Pulmonary and Gastro Genetics Flashcards
What are the clinical features associated w Thanatophoric Dysplasia
short limb skeletal dysplasia, usually lethal in perinatal period; short ribs, narrow thorax, relative macrocephaly, distinctive facial features (frontal bossing, depressed nasal bridge, ocular proptosis), brachydactyly, hypotonia, and redundant skin folds along the limbs; most affected infants die of respiratory insufficiency shortly after birth.
type 1: micromelia w bowed femurs, and uncommonly, the presence of craniosynostosis of varying severity (coronal, lambdoid, sagittal)
type 2: micromelia w straight femurs and uniform presence of moderate to severe craniosynostosis w cloverleaf skull deformity
How is the dx of Thanatophoric Dysplasia established
heterozygous PVs in FGFR3
if type 2 is suspected, p.Lys650Glu PV identified in >99% of individuals; sequence analysis of exon 15 in FGFR3 can be considered next if no PV is identified
if type 1 analysis, do sequence analysis of FGFR3
What is the management for pts w Thanatophoric Dysplasia
most individuals die in the perinatal period bc of the multisystem complications of the disorder
shunt placement for hydrocephalus, suboccipital decompression for relief of craniocervical junction constriction, ASM to control seizures, hearing aids
What pregnancy management is recommended for a fetus w Thanatophoric Dysplasia
tx goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly and/or a flexed and rigid neck; cephalocentesis and C section may be considered to avoid maternal complications
What is the recurrence for Thanatophoric Dysplasia
majority of probands have a de novo PV in FGFR3
Risk of sib recurrence for parents who have had one affected child is not significantly increased over that of the general population
What u/s findings would be consistent w Thanatophoric Dysplasia
cloverleaf skull, very short extremities, small thorax
What is the molecular pathogenesis of Thanatophoric Dysplasia
FGFR3 is a negative regulator of bone growth
GOF variants cause this conditon
What are the biological features associated w primary ciliary dyskinesia
retention of mucus and bacteria in the respiratory tract and lead to chronic otosinopulmonary disease
abnormal flagellar structure resulting in abnormal sperm motility
What are the clinical features associated w primary ciliary dyskinesia
> 75% of neonates have neonatal respiratory distress requiring supplemental O2 for days to wks despite term gestation
chronic airway obstruction in early childhood, year round wet cough, sputum production, and chronic wheezing; chronic airway infection results in bronchiectasis, uniformly present in adulthood on chest CT exam
digital clubbing, some develop end-stage lung dz in mid-adulthood and several have undergone lung transplant
chronic otitis media associated w transient hearing loss; virtually all men are infertile due to abnormal sperm motility and some women have normal fertility due to impaired ciliary function in the oviduct
What are the situs abnormalities seen in pts w primary ciliary dyskinesia
situs inversus totalis: observed in 50% of individuals
heterotaxy in 12%; heterotaxy often categorized clinically as asplenia (right isomerism) or polysplenia (left isomerism)
in those w heterotaxy, congenital cardiovascular malformations are common and complex (atrial isomerism, transposition of the great vessels, double outlet right ventricle, etc.), and often the cause of death
How is the clinical dx of primary ciliary dyskinesia established
four key clinical features (need at least 2):
unexplained neonatal respiratory distress
laterality defect
early onset, yr round wet cough
early onset, yr round nasal congestion
nasal nitic oxide measurement can be performed as an adjunctive test in children >5yo to provide additional support for the dx
semen analysis will show normal sperm count w immotile or severely limited mobility
20-30% do not have an identifiable PV
How is the molecular dx of primary ciliary dyskinesia established
multigene panel
most are AR, one is AD (FOXJ1) and two are XLR (PIH1D3, OFD1)
What tx is recommended for pts w primary ciliary dyskinesia
aimed at treating consequences of dysfunctional cilia and sperm flagella
aggressive measures to eliminate clearance of mucus, prevent respiratory infections, and tx bacterial infections
routine immunizations
prompt antibiotic tx for bacterial infections of the airways to prevent irreversible damage
lung transplant for those w end stage lung dz
speech therapy/hearing aids for those w hearing loss and delayed speech
IVF using ICSI for male infertility
How is the dx of CF established
positive NBS for CF (elevated immunoreactive trypsinogen)
signs/symptoms suggestive of CF
FH of CF in a first degree relative
AND
