Syndromes Flashcards
Carney Complex. AKA (3)?
AKA LAMB syndrome (Lentigenes, Atrial myxomas, Mucocutaneous myxomas, Blue nevi), NAME syndrome (Nevi, Atrial myxomas, Myxoid neurofibroma, Ephelides), or Swiss syndrome. AD condition. The majority (Carney Complex type I) are caused by mutations in the PRKAR1-alpha gene on 17q24, which has been suggested to function as a tumor-suppressor gene. Carney Complex type II involves chromosome 2. 7% of all cardiac myxomas are associated with Carney complex. M=F. Mean age at Dx: 10-20 years.
Carney Triad.
Characterized by the presence of at least 2 of the following 3: Gastric epithelioid leiomyosarcoma (now called GIST), extraadrenal paraganglioma, pulmonary hamartoma/chondroma. Primarily affects young women. Not familial.
TSC1 and TSC2 genes.
Tuberous Sclerosis Complex genes. TSC1 is located on 9q34 and encodes the protein hamartin (130 kDa). TSC2 is located on 16p13.3 and encodes the protein tuberin (198 kDa). Both proteins are highly conserved and ubiquitously expressed. Hamartin and tuberin form a physical and functional heterodimer complex, in which hamartin functions as the regulatory component, stabilizing tuberin and facilitating the tuberin catalytic function as a GTPase-activating protein. Tuberin, which is assumed to be the functional component of this protein complex, is multifunctional, and involved in the regulation of cell size, cell cycles, translation, transcription, apoptosis, and cell differentiation. A major function of the TSC1 (hamartin)-TSC2 (tuberin) complex is its role as a GTPase-activating protein against Rheb (Ras homolog enriched in brain), which in turn regulates mTOR (mammalian target of rapamycin) signaling. The major function of mTOR is to phosphorylate and activate downstream targets p70S6K (p70 ribosomal protein S6 kinase) and 4E-BP1. Deficiency or dysfunction of the encoded proteins, hamartin or tuberin, respectively, result in constitutive activation of mTOR and downstream S6K and 4E-BP1, leading to increased protein translation and, ultimately, to inappropriate cellular proliferation, migration, and invasion.
What are 3 tumors in the PEComa famiy that are seen in tuberous sclerosis?
Angiomyolipoma, clear cell “sugar” tumor, and lymphangioleiomyomatosis.
What are 4 familial hyperparathyroidism syndromes?
MEN1, MEN 2A, HPT-JT (hyperparathyroidism-jaw tumor syndrome), FIHP (familial isolated hyperparathyroidism).
What is HPT-JT syndrome?
HPT-JT (hyperparathyroidism-jaw tumor) syndrome is an inherited disorder with incomplete penetrance. The disorder may be characterized by parathyroid adenoma or carcinoma, benign fibro-osseous lesions of the mandible or maxilla, and renal cysts or tumors. Approximately 80% of patients have hyperparathyroidism and up to 15% of these patients have parathyroid carcinoma. The HRPT2 gene (for ‘‘hyperparathyroidism 2’’) is a putative tumor suppressor gene that was identified and has been mapped to 1q25–q31. The gene encodes a protein named parafibromin for its relationship to parathyroid disease and fibro-osseous jaw lesions. While HPT-JT syndrome is an exceedingly uncommon entity, with an unknown incidence or prevalence, like MEN, it should be considered in the differential diagnosis for the adolescent presenting with hyperparathyroidism.
What renal neoplasms are seen in patients with Birt-Hogg-Dube syndrome?
Patients with BHD syndrome have multifocal renal tumors that include hybrid tumors (renal oncocytoma + chromophobe RCC), oncocytomas, chromophobe RCCs, clear cell RCCs, and papillary RCCs.
What determines type 1 and type 2 von Hippel-Lindau syndrome?
The absence of pheochromocytoma (type 1) or the presence of pheochromocytoma (type 2). Certain genotype-phenotype correlations have been established; Type 1 disease is associated with loss of VHL protein through large deletions or nonsense mutations, while type 2 disease is associated with germline VHL missense mutations.
For the following renal cystic diseases, give the cancer risk and the most common renal tumor types: ESRD and ACD of the kidney, von Hippel-Lindau disease, tuberous sclerosis complex, autosomal-dominant polycystic kidney disease.
ESRD and ACD of the kidney; cancer risk 3-7%; ACD-associated RCC, clear cell papillary RCC, usual types of RCC (papillary, clear cell, chromophobe). von Hippel-Lindau disease; cancer risk 45-60%; clear cell RCC. Tuberous sclerosis complex; cancer risk 2-3%; angiomyolipoma, clear cell RCC, oncocytoma, RCC unclassified/TSC-related. Autosomal-dominant polycystic kidney disease; cancer risk equivocal; clear cell RCC, papillary RCC.
What is Austrian syndrome?
Austrian syndrome was first described by Robert Austrian in 1957. The classical triad consists of meningitis, pneumonia, and endocarditis all caused by Streptococcus pneumoniae. It is associated with alcoholism, due to the presence of hyposplenia, and can been seen in males between 40–60 years old.
___% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
15-20% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
Overview of MEN syndromes, prevalence, and gene(s) involved.
MEN1 (eponym Wermer syndrome). MEN2 encompasses MEN 2A (eponym Sipple syndorome), MEN 2B (Gorlin syndrome; multiple other eponyms such as Gorlin-Vickers syndrome, Williams-Pollock syndrome, and Wagenmann-Froboese; also used to be called MEN3), and FMTC (Familial Medullary Thyroid Cancer, no eponym). For prevalences, MEN1 = 1 in 35,000; MEN 2A = 1 in 40,000; MEN 2B = 1 in 40,000. For gene mutations, MEN1 = MEN1 gene; MEN 2A = RET gene; MEN 2B = RET gene; FMTC = RET and NTRK1 genes. MEN1 is due to a variety of germline mutations of the MEN1 gene, which is located on 11q13. MEN2 is due to germline mutations in the RET proto-oncogene, which is located on 10q11.2.
