Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1260-1265 (doi:10.1542/peds.2006-0399)

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EXPERIENCE & REASON

Early Pulmonary Manifestation of Cystic Fibrosis in Children With the F508/R117H-7T Genotype

Brian P. O’Sullivan, MD^a, Robert G. Zwerdling, MD^a, Henry L. Dorkin, MD^b,c, Anne Marie Comeau, PhD^a,d and Richard Parad, MD^c,d,e

^a Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts
^b Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts
^d New England Newborn Screening Program, University of Massachusetts Medical School, Jamaica Plain, Massachusetts
^e Department of Newborn Medicine, Brigham and Women’s Hospital and Children’s Hospital, Boston, Massachusetts
^c Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

ABSTRACT

We report 3 cystic fibrosis newborn screen–positive infants with the F508/R117H-7T genotype who had Pseudomonas aeruginosa detected in oropharyngeal cultures early in life and a fourth who had pulmonary symptoms and Gram-negative growth on multiple oropharyngeal cultures. All 4 patients were followed prospectively from the time of genetic diagnosis. As many regions implement newborn screening for cystic fibrosis, there is concern regarding which mutations should be included in genetic panels used to make the cystic fibrosis diagnosis. Some have recommended that mutations not specifically associated with classic cystic fibrosis be excluded. Our cases highlight the importance of considering keeping so-called mild mutations on cystic fibrosis newborn screening panels and the need to follow children with these mutations closely.

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Key Words: cystic fibrosis • pulmonary • newborn screening • gene mutation • R117H

Abbreviations: CF, cystic fibrosis • IRT, immunoreactive trypsinogen • CFTR, cystic fibrosis transmembrane conductance regulator • nT, n-thymidine sequence • CBAVD, congenital bilateral absence of the vas deferens

The Centers for Disease Control and Prevention have indicated that the risk/benefit ratio favors newborn screening for cystic fibrosis (CF),¹ and the US CF Foundation has recommended nationwide implementation. Massachusetts began CF newborn screening in February 1999 using a 2-tiered process.² Initially, the newborn screen dried blood spot is tested for immunoreactive trypsinogen (IRT), which is typically elevated in infants with CF. Infants who have IRT values in the top 5% each day are designated as being suspicious for having CF. The same blood spots from these infants are then analyzed for the presence of a limited number of CF mutations. Using this algorithm, CF screening programs need to determine which mutations will be included on their genetic panels and to determine follow-up protocols for all infants who screen positive. Typically, the choice of mutations screened for has taken into account mutation frequency and the phenotypic correlates of the mutation. Whether to include so-called mild CF mutations (classes IV, V, and VI)³ in such a panel has been debated because of the implications of making a genetic diagnosis of CF in newborns who might not become symptomatic for years, if at all.^4,5

One mutation that generates debate in the CF newborn screening community is R117H, a substitution of arginine for histidine at the 117th position in the CF transmembrane conductance regulator (CFTR) protein, which is in a membrane-spanning domain.⁶ R117H is a missense mutation in exon 4 that reduces single-channel conductance and reduces chloride-ion transport.⁶ The expression of a CFTR gene containing R117H is influenced by the polythymidine sequence of intron 8, which precedes the exon 9 splicing acceptor site. The CFTR gene occurs with 5, 7, or 9 thymidines in the intron 8 sequence. The more thymidines, the more efficient the splicing. Alone, R117H may not cause sufficient malfunction of the CFTR protein to contribute to overt CF disease; however, when it is found in cis with a shortened polythymidine sequence in intron 8, the combination can lead to significantly decreased function of the CFTR protein. The clinical characteristics of a person who is a compound heterozygote for a severe CFTR mutation on one chromosome and R117H on the other depends in part on the length of the polythymidine sequence inherited along with R117H. When R117H with a 5-thymidine sequence (R117H-5T) is inherited along with a severe CFTR mutation (the most common of which is a loss of phenylalanine at the 508th position, F508) a child may have an elevated or borderline sweat test, moderate lung disease, pancreatic exocrine sufficiency, and male infertility.⁷ In contrast, it has been thought that when a person is a compound heterozygote for F508 and R117H with the 7T sequence (F508/R117H-7T), the individual may have a negative or borderline sweat test, late-onset CF, congenital bilateral absence of the vas deferens (CBAVD) alone, or no disease at all.^4,5,8,9

Several groups have found no evidence of CF-related lung disease in men with CBAVD when R117H-7T is found on one chromosome and the F508 mutation on the other,^10–12 and one report strongly urged clinicians not to diagnose CF on the basis of this genotype alone.⁵ Furthermore, the US CF Foundation consensus statement on the diagnosis of CF states that "diagnosis of CF in patients carrying R117H-7T or 5T will require demonstration of a CFTR abnormality by sweat testing or nasal potential difference testing."¹³ Therefore, when an asymptomatic infant is found to have an elevated IRT and the F508/R117H-7T genotype, it is difficult for the treating physician to know what to tell the parents; in fact, at present, the literature concludes that physicians should refrain from calling such a child a CF patient.^4,5,11,14

