SOME OTHER CONDITIONS IN PEOPLE WITH CYSTIC FIBROSIS
Primary sclerosing cholangitis
2009 Perera E, Massie
J, Phillips RJ. Treatment of acne with oral isotretinoin in patients with cystic
fibrosis. Arch Dis Child 2009; 94:583-586.[PubMed]
Theoretical concerns about liver disease and vitamin A deficiency have limited the use of oral isotretinoin for troublesome acne in adolescents with cystic fibrosis. Oral isotretinoin was administered to nine patients with cystic fibrosis who had troublesome acne unresponsive to antibiotics. All patients were followed for 1-4 years after cessation of treatment. Isotretinoin treatment cleared active acne lesions in all patients. It was well tolerated, and no patient had significant side effects. All nine patients were pleased or delighted with the improvement in their skin. Adolescents with cystic fibrosis and acne can be treated with oral isotretinoin. Oral isotretinoin should be considered for adolescents with cystic fibrosis who have acne associated with scarring, acne not clearing with topical and antibiotic treatment, acne associated with depression or severe cystic acne.
This is a helpful paper for those considering the use of isotretinoin but who may have reservations regarding liver toxicity.
2011 Patel AJ, Raol VH, Jea A. Rare association between cystic fibrosis, Chiari I malformation, and hydrocephalus in a baby: a case report and review of the literature. J Med Case Reports [Electronic Resource] 2011; 5:366.[PubMed]
The ninth case of a baby with cystic fibrosis and Chiari I malformation, in this case in a 10-month-old, full-term Caucasian baby boy. There was developmental delay, macrocephaly, bulging anterior fontanelle, and papilledema. An MRI scan demonstrated an extensive Chiari I malformation with effacement of the fourth ventricle, obliteration of the outlets of the fourth ventricle and triventricular hydrocephalus without aqueductal stenosis. A ventriculoperitoneal shunt was inserted. The authors suggest that the cystic fibrosis transmembrane conductance regulator gene may play a previously unrecognized role in central nervous system development; alternatively, this central nervous system abnormality may have been acquired due to constant valsalva from recurrent coughing or wheezing or metabolic and electrolyte imbalances that occur characteristically in cystic fibrosis.
See also Needleman JP et al. Pediatr Pulmonol 2000; 30:490-492. [PubMed]. Also this entry in year 2000 section for illustration of example of the Arnold Chiari malformation.
2009 Berk DR, Ciliberto HM, Sweet SC, Ferkol TW, Bayliss SJ. Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations. Arch Dermatol 2009; 145:1296-1299.
The biggest article so far on wrinkling confirms the association between aquagenic wrinkling of the palms and CF. Among patients with CF, greater AWP occurs in those who are homozygous for the DeltaF508 mutation.
2010 Gild R, Clay CD, Morey S. Aquagenic wrinkling of the palms in cystic fibrosis and the cystic fibrosis carrier state: a case-control study. Brit J Dermatol 2010; 163:1082- 1084. [PubMed]
Aquagenic wrinkling of the palms (AWP) is hyperwrinkling occurring within 3 min of exposure to water. It is associated with cystic fibrosis (CF) and has been reported in a CF carrier. Twenty-one patients, 13 carriers and 15 controls were studied. Mean time to wrinkling was 11 min in controls, 7 min in carriers and 2 min in patients with CF. AWP was not seen in controls, but occurred in 80% of patients with CF and 25% of carriers. There was a significant difference between groups (P < 0. 001). The study demonstrated that AWP is a sign of both CF and the carrier state. It suggests that time to wrinkling decreases with decreased CFTR protein function. Patients presenting with AWP should be offered screening for both CF and the carrier state.
Apologies for including yet another paper on finger wrinkling in CF which was first described by Professor Bob Elliott in New Zealand in 1974 (Lancet 1974; ii: 108. above). This present study is the first to show that finger wrinkling was increased in some 25% of CF carriers. In an unpublished study from Leeds by Jeanette Firth there was no relation between the wrinkling time and the sweat electrolyte values. However, it would seem wise to exclude CF in people with significant aquagenic finger wrinkling. Also recently Garcon-Michel N et al,(Brit J Dermatol 2010; 163:162-166. [PubMed]) found the sign in 41% of people with CF.