What tumors are seen in the subtypes of MEN syndrome?
MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.
Compare and contrast the two main methods of testing for defective mismatch repair function in Lynch syndrome.
IHC and PCR are the two main methods. IHC analysis of mismatch repair protein expression in tumor tissue (MMR-IHC) can reveal the identity of the defective protein for targeted genomic sequencing yet will “miss” a small percentage of cases with expressed but functionally defective MMR proteins. PCR analysis of a panel of microsatellite DNA sequences (MSI-PCR) demonstrates defective mismatch repair function. MSI-PCR, if abnormal, does not elucidate which gene is defective and will “miss” a small percentage of cases with a weak phenotype, as may be seen in MSH6 loss. It should also be noted that loss of MLH1 expression may be associated with non-heritable, epigenetic events, especially in older patients.
Lynch syndrome has mutations in what genes?
The hallmark of Lynch syndrome is a genetic mutation in one of the family of DNA mismatch repair (MMR) protein genes (MLH1, MLH3, MSH2, MSH6, PMS2). These proteins function to repair errors in replication of DNA at short repetitive sequences (microsatellites). Lynch syndrome is associated with a high risk of colon and endometrial cancers, as well as increased risk of urothelial, small bowel, hepatobiliary, and pancreatic cancer. Further, 10-15% of sporadic colon, endometrial, and gastric tumors may harbor a somatic, non-germline MMR mutation or loss of expression.
What antibody panel is typically used for mismatch repair detection for Lynch syndrome?
Most labs have an MMR-IHC panel consisting of antibodies to four MMR proteins: MLH1, MSH2, MSH6, and PMS2. For efficiency and cost savings, some advocate primary screening with only MSH6 and PMS2. Intact expression of MSH6 and PMS2 generally translates to intact expression of MLH1 and MSH2; aberrant expression of MSH6/PMS2 then requires further IHC characterization. This strategy is based on the endogenous pairing of mismatch repair proteins, and an understanding of pairing is also necessary to interpret staining results. MLH1 and PMS2 form a heterodimer; if MLH1 is lost, PMS2 is also destabilized and expression is undetectable. However, since PMS2 has other binding partners, mutation or loss of PMS2 does not affect expression of MLH1. The MSH2/MSH6 heterodimer functions similarly; an MSH2 defect leads to loss of both MSH2 and MSH6, while an MSH6 mutation shows loss of MSH6 expression and intact MSH2 expression.
For testing for Lynch syndrome, most labs have an MMR-IHC panel consisting of antibodies to four MMR proteins: MLH1, MSH2, MSH6, and PMS2. Why do some advocate primary screening with only MSH6 and PMS2?
For efficiency and cost savings, some advocate primary screening with only MSH6 and PMS2. Intact expression of MSH6 and PMS2 generally translates to intact expression of MLH1 and MSH2; aberrant expression of MSH6/PMS2 then requires further IHC characterization. This strategy is based on the endogenous pairing of mismatch repair proteins, and an understanding of pairing is also necessary to interpret staining results. MLH1 and PMS2 form a heterodimer; if MLH1 is lost, PMS2 is also destabilized and expression is undetectable. However, since PMS2 has other binding partners, mutation or loss of PMS2 does not affect expression of MLH1. The MSH2/MSH6 heterodimer functions similarly; an MSH2 defect leads to loss of both MSH2 and MSH6, while an MSH6 mutation shows loss of MSH6 expression and intact MSH2 expression.
How is the MMR-IHC panel for Lynch syndrome testing interpreted?
Since MMR proteins function in DNA repair, nuclear staining of replicating cells is expected normally. Epithelial cells at the base of normal colonic crypts are convenient internal controls, as are lymphocytes; in the uterus, endometrial stroma and myometrium may serve as internal control. MMR-IHC assays are particularly susceptible to under-fixation, especially MLH1 and PMS2. If internal controls are negative, repeat staining on another tissue block should be attempted; submission of additional tissue sections after longer fixation might also be helpful. MMR proteins may show patchy expression, especially MSH6 in post-chemotherapy specimens. Thus, even a low percentage of cells with nuclear staining should be scored as intact protein expression. In the case of MMR-IHC, positive staining is a normal result, while negative (lack of staining) is abnormal and suggests the need for further testing or genetic counseling. Other considerations in interpretation of IHC results include the fact that loss of expression of MLH1 may be due to a germline mutation in the MLH1 gene (Lynch syndrome), but is perhaps more commonly due to hypermethylation of the MLH1 promoter in older individuals. BRAF point mutations (V600E) are closely associated with this hypermethylation, and many testing algorithms advocate BRAF mutational analysis before embarking on genetic testing in patients whose colon cancers show loss of MLH1 expression.
What are histologic features seen in cortical tubers associated with tuberous sclerosis?
Histological sections of cortical tubers can show variable features. Common to all tubers is a disorganized cortical architectural pattern or cortical dysplasia (malformation of cortical development). This usually consists of an altered cortical architecture, including abnormal cortical layering, an abnormal orientation or positioning of neurons within the cortex, occasional dysmorphic neurons, and large ballooned cells. The ballooned cells are characterized by abundant eosinophilic cytoplasm with eccentrically placed round to oval nuclei. The cortex usually demonstrates marked reactive gliosis, most pronounced under the cortical surface (subpial gliosis) and around blood vessels in the superficial cortex. Dystrophic calcification is variably present.
