Pulmonary and Gastro Genetics

Question 1

What are the clinical features associated w Thanatophoric Dysplasia

Answer 1

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

Question 2

How is the dx of Thanatophoric Dysplasia established

Answer 2

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

Question 3

What is the management for pts w Thanatophoric Dysplasia

Answer 3

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

Question 4

What pregnancy management is recommended for a fetus w Thanatophoric Dysplasia

Answer 4

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

Question 5

What is the recurrence for Thanatophoric Dysplasia

Answer 5

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

Question 6

What u/s findings would be consistent w Thanatophoric Dysplasia

Answer 6

cloverleaf skull, very short extremities, small thorax

Question 7

What is the molecular pathogenesis of Thanatophoric Dysplasia

Answer 7

FGFR3 is a negative regulator of bone growth
GOF variants cause this conditon

Question 8

What are the biological features associated w primary ciliary dyskinesia

Answer 8

retention of mucus and bacteria in the respiratory tract and lead to chronic otosinopulmonary disease
abnormal flagellar structure resulting in abnormal sperm motility

Question 9

What are the clinical features associated w primary ciliary dyskinesia

Answer 9

> 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

Question 10

What are the situs abnormalities seen in pts w primary ciliary dyskinesia

Answer 10

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

Question 11

How is the clinical dx of primary ciliary dyskinesia established

Answer 11

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

Question 12

How is the molecular dx of primary ciliary dyskinesia established

Answer 12

multigene panel
most are AR, one is AD (FOXJ1) and two are XLR (PIH1D3, OFD1)

Question 13

What tx is recommended for pts w primary ciliary dyskinesia

Answer 13

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

Question 14

How is the dx of CF established

Answer 14

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

Question 15

How is CF detected on NBS

Answer 15

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

Question 16

What is the utility of a sweat chloride test in CF

Answer 16

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

Question 17

What kind of molecular testing should be ordered for CF

Answer 17

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

Question 18

What are the systems affected by CF

Answer 18

multisystem dz primarily involving the respiratory, GI, genitourinary, and endocrine systems and the sweat glands

Question 19

What are the respiratory features seen in CF

Answer 19

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)

Question 20

What are the pancreatic features associated w CF

Answer 20

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

Question 21

What are the GI features associated w CF

Answer 21

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%

Question 22

What are the endocrine features in CF

Answer 22

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

Question 23

What are the musculoskeletal and genitourinary features in CF

Answer 23

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

Question 24

What is salt loss syndrome in CF

Answer 24

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.

Question 25

What is the prognosis for pts w CF

Answer 25

median predicted survival is 53yo

Question 26

What are heterozygotes for CF PVs at increased risk for

Answer 26

increased risk for bronchiectasis, allergic bronchopulmonary aspergillosis, asthma, chronic rhinosinusitis / nasal polyposis, aquagenic palmoplantar keratoderma, acute recurrent pancreatitis, chronic pancreatitis, atypical mycobacterial infections, and bronchiectasis

Question 27

Describe CF related metabolic syndrome/screen positive indeterminate dx

Answer 27

asymptomatic infants with an elevated trypsinogen on newborn screening and either:

A normal sweat chloride (<30 mmol/L) and biallelic CFTR variants including at least one variant of uncertain significance; OR
An intermediate sweat chloride (30-59 mmol/L) and heterozygous or no CF-causing CFTR variant(s) identified.

need to be monitored

Question 28

What are the CF related disorders and what are the features associated w each

Answer 28

include disorders associated with biallelic CFTR pathogenic variants but without additional clinical manifestations of CF

CFTR-related isolated congenital bilateral absence of the vas deferens (CFTR-CBAVD): isolated CBAVD usually results from compound heterozygosity for a severe loss-of-function CFTR variant with a non-CF-causing variant (e.g., c.1210-12T[5]) or two non-CF-causing variants
CFTR-related pancreatitis. Biallelic CFTR pathogenic variants have been identified in a minority of individuals with acute recurrent pancreatitis or chronic pancreatitis and no additional features of CF
CFTR-disseminated bronchiectasis: An increased incidence of CFTR pathogenic variants has been reported in individuals with bronchiectasis, especially c.1210-12T[5] (IVS8-5T)