2010 Tolland JP, Boyle J, Hall V, McKenna KE, Elborn JS. Aquagenic wrinkling of the palms in an adult cystic fibrosis population. Dermatology 2010; 221:326-330. [PubMed]
A study to determine the incidence and characteristics of aquagenic wrinkling of the palms (AWP) in the adult CF population in Northern Ireland. 105 patients were asked whether they noticed excess wrinkling of the hands when exposed to water. If they answered 'yes', further questions were asked regarding clinical characteristics. The atopic status, CF genotype and drug history were recorded for each patient. Formal testing of 7 patients was carried out. 43 of 105 (41%) described AWP; 20 were male and 23 were female. There was no association with genotype, atopy or concomitant drug intake. The authors suggest that condition is under reported in CF.
The first descriptions of finger wrinkling caused great excitement as there was a suggestion the sign may be related to the basic defect which was quite unknown at the time (Elliott RB, 1974 [PubMed]; Norman AP et al, 1974 [PubMed]); Johns M K (J Med Biol Illus 1975; 25:205-210.[PubMed]) suggested the wrinkling was due to the excessive salt concentration which increased the water binding capacity of keratin. Later it was suggested as a test of autonomic function (Bull C, Henry JA BMJ 1977; 551-552.[PubMed]).
In the Leeds CF unit Jeanette Firth, the CF centre clinic nurse, performed the test under controlled conditions on many children with CF who were attending the unit for Comprehensive Assessments of their CF and confirmed the phenomenon, but disappointingly we found it quite unrelated to the sweat electrolyte levels or any other clinical or laboratory feature of the patient’s condition (unpublished data). Subsequently there was considerable discussion as to autonomic abnormalities in CF of which skin wrinkling is a feature (see Davies et al, 1980).
2013 Gunduz O, Ozsarac KC, Ercin ME. Aquagenic palmar wrinkling induced by combined use of salazopyrin and indomethacin. Case Reports Dermatology 2013; 5:21-26. [PubMed]
Despite some studies implying a relationship between cystic fibrosis and aquagenic palmar wrinkling (APW), there are also reports of APW cases without an accompanying CF. In this report the authors describe a 19-year-old ankylosing spondylitis patient, who developed APW lesions after the start of combined salazopyrin and indomethacin treatment. His palmar lesions were resistant to topical corticosteroid and aluminium hydroxide therapy and disappeared only after stopping the anti-inflammatory drugs.
2013 Coelho-Macias V. Fernandes S. Lamarao P. Assis-Pacheco F. Cardoso J. Aquagenic keratoderma associated with a mutation of the cystic fibrosis gene.
Rev Port Pneumol 2013; 19:125-8. [PubMed]
Reported for the first time in 1996, aquagenic keratoderma is a rare condition which is characterized by edematous flat-topped papules appearing on palmar skin after water immersion. Multiple anecdotal associations have been described but, recently, the association with cystic fibrosis gene mutations (CFTR) has been highlighted. The authors describe an 18 year-old female, with one-month complaints of pruritus and swelling of palmar skin after water immersion. On examination, palmar skin was unremarkable but, 5 minutes after water immersion, multiple whitish papules became apparent. CFTR genotype study showed a F508del mutation in one allele. She had no other symptoms and no relevant family history. Aquagenic keratoderma is probably an under-diagnosed entity that might represent a manifestation of CFTR mutations, making carrier state identification and genetic counseling possible.
There has been much published on the reactions of the hands to water in CF since the first description of finger wrinkling by Prof. Bob Elliott from New Zealand in 1974 (above)
2013 Grasemann H, Ratjen F, Solomon M. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Engl J Med. 2013 Dec 12;369(24):2362-3. doi: 10.1056/NEJMc1308349. [PubMed]
An 11-year-old patient with cystic fibrosis (CFTR genotype F508del/G551D) who received maintenance therapy with other drugs for cystic fibrosis in addition to ivacaftor. Aquagenic wrinkling of his palms was assessed by putting his left hand into a water bath at 37°C for 5 minutes before treatment and after 1 month of treatment. Although considerable wrinkling was observed at baseline, the phenomenon had resolved after treatment. In parallel, the patient's sweat chloride concentrations decreased from 90 mmol per liter before treatment to 32 mmol per liter after treatment.
