Clinical Case Examples III

Which of the following symptoms is usually not observed in diseases due to mitochondrial mutations:

a. Hydrocephalus
b. Deafness
c. Cerebellar ataxia
d. Blindness
e. Heart block
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Which of the following symptoms is usually not observed in diseases due to mitochondrial mutations:

a. Hydrocephalus
b. Deafness
c. Cerebellar ataxia
d. Blindness
e. Heart block
a. Hydrocephalus
Non-Mendelian inheritance is observed in all of the following except:

a. A germinal mosaicism
b. Somatic mosaicism
c. Mitochondrial DNA transmission
d. Uniparental disomy
e. Genomic imprinting
b. Somatic mosaicism
Genomic imprinting is characterized by:

a. Gene expression is determined by the sex of the child
b. Represents mutation of gene's promoter
c. Represents an epigenetic phenomenon related to the hypermethylation of DNA
d. All of the above
e. None of the above
c. Represents an epigenetic phenomenon related to hypermethylation
Which of the following statements about UPD is true:

a. May occur as isodisomy or heterodusomy
b. Paternal disomy of chromosome 15 is observed in Angelman
c. Maternal dusomy of chromosome 15 is observed in PRader-Willi syndrome
d. The origin of isodisomy is during 1st meiotic division
e. All of the above
e. All of the above
Which statement is false:

a. Homo and heteroplasmy refer to mitochondrial disorders
b. Uniparental heterodiusomy is due to chromosomal nondisjunction during 1st meiotic division
c. Genomic imprinting occurs when DNA is hypomethylated
d. 70% of Angelman syndrome is due to maternal chomrosme 15 deletion
c. Genomic imprinting occurs when DNA is hypomethylated [it occurs wen it is hypermethylated]
Guanine nucleotide binding proteins play regulatory role in many signal transduction pathways within the cell. Abnormalities of guanine nucleotide binding protein have been associated with several clinical disorders. Which of the following disorders results from inactivating mutations of the guanine nucleotide binding protein Gs?

A. Albright hereditary osteodystrophy
B. insulin unresponsiveness
C. McCune-Albright syndrome
D. nephrogenic diabetes insipidus
E. type II diabetes mellitus
Answer: A.

Mutations causing deficiency of G proteins occur in Albright osteodystrophy while activating mutations in the same gene cause McCune-Albright.
An infant dies at ten days of age, and autopsy reveals clinical features that include: agyria, cerebellar hypoplasia, Dandy-Walker cyst, microphthalmia, and retinal detachment with retinal dysplasia. Which of the following syndromes if the most likely diagnosis?

A. Meckel-Gruber syndrome
B. Miller-Dieker syndrome
C. Neu-Laxova syndrome
D. Pallister-Hall syndrome
E. Warburg syndrome
Answer: E. This is a typical description for a patient with Warburg syndrome.

A patient wlth Meckel-Gruber syndrome would more likely have encephalocele, polydactyly, and polycystic kidney disease. The Pallister-Hall syndrome is characterized by hypothalamic hamartoblastoma, hypopitutarism, imperforate anus, and postaxial polydactyly. The Neu-Laxova syndrome is characterized by microcephaly or lisssencephaly, elfin-facies with exophthalmos, and syndactyly with subcutaneous edema. The Miller-Dieker syndrome is characterized by lissencephaly.
Prader-Willi is a genetic syndrome characterized by failure to thrive during the first year of life, developmental delay in most patients, small hands and feet (more noticeable in late childhood), crytorchidism in males, a facial gestalt that is recognizable in many patients and food- seeking behaviour after age two. Even so clinical diagnosis can be difficult because of the variability in the phenotype and laboratory studies have become the mainstay of diagnosis. Which of the following laboratory analyses is most likely to reveal a positive finding in a young child where the constellation of clinical features above is not readily identifiable?

A. FISH analysis for missing SNRPN locus
B. High-resolution chromosome analysis
C. Imprinting assessment with DNA methylation assay
D. Routine chromosome analysis and karyotype
E. Subtelomeric probe analysis by FISH studies
Answer C.

