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.