Here we report 4 infants with the F508/R117H-7T genotype who were identified very early in life through newborn screening or prenatal testing and then followed prospectively at accredited CF centers. All 4 patients have clinical signs and symptoms of pulmonary disease and have grown Pseudomonas aeruginosa or other Gram-negative organisms from oropharyngeal cultures. Knowledge of the surprisingly early onset of overt disease in at least some children with the F508/R117H-7T genotype is crucial for physicians in regions that are starting CF newborn screening programs who might otherwise consider children with this genotype to be unaffected.

CASE REPORTS

Case1.
A.B. was born at term without complications. Her newborn dried blood spot demonstrated an elevated IRT, which led to mutation analysis. This proved the child to be a compound heterozygote for F508 and R117H. Determination of her intron 8 thymidine sequences revealed 7T and 9T variants. Because F508 is generally (but not always) seen in conjunction with the 9T variant,^15,16 the child was assumed to have both R117H and 7T on the same chromosome. Sweat samples were collected in duplicate at 6 weeks of age, and her chloride concentrations were normal (Table 1). The family was apprised of the normal sweat test results and the uncertainty of the significance of the F508/R117H-7T genotype. The child was monitored in a CF clinic as previously determined by the Massachusetts CF Newborn Screening Workgroup protocol. A repeat sweat test performed at 21 months of age showed sweat chloride concentrations of 52 and 54 mmol/L. An oropharyngeal swab culture at the same time showed growth of 3 strains of nonmucoid P aeruginosa and Escherichia coli. Therapy with inhaled tobramycin was given for 28 days, and (at the time of this writing) Pseudomonas has not been isolated from subsequent oropharyngeal cultures, although a later culture did grow Serratia marcescens. A chest radiograph obtained at 24 months of age showed hyperinflation and peribronchial cuffing consistent with small-airways inflammation.

View this table: [in this window] [in a new window]   TABLE 1 Data Regarding Infants With the F508/R117H-7T Genotype

 
Case2.
J.B., the younger brother of A.B., also had an elevated IRT at birth. He was found to have the same genotype as his sister, F508/R117H-7T. A sweat chloride test was performed at 4 weeks of age and was normal. Because of his sister’s course of early colonization with P aeruginosa, oropharyngeal cultures were obtained at 2, 7, and 10 months of age. At all 3 times the cultures were positive for 2 strains of E coli. A chest radiograph at 5 months of age was normal, but when repeated at 18 months of age, the chest radiograph showed peribronchial thickening and mild hyperinflation.

Case3.
A.Z. was born at term. Her parents had had prenatal testing and were aware that the mother carried the F508 mutation and the father carried the R117H mutation. They were informed of the 1-in-4 risk of having a child with mutations on both chromosomes, but they understood the genetic counselor to say that even if the child had both mutations, he or she would likely not have serious disease. The infant had an elevated IRT value on the newborn screen dried blood spot, and genetic analysis confirmed the F508/R117H genotype with 7T/9T sequences. She was referred to a CF center, where her sweat chloride concentrations were in the borderline range (Table 1). At 10 months of age the child developed a cough, increased work at breathing, and fever. A chest radiograph was remarkable for bilateral lower lobe infiltrates. An oropharyngeal culture obtained at the time of this illness was positive for nonmucoid P aeruginosa. She was treated with oral ciprofloxacin for 2 weeks and inhaled tobramycin for 28 days and has been Pseudomonas-negative since that time; however, she has had Staphylococcus aureus recovered from several throat swabs.

Case4.
J.E. was born at term. He had been diagnosed as having F508/R117H-7T via amniocentesis prenatally. The family denied permission for CF newborn screening because they already knew the child’s genotype. A sweat chloride test was in the borderline range. At 30 months of age, pan-sensitive, nonmucoid P aeruginosa was recovered from an oropharyngeal culture. The child was treated with inhaled tobramycin in 28-day cycles for 1 year. Repeat cultures have not grown any Pseudomonas species, and the child is asymptomatic. Of note, a chest radiograph at 2 months of age showed signs of mild small-airways disease, with the changes persisting on subsequent films. By 12 months of age there were persistent increases in interstitial markings and hyperinflation.

