, glycosuria, and phosphaturia (similar to Fanconi renal syndrome). Leads inclusions are detectable ultrastructurally as highly electron-dense founded intracellular bodies.
The CDC recommendation, made in 1978 and still upheld today, is that a blood lead level greater than or equal to ___ ug/dL should be considered elevated.
The CDC recommendation, made in 1978 and still upheld today, is that a blood lead level greater than or equal to 10 ug/dL should be considered elevated.
In the past free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) were used to screen for lead exposure. However, these tests are insensitive at levels of lead below 35 ug/dL (10 or more is considered elevated). Furthermore, they may be elevated in other conditions, most notably iron deficiency. But what advantages do they have?
Their advantage is they can be performed on capillary blood samples and they easily detect moderate to severe lead toxicity. One further advantage is that blood lead levels tend to misleadingly “rebound” during treatment, so that the FEP and ZPP can be used to distinguish this phenomenon from a true increase in lead toxicity.
What is the preferred method and specimen to screen for lead toxicity?
Atomic absorption spectrophotometry is the preferred method for screening for lead toxicity. It is capable of detecting lead levels below the 10 ug/dL threshold. A venous sample is necessary for this determination, as capillary blood obtained from heel- or finger-sticks can give erroneous results. Furthermore, a repeat for confirmation of any abnormal screening test is advised.
What is the calcium disodium ethylenediaminic acid test used for?
CaNa-EDTA test is designed to assess the degree to which lead will be mobilized by chelation therapy. An IV dose of CaNa-EDTA is given, followed by an 8-hour urine collection, and the amount of lead excreted in the urine is determined. This test is sometimes administered prior to initiation of chelation therapy.
A blood lead level greater than or equal to 10 ug/dL should be considered elevated. How is an elevated lead level treated?
At low levels (10-20 ug/dL), environmental interventions may be all that is indicated. Beyond that, both environmental intervention and chelation are indicated. A level >70 ug/dL is considered an indication for inpatient monitoring and treatment. Chelators include dimercaprol (also known as British antilewisite or BAL), CaNa-EDTA, D-penicillamine, and succimer.
What are the congenital dyserythropoietic anemias?
The CDAs include types I, II, III, and IV, and are a rare group of disorders that result in anemia caused by ineffective erythropoiesis and multinuclear erythroblasts. These disorders have pathognomonic cytopathologic findings consisting of nuclear abnormalities in bone marrow erythroid precursors. Type II is also called HEMPAS and is the only one out of the 4 types to have a positive acidified serum test and increased i antigen (the others have normal levels of i antigen). It is also the most common subtype.
Congenital dyserythropoietic anemia type II is also called ___.
HEMPAS (Hereditary Erythroblastic Multinuclearity with Positive Acidified Serum test).
Congenital dyserythropoietic anemia type II (also called HEMPAS (Hereditary Erythroblastic Multinuclearity with Positive Acidified Serum test)), is the most common subtype of the CDAs. At what age does it usually present?
The mean age at presentation is 5 yrs (range 1 mo to 25 yrs), but the mean age at time of correct diagnosis is 16 yrs (range 4 mos to 65 yrs).
The 3 general categories of sideroblastic anemias are: congenital sideroblastic anemia, acquired clonal sideroblastic anemia/MDS (refractory anemia with ring sideroblasts), and acquired reversible/metabolic sideroblastic anemia. Other than the MDS (of which it is the only one in that category), what are subtypes of the other 2?
Congenital sideroblastic anemia: X-linked sideroblastic anemia. Mitochondrial transporter SLC25A38 defects. Glutaredoxin 5 (GLRX5) deficiency. Erythropoietic protoporphyria. Congenital sideroblastic anemia without identified molecular defects. Sideroblastic anemia as a component of genetic syndromes (X-linked sideroblastic anemia with ataxia. Myopathy, lactic acidosis, and sideroblastic anemia. Sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay. Pearson marrow-pancreas syndrome. Thiamine-responsive megaloblastic anemia syndrome). Acquired reversible/metabolic sideroblastic anemia: Alcohol. Drugs (Isoniazid. Chloramphenicol. Linezolid.). Copper deficiency/Zinc toxicity (excess zinc ingestion leads to copper deficiency). Hypothermia.