Auagenic palmar wrinkling before (top) and after ivacaftor
|Aquagenic wrinkling before (top) and after ivacaftor|
The authors comment that their findings show that CFTR-directed therapy had an effect on aquagenic wrinkling in a patient with cystic fibrosis and indicate an association of this phenomenon with CFTR dysfunction. Ivacaftor trials have shown considerable variability in treatment response when it is assessed according to the sweat chloride and nasal potential difference, two distinct measures of CFTR function. As new CFTR-directed therapies are being explored, additional measures of CFTR function could help to better capture the individual variability in response. Their observation related to ivacaftor therapy raises the potential that aquagenic wrinkling of the palms could serve as an additional and simple test of CFTR function to monitor the success of drug treatment.
2014 Chinazzo C. De Alessandri A. Menoni S. Romanisio G. Rebora A. Rongioletti F. Aquagenic wrinkling of the palms and cystic fibrosis: an Italian study with controls and genotype-phenotype correlations. dermatology 2014; 228(1):60-5.[PubMed]
Fifty-eight patients with CF underwent a hand immersion test in tap water. Twenty-three of their CF carrier relatives and 7 subjects with a negative genetic test for CF were recruited as controls. Secondary analyses explored associations with genotype, pulmonary function, and sweat electrolyte levels in all subjects with and without AWP. Additional information about atopic diathesis, hyperhidrosis of the palms and drug intake were also collected.
Thirty-one of the patients with CF (53.4%) exhibited AWP, in contrast to only 2 carriers (8.7%) and none in the control group. No correlation was found between CF genotype and AWP score severity. Twenty-three (39.7%) CF patients reported a history of hyperhidrosis, and in 17 of them (74%) AWP had been provoked. No correlation with history of atopy and lung function was noted. The difference between CF patients with hyperhidrosis and those without was highly significant (p = 0.016). Salt concentrations were significantly higher in patients with AWP.
Aquagenic wrinkling of the palms is obviously linked to CF and recognition indicates the need for a sweat test for CF. The authors found a significant association with hyperhidrosis and sweat electrolytes which they consider supports the 'hyperconcentrated sweat' pathogenetic theory of AWP.
2014 Tchernev G. Semkova K. Cardoso JC. Ananiev JJ. Wollina U. Aquagenic keratoderma. Two new case reports and a new hypothesis. Dermatology Online Journal 2014; 5(1):30-3. [PubMed]
Aquagenic keratoderma has been described as a transient condition affecting predominantly young females and defined clinically by the appearance of palmar hyper-wrinkling accentuated after immersion in water. We present two new cases with aquagenic palmoplantar acrokeratoderma - a child and a young male. A significant clinical improvement was achieved after topical treatment with aluminium salts. Aquagenic palmar keratoderma may be a clue to cystic fibrosis in adolescents and young adults. Theses authors developed a new hypothesis on its pathogenesis.
2015 Bielicky L; Braun-Falco M; Ruzicka T; Maier T. Aquagenic wrinkling of the palms: morphological changes in reflectance confocal microscopy and high-definition optical coherence tomography. Dermatology 2015; 230(3):208-12[PubMed]
Aquagenic wrinkling of the palms (AWP) is a rare condition, which is characterized by appearance of whitish papules and plaques, and an excessive wrinkling and swelling of the palmar skin after exposure to water. In most cases, young women are affected, and an association of AWP with cystic fibrosis (CF) has been described.
Two cases of AWP, not related to CF, in whom we used two innovative imaging techniques, namely high-definition optical coherence tomography and reflectance confocal microscopy, to show in vivo skin changes occurring after exposure of the skin to tap water in comparison to the findings in a healthy control person.
The image is from Grasemann H et al. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Eng J Med 2013; 369:2362-2363. Letter.
The patient's palm (figure) is shown before (top Panel A) and after (Panel B) 1 month of treatment with ivacaftor. The images shown were obtained after the patient's left hand was submerged in a water bath at 37°C for 5 minutes.