Consensus clinical diagnostic criteria are accurate, but the mainstay of diagnosis is DNA-based methylation testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR) on chromosome 15, this testing determines whether the region is maternally inherited only (i.e., the paternally contributed region is absent) and detects more than 99% of affected individuals. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who have atypical findings or are too young to manifest sufficient features to make the diagnosis on clinical grounds.
Soft cystic masses in the auricle which develop into hypertrophic cartilage are a typical feature of which of the following skeletal dysplasias?

Achondroplasia
Camptomelic dysplasia
Chondroectrodermal dysplasia
Diastrophic dwarfism
Larsen syndrome
Answer: D.
This description of the changes in the ear is typical of diastrophic dwarfism. It is a very distinctive change but is usually not present in the neonatal period.
A 28-year-old woman underwent amniocentesis for chromosomal analysis when her fetus was found to have limbs that were short for the assigned dates. The karyotype was 46,XY. At birth the baby had female appearing genitalia. These clinical findings are most consistent with which
of the following syndromes?

Achondrogenesis type IA
Achondrogenesis type II
Campomelic dysplasia
Jeune thoracic dystrophy
Thanatophoric dysplasia
Answer: C.
Female appearing genitalia in an XY infant is a common feature of campomelic dysplasia, but is not a feature of the other disorders.
Haploinsufficiency is the mechanism underlying the genotype/phenotype relationship for which of the following disorders? A. achondroplasia B. acute intermittent porphyria C. Huntington disease D. multiple endocrine neoplasia, type 2A E. transthyretin amyloidosisAnswer: B. All the conditions listed are autosomal dominant disorders. Missense mutations with some type of aberrant function are involved in MEN2A and achondroplasia. The mechanism is not clear for Huntington disease, but there is no evidence that deletion of this region causes the disease, and the evidence favors some type of gain of function. A harmful effect of the mutant protein is involved in amyloidosis. Many of the mutations in acute intermittent porphyria and in some of the other porphyries are obvious loss of function mutations indicating that haploinsufficiency is the mechanism of dominance for AIP.Which chromosomes are acrocentric?13, 14, 15, 21, 22What is Phenocopy? Genocopy?BOTH REFER TO PHENOTYPE Phenocopy - a phenotype produced by non-genetic causes, that is similar to a phenotype produced by genetic causes (caused by environment or genetic causes) Genocopy - similar phenotypes produced by different genotypes (caused by different genetic causes)define: Allelic heterogeneity Locus Heterogeneityallelic: multiple mutations within the same gene can produce the same phenotype locus: different genes have mutations causing the same phenotype Allelic heterogeneity - Similar phenotypes produced by different mutations at the same gene Locus Heterogeneity - similar phenotypes produced by mutations at different gene loci (are both form of genocopy)what is meant by pleiotropy?A single gene controls multiple traitsInfants of mothers with HELLP syndrome should be screened for _____?LCHADWhich of the following is FALSE about the philadelphia chromosome? A. It is present in 92% of CML cases B. It is treated with Gleevac C. It is the result of a reciprocal translocation between chromosome 9 and 22 D. It is a proto-oncogeneA. Present in 95%What is TRUE about Cri-du-chat syndrome? A. 5% are offspring of translocation carriers B. It affects females 2x more than males C. 80% cases are deletions on the paternal chromosome D. Deletion of the short arm of chrom 7C Affects females 3x 10-15% are offspring of translocation carriers Deletion of the short arm of chrom 5You see a patient with midline defects, delayed bone development and intellectual disabilities. What is the most likely diagnosis? A. Trisomy 13 B. Trisomy 18 C. Wolf-hirschhorn syndrome D. Fragile X E. Cri-du-chat syndromeGenetics- del(4p), critical region 4p16.3(WHSC 1/2 genes)How is BWS inherited?11p15, IGF2 gene, maternally imprinted.What is NOT a feature of FXS? A. Macrocephaly B. Hypo/hyperpigmentation C. Hyperextendable joints D. AutismBWhat are two differences between NF1 and NF2?NF2= no Lisch nodules and less Cafe au lait spots NF1= no schwanomas Type 1- complete penetrance, 1:3500, NF1 on 17q11.2 (signal transduction role) Type 2- high penetrance, 1:50,000 Merlin gene on chr 22.