What is the most common non-syndromic congenital form of sideroblastic anemia?
X-linked sideroblastic anemia (XLSA). One-third of patients are women, who express the disorder because of highly skewed inactivation of their X chromosomes in hematopoietic tissue, favoring expression of the mutant allele. Numerous distinct mutations in the ALAS2 (the erythroid-specific form of 5-aminolevulinate synthase) gene have been identified. This type of sideroblastic anemia may be responsive to high doses of pyridoxine (B6).
X-linked sideroblastic anemia is the most common non-syndromic congenital form of sideroblastic anemia. Why are one-third of patients women?
One-third of patients are women, who express the disorder because of highly skewed inactivation of their X chromosomes in hematopoietic tissue, favoring expression of the mutant allele.
What is the eponym for congenital pure red cell aplasia?
Diamond-Blackfan anemia. Aase syndrome has been described as another congenital pure red cell aplasia, but is not thought to probably be a variant of DBA rather than a distinct clinical entity.
Diamond-Blackfan anemia is a congenital erythroid aplasia caused by genetic mutations affecting ribosome synthesis. What are some clinical and pathologic features of this entity?
Progressive normochromic, usually macrocytic anemia in infancy or early childhood. Reticulocytopenia. Normal cellularity of the bone marrow with markedly decreased or absent erythroid precursors. WBC count is generally normal; platelet counts are generally normal but can be increased or decreased. Congenital malformations (50 percent of patients). Increased risk of malignancies.
How can transient erythrocytopenia of childhood be distinguished from Blackfan-Diamond anemia based on expression of i antigen on red cells and amount of HbF?
In Blackfan-Diamond anemia, i antigen ifs often over-expressed on red cells, and the HbF is increased, whereas in TEC, both are normal.
What are the 4 main inherited causes of aplastic anemia?
Fanconi anemia. Dyskeratosis congenita. Shwachman-Diamond syndrome. Amegakaryocytic thrombocytopenia. Other inherited causes include reticular dysgenesis and Down syndrome.
The term “congenital neutropenia” primarily refers to severe congenital neutropenia (SCN). (Under the term “congenital neutropenia” are also cyclic neutropenia and Shwachman-Diamond syndrome.) The genetics of SCN are heterogeneous and depend upon the specific defect. Explain.
SCN due to ELANE (neutrophil elastase gene) mutations have autosomal dominant inheritance and occurs in 60 percent of patients. SCN due to HAX1 (HCLS1-associated X1) mutations have autosomal recessive inheritance. SCN due to WASP (Wiskott-Aldrich Syndrome Protein) gene mutations have X-linked inheritance.
Fanconi anemia is the most common form of inherited aplastic anemia. What is the mode of inheritance?
It is an autosomal recessive or X-linked chromosomal breakage syndrome that occurs in all races and ethnic groups.
Characteristic congenital malformations are present in up to __% of children affected with Fanconi anemia, including short stature, hypopigmentation and cafe-au-lait spots, hypoplastic thumbs, microcephaly or hydrocephaly, renal abnormalities such as horseshoe kidney, and developmental delay.
Characteristic congenital malformations are present in up to 60-70% of children affected with Fanconi anemia, including short stature, hypopigmentation and cafe-au-lait spots, hypoplastic thumbs, microcephaly or hydrocephaly, renal abnormalities such as horseshoe kidney, and developmental delay.
The hematologic findings in patients with Fanconi anemia evolve over months to years. At what age does cytopenia typically develop and at what age is bone marrow failure typically evident?
Cytopenia develops at a median age of 7 (often mild to moderate thrombocytopenia, but mild leukopenia may also may seen as an initial presentation; anemia, when detected, is typically mild on presentation). 70% of patients have bone marrow failure by age 10.