Spinal muscular atrophy is a recessive disorder caused by loss of what genes?
Spinal muscular atrophy is a recessive disorder caused by loss of the survival motor neuron (SMN1 and SMN2) genes. Spinal muscular atrophy, types I, II, III, and IV, reflect increasing age of onset and decreasing disease severity.
Amyotrophic lateral sclerosis is a disease of motor neurons, linked to the accumulation of pathogenic proteins in the central nervous system, including __ and __. About __% of individuals with ALS have at least one other affected family member (familial ALS). Superoxide dismutase gene mutations occur in __% of patients with familial ALS and __% of sporadic cases.
Amyotrophic lateral sclerosis is a disease of motor neurons, linked to the accumulation of pathogenic proteins in the central nervous system, including TDP-43 and ubiquitin. About 10% of individuals with ALS have at least one other affected family member (familial ALS). Superoxide dismutase gene mutations occur in 20% of patients with familial ALS and 3% of sporadic cases.
Locations of hemangioblastoma.
Hemangioblastomas are relatively uncommon neoplasms that can occur sporadically or in the setting of von Hippel- Lindau disease. Sporadic cases are usually seen in the cerebellum as a single lesion in patients with a mean age of 45 years. Tumors associated with von Hippel-Lindau disease present at a younger age (mean, 36 years), they can be multiple, and they can occur in unusual locations, such as retina, brain, and spinal cord.
What two syndromes have Lynch syndrome-like findings (can be considered Lynch syndrome variants) and may also have germline mismatch repair gene mutations?
Muir-Torre syndrome (sebaceous neoplasms of the skin and internal malignancies typical of Lynch syndrome) and Turcot syndrome (central nervous system tumors and colorectal adenomas or cancer).
In what syndrome is the STK11 gene mutated?
Peutz-Jeghers syndrome. The STK11 gene is also called STK11/LKB1. STK11 = Serine-Threonine Kinase 11. LKB1 = Liver Kinase B1. It encodes a member of the serine/threonin kinase and regulates cell polarity and functions as a tumor suppressor.
STK11/LKB1 gene.
The STK11/LKB1 gene, also called just the STK11 gene, encodes a member of the serine/threonine kinase, and regulates cell polarity and functions as a tumor suppressor. It is located on chromosome 19p13.3. The protein kinase encoded by the gene is Serine/threonine kinase 11 (STK11), AKA liver kinase B1 (LKB1), AKA renal carcinoma antigen (NY-REN-19). Germline mutations in this gene have been associated with Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the GI tract, pigmented macules on the skin and mouth, and other neoplasms. Recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in lung, cervical, breast, intestinal, testicular, pancreatic and skin cancer.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called ___ syndrome.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called McCune-Albright syndrome.
What gene mutation is associated with fibrous dysplasia and McCune Albright syndrome?
Molecular findings in FD, and especially those for MAS, suggest it is caused by a somatic mutation early in embryonic life that causes a gene mosaicism. The earlier the mutation occurs, the more widespread the effects will be. The gene is located on 20q13, an area that codes for the alpha subunit on G-protein receptors. This mutation is also present in various endocrine tumors as well as FD. The G-proteins begin a cascade that ultimately leads to activation of the enzyme adenylyl cyclase that produces cAMP. In MAS, there is a missense mutation that causes the substitution of arginine in position 201 of the Gs-alpha gene. Normally, there is an almost immediate deactivation of adenylyl cyclase and a breakdown of the cAMP. In MAS, that does not occur. Overproduction of cAMP leads to increased amounts of activity that affect each tissue differently based on its designated function.
Whereas autosomal-dominant hyperimmunoglobulin E syndrome is caused by mutations in (gene), (gene) and (gene) mutations are implicated in the comparatively rare autosomal-recessive forms of the disease.
Whereas autosomal-dominant hyperimmunoglobulin E syndrome is caused by mutations in STAT3, DOCK8 and TYK2 mutations are implicated in the comparatively rare autosomal-recessive forms of the disease.
Twin-twin transfusion syndrome (TTTS) is a serious condition that affects __% to __% of twin pregnancies with monochorionic diamniotic placentation.
Twin-twin transfusion syndrome (TTTS) is a serious condition that affects 10% to 15% of twin pregnancies with monochorionic diamniotic placentation. It occurs due to intrauterine blood transfusion from one twin (donor) to another twin (recipient) through placental vascular anastomoses from shared placental cotyledons. This results in increased fetal and neonatal mortality, premature delivery and neurologic complications in the surviving twin(s).
Lymphangioleiomyomatosis. Locations? Association with a syndrome?
Lymphangioleiomyomatosis (or lymphangiomyomatosis) (LAM) occurs almost exclusively in reproductive age women and consists of a proliferation of immature myoid cells which are currently thought to derive from perivascular epitheliod cells (PEC). LAM may involve the lungs and axial thoraco-abdominal lymphatic system including both lymph nodes and the thoracic duct. Supraclavicular and inguinal nodes may rarely be involved. In most cases, the pulmonary manifestations dominate but LAM may occasionally present exclusively in the abdomen. Abdominal LAM may mimic ovarian carcinoma radiographically and patients may present with pain, often due to hemorrhage. LAM may occur in association with tuberous sclerosis (TS) or in isolation (sporadic LAM), although in either form the LAM cells may be associated with mutations of the TS genes, TSC-1 or TSC-2. Whether LAM is sporadic or associated with TS, the histologic appearance is the same but lymph node involvement is more frequent in patients without TS.
Cirrhosis, hemolysis, Gilbert syndrome, and Crigler-Najjar syndrome all cause (conjugated or unconjugated?) hyperbilirubinemia.