2015 Wilder-Smith EP. Stimulated skin wrinkling as an indicator of limb sympathetic function. Clin Neurophysiol 2015; 126(1):10-6. [PubMed]
Skin wrinkling upon water immersion has been used as an indicator of limb nerve function for more than 80 years. Until recently, a poor understanding of the physiology and lack of standardisation have hampered routine use of the test. The process underlying stimulated skin wrinkling has been recently identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibres. Vasoconstriction is postulated to drive wrinkling through loss of digit volume, which induces a negative pressure in the digit pulp and exerts a downward pull on the overlying skin and ultimately results in wrinkles. Improved test standardisation has been achieved through substituting water with EMLA for inducing skin wrinkling. This has made testing much easier and has helped implement stimulated skin wrinkling as a practical routine clinical bedside test. A literature search identified 10 studies of sufficient
quality for evaluating stimulated skin wrinkling as a diagnostic test of sympathetic under or over function. Seven studies provide level 1 or 2 evidence as a diagnostic test of small fibre neuropathy and three provide level 1 or 2 evidence for cystic fibrosis. There is reasonable evidence allowing the test to be employed as a simple and effective marker for small fibre neuropathy and cystic fibrosis.
Nadal M; Laudier B; Malinge MC; Binois R; Esteve E. [Aquagenic palmar keratoderma in a patient heterozygous for the mutation c.3197G>C in the CFTR gene]. [French] Annal Dermat Venereol 2015; 142(3):201-5.[PubMed]
The first case of aquagenic keratoderma associated with a new mutation in the CFTR gene. An 18-year-old patient with no particular history was referred for a painful rash on both palms occurring whenever she showered, and which had been ongoing for several months. The clinical examination was normal except for an appearance of moderate palmar hyperhidrosis. Following a test in which both hands were immersed in cold water for 5 minutes, the patient presented itching, burning and pain localised to the hands. The palms were wrinkled and oedematous with white, translucent and confluent papules. A clinical diagnosis of aquagenic palmar keratoderma was made. A genetic study revealed the presence of a new mutation in the CFTR gene for cystic fibrosis in the heterozygous state inherited from her mother: c.3197G>C or p.Arg1066.Pro and a heterozygous polypyrimidic 5T variant inherited from her father.
- Several studies have shown association of acquagenic keratoderma with the CFTR gene for heterozygotes (carriers without cystic fibrosis), for patients with cystic fibrosis and for a patient with CFTRopathy and pancreatitis.
2011 Dalgic B, Egritas O. Gray hair and acrodermatitis enteropathica-like dermatitis: an unexpected presentation of cystic fibrosis. Eur J Pediatr 2011; 170:1305-8. [PubMed]
Presentation of cystic fibrosis (CF) with an acrodermatitis enteropathica-like skin rash, anemia, and hypoproteinemia without pulmonary disease is rarely reported before. We describe an 11-month-old boy with rash and edema as the presenting signs of cystic fibrosis. The interesting additional finding in this patient was the graying hair after 3 months of age. A reversal of the gray hair was observed following pancreatic enzyme replacement therapy. In conclusion, acrodermatitis-like eruption and hypoproteinemia can be a presenting sign of CF. Graying hair has not been noticed so far as a sign of CF in these patients
Yet another presentation of CF. The acrodermatitis as the presenting disorder of CF has been described previously, related to the multiple dietary deficiencies in untreated patients, but the greying hair is new and interestingly was reversed after pancreatic enzyme therapy was started.
1985 Castile R,
Shwachman H, Travis W, Hadley CA, Warwick W, Missmahl HP. Amyloidosis as a complication
of cystic fibrosis. Am J Dis Child 1985; 139:728-732. [PubMed]
Three patients with amyloidosis complicating CF are reported to add to the six patients previously recorded. The presenting problem was proteinuria in five patients, enlarged thyroid in three patients, and hepatosplenomegaly in one patient. The progression of proteinuria to nephrotic syndrome and oedema occurred in eight of the nine patients and indicated a very poor prognosis. The kidneys, adrenal glands, spleen, thyroid gland, liver, heart, and bowel were most frequently involved. Renal involvement was a frequent and devastating complication of amyloidosis in patients with cystic fibrosis. Amyloidosis is a surprisingly rare complication of cystic fibrosis considering the severity and duration of pulmonary sepsis in most patients.Two cases had been reported by Ristow SC, et al, (1977; 131:886-888.[PubMed]) and others have been reported subsequently. Often the renal or thyroid problems are associated.