Patients with Fanconi anemia are at increased risk for what types of malignancy?
Patients with FA are at high risk for developing malignancy, particularly MDS, AML (predominant type is with monocytic differentiation - M4 or M5), squamous cell carcinoma of the head and neck or vulva, as well as HCC and gastric carcinoma.
How is Fanconi anemia diagnosed?
The diagnosis is made by the presence of increased chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking agents such as mitomycin C (MMC) or diepoxybutane (DEB).
In addition to the SS genotype, sickled cells can also be seen in what genotypes?
S-beta-thalasssemia, S-C, S-D, C Harlem.
The hemoglobin electrophoresis in SS shows what %s of HbA, HbA2, HbF, and HbS?
HbA - 0%. HbA2 - 1-4%. HbF - 1-20%. HbS - >80%.
Why does sickle cell usually not clinically manifest until about 6 months of age?
HbF, present at birth, has an inhibitory effect on HbS polymerization; thus, the manifestations of sickle cell disease are not apparent until HbS levels increase beyond 50%, which is usually about 6 months of age.
What are the normal hemoglobins seen in early and late fetal, and in adult stages?
Major early fetal Hb: Hb Gower1. Minor early fetal Hb: Hb Gower2. Major late fetal Hb: HbF. Major adult Hb: HbA. Minor adult Hb: HbA2.
What are the components of HbA, HbA2, HbF, Hb Gower1, and Hb Gower2?
HbA: alpha2-beta2. HbA2: alpha2-delta2. HbF: alpha2-gamma2. Hb Gower1: zeta2-episilon2. Hb Gower2: alpha2-epsilon2.
What are the hemoglobins with the following components: alpha2-beta2, alpha2-delta2, alpha2-gamma2, zeta2-episilon2, alpha2-epsilon2?
HbA: alpha2-beta2. HbA2: alpha2-delta2. HbF: alpha2-gamma2. Hb Gower1: zeta2-episilon2. Hb Gower2: alpha2-epsilon2.
What can cause acute episodes of anemia in sickle cell disease, as well as slowly progressive worsening of anemia?
Acute episodes of anemia: Aplastic crisis (Parvovirus B19 accounts for nearly 70% of aplastic crises in children). Splenic sequestration (these episodes often occur during a viral illness). Hyperhemolytic crisis (this complication has been associated in many patients with concomitant G6PD deficiency). Slowly progressive worsening of anemia: Progressive renal insufficiency (with decreasing erythropoietin) or supervening iron/folate/B12 deficiency.
In sickle cell disease, what is acute pain crisis and acute chest syndrome thought to be caused by?
Acute pain crisis is thought to be due to a vasoocclusive event within bone. Acute chest syndrome is thought to be related to either vasoocclusive events or bacterial PNA.
What is the most common organism causing infection in patients with sickle cell disease?
S. pneumoniae infections, including pneumococcal sepsis, pneumonia, meningitis, and arthritis, are the most common overall. Other common infections include Salmonella, Haemophilus (HITB), and M. pneumoniae.
What neurologic complications are seen in sickle cell disease?
Neurologic complications are frequent in sickle cell disease, manifesting as TIA, cerebral infarcts, cerebral hemorrhage, cord infarction, sensorineural hearing loss, and meningitis. About 1 in 3 patients will have an angiographic appearance of moyamoya disease (segmental arterial stenoses with “puff of smoke” collaterals).
What is acute hepatic cell crisis/acute sickle hepatic crisis/right upper quadrant syndrome? What is hepatic sequestration crisis?
Acute sickle hepatic crisis presents with acute RUQ pain, jaundice, elevated LFTs (but not to the level seen in viral hepatitis). The pathogenesis is likely related to ischemia caused by sinusoidal obstruction, and histology may show sickle cell thrombi within sinusoidal spaces with engorgement by RBCs. Patients with SCD may acutely sequester large numbers of RBCs in the spleen, the pulmonary vasculature, and less commonly the liver. Patients with hepatic sequestration usually present with RUQ pain, rapidly increasing hepatomegaly, and a falling Hgb/Hct. The pathophysiology is believed to be obstruction of sinusoidal flow by the masses of sickled RBCs, with trapping of RBCs within the liver.