Cirrhosis, hemolysis, Gilbert syndrome, and Crigler-Najjar syndrome all cause unconjugated hyperbilirubinemia.
Lynch syndrome is the most common hereditary CRC syndrome. What are the 4 genes/proteins involved and what chromosomes are they on?
The four genes that are involved in encoding proteins that participate in DNA mismatch repair are: MLH1 (3p21), MSH2 (2p22-p21), MSH6 (2p16), and PMS2 (7p22). Tumors in patients with Lynch syndrome have a germline mutation of one allele of a DNA MMR gene and a somatic mutation in the other allele. The presence of two inactivating mutations results in defective DNA mismatch repair. If the MSI or DNA MMR IHC results show evidence of defective DNA MMR, then the patient may be evaluated further for Lynch syndrome by assessing a peripheral blood sample for germline mutations for one of the four DNA MMR genes.
What is the significance of the five common staining combinations seen in DNA mismatch repair protein IHC (MLH1, PMS2, MSH2, MSH6) in CRC? Give the MSI phenotype, clinical interpretation, and etiology.
Pattern #1: MLH1+, PMS2+, MSH2+, MSH6+; MSI phenotype is MSS or MSI-L; clinical interpretation is most likely sporadic CRC (Lynch syndrome very unlikely). Pattern #2: MLH1-, PMS2-, MSH2+, MSH6+; MSI phenotype is MSI-H; clinical interpretation is LS or sporadic CRC; etiology is germline hMLH1 mutation or hMLH1 promoter hypermethylation. Pattern #3: MLH1+, PMS2+, MSH2-, MSH6-; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline hMSH2 mutation. Pattern #4: MLH1+, PMS2+, MSH2+, MSH6-; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline hMSH6 mutation. Pattern #5: MLH1+, PMS2-, MSH2+, MSH6+; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline PMS2 mutation.
Somatic BRAF mutations are (often seen/generally not seen) in tumors from those with Lynch syndrome.
Somatic BRAF mutations are generally not seen in tumors from those with Lynch syndrome. In patients with a BRAF mutation, LS can be ruled out in most cases.
Hantavirus pulmonary syndrome. During the HPS prodrome, thrombocytopenia is the only dependable finding. Once pulmonary edema is established, however, there is a highly reproducible pentad of findings:_____.
Hantavirus pulmonary syndrome. During the HPS prodrome, thrombocytopenia is the only dependable finding. Once pulmonary edema is established, however, there is a highly reproducible pentad of findings: thrombocytopenia, left-shifted neutrophilia, neutrophils with lack of significant toxic granulation, increased hemoglobin concentration (hemoconcentration), and >10% of lymphocytes having immunoblastic morphology. Having 4 of these 5 has a high sensitivity and specificity for HPS.
Several named syndromes are associated with eosinophilia and eosinophilic infiltration of specific organs: eosinophilic cellulitis (__ syndrome), eosinophilic pneumonia (__ syndrome), eosinophilic fasciitis (__ syndrome), and eosinophilic vasculitis (__ syndrome).
Several named syndromes are associated with eosinophilia and eosinophilic infiltration of specific organs: eosinophilic cellulitis (Well syndrome), eosinophilic pneumonia (Loeffler syndrome), eosinophilic fasciitis (Shulman syndrome), and eosinophilic vasculitis (Churg-Strauss syndrome).
List the constitutional neutropenias.
Cyclic/congenital (ELA2-related) neutropenia. Kostmann syndrome. Schwachman-Diamond syndrome. Chediak-Higashi syndrome. Fanconi anemia. Dyskeratosis congenita. Benign familial neutropenias. Glycogen storage disease type Ib. WHIM syndrome (myelokathexis). Reticular dysgenesis. Wiskott-Aldrich syndrome.
Separate these constitutional neutropenias into an isolated neutropenia category and a with other cytopenias category: Cyclic/congenital (ELA2-related) neutropenia. Kostmann syndrome. Schwachman-Diamond syndrome. Chediak-Higashi syndrome. Fanconi anemia. Dyskeratosis congenita. Glycogen storage disease type Ib. WHIM syndrome (myelokathexis). Reticular dysgenesis. Common variable immunodeficiency. Congenital amegakaryocytic thrombocytopenia.
Isolated neutropenia: Kostmann syndrome. Cyclic neutropenia. Glycogen storage disease type Ib. WHIM (myelokathexis) syndrome. Chediak-Higashi syndrome. Reticular dysgenesis. With other cytopenias: Shwachman-Diamond syndrome. Dyskeratosis congenita. Fanconi anemia. Common variable immunodeficiency. Congenital amegakaryocytic thrombocytopenia.
Peutz-Jeghers (hamartomatous) polyps overview.
Peutz-Jeghers polyps (hamartomatous polyps) are supported by broad bands of muscularis mucosa smooth muscle, which is thicker centrally, and resembles a Christmas tree at low power. The polyp has superficial columnar and goblet cells, but Paneth and endocrine cells at its base. Peutz-Jeghers polyps are large, pedunculated polyps of the gut almost always seen in association with Peutz-Jeghers syndrome. This rare autosomal dominant disorder is usually diagnosed at ages 20-30, with hamartomatous polyps in the small bowel (100%), stomach and colon (25%), and associated adenomatous lesions that may give rise to adenocarcinoma of the stomach, large or small bowel; adenoma malignum of the cervix, ovarian mucinous tumors, and carcinoma of the breast, lung and pancreas. The syndrome is also associated with sex-cord tumor with annular tubules (almost all patients) and melanotic pigmentation of the digits, genitalia, lips, oral mucosa, palms and soles. Peutz-Jeghers syndrome is caused by mutations in STK11/LKB1, a serine threonine kinase that may play a role in cell polarity.
What is the most common endocrine tumor associated with MEN1?