2014 Stankovic Stojanovic K. Hubert D. Leroy S. Dominique S. Grenet D. Colombat M. Clement A. Fayon M. Grateau G. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014; 21:231-7. [PubMed]
A 30-year retrospective survey identified nine cases of AA amyloidosis in approximately 6000 patients over 30 years and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goitre in one case, and epigastric pain in one case. Five patients had died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.
This study supports previous evidence that amyloidosis is a surprisingly rare in CF and that, when it does occur, renal involvement is predomina. .In AA amyloidosis the deposited protein is amyloid A protein, an acute phaseprotein which is normally soluble and whose plasma concentration is highest during inflammation.
Stankovic Stojanovic K, Hubert D, Leroy S, Dominique S, Grenet D, Colombat M, Clement A, Fayon M, Grateau G. Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network. Amyloid 2014; 21(4):231-7. doi: 10.3109/13506129.2014.943834. Epub 2014 Jul 23. [PubMed]
Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goitre in one case, and epigastric pain in one case. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.
- AA amyloidosis is a rare but important complication of CF. As in these patients, renal involvement is predominant.
Janssen KM, de Smit MJ, Brouwer E, de Kok FA, Kraan J, Altenburg J, Verheul MK, Trouw LA, van Winkelhoff AJ, Vissink A, Westra J. Rheumatoid arthritis-associated autoantibodies in non-rheumatoid arthritis patients with mucosal inflammation: a case-control study. Arthritis Res Ther 2015; 9;17:174. doi: 10.1186/s13075-015-0690-6. [PubMed] Free PMC Article
Rheumatoid arthritis-associated autoantibodies (RA-AAB) can be present in the serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or in the case of CF in the lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.
The non-RA patients had periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group.
Although overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.
- Suggest reading full abstract for more detail. An interesting study lending further support to one of the more remote effects of chronic lung inflammation in people with CF. The association between the increasing lung inflammation associated with pulmonary exacerbations and worsening of painful joints in CF is well documented (Bowler IM, Littlewood JM. Lancet 1992; 340(8813):244. [PubMed])
2011 Kongsgaard UE. Frederic Chopin and his suffering. Tidsskrift for Den Norske Laegeforening 2011; 131:707-710. [PubMed]
2010 was the bicentennial of Chopin's birth. He left more than 230 fantastic compositions, often described as romantic, emotional and poetic. Chopin composed almost exclusively for piano solo and has been called the pianists' composer. From his teens he suffered from respiratory tract infections, gradually accompanied by haemoptysis, pronounced breathing problems, diarrhoea and loss of weight. He experienced part of his adult life as a period of great suffering. He was 39 years old when he died. The assumed cause of death was tuberculosis, but other possible differential diagnoses have been suggested in recent years. In order to examine the different diagnostic alternatives, a non-systematic search of the literature was carried out in PubMed, Embase, Current Contents, Google and relevant reference books. The official cause of death was tuberculosis, but the autopsy report has never been found. Both cystic fibrosis and alpha-1-antitrypsin deficiency are possible differential diagnoses that can explain his symptoms. In spite of a disabling disease, Chopin was musically creative right to the end of his life. His suffering must have influenced his musical expression, which is characterized by intimacy and sentimentality. It is unlikely that we will ever find the true cause of death.
There are numerous references to Frederick Chopin and speculation as to his illness - this is the latest. A Medline search for "Chopin" will retrieve most of these which are interesting and worth reading.
2014 Leigh F. Fryderyc-Francois Chopin (1810-1849): music and malady. J Med Biogr 2014; 22(3):144-52. 24585613+[PubMed]
Chopin was born in Zelazowa Wola in Western Poland. He had no formal piano tuition and one could say that his skill as a pianist was self-taught, close to a miracle. All his compositions included the piano; this was not a restriction for him. The illnesses that plagued him and the cause of his death are the subject of articles by retrospective diagnosticians. The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
2010 Vincenzi F, Bizzarri B, Ghiselli A, de' Angelis N, Fornaroli F, de' Angelis GL. Cystic fibrosis and Crohn's disease: successful treatment and long term remission with infliximab. World J Gastroenterol 2010; 16:1924-7. [PubMed]
The association of cystic fibrosis and Crohn's disease (CD) is well known, but to date, there are very few cases in the literature of patients suffering from mucoviscidosis who have required treatment with infliximab. The authors report the case of a 23-year-old patient suffering from cystic fibrosis and severe CD treated successfully with infliximab without any infective complications or worsening of the pulmonary disease and with a long term (2 years) complete remission
Infliximab is a monoclonal antibody against tumour necrosis factor alpha used to treat autoimmune disease.
