What is penetrance?
-penetrance of a dz causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms
What is variable expressivity?
-occurs when a phenotype is expressed to a different degree among individuals with the same genotype
What is neurofibromatosis type 1 (NF-1)?
-causes effects to the nervous system, skin and skeleton
-most common inherited disorder caused by a single gene
-higher incidence of LD, migraine HA, idiopathic HTN, and pruritis
What causes NF-1?
-a mutation of neurofibromin on the long arm of chromosome 17. The gene product encodes for a protein which plays a role in intracellular signaling.
How is NF-1 inherited?
-1/3-1/2 of the people diagnosed with this condition have no family hx, so high sporadic mutation rate
How does NF-1 present?
-individuals with multiple cafe-au-lait spots
-ascertainment of the diagnosis in 1st degree relatives
How do you diagnose NF-1?
-clinical criteria: 2 of the following: >5 cafe au lait spots, >15mm in postpubertal, >5mm prepubertally; >1 neurofibromas of any type or one plexiform neurofibroma, frecking in the axilla or groin, optic pathway glioma, >1 lisch nodule, a syndrome specific skeletal dysplasia, a first degree relative with NF-1
- CAFESPOT acronym
How do you manage a pt with NF-1?
-anticipatory guidance: because pathologies can develop anywhere there are nerves, NF-1 related features can happen anywhere. In short, advise people to pay attention to their bodies more and that they should seek formal evaluation for a new sign or symptom that has no obvious cause and is persistent- lasting more than 30 days
What is osteogenesis imperfecta?
-community of disorders characterized by congenital bone fragility leading to fx's with minimal or absent trauma
-age when symptoms begin varies widely with the specific form of OI that an individual is affected by. Pts with mild forms may not have fx's until adulthood, or they may present with fx's in infancy. Pt's with severe cases present with fx's in utero.
What causes OI?
-caused by mutations in the genes that codify for type 1 collagens.
How is OI inherited?
-de novo mutations
How does OI present?
-childhood with fx's after minor trauma
-mildy affected parents may be ascertained after the diagnosis in a child
-in more severe cases, prenatal U/S may show bowing of long bones, fx's, limb shortening, and decreased skull echogenicity
What is Marfan syndrome?
-systemic syndrome of connective tissue with cardinal manifestations of ocular, skeletal, and cardiovascular systems
What causes Marfan syndromde?
-caused by mutations in the FBN1 gene on chromosome 15
-the extracellular matrix is critical for both the structural integrity of connective tissue but also serves as a reservoir for growth factors
What is the biological basis of Marfan syndrome?
-new evidence has shown that in addition to playing a role in structural integrity of the extracellular matrix, fibrillin-1 also plays an important role in binding up a growth factor called Transforming beta (TGFB-1), keeping it sequestered and so that it is unable to exert its biological activity.
-these new findings are the basis for trying new pharmaceutical strategies (ACE and ARB's) aimed at keeping the levels of TGFB-1 in check.
How is Marfan syndrome inherited?
How does Marfan syndrome present?
-by adolescence, typical skeletal features are present and prompt evaluation
-children of affected individuals are evaluated for subtle features
-individuals with marfan can present with aortic dissection- 50% which are fatal
How do you diagnose Marfan syndrome?
-when in doubt, sequence analysis of FBN1 is performed
What are important management issues with Marfan syndrome?
-monitoring of the CV system, which may require pharmaceutic or surgical interventions, mitral valve ascending aorta
-anticipatory guidance for the participation in physical activities
What is imprinting?
-genomic imprinting leads is a phenomenon in which the expression pattern of a gene can be influenced by whether it is paternally or maternally inherited.
What is the most common mechanism for imprinting?
-methylation of cytosine
How does methylation inhibit transcription?
-via the action of a protein that specifically binds to methylated DNA
-with DNA methylation or acetylation of histones, the configuration of specific chromosomes regions can be altered to suppress or promote local gene expression
Gene clusters may be regulated by impriniting:
-Beckwith Wiedemann/Russell Silver syndromes: CDKN1C, IGF2
-Prader-Willi/Angelman syndrome: SNRPN, VBE3A
What is angelman syndrome?
-neurogenetic disorder with the findings of acquired microcephaly, seizures, an ataxia, severe language delays and inappropriate laughter
-5X more common in an identical twin or in pregnancies assisted by in vitro fertilization
What causes Angelman syndrome?
-alterations or deletion of regulatory genes on the maternally derived chromosome 15q11.2
-a small de novo deletion of the maternal chromosome 15q11
What are the most common presentations of Angelman syndrome?
-in early childhood: acquired microcephaly, seizures, severe global developmental delays
How is the diagnosis of Angelman syndrome made?
What is Prader-Willi syndrome?
-mental retardation condition characterized by neonatal hypotonia, feeding difficulties, failure to thrive, hypogonadism, developmental delays and paradoxically, hyperphagia and obesity starting in early childood.
-dysfunction of the hypothalamic axis
What causes Prader-Willi syndrome?
-a small de novo deletion of the paternal chromosome 15q11
How does Prader-Willi syndrome present?
-Neonatal hypotonia/failure to thrive
-characterisitic facial appearance
-developmental delay/mild MR
-short stature, hypogonadism
-characteristic behavior disorder
How do you diagnose Prader-Willi syndrome?
-methylation analysis of chromosome 15q11.2
What are the important management issues with Prader-Willi syndrome?
-monitor failure to thrive
-monitor for hyperphagia/obesity
-growth hormone supplementation
What is Beckwith Wiedemann syndrome?
-genetic condition that presents with pre- and postnatal overgrowth macroglossia, and anterior abdominal wall defects (most specifically omphalocele)
-up to 5X more common in an identical twin or in pregnancies assisted by in vitro fertilization
What causes Beckwith Wiedemann syndrome?
-imprinted alterations of growth regulatory genes on chromosome 11p15
How does Beckwith Wiedemann syndrome present?
-in the neonatal period with: macrosomia, LGA, macroglossia, omphalocele, umbilical hernia, hypoglycemia
What are the important management issues with Beckwith Wiedemann syndrome?
-aggressively monitor and correct for hypoglycemia
-regular monitoring for wilms tumor and hepatoblastoma