Gastrinoma.
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.
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.
Mucosal neuroma. What syndromes are associated with it?
Multiple endocrine neoplasia, specifically MEN2B. Most cases of multiple mucosal neuromas are associated with MEN2B. Also, mucosal neuromas are associated with PTEN hamartoma tumor syndrome (PHTS), including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.
When McCune-Albright syndrome is associated with intramuscular myxomas, it is called ___ syndrome.
When McCune-Albright syndrome (hyperfunctioning endocrinopathies, including precocious puberty, fluctuating thelarchy, hyperthyroidism, growth hormone excess, rickets/osteomalacia; as well as skin hyperpigmentation/cafe au lait spots) is associated with intramuscular myxomas, it is called Mazabraud syndrome.
Keratocystic odontogenic tumor. Microscopic appearance. DDx.
AKA odontogenic keratocyst AKA odontogenic keratocystoma AKA primordial cyst. Micro: Epithelial lining (6-8 cells thick; lacks rete ridges and epithelium is often detached from fibrous wall, creating cleft; basal layer shows palisading and hyperchromicity; parakeratotic epithelial cells; wavy or corrugated surface keratinization; keratineceous debris in lumen) and fibrous connective tissue (may be detached from overlying epithelium). When inflamed, epithelium is altered and rete ridges are noted. Epithelial hyaline bodies (Rushton bodies) may be seen. By IHC, high Ki-67 confirms proliferation, and TP53 is overexpressed. By molecular genetics, there are mutations in the PTCH gene (chromosome 9q22.3-q31), a tumor suppressor gene, with loss of function. The mutation results in overexpression of BCL-1 and TP53. DDx: Orthokeratinized odontogenic cyst. Dentigerous cyst. Periapical cyst.
How does the microscopic appearance of odontogenic keratocysts differ in those with Gorlin syndrome (nevoid basal cell carcinoma syndrome)?
Patients with Gorlin syndrome develop multiple odontogenic keratocysts. There are more satellite cysts, daughter cysts, budding, and proliferative odontogenic epithelial rests.
Multiple odontogenic keratocysts are associated with ___ syndrome.
Multiple odontogenic keratocysts are associated with Gorlin syndrome (nevoid basal cell carcinoma syndrome). Mutations in PTCH gene (chromosome 9q22.3-q31), a tumor suppressor gene, with loss of function.
Keratocystic odontogenic tumor. Epidemiology.
AKA odontogenic keratocyst (old term) AKA odontogenic keratocystoma AKA primordial cyst. Is a distinct developmental odontogenic cyst that may be locally aggressive. Age range 10-40 years, with cysts found at an earlier age in those with Gorlin syndrome. 60-80% in mandible.
In women with Lynch syndrome, is the incidence of endometrial cancer or colorectal cancer greater?
Endometrial cancer. Lynch syndrome accounts for ~2-3% of CRC and 2.3% of EC, with an overall risk of developing CRC of 68% and EC of 62% in Lynch patients. However, when looking at the two genders separately, the risk of CRC for men is 83% versus 48% for women. Therefore, women with Lynch syndrome are at a substantially greater risk of developing EC than CRC.
What are histopathologic features of endometrial cancer that seem to correlate with Lynch syndrome?
Peritumoral lymphocytes, tumor infiltrating lymphocytes, presence of tumor heterogeneity, undifferentiated/dedifferentiated morphologies, lower uterine segment localization, and synchronous ovarian clear cell carcinoma.
The differential diagnosis of hypertrophic cardiomyopathy includes several syndromes that typically manifest with multiorgan involvement but that can also present with isolated or predominant left ventricular hypertrophy. What syndromes are in the DDx?
Metabolic (storage) cardiomyopathies such as Danon disease and Wolff-Parkinson-White syndrome, and the lysosomal storage disorder Fabry disease. LVH in these conditions is not accompanied by myocyte disarray or fibrosis but by a characteristic accumulation of glycogen or glycospingolipids in cellular vacuoles. LVH is also part of the phenotypic spectrum of Noonan syndrome and Friedreich ataxia.
Dilated cardiomyopathy is defined by LV dilatation and systolic dysfunction (a reduction in myocardial force generation characterized by an ejection fraction of
DCM is defined by LV dilatation and systolic dysfunction (a reduction in myocardial force generation characterized by an ejection fraction of
Pathogenic variants for hypertrophic cardiomyopathy have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the ___ and ___ genes. Storage cardiomyopathies masquerading as HCM are caused by mutations in ___ (Danon disease), ___ (Wolff-Parkinson-White syndrome), and ___ (Fabry disase).
Pathogenic variants for HCM have been described in eight genes encoding sarcomere proteins, with most (∼80%) present in the MYH7 and MYBPC3 genes. Storage cardiomyopathies masquerading as HCM are caused by mutations in LAMP2 (Danon disease), PRKAG2 (Wolff-Parkinson-White syndrome), and GLA (Fabry disase).
Overview of left ventricular noncompaction.
Isolated LVNC is characterized by a heavily trabeculated or spongy appearance of the LV myocardium. An arrest of myocardial compaction during the first trimester of embryonic development is widely believed to be a cause. The left ventricle is typically affected, but 50% of patients with LVNC also have right ventricular involvement. There is a suggestion that LVNC is frequently associated with mitochondrial disorders, followed by Barth syndrome. Because LVNC is rare, its genetic etiology is not well understood. Variants have been described in known DCM and HCM genes encoding components of the sarcomere (ACTC1, MYH7, MYBPC3, and TNNT2), the Z-disk (LDB3), the nuclear lamina (LMNA), the dystrophin-associated glycoprotein complex (DTNA), as well as the Barth syndrome gene tafazzin (TAZ), a nuclear-encoded mitochondrial protein.