What are the 7 classic sickle cell nephropathies?
Gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, isosthenuria, pyelonephritis, renal medullary carcinoma.
Is renal medullary carcinoma seen in sickle cell disease, sickle cell trait, or both?
Both.
True or false. Ocular complications (proliferative retinopathy) occurs with greater frequency in SC disease and sickle cell-beta+-thalassemia than in SS.
True.
Sickle cell-beta thalassemia is divided into what 2 subtypes?
Sickle cell-beta thalassemia is divided into S-beta0 thalassemia and S-beta+ thalassemia, based upon the complete absence of beta globin or the presence of reduced amounts of beta globin, respectively, which in turn determines the level of HbA. The percentage of HbA produced in individuals with beta+ thalassemia varies from 5 to 30 percent, depending upon the molecular defect of the mutation. Compound heterozygous beta0 thalassemia, results in the production of no normal beta chains and therefore no HbA.
Do most beta thalassemia mutations among African-Americans result in beta0 thalassemia or beta+ thalassemia?
Most beta thalassemia mutations among African-Americans result in beta+ thalassemia.
Sickle cell trait (SA) is usually asymptomatic, but what symptoms can they potentially manifest/are they at risk for?
They may manifest mild isosthenuria, are at risk for splenic infarcts at high altitudes, and have a risk for renal medullary carcinoma.
Do patients with sickle cell trait (SA) have sickle cells on peripheral blood smear?
No.
The hemoglobin electrophoresis in SA shows what %s of HbA, HbA2, HbF, and HbS?
HbA - 50-55%. HbA2 - 1-3%. HbF - <1%. HbS - 35-45%.
What are the six “classical” infectious childhood exanthems, and what are the causes?
First disease (Measles, Hard measles, 14-day measles, Rubeola, Morbilli) - Measles virus. Second disease (Scarlet fever, Scarlatina) - Streptococcus pyogenes. Third disease (Rubella, German measles, 3-day measles) - Rubella virus. Fourth disease (Staphylococcal scalded skin syndrome, Ritter’s disease, Filatow-Dukes’ disease) - Staphylococcus aureus. Fifth disease (Erythema infectiosum, slapped cheek disease) - Parvovirus (Erythrovirus) B19. Sixth disease (Roseola infantum, Exanthem subitum, 3-day fever, rose rash of infants, “sudden rash”) - HHV6B or HHV7.
The hemoglobin electrophoresis in SS and in SA shows what %s of HbA, HbA2, HbF, and HbS?
SS: HbA - 0%. HbA2 - 1-4%. HbF - 1-20%. HbS - >80%. SA: HbA - 50-55%. HbA2 - 1-3%. HbF - <1%. HbS - 35-45%.
The hemoglobin electrophoresis in SA shows HbA - 50-55%. HbA2 - 1-3%. HbF -
The hemoglobin electrophoresis in SA shows HbA - 50-55%. HbA2 - 1-3%. HbF -
In sickle cell trait (SA), are the metabisulfite and dithionate tests positive?
As with all individuals with HbS, the 2 tests are positive.
What disease does HHV6 cause?
HHV6 is the etiologic agent of roseola infantum (sixth disease, exanthem subitum, 3-day fever, rose rash of infants, “sudden rash”). Fully-developed roseola manifests in 10% of those with acute HHV6 infection, with the remaining children displaying a nonspecific febrile illness. HHV6 is highly neurotropic and is one of the causes of viral encephalitis. Due to its combined propensity to produce fever and CNS infection, HHV6 is responsible for a significant proportion of childhood febrile seizures.
Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes __-__, with types __ and __ associated with epidemic outbreaks of respiratory disease. Types __ and __ are associated with hemorrhagic cystitis. Types __ and __ are associated with childhood gastroenteritis.
Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes 1-14, with types 4 and 7 associated with epidemic outbreaks of respiratory disease. Types 11 and 21 are associated with hemorrhagic cystitis. Types 40 and 41 are associated with childhood gastroenteritis.
What are acrodynia and erethism?
Conditions that result from chronic exposure to mercury. Other names for acrodynia are hydrargyria, mercurialism, erythredema, erythredema polyneuropathy, Pink’s disease, Bilderbeck’s disease, Selter’s disease, Swift’s disease, Swift-Feer disease, and Feer syndrome. Another name for erethism is erethism mercurialis.
What symptoms are seen in acrodynia (AKA hydrargyria, mercurialism, erythredema, erythredema polyneuropathy, Pink’s disease, Bilderbeck’s disease, Selter’s disease, Swift’s disease, Swift-Feer disease, and Feer syndrome)?
Acrodynia results from chronic exposure to mercury and occurs most often in infants and young children. Symptoms include irritability, photophobia, polyneuritis, autonomic manifestations (sweating, hemodynamic instability), and a desquamative erythematous rash on the palms and soles. It is associated with increased urinary catecholamines and can in many ways mimic pheochromocytoma. The presentation may also be similar to Kawasaki disease.
What are the biochemokinetics of mercury toxicity in its metallic/elemental, inorganic, and organic forms?
Pulmonary absorption of mercury vapor (elemental form) is high; however, this form of mercury is only poorly absorbed from the GI tract and across the skin. The kidney is the major site of deposition for mercury derived from inhalation exposure of mercury vapor. A significant fraction of the mercury vapor taken into the lung is eliminated via exhalation; most of the absorbed mercury is eliminated in the feces. GI absorption of inorganic mercury is on the order of 15 percent. The kidney is the major site of deposition for inorganic mercury compounds. Organic mercury compounds such as methylmercury are highly absorbed from the GI tract and later de-alkylated. The kidney, hair, and CNS are major sites of deposition. Organic mercury readily crosses the placenta, causing severe neurologic impairments in the fetus.
What are symptoms of exposure to organic mercury?
Clinical manifestations include paresthesias around the mouth, peripheral neuropathy, tremor, malaise, constriction of the visual field, deafness, and ataxia. The fetus is particularly vulnerable (organic mercury crosses the placenta readily), even if the pregnant mother shows no signs of toxicity.
Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS) are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. In what populations/conditions is it seen?
Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. They are also seen in neonates, pregnant women, and renal failure.
What is fetal hydantoin syndrome?
AKA dilantin embryopathy or fetal dilantin syndrome. A congenital syndrome resulting from in utero phenytoin exposure. It occurs in <10% of exposed fetuses. It is characterized by IUGR, microcephaly, mental retardation, nail and distal phalanx hypoplasia, midfacial hypoplasia, hypertelorism, flattened philtrum, and shortened nose.
___ testing is performed on all amniotic fluids having elevated AFP concentrations.
AChE testing is performed on all amniotic fluids having elevated AFP concentrations. The odds of having a fetus with a NTD are considerably greater if both the AFP is elevated and the AChE is positive.
Recurrent respiratory papillomatosis is caused by HPV 6 and HPV 11. What are the 2 main clinical types?
Juvenile-onset form (presents at 2-4 years of age), in which HPV is thought to be acquired during passage through the birth canal and is more aggressive. Adult form (presents at 20-40 years of age), thought to be sexually transmitted, in which papillomas are fewer.
Recurrent respiratory papillomatosis is caused by HPV 6 and HPV 11. The 2 main clinical types are juvenile-onset form and adult form. Where do the papillomas most commonly occur? How often does malignant transformation occur? Why is an HPV subtyping sometimes requested?
The papillomas arise most often on the true vocal cords. Malignant transformation is rare, but the lesions can be life-threatening because of airway obstruction, particularly in children. An HPV subtype is sometimes requested as HPV 11 is associated with more aggressive disease than HPV 6.