1962 Muir D. Batten
J. Simon G. Mucoviscidosis and adult chronic bronchitis. Their possible relationship.
Lancet 1962; i: 181-3. [PubMed]
One hundred adults with chronic bronchitis, 42 patients with other chest diseases and 25 controls were screened with the fingerprint method for raised chloride levels in the sweat (method of Shwachman & Gahm, 1956 above). None of the patients had excessive sweat chloride levels as judged by the plate test and the authors concluded that cystic fibrosis, in the homozygous state, could not be implicated as a cause of their chronic bronchitis.
It was reasonable to search for people with CF amongst those with similar chronic disorders. As in the present study, usually there were no patients with CF amongst the patients studied. Later this group, at the Royal Brompton Hospital in London, also failed to find an increase in respiratory disease amongst obligate heterozygotes for CF – that is to say the parents of people who had cystic fibrosis (Batten et al, 1963 below).
2000 Kostuch M,
Semczuk A, Szarewicz-Adamczyk W, Gasowska-Giszczak U, Wojcierowski J, Kulczycki
L. Detection of CFTR gene mutations in patients suffering from chronic bronchitis.
Arch Med Res 2000; 31: 97-100. [PubMed]
The purpose of this study from Poland was to search for CF gene mutations in patients suffering from chronic bronchitis. No less than five of 32 (16%) patients admitted to the Lublin School of Medicine, Poland between 1995 and 1996 with chronic bronchitis had CF gene mutations, all within the DeltaF508 region of the CFTR gene. All positive samples were obtained from patients heterozygous for the DeltaF508 mutation. The presence of the DeltaF508 mutation was considered statistically significant when the study group was compared to the study of Poland's general population. The results suggested an increased presence of the DeltaF508 mutation in Polish patients suffering from chronic bronchitis.
Earlier clinical studies
using sweat plate method from the UK did not show people with unrecognised or
mild CF were present among patients considered to have chronic bronchitis (Muir
D et al. 1962 above). Also in another study, perhaps more relevant to the present
report, there was no increase in the frequency of chronic bronchitis among obligate
CF heterozygotes (Batten et al, 1963 above). However, the prevalence of chronic
bronchitis was very high in the UK general population at that time (presumably
due to the high proportion of smokers and atmospheric pollution) and this may
have obscured the influence of the CF carrier state. More recently complete
mutational screening of 120 patients with chronic pulmonary disease detected
mutations in 11/23 disseminated bronchiectasis, 7/25 emphysema, 5/27 chronic
bronchitis, 5/26 lung cancer, 5/8 sarcoidosis (Bombieri et al, 1998 [PubMed]).
In a more recent study 17.74% of 31 patients with chronic obstructive
pulmonary disease had a CFTR mutation (Divac et al, 2004. [PubMed]).
Although others searching for only the six common mutations found no increase
in CFTR mutations in 100 patients with chronic bronchitis (Entzian P et al,
However, 5/11 non-CF individuals who had allergic bronchopulmonary aspergillosis
(ABPA) had one CFTR mutation (Miller PW et al, 1996. [PubMed]
Also CFTR function has been reported as significantly depressed in smokers (Cantin AM et al. Am J Resp Crit Care Med 2006; 173:1139-1144. [PubMed])
2006 Ziedalski TM,
Kao PN, Henig NR, Jacobs SS, Ruoss SJ. Prospective analysis of cystic fibrosis
transmembrane regulator mutations in adults with bronchiectasis or pulmonary
nontuberculous mycobacterial infection. Chest 2006; 130:995-1002.[PubMed]
Fifty adult patients at Stanford University Medical Center with a diagnosis of bronchiectasis and/or pulmonary NTM infection were prospectively characterized by sweat chloride measurement, comprehensive mutational analysis of CFTR, and sputum culture results. A new diagnosis of cystic fibrosis (CF) was established in 10 patients (20%). Sweat chloride concentration was elevated