Pancreatoblastoma can occur sporadically, or in association with what genetic syndromes?
Beckwith-Wiedemann syndrome or familial adenomatous polyposis syndrome.
Familial dyslipidemias: Types I, IIa, IIb, III, IV, and V. Which one is the most common? Which one(s) has the highest risk of CAD? Which one(s) can be treated with diet changes only?
Type IIb is the most common. Types IIa and IIb have the highest risk of CAD. Type I can be treated with diet changes only.
Familial dyslipidemias: Types I, IIa, IIb, III, IV, and V. Which one(s) will have visible lipemia in the blood collection tube (assuming the person is truly fasting and not postprandial)?
Types I and V. But they have no increase in risk for atherosclerosis.
In unconjugated hyperbilirubinemia… If the step affected is heme conversion to unconjugated bilirubin, the pathologic process is ___. If the step affected is delivery of unconjugated bilirubin to liver, the potential pathologic processes are ___. If the step affected is uptake of unconjugated bilirubin into hepatocyte, the potential pathologic processes are ___. If the step affected is conjugation of bilirubin in hepatocyte, the potential pathologic processes are ___.
In unconjugated hyperbilirubinemia… If the step affected is heme conversion to unconjugated bilirubin (increased production), the pathologic process is extravascular hemolysis. If the step affected is delivery of unconjugated bilirubin to liver, the potential pathologic processes are blood shunting (cirrhosis) or right heart failure. If the step affected is uptake of unconjugated bilirubin into hepatocyte, the potential pathologic processes are Gilbert syndrome and drugs such as rifampin. If the step affected is conjugation of bilirubin in hepatocyte, the potential pathologic processes are Crigler-Najjar syndrome and hypothyroidism.
In conjugated hyperbilirubinemia… If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are ___. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is ___.
In conjugated hyperbilirubinemia… If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are Dubin-Johnson syndrome, hepatitis, endotoxin (sepsis), pregnancy (estrogen), and drugs such as estrogen and cyclosporine. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is mechanical obstruction such as from PBC, PSC, tumor, stricture, or stone.
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 tumors are seen commonly in tuberous sclerosis (the “major features” as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association)?
Facial angiofibromas (adenoma sebaceum) or forehead plaque. Nontraumatic ungual or periungual fibroma. >3 hypomelanotic macules. Shagreen patch (connective tissue nevus). Multiple retinal nodular hamartomas. Cortical tuber. Subependymal nodule. SEGA. Cardiac rhabdomyoma, single or multiple. LAM. Renal AML. Definite TSC is either 2 major features or one major plus 2 minor features.
What tumors are seen in patients with vHL disease?
Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.
~__% of cases of vHL disease are caused by de novo mutations, with the remaining caused by inherited vHL gene mutations.
~20% of cases of vHL disease are caused by de novo mutations, with the remaining caused by inherited vHL gene mutations.
vHL disease can be subtyped according to the clinical manifestations (although these groups often correlate with certain types of mutations present in the VHL gene). What are the subtypes?
Type 1 often has deletion or nonsense mutations. This group manifests mostly as hemangioblastomas whereas clear cell RCC and pheos are rare. Type 2 is subdivided into types 2A, 2B, and 2C, and are characterized mostly by missense mutations. Type 2A is at risk of hemangioblastomas and pheos, but not clear cell RCC. Type 2B is at risk of all 3 tumors, with a higher risk of clear cell RCC. Type 2C is at risk for only pheos. Type 3 has a risk of Chuvash polycythemia.
VHL disease is an AD disorder caused by a germline mutation in the VHL gene, a tumor suppressor gene on (chromosome).
VHL disease is an AD disorder caused by a germline mutation in the VHL gene, a tumor suppressor gene on 3p25-26. The VHL protein (pVHL) is involved in the regulation of the protein hypoxia inducible factor 1-alpha.
What are causes of increased or decreased serum ceruloplasmin levels?
A falsely normal or increased ceruloplasmin may be seen in inflammatory states (ceruloplasmin is an acute phase reactant) or pregnancy. Decreased ceruloplasmin is seen with Wilson disease, hepatic failure, malnutrition, and Menke syndrome.
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 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.
Bone island AKA enostosis AKA spotted bone disease is a benign bone-forming tumor composed of cortical-type bone that develops within the medullary cavity. What is the syndrome characterized by multiple bone islands?
Osteopoikilosis, which may be inherited in an AD fashion. Bone islands in osteopoikilosis are histologically identical to sporadic, solitary bone islands.
What are some genetic syndromes associated with bone lesions?
Ollier disease (enchondromas, chondrosarcoma). Mafucci syndrome (enchondromas, chondrosarcoma). Bloom syndrome (osteosarcoma). Li-Fraumeni (osteosarcoma). Rothmund-Thompson syndrome (osteosarcoma). Werner syndrome (osteosarcoma). McCune-Albright syndrome (polyostotic fibrous dysplasia, osteosarcoma). Mazabraud syndrome (polyostotic fibrous dysplasia, osteosarcoma).
What bone lesions are the following syndromes associated with? Ollier disease. Mafucci syndrome. Bloom syndrome. Li-Fraumeni. Rothmund-Thompson syndrome. Werner syndrome. McCune-Albright syndrome. Mazabraud syndrome.
Ollier disease (enchondromas, chondrosarcoma). Mafucci syndrome (enchondromas, chondrosarcoma). Bloom syndrome (osteosarcoma). Li-Fraumeni (osteosarcoma). Rothmund-Thompson syndrome (osteosarcoma). Werner syndrome (osteosarcoma). McCune-Albright syndrome (polyostotic fibrous dysplasia, osteosarcoma). Mazabraud syndrome (polyostotic fibrous dysplasia, osteosarcoma).