HBV chronicity develops in __% of healthy adults, __% of immunocompromised adults, and __% of neonates who have become infected transplacentally.
HBV chronicity develops in 5% of healthy adults, 10% of immunocompromised adults, and 90% of neonates who have become infected transplacentally.
What population is affected, and what hematology findings and histologic findings are characteristic of the avian influenza (H5N1)?
Unlike the more common flu strains, H5N1 affects predominantly children and young adults, with a median age of 15 yrs. Lymphopenia is characteristic, without significant changes in the neutrophil, RBC, or platelet counts. The virus has tropism for non-ciliated epithelial cells of the lower respiratory tract, leading to an ARDS/DAD-like clinicopathologic picture and may explain the low rate of human-to-human transmission.
What virus is the most common cause of croup in children between the ages of 2 and 6? What virus is the most common cause of respiratory bronchiolitis (“viral pneumonia”) in infants under age 2?
Parainfluenza viruses 1 and 2 cause the most cases of croup in children between the ages of 2 and 6. RSV is the most common cause of respiratory bronchiolitis (“viral pneumonia”) in infants under age 2.
What are the clinical syndromes caused by measles virus infection?
Classic measles infection in immunocompetent patients. Modified measles (an attenuated infection in patients with preexisting, but incompletely protective, anti-measles antibody). Atypical measles (in patients immunized with the killed virus vaccine and subsequently exposed to wild-type measles virus; is rare since the killed virus vaccine was used in the US from 1963-67). Neurologic syndromes following measles infection, including acute disseminated encephalomyelitis (ADEM) and subacute sclerosing panencephalitis (SSPE). Severe measles. Complications of measles including secondary infection, giant cell pneumonia, and measles inclusion body encephalitis.
What are symptoms of mumps infection?
Mumps infection is frequently accompanied by a nonspecific prodrome consisting of low-grade fever, malaise, HA, myalgias, and anorexia. These symptoms are generally followed within 48 hrs by the development of parotitis, a classic feature of mumps infection seen in 95% of symptomatic cases. The parotitis is due to direct infection of ductal epithelium and local inflammation. Symptomatic infection in adults is usually more severe than in children.
RSV causes __% of respiratory bronchiolitis in infants and __% of lower respiratory tract infections in children.
RSV causes 90% of respiratory bronchiolitis in infants and almost 50% of lower respiratory tract infections in children. Immunity to RSV is short-lived, and recurrence throughout childhood is the rule, although infections are progressively less severe with bronchiolitis uncommon after 12 mos.
Rubella virus causes German measles, which is only really consequential in pregnancy. Which trimester infections have the most serious fetal implications?
First trimester infections have the most serious fetal implications. Defects in neonates infected in the first trimester include hearing impairment (60%), heart defects (45%) (PDA in 20% and peripheral pulmonic stenosis in 12%), microcephaly (27%), cataracts (25%), low birth weight (<2500 g) (23%), hepatosplenomegaly (19%).
True or false. Medulloblastomas are composed of primitive cells that may show features of neuronal or glial differentiation. Rare tumors contain mutations in the patched gene, an important regulator of sonic hedgehog signaling. Tumor cells tend to be dyscohesive, and seeding through the CSF pathways is common.
All true.
What is periventricular leukomalacia?
PVL refers to injury of cerebral white matter that occurs in a characteristic distribution and consists of periventricular focal necrosis, with subsequent cystic formation, and more diffuse cerebral white matter injury. It can be caused by ischemia or infection. It is the major form of brain white matter injury that affects premature infants, and is associated with the subsequent development of cerebral palsy, intellectual impairment, and visual disturbances.
Intraventricular hemorrhage (AKA subependymal or germinal matrix hemorrhage) is an important cause of brain injury in premature infants. What is the pathogenesis?
Pathogenesis is twofold: Germinal matrix fragility from the lack of structural support of rete of immature blood vessels due to immaturity. Disturbances of cerebral blood flow, particularly ischemia-reperfusion, increased arterial flow, or increased venous pressure.