Question 29

What are the targeted therapies available for CF

Answer 29

Ivacaftor: In those age ≥4 mos w/at least 1 responsive CFTR pathogenic variant 2
Lumacaftor/ivacaftor: In those age ≥1 yr & homozygous for p.Phe508del
Tezacaftor/ivacaftor: In those age ≥6 yrs & homozygous for p.Phe508del
Elexacaftor/tezacaftor/ivacaftor: In those age ≥6 yrs & heterozygous for p.Phe508del & a minimal function variant 3 or other known responsive pathogenic variant

Question 30

What tx is available for a newborn w CF

Answer 30

Pulm: encourage feeding w breast milk, routine vaccines; antibiotics for chronic suppression
exocrine pancreatic insufficiency: pancreatic enzyme replacement therapy, fat soluble vitamin supplements
meconium ileus needs sx if obstructive, if not, tx w laxitives
salt supplementation for salt loss syndromes/dehydration

Question 31

What tx is available for adults w CF

Answer 31

pulmonary: airway clearance, chronic pulmonary meds to open airway, standard tx for pneumothorax or hemoptysis, consider double lung transplant for those w advanced lung disease
infection: childhood vaccinations, antibiotics for chronic suppression and to tx pulmonary exacerbations
Exocrine pancreatic insufficiency: pancreatic replacement therapy, fat soluble vitamin supplements
liver dz: persistent elevation in liver function tests are tx w ursodiol
CFRD: tx w glucose monitoring and insulin therapy
infertility: u/s of males to assess for absence of vas deferens; IVF w ICSI
salt loss syndromes: salt supplementation, extra salt and water for hydration and salt loss in situations

Question 32

What are the most important predictors of pregnancy outcome in a person w CF

Answer 32

severity of maternal pulmonary impairment and nutritional status
maternal and fetal complications are high in women w CF who have received lung transplant
gestational diabetes is common among pregnancies of women w CF

Question 33

What are ACOG recommendations for CF

Answer 33

core panel of 23 CFTR PVs has been recommended by the ACMG for pan ethic targeted carrier screening

Question 34

What can be seen on u/s in a fetus w CF

Answer 34

The finding of fetal echogenic bowel and/or intestinal loop dilatation and nonvisualization of the fetal gallbladder (NVFGB) on ultrasound examination is associated with an increased risk for CF in a pregnancy previously not known to be at increased risk for CF. The risk for CF ranges from 0.5% to 9.9% in fetuses with hyperechogenic bowel

Question 35

What are the genetic modifiers present in CFTR

Answer 35

poly T tract: A poly T tract, a string of thymidine bases located in intron 8 of CFTR, can be associated with CFTR-related disorders depending on its size. The three common variants of the poly T tract are 5T, 7T, and 9T. Both 7T and 9T are benign variants, and 5T is a variably penetrant variant. The 5T variant is predicted to decrease the efficiency of intron 8 splicing, such that approximately 50% of full-length CFTR is produced (compared to almost 75% of full-length CFTR in those with 7T and 9T alleles)

poly TG tract: A TG tract lies just 5’ of the poly T tract. It consists of a short string of TG (thymidine-guanine) repeats that commonly number 11, 12, or 13. The number of TG repeats modulate phenotype in individuals with a 5T allele. Individuals with a longer TG tract (12 or 13 TG repeats) in cis with a shorter poly T tract (5T) have a full-length CFTR reduction to approximately 25%, which has the strongest adverse effect on proper intron 8 splicing

Question 36

What are the clinical features associated w alpha 1 antitrypsin deficiency

Answer 36

hepatic dysfunction in infancy to adulthood and with chronic obstructive lung dz (emphysema and/or bronchiectasis) >30yo
increased risk of panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen)
In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal lifespan but can also develop lung and/or liver disease
AATD-associated liver dz, which is present in only a small portion of affected children, manifests as neonatal cholestasis
incidence of liver dz increases w age. in adults, manifests as cirrhosis and fibrosis occurs in the absence of a hx of neonatal or childhood liver dz (the most common manifestation of AATD-associated liver dz is neonatal cholestasis: jaundice, w hyperbilirubinemia and raised serum aminotransferase levels in the early days and months of life)
risk for hepatocellular carcinoma is increased