What are the most frequent genetic abnormalities seen in giant cell tumor of bone? What genetic syndrome predisposes to giant cell tumor of bone?
While no specific translocation or chromosomal anomalies are found in GCT, normal karyotypes are rarely encountered. The most frequent genetic abnormality seen in giant cell tumor of bone is reduction in telomere length (11p, 13p, 14p, 15p, 19q, 20q, 21p). Telomeric fusion is detected in ~70% of GCT. A higher incidence of chromosomal anomalies have been reported for recurrent benign GCT or metastatic GCT than for GCT cured after initial surgery. There are no known genetic syndromes predisposing to giant cell tumor.
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.
Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas __x more frequently than an age-matched population.
Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas 25x more frequently than an age-matched population.
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).
The association of adenomatous polyposis with prominent skin and soft tissue manifestations has been designated ___ syndrome. The association of adenomatous polyposis and a brain tumor is called ___ syndrome.
The association of adenomatous polyposis with prominent skin and soft tissue manifestations (osteomas, epidermal cysts, lipomas, and soft tissue fibromatosis) has been designated Gardner syndrome. The association of adenomatous polyposis and a brain tumor (most commonly medulloblastoma, ependymoma, or anaplastic astrocytoma) is called Turcot syndrome.
What is “attenuated FAP”?
Attenuted FAP is a phenotype with fewer adenomas (<100), more proximal colonic location of polyps, delayed age of onset of carcinoma, and lower overall lifetime risk of carcinoma (69%) as compared to classic FAP. Patients with attenuated FAP also often lack family history of polyposis or extraintestinal manifestations. Attenuated FAP is typically caused by mutations in the most proximal or most distal portions of the APC gene.
~__% 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 genetic mutations cause primary/familial forms of hemophagocytic lymphohistiocytosis (FHLH)? What are causes of secondary/acquired forms of HLH?
~30% of FHLH cases are due to mutations in the gene encoding perforin (PRF1, 10q21-22), and 20-25% of cases are due to mutations in Munc 13-14 (UNC13D, 17q25). Acquired forms of HLH are typically triggered by infections, especially viral infection such as EBV, CMV, other herpes viruses, and parvovirus B19. Other forms of infection which trigger HLH include bacterial, fungal, and protozoan infections, especially Leishmaniasis. It is important to note that genetic forms of HLH may also be triggered by infection, and isolation of a causative agent does not distinguish primary and secondary forms. Malignancies associated with HLH include primary lymphomas, an association that is more common in adults than in children. Specifically, ALCL is a frequent associated malignancy. HLH in the setting of autoimmune disease has been distinguished from other forms and is called “macrophage activation syndrome” or “ reactive hemophagocytic syndrome.” This is most often reported in association with systemic-onset juvenile idiopathic arthritis, but may also be seen with LE and other collagen vascular diseases.
What are causes of hypercalcemia?
PTH-mediated: primary hyperparathyroidism, familial (MEN-I and -IIa, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia), tertiary hyperparathyroidism. PTH-independent: hypercalcemia of malignancy, vitamin D intoxication, chronic granulomatous disorders, medications (thiazide diuretics, lithium, teriparatide, theophylline toxicity, excessive vitamin A), miscellaneous (hyperthyroidism, acromegaly, pheochromocytoma, adrenal insufficiency, immobilization, parenteral nutrition, milk-alkali syndrome).
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%.
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.
CD__ is defective or deficient in lymphocytes of patients with Wiskott-Aldrich syndrome.
CD43 (AKA sialophorin or leukosialin) is defective or deficient in lymphocytes of patients with Wiskott-Aldrich syndrome. Wiskott-Aldrich syndrome is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections.
What is Felty syndrome?
An autosomal dominant disorder characterized by rheumatoid arthritis, splenomegaly, and neutropenia. It is seen mainly in white males. The low frequency in blacks may be related to the low frequency of HLA-DRw4, which shows association with Felty syndrome. Risk factors including long-standing RA with high RF titers.
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.
What is POEMS syndrome?
POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is characterized by the presence of a monoclonal plasma cell disorder, peripheral neuropathy, and one or more of the following features: osteosclerotic myeloma, Castleman’s disease (angiofollicular lymph node hyperplasia), increased levels of serum VEGF, organomegaly, endocrinopathy, edema, typical skin changes, and papilledema.
Castleman’s disease is seen in 15% of cases of what syndrome?
POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes).
What conditions are caused by mutations in the PTCH1/patched 1 gene?
More than 225 mutations in PTCH1 have been found to cause Gorlin syndrome/nevoid basal cell carcinoma syndrome. Somatic mutations are associated with sporadic basal cell carcinoma, medulloblastoma, breast cancer, colon cancer, and keratocystic odontogenic tumors. At least seven mutations in PTCH1 have been found to cause nonsyndromic holoprosencephaly.
The classic Wiskott-Aldrich syndrome phenotype includes what 3 characteristics?
Thrombocytopenia. Eczema. Recurrent bacterial, viral, and fungal infections (susceptibility to infections associated with adaptive and innate immune deficiency).
Lymphangioleiomyomatosis. What family of tumors does it belong to? What are the 2 main forms? What gender does it affect? Clinical features?