elevated sweat chloride values >60mmol/L on sweat chloride testing
identification of biallelic PVs in CFTR
nasal transmembrane epithelial potential difference measurement consistent w CF
intermediate sweat chloride 30-59mmol/L should prompt further eval w a CF specialist
How is CF detected on NBS
Infants have increased IRT levels as a result of inspissated (thickened consistency) secretions in the pancreatic ducts leading to an increase of trypsinogen in the blood
f/u testing may include a second IRT, targeted DNA analysis for common CF causing CFTR variants, or sequence analysis of CFTR. Infants w an elevated IRT should have a sweat chloride test
What is the utility of a sweat chloride test in CF
The gold standard for dx of CF
Sweat chloride testing in an infant w an elevated IRT should be completed before 28d of life to ensure prompt tx of affected infants. Normal sweat chloride is <30mmol/L
What kind of molecular testing should be ordered for CF
Sequence analysis of CFTR is performed first then deldup
targeted analysis available for individuals of Amish, AJ, Faroe Islander, Hutterite, or Zuni ancestry
Nasal transmembrane epithelial potential difference (NPD) provides an indirect measurement of CFTR function in nasal epithelium; abnormal NPD can establish the dx in individuals w inconclusive sweat chloride and/or molecular genetic testing
What are the systems affected by CF
multisystem dz primarily involving the respiratory, GI, genitourinary, and endocrine systems and the sweat glands
What are the respiratory features seen in CF
Lung dz is the major cause of morbidity and mortality
without adequate ion transport OUT of the respiratory epithelium (CFTR), the airway surface layer is not well hydrated leading to thickened airways that attract bacteria; the subsequent WBC rxn leads to bronchiectasis
additional complications from airway damage include hemoptysis and pneumothorax; progression to severe lung dz occurs in many ppl w CF, in whom lung transplantation is a tx option
specific to CF, gram-negative bacteria are especially common; bacterial infections accelerate CF lung dz by increasing cough and sputum production, decreased lung function
anatomic differences (sinus hypoplasia, medial bowing of the lateral nasal wall) and thickened nasal secretions lead to chronic rhinosinusitis and diffuse pansinusitis (inflammation around the nose and eyes)
What are the pancreatic features associated w CF
enzymes auto digest the pancreas, w ultimate interstitial fibrosis leading to pancreatic insufficiency
inadequate absorption of protein and fat causing steatorrhea, excessive gassiness, malnutrition, poor weight gain, growth deficiency
pancreatitis is more likely to occur in individuals w milder CFTR PVs; pancreatitis can be a presenting features of CF in adults and children
What are the GI features associated w CF
decreased stomach and bowel transit time, which can contribute to bowel blockage
inspissated meconium may cause ileus and requires sx intervention (left sided stool retention and constipation)
may also lead to appendiceal obstruction, intussusception, and rectal prolapse
celiac dz, GERD, and IBS have increased prevalence; incidence of GI cancers is 23 fold increased over lifetime risk
Transient elevations in liver function tests to focal biliary cirrhosis
liver dz, both cirrhotic and noncirrhotic occurs in 3.1% and 3.6% respectively, and is the cause of mortality in 2.3%
What are the endocrine features in CF
CF related diabetes increases in prevalence w age (20% in adolescents and 50% of adults)
Glucose metabolism in CFRD is impaired due to a loss of islet cells leading to absence of insulin and glucagon; fluctuating insulin resistance secondary to inflammation; need for high caloric intake; gut abnormalities; altered intestinal motility; and liver disease
delayed puberty, delayed linear growth w reduced adult height
What are the musculoskeletal and genitourinary features in CF
Musculoskeletal: osteopenia/osteoporosis, clubbing of the digits
GU: fertility is altered in both men and women
men often have congenital bilateral absence of the vas deferens, will have obstructive severe oligospermia or azoospermia; most men are infertile but not sterile because the testicular development and spermatogenesis can be normal
women are typically fertile; pH imbalanced, and thickened cervical mucus causes reduced fertility and infertility in some women w CF
What is salt loss syndrome in CF
People with CF are at increased risk for excessive sodium chloride loss across various epithelial surfaces. This is particularly true during infancy and during episodes of sweating, vomiting, or diarrhea.
Because of increased salt losses, people with CF are at increased risk for developing hyponatremic, hypochloremic dehydration.