DISCUSSION

In Massachusetts, the panel of mutations used for CF newborn screening includes R117H with automatic testing for the 5T, 7T, and 9T variants in intron 8 for any child found to have R117H.² The degree of CFTR dysfunction resulting from the R117H mutation depends, in part, on the number of thymidine repeats in intron 8. Prognosis for an asymptomatic infant whose genotype consists of a severe mutation on one chromosome and R117H on the other (eg, F508/R117H) is not always clear. When the R117H chromosome also has the 5T sequence, 90% of its CFTR messenger RNA transcripts will not include exon 9; thus, individuals with the genotype F508/R117H-5T may have pancreatic-sufficient CF with mild-to-moderate lung disease.^7,8,14 The majority of diagnostic and prognostic dilemmas occur when a 7T sequence is on the R117H chromosome. Infants with the genotype F508/R117H-7T may have mild lung disease, CBAVD without lung disease, or no disease at all.^4,5,8,9 Complicating the issue for both F508/R117H-5T and 7T, other factors may further influence splicing efficiency of exon 9. Just upstream from the polythymidine track in intron 8 are a series of thymidine-guanine repeats. A smaller number of repeats is associated with better splicing efficiency and, thus, more messenger RNA transcripts including exon 9.^17,18 Thus, the splicing efficiency of exon 9 depends on several factors, which in part explains the variable penetrance of intron 8 sequence variants.

Current newborn screening data do not provide the incidence of F508/R117H in our total population. We are aware of 2 infants who have F508/R117H and who were CF screen–negative because their IRT was below the designated cutoff value. One of these 2 infants (who has the 5T sequence, genotype F508/R117H-5T) presented clinically at 3 months of age. The other (with the 7T sequence, genotype F508/R117H-7T) was identified at 3 years of age after a younger sibling’s screen prompted parental testing that showed that both parents were carriers. We do not know how many other such nonhypertrypsinogenemic infants there are in Massachusetts who have yet to come to our attention. In addition, we do not know how many of the infants with R117H who were detected by the newborn screen might yet develop pulmonary symptoms. Thus, any statement about the percentage of children with F508/R117H-7T who develop CF lung disease is unsupportable at this time. A more complete, prospective study of a larger population is needed to answer this important question.

Evidence for a lack of lung disease with the F508/R117H-7T genotype comes from reviews of men with CBAVD^10–12 and retrospective cross-sectional studies of limited populations.^8,14 The report by Dumur et al¹² includes 3 men evaluated for CBAVD who had the F508/R117H-7T genotype. All 3 of these men had elevated sweat chloride concentrations (90, 78, and 71 mmol/L), but none had respiratory symptoms; they were well except for their infertility issues. Another 3 men with F508/R117H-7T were among the cohort with CBAVD reported by Colin et al.¹¹ Again, these men had elevated sweat chloride concentrations (106, 80, 79 mmol/L); however, all 3 had normal pulmonary-function testing (forced expiratory volume in 1 second > 100% of predicted), with evidence only of mild asthma in one of them. Conclusions drawn from these reports are confounded by patient-selection bias. Had the population screened been attendees at a clinic for sinus or pancreas disease rather than an infertility clinic, the degree of lung disease discovered might have been quite different. Conversely, women with this genotype may not come to clinical attention at all because they do not suffer from CBAVD.

Massie et al⁴ studied a more general sample. They examined 57 infants identified by newborn screening, all of whom had elevated IRT levels, one F508 mutation, and sweat chloride concentrations <60 mmol/L. Of these 57 infants, 5 had the F508/R117H-7T genotype, and none had clinical symptoms of CF. The authors concluded that newborn screen genetic test panels should be limited to severe mutations associated with classic clinical CF.⁴ In a subsequent publication, this group looked at all individuals with the R117H mutation known to CF clinics in Australia and New Zealand.¹⁴ They found 20 individuals with the F508/R117H-7T genotype, 16 of whom were diagnosed via newborn screening. One patient who presented in adulthood with pulmonary symptoms grew S aureus and Haemophilus influenzae from her sputum. Two children identified by newborn screening had pulmonary symptoms; a 6-year-old was reported to have recurrent bronchitis, and a 1-year-old was reported to have persistent cough. Unfortunately, most of these patients did not produce sputum, and the authors did not report the results of oropharyngeal swab cultures. The authors concluded that, on the basis of their experience, most individuals with the F508/R117H-7T genotype do not have clinical CF but should be observed over time for development of symptoms.¹⁴