Characterized by the progressive proliferating and infiltrating smooth musclelike cells (lymphangioleiomyomatosis cells/LAM cells) which lead to the cystic destruction of the lung parenchyma; obstruction of airways, blood vessels, and lymphatics; and loss of pulmonary function. LAM cells were recently recognized as perivascular epithelioid cells, and LAM is categorized as one of the perivascular epithelioid cell tumor family, which includes angiomyolipomas, clear cell “sugar” tumors of the lung and extrapulmonary sites, clear cell myomelanocytic tumors of the falciform ligament or ligamentum teres, and rare clear cell tumors of other anatomic sites. LAM occurs in 2 main forms: tuberous sclerosis complex (TSC-)-associated LAM, and sporadic LAM (S-LAM), with most being the latter form. Primarily affects women of childbearing age and worsens during pregnancy and following the administration of estrogens. Dyspnea on exertion and recurrent pneumothorax are the MC clinical features.
Lymphangioleiomyomatosis. Macroscopic and microscopic appearance.
Macroscopic features are enlarged lungs with a cystic, honeycomb appearance. The cysts are usually evenly distributed through the lung and may contain air or fluid (serosanguinous or chylous). Microscopically, the LAM cells are characteristically found in small clusters or nests at the edges of the cysts and along the alveolar walls, pulmonary blood vessels, lymphatics, and bronchioles. The proliferating LAM cells are morphologically heterogenous and can be classified into 2 types: spindle-shaped cells (usually centrally located) and epithelioid cells (usually in the peripheral regions of the LAM cell nodules). Lymphangioleiomyomatosis cells coexpress smooth muscle markers and melanocytic markers. Somatic or genetic mutations of tumor suppressor genes TSC1 or TSC2 (Tuberous Sclerosis Complex 1 or 2) are closely related to LAM.
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.
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.
Greater than 99% of fragile X cases are caused by expansions of CGG repeats in the FMR1 5’ UTR. What is the other 1 % caused by?
The other 1% is caused by a variety of other mutations, primarily including gross deletions and duplications, regulatory mutations, and missense and nonsense mutations.
What number of CGG repeats is considered the gray zone/intermediate range in fragile X?
45 to 54 CGG repeats. This range is not associated with fragile X syndrome, and gray zone alleles expanding to a full mutation in one generation have not been observed.
Malignant peripheral nerve sheath tumors. What % arise from preexisting neurofibromas vs de novo? What % are associated with NF1?
33-50% are thought to arise from preexisting neurofibromas, and 50% arise de novo. 50% of MPNSTs are associated with NF1.
What are the mutation rates of MSH2, MSH6, MLH1, PMS2, and EPCAM in Lynch syndrome?
MSH2 - 40%. MSH6 - 7-10%. MLH1 - 50%. PMS2 - less than 5%. EPCAM - 1-3%.
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome. Most are due to mutations in FGFR2. Which are due to mutations in FGFR1 or FGFR3?
5% of Pfeiffer syndrome type 1 are due to mutations in FGFR1. 100% of Crouzon syndrome with acanthosis nigricans (AN) and Muenke syndrome are due to mutations in FGFR3.
What are the eight disorders comprising the FGFR-related craniosynostosis spectrum?
Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome.
MEN1 and all MEN2 subtypes (MEN 2A, FMTC, and MEN 2B) are inherited in an ___ manner.
MEN1 and all MEN2 subtypes (MEN 2A, FMTC, and MEN 2B) are inherited in an autosomal dominant manner.
What % of cases of MEN1, MEN 2A, and MEN 2B are caused by a de novo pathogenic variant?
MEN1: 10%. MEN 2A:
What is the main MEN1-associated endocrinopathy?
Parathyroid tumors. Onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years.
Approximately 95% of all individuals with the MEN 2B phenotype have a single nucleotide variant (SNV) in the tyrosine kinase domain of RET at codon __ in exon __, which substitutes a threonine for methionine.
Approximately 95% of all individuals with the MEN 2B phenotype have a single nucleotide variant (SNV) in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine.
Molecular pathogenesis of Bloom syndrome?
Caused by biallelic mutations in the BLM gene (most commonly homozygous; less frequently compound heterozygous). Described mutations include missense, nonsense, insertions/deletions, and splicing defects due to intron mutations.
Mutations in the BLM gene cause Bloom syndrome. What is the function of the gene?
BLM is a tumor suppressor gene and belongs to the family of RecQ DNA helicases. RecQ helicases are important for repair of DNA damage. The protein product BLM permits unwinding of DNA in order to resolve disruptive structures that have developed during replication.
Up to 50% of patients with Bloom syndrome will develop a malignancy, with a mean age of cancer diagnosis of ~24 years. What types of neoplasms are associated with Bloom syndrome?
Hematolymphoid malignancies (AML, ALL, non-Hodgkin lymphoma) predominate in the first 2 decades of life while carcinomas (varied sites) predominate after the first 2 decades of life.
Large cell calcifying Sertoli cell tumor is seen in what 2 syndromes?
Carney complex and Peutz-Jeghers syndrome.
What testicular tumor is seen in common in Carney complex and Peutz-Jeghers syndrome?
Large cell calcifying Sertoli cell tumor.
Mutation in what gene is present in 80-90% of cases of Costello syndrome?
HRAS mutation is seen in 80-90% of cases. The most common mutation is p.G12S.
What % of cases of Costello syndrome are de novo?
Almost all reported cases are secondary to new mutation (no prior history in family members).
What neoplasms are associated with Costello syndrome?
Skin papillomas, rhabdomyosarcoma, urothelial carcinoma, neuroblastoma, fibrosarcoma.
Germline mutations in what genes cause dyskeratosis congenita?
Germline mutations in TERT, TERC, DKC1, or TINF2 genes are seen in 50% of cases. All of these genes function in maintaining telomeres.
What is the mode of inheritance of dyskeratosis congenita?
X-linked recessive when secondary to DKC1 mutations. Autosomal dominant when secondary to TERC or TINF2 mutations. Autosomal dominant or recessive when secondary to TERT mutations. Autosomal recessive when secondary to CTC1, WRAP53, NHP2, or NOP10 mutations.
