March 7, 2015

Jacquelyn M Zirbes, DNP

CF or CRMSWhat is the Difference ?

Clinical disease

Sweat Chloride > 60 mmol/L *

Or Intermediate Range of 40-59mmol/L

And 2 CFTR Gene Mutations identified

Adult Diagnosis

• Allergic bronchopulmonary aspergillosis

• Chronic pansinusitis or nasal polyposis

• Bronchiectasis

• Haemoptysis

• Idiopathic recurrent pancreatitis

• Portal hypertension

• Delayed puberty

• Azoospermia secondary to congenital bilateral absence of the vas deferens

Cystic Fibrosis in the Adult/Adolescent

Chronic Sinopulmonary Disease

Characteristic GI abnormalities

Nutritional Abnormalities

Salt Loss

Male Genital abnormalities resulting a azoospermia

Classic CF Characteristics

Sinus Disease

Health Lung CF Lung Disease

Gastrointestinal Abnormalities

Nutritional Needs

Male Azoospermia

The Younger Age Group

Infancy

Chest xray

FTT

Low Protein

Chronic Diarrhea

ABD Distension

Cholestasis

S.a. Pneumonia

Vit A & E deficiency

Classic Signs and Symptoms

Neonatal

Meconium ileus

Protracted jaundice

Abdominal

Intestinal atresia

CRMS=

CFTR-Related Metabolic Syndrome=

Cystic Fibrosis Transmembrane Conductance Regulator Protein Related Metabolic Disorder

The Word: The Initials

Older individuals with sweat chloride < 60 and combination of mutations have been characterized as ‘‘atypical CF,’’ ‘‘non-classical CF,’’ ‘‘CFTR-related disorders,’’ ‘‘low-risk genotype,’’ or ‘‘mild variant CF,’’

But the adults now present for diagnostic evaluation because of signs or symptoms, whereas infants identified by CF NBS are symptom free.

The Adult

The Adult

High IRT on NBS

Sweat chloride values <60 mmol/L And

Up to 2 CFTR mutations, at least 1 of which is not clearly categorized as a “CF disease causing mutation”

No multi-organ symptoms of cystic fibrosis

Does not imply CF is present at this time

What is CRMS

Newborn Screening

CRMS and NBS

Step 1: IRT testingNBS State Laboratories

< 98.4%ileScreen Negative

≥ 98.4%ileHigh IRT

Step 2: CFTR mutationtesting at Stanford University

(40 mutations panel)No mutations

Screen Negative

2 mutationsScreen Positive

1 mutationIndeterminate

Step 4:Referral to CF Center

Step 3: DNA Scanning and Focused sequencingStanford University

2 mutations/variantsScreen Positive

1 mutationCarrier

Genetic CounselingServices Offered

CFTR2 Reference

http://www.cftr2.org

CFTR and Sweat Chloride

Sullivan & Freedman, 2009

Milder clinical course than CF

Pancreatic Sufficient

Well nourished, do not require PERT or caloric supplements

CF pseudomonas>CRMS pseudomonas

Some individuals do develop CF disease

CRMS in Infants

Ren, et. al 2010

Genetic concepts and formal counseling

Refer to correct resources

Explain difference between CF and CRMS

Uncertainty of Prognosis

Full Life expectancy

CRMS symptoms DO need to be treated

Baseline and ongoing follow-up with monitoring plan

Recommendation CRMS

Repeat sweat chloride at 6 months

Symptom free infants twice yearly visits during first year then once yearly.

Oropharyngeal culture with every visit

X-rays if symptomatic– airway clearance if signs

Spirometry when able

Smoke free environment

Influenza vaccine

Recommendations Continues

High IRT on NBS

Sweat chloride values <60 mmol/L And

Up to 2 CFTR mutations, at least 1 of which is not clearly categorized as a “CF disease causing mutation”

No multi-organ symptoms of cystic fibrosis

Does not imply CF is present at this time

Recap of CRMS

Phenotype more important than genotype

CFF recommends genetic counselor discussion

Communication with primary care to concurrently provide care

Many infants with CRMS will be healthy during early childhood

Male higher risk of infertility

Benefit from new treatments

Update families as information becomes available

Treat P aeruginosa.

Research biomarkers and identification of genetic modifier to help with more accurate prognosis

Consensus

References

Borowitz, D., Robinson, K., Rosenfeld, M., Davis, S., Sabadosa, K., Spear, S., Michel, S. Parad, R., White, T., Farrell, P., Marshall, B., Accurso, F. (2009). Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. Journal of Pediatrics, 155, 6, suppl.4, 73-93.

Borowitz, D., Parad, R., Sharp, J., Sabadosa, K., Robinson, K., Rock, M., Farrell, P., Sontag, M., Rosenfeld, M. Davis, S., Marshall, B., & Accurso, F. (2009). Cystic Fibrosis Foundation Practice Guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. Journal of Pediatrics: 155: S106-16.

Castellani, C., Cuppens, H., Macek, M. Jr., Cassiman J., Kerem E., Durie, P., et al. (2008) Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. Journal of Cystic Fibrosis: 7: 179-96.

Farrell, P., Rosenstein, B., White, T., Accurso, F., Castellani, C., Cutting G., et al. (2008) Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. Journal of Pediatrics,: 153: S4-14.

Feldmann, D., Couderc, R., Audrezet, M., Ferec, C., Bienvenu, t., Desgeorges, M., et al. (2003) CFTR genotypes in patients with normal or borderline sweat chloride levels. Human Mutation, 22: 340.

O’Connor GT, Quinton HB, Kahn R, et al.; ( 2002). Northern New England Cystic Fibrosis Consortium .Case-mix adjustment for evaluation of mortality in cystic fibrosis. Pediatric Pulmonology, ;33(2):99-105.

O’Connor GT, Marshall, B, Quinton H, et al.( 2006). Public Reporting of Cystic Fibrosis Outcomes: Methods for Case-Mix Adjustment [abstract]. Pediatric Pulmonology - Supplement.;29S:119-120.

O’Sullivan, B. & Freedman, S. (2009). Cystic Fibrosis. The Lancet, 373, 1891-1904

Sosnay PR. Siklosi KR. Van Goor F. Kaniecki K. Yu H. Sharma N. Ramalho AS. Amaral MD. Dorfman R. Zielenski J. Masica DL. Karchin R. Millen L. Thomas PJ. Patrinos GP. Corey M. Lewis MH. Rommens JM. Castellani C. Penland CM. Cutting GR. (2013). Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nature Genetics. 45(10):1160-7.

Watts KD, Seshadri R, Sullivan C, McColley, SA. (2009) Increased prevalence of risk factors for morbidity and mortality in the US Hispanic CF population. Pediatric Pulmonology ;44(6):594-601.

Watts, K.& Schechter, M. (2010). Origins of outcome disparities in pediatric respiratory disease. Pediatric Annals, 39: 12, 793-799. doi: 10.3928/00904481-20101116-10

References continued

Charles Mayo, 1913

“The prevention of disease today is one of the most important factors in line of human endeavor.”

Many Thanks to Our Families

Questions and Discussion