Reports such as these have led physicians who care for asymptomatic newborns found to have the F508/R117H-7T genotype to hesitate before telling parents that their children have true clinical CF. Our report emphasizes that the genotype F508/R117H-7T may not be benign. In fact, 3 of the 4 children reported here have grown the typical CF pathogen, P aeruginosa, which is found in only approximately one third of infants with CF <2 years of age but in 80% of adults with CF.¹⁹ The fourth child has had multiple cultures positive for E coli. Two of the infants have symptoms referable to small-airways disease, consistent with CF, and all 4 have had abnormal chest radiograph results. Thus, although many people with the genotype F508/R117H-7T may not have significant pulmonary disease, our experience indicates that children identified as having this genotype should be considered to be at increased risk for developing infection or colonization of the oropharynx with CF-related organisms. Positive oropharyngeal culture results do not necessarily reflect lower-airway infection²⁰; however, Ramsey et al²¹ found a strong positive predictive value for the presence of P aeruginosa in the lower airways when oropharyngeal swabs from nonexpectorating patients with CF were positive for this organism. It is possible that the presence of P aeruginosa in the upper airway predisposes these children to lower-airway infection even if the lungs are not infected at the time of the first positive oropharyngeal culture.

Although it is not commonly recognized that children with the F508/R117H-7T genotype are at risk for CF infections, our experience is not unique. Lording et al²² reported 10 children with F508/R117H-7T, several of whom were diagnosed via newborn screening. Eight of these children grew CF-related pathogens from respiratory cultures, although only one had a definitively positive sweat test. In another series, Padoan et al²³ reported 2 children with F508/R117H-7T who had pulmonary symptoms consisting of recurrent upper-airway infections. These children were felt to have CF because of their pulmonary symptoms and an increase in sweat chloride concentrations over time. Unfortunately, results of oropharyngeal or lower-airway cultures from these children were not included in the report. Finally, a case series focusing on adult men with CBAVD included 2 men with the F508/R117H-7T genotype who had mildly elevated sweat chloride concentrations (50 and 67 mmol/L) and normal pulmonary-function tests (forced expiratory volume in 1 second > 100% of predicted).²⁴ These men were seen at a center in which many patients with CF are infected with Burkholderia cepacia. When they had bronchoalveolar lavage performed, both men grew strains of B cepacia (genomovars 4 and 11) from their lower airways.²⁴

Population-based newborn screening for CF is not a comprehensive diagnostic program. By definition, any newborn screen will miss some infants with the disease in question. Which children it is permissible to miss is open for debate. Most CF centers now treat initial P aeruginosa infections aggressively, because early infection seems to be associated with worsening disease.^25,26 Eradication of Pseudomonas infection is easier before mucoid, biofilm-producing colonies are established. The 4 infants we report and the 10 reported by Lording et al²² illustrate that although CF genotypes with mild mutations may not cause classic CF, they can make children susceptible to serious infection with CF-related organisms. Failure to follow these children even after a negative sweat test might put them at increased risk of early, sustained Pseudomonas infection, which would be contrary to the goal of newborn screening—to detect disease before it become irreversible.

The conundrum is that the act of observing these children closely may, in actuality, increase the odds of their becoming infected with a virulent organism. It is possible that some of the positive airway cultures reported from children and adults with F508/R117H-7T reflect acquisition of these organisms at the CF center.²⁷ Great care must be taken to isolate newborn infants with CF from older patients with established infection. Newborn screen–positive infants should be seen at a separate time and place from other patients with CF to minimize patient-to-patient and caregiver-to-patient transmission of CF-related bacteria. However, the marked nutritional benefits and improved survival for those seen at CF care centers mitigate in favor of these children being seen at such a center. With these caveats, we feel that relatively common mild mutations (specifically, R117H) should be considered for inclusion in newborn screening mutation panels. Furthermore, children with these mutations should have frequent oropharyngeal cultures to detect the onset of serious infections, even if their sweat tests are negative.

The complexity of these issues highlights that physicians embarking on CF newborn screening should have a plan in place for counseling parents of children with the F508/R117H-7T genotype.²⁸ Clearly, much work is yet to be done to fully understand the reason why some children with F508/R117H-7T become symptomatic at an early age and others may have an extremely late onset of symptoms or no symptoms at all. Long-term follow-up of all those identified with this genotype will be necessary to delineate the true clinical relevance of the F508/R117H-7T mutation. Patients with this genotype should have clinical assessments, biochemical tests of CFTR dysfunction, and airway cultures performed prospectively. Finally, as more information regarding the role of thymidine-guanine repeats and non-CFTR genetic modifiers of CF becomes available, it may be possible to better identify which children with the F508/R117H-7T genotype will develop CF lung disease.

FOOTNOTES

Accepted May 3, 2006.

Address correspondence to Brian P. O’Sullivan, MD, Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Ave, Worcester, MA 01655. E-mail: osullivb{at}ummhc.org

The authors have indicated they have no financial relationships relevant to this article to disclose.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by O’Sullivan, B. P. Articles by Parad, R. Search for Related Content PubMed PubMed Citation Articles by O’Sullivan, B. P. Articles by Parad, R. Related Collections Respiratory Tract Social Bookmarking                         What's this?