Question 37

How is the dx of alpha 1 antitrypsin deficiency

Answer 37

dx relies on demonstration of low serum concentration of alpha 1 antitrypsin (AAT) and either identification of biallelic PVs in SERPINA1 or detection of a functionally deficient AAT

alleles were named w the prefix PI* (protease inhibitor) serving as an alias for the gene. Using this nomenclature, the most common (normal) allele is PIM and the most common pathogenic allele is PI*Z

Question 38

What are the tx recommendations for alpha 1 antitrypsin deficiency

Answer 38

augmentation therapy w periodic IV infusion of pooled human serum alpha 1 antitrypsin is used in individuals who have established emphysema
lung transplantation for individuals w end stage lung dz. Liver transplantation is the definitive tx for severe dz

Question 39

What is the recommended surveillance alpha 1 antitrypsin deficiency

Answer 39

q6-12mo; pulmonary function tests including spirometry with bronchodilators and diffusing capacity measurements; liver function tests, platelet count and liver u/s, elastography, MRI

Question 40

What should pts w alpha 1 antitrypsin deficiency avoid

Answer 40

smoking (both active and passive); occupational exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes; excessive use of alcohol

Question 41

What is the inheritance of alpha 1 antitrypsin deficiency

Answer 41

autosomal codominant
unless an individual w AATD has children w an affected individual or a heterozygote, offspring will be obligate heterozygotes for PV. (Risk of lung dz may be increased in heterozygous individuals depending on their environmental exposures such as smoking)

Question 42

What testing should be ordered for alpha 1 antitrypsin deficiency

Answer 42

single gene testing: targeted analysis for PIZ, PIS, PII, PIF alleles may be performed first
sequence analysis of SERPINA1

targeted analysis detects 95% of PVs, sequence analysis detects 99%
PI typing is performed by polyacrylamide gel isoelectric focusing (IEF)- biochemical gold standard for establishing the dx; designated by letters based on their migration pattern

Question 43

What do each of the alleles in alpha 1 antitrypsin deficiency correlate to

Answer 43

PIM: the most common allele in all populations. Some benign variants of the PIM allele are designated M1, M2, M3
PIZ: the most common pathogenic allele, resulting in a quantitative and functionally deficient AAT protein. Individuals homozygous for PIZ have severe alpha 1 antitrypsin deficiency
PIS: a pathogenic allele resulting in a quantitatively and functionally deficient AAT. It is usually of clinical consequence only in the compound heterozygous state w another pathogenic allele and when the serum AAT level is <57
PIF: a pathogenic allele that is distinctive bc the resulting protein is functionally impaired in binding neutrophil elastase but quantitatively normal
PII: an allele that is associated w mild quantitative deficiency
Null alleles (PIQO): pathogenic alleles that result in either no mRNA product or no protein production

Question 44

What clinical indication should prompt an alpha 1 antitrypsin deficiency testing

Answer 44

all people w COPD regardless of age or ethnicity
all persons w unexplained bronchiectasis
all persons w unexplained chronic liver dz
all persons w necrotizing panniculitis
all people w granulomatosis w polyangiitis
adult sibs of persons w abnormal AATD-related gene
parents/offspring/minor sibs/extended family of persons w any abnormal AATD-related gene
children who do not fit previous indications

Question 45

What are the lifetime emphysema risks for the following alpha 1 antitrypsin deficiency protein variants: MM, MS, MZ, SS, SZ, ZZ, null-null

Answer 45

MM: background
MS: background
MZ: background
SS: background
SZ: 20-50%
ZZ: 80-100% (2% risk for severe liver dz)
Null-null: 100%

Question 46

What is the molecular pathogenesis alpha 1 antitrypsin deficiency

Answer 46

the AAT disease mechanism can be either loss of function or gain of function
lung dz: excessive destruction of the elastin in the alveolar walls. Thus, lung dz is considered to result from LOF mechanism
liver dz: accumulation of abnormal AAT protein is associated w liver dz through a GOF mechanism