Intraventricular hemorrhage (AKA subependymal or germinal matrix hemorrhage) is an important cause of brain injury in premature infants. What is the specific location of hemorrhage?
In preterm infants, the site of origin of bleeding is generally the subependymal germinal matrix, which is located between the caudate nucleus and the thalamus at the level of the foramen of Monro (“subventricular zones at the angles of the lateral ventricles at the coronal level of the head of the caudate nucleus”). In term infants, the locations may be more variable.
Defective B cell function often presents after 6 mos of age, due to persistence of maternal Abs in the infant serum. What are characteristic infections?
Recurrent bacterial sinopulmonary infections due to staphylococci, streptococci, and hemophilus. Also, recalcitrant intestinal infection with G. lamblia. Opportunistic fungal and viral infections are not a particular problem.
Bruton (X-linked) agammaglobulinemia. What are characteristic histologic and lab findings?
Absence of plasma cells in lamina propria of intestinal mucosa. Lymph nodes lack germinal centers, and plasma cells are absent. Tonsils are rudimentary. Serum IgG levels are markedly reduced as are circulating mature B cells. Pre-B cells are found in lymph nodes and bone marrow where they do not mature normally into B cells.
Patient’s with Bruton (X-linked) agammaglobulinemia have normal immunity against most viral and fungal pathogens, but they do show susceptibility to what 3 viruses?
Polio, hepatitis, and enteroviruses.
Bruton (X-linked) agammaglobulinemia is due to mutation in what gene?
A gene on the X chromosome encoding a tyrosine kinase called Atk (agammaglobulinemia tyrosine kinase) or Btk (Bruton’s tyrosine kinase).
What is common variable immunodeficiency?
CVID is a group of approximately 150 primary immunodeficiencies characterized by hypogammaglobulinemia (low IgG, IgA, and IgM) but which have different underlying causes. In CVID, the B cells are normal in numbers but they lack the capacity to differentiate into plasma cells, so the pts do not make an effective amount of Ig. The clinical severity and age of onset are somewhat variable; the typical onset is around the 2nd or 3rd decade.
In common variable immunodeficiency, B cells are normal in numbers in blood and tissue but they lack the capacity to differentiate into plasma cells, so the pts do not make an effective amount of Ig. What are characteristic histologic features?
Germinal centers are hyperplastic; the typical small bowel morphology includes pronounced reactive follicular lymphoid hyperplasia in the face of a distinctly low number of plasma cells.
What common infections are seen in common variable immunodeficiency?
Most pts suffer from recurrent upper and lower respiratory tract infections (S. pneumonia, H. influenza, and Mycoplasma), intestinal bacterial overgrowth, and intestinal G. lamblia infection. The development of bronchiectasis is extremely common.
Job (hypergammaglobulinemia E) syndrome presents with abnormally high serum IgE. What conditions are they susceptible to?
They have high levels of specific IgE anti-staphylococcal antibody, exquisite susceptibility to staphylococcal infection, eosinophilia and eczema. These appear to result from a defect in granulocyte chemotaxis.
What is the clinical utility of anti-SS-A and anti-SS-B?
SS-A (Ro) is present in 70% of patients with Sjogren syndrome and 30% of patients with SLE. SS-B (La) is present in 50% of patients with Sjogren syndrome and 15% of patients with SLE. Anti-SS-A/SS-B are found in children with neonatal lupus. Patients who are ANA+, SS-A+ but SS-B neg are very likely to have lupus nephpritis.
Wilms’ tumor/nephroblastoma is a triphasic neoplasm with variable amounts of blastema, epithelial, and stromal components. Describe each component.
Blastema is present in almost all Wilms’ tumors and is characterized by small blue cells with fine chromatin, inconspicuous nucleoli and very scanty cytoplasm. Occasionally, the blastema cells may form rosettes, which may suggest an erroneous diagnosis of neuroblastoma. The cells in the epithelial component are larger and have more abundant cytoplasm than blastema cells. They can form nests, glands, tubules, and glomeruloid bodies. Stroma is present in only one-third of cases and appears as metachromatic, myxoid material with spindle cells. Uncommonly, stromal elements such as muscle, fat, bone, or cartilage may be present.
In contrast to a blood collection center, weak D testing is not routinely performed in Rh-typing in a hospital blood bank. What situation is the exception?
Rh negative mother with her newborn testing anti-D negative by the immediate spin D testing. Do the weak D testing (incubation period at 37 C for 15-30 min, and includes antiglobulin reagent) to make sure the baby isn’t actually a weak D instead of a true D negative.
What do you call a CML-like disease without the Philadelphia chromosome in juveniles?
JMML.
What are the mixed MPD/MDS?
These look like CML but don’t have the Philadelphia chromosome. JMML, aCML, and CMML.
Patterns include of nephrogenic rests include intralobar (randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules) and perilobar (peripheral with sharply demarcated margins, composed of blastema and tubules with scanty or sclerotic stroma, often solitary). What are intralobar rests associated with? What are perilobar rests associated with?
Intralobar rests have an increased rate of progression to Wilm tumor, and are more commonly associated with WT1 mutations, Denys-Drash syndrome and WAGR syndrome. Perilobar rests are seen in sporadic tumors and are associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome.
Autosomal recessive polycystic kidney disease is due to mutations in the ___ gene.
Autosomal recessive polycystic kidney disease is due to mutations in the PKHD1 gene. The high phenotypic variability of this disease is due to alternative splicing of 86 exons assembling a variable number of transcripts with the longest being fibrocystin/polyductin.
What is renal dysplasia and how is it defined?
Renal dysplasia is an aberrant developmental disease usually diagnosed during the perinatal and childhood years. It is defined as abnormal metanephric differentiation diagnosed histopathologically, which can be diffuse, segmental, or focal. Renal dysplasia may be combined with abnormalities in the collecting system, or associated with complex syndromes.
What are the renal dysplasia-associated syndromes?
Meckel syndrome, VATER association, renal-coloboma syndrome, Herlyn-Werner-Wunderlich syndrome, pruce belly syndrome, branchio-oto-renal dysplasia, renal-hepatic-pancreatic dysplasia, and MEN 2A.
Microscopic features of renal dysplasia?
Renal dysplasia is characterized principally by primitive
ducts with a fibromuscular collar and lobar disorganization. Primitive ducts, which may be cystic, are considered as altered collecting ducts lined by undifferentiated or columnar-to-cuboidal epithelium. The fibromuscular collar is comprised of spindle cells arranged circumferentially around the primitive ducts. Incomplete and abnormal corticomedullary relationships and rudimentary medullary development constitute lobar disorganization. The cysts derived from primitive ducts may be large or small and numerous or scarce, and eventually lead to divergent macroscopic features of multicystic, hypoplastic, or aplastic renal dysplasia. The other pathologic findings include metaplastic cartilage, bone, basement membrane thickening of the primitive ducts, nodular renal blastema, and proliferating nerves.
What entities are in the differential diagnosis of renal dysplasia?
Polycystic kidney disease, fetal kidney, renal hypoplasia, and renal atrophy.
The entities in the differential diagnosis of renal dysplasia are polycystic kidney disease, fetal kidney, renal hypoplasia, and renal atrophy. How can these be distinguished?
The dysplastic kidney contains primitive ducts with or without dilated cysts. The kidney with concomitant multiple cysts and dysplasia is diagnosed as multicystic renal dysplasia, although it grossly resembles polycystic kidney disease. Additionally, these cysts in multicystic renal dysplasia are usually smaller than those in PCKD. The fetal kidney contains poorly differentiated tissues that are compatible with gestational development. The hypoplastic kidney has fewer nephrons than the normal kidney, but no dysplastic elements. The atrophic kidney exhibits segmental loss of parenchyma due to renal scarring, and compensatory hypertrophy in the remnant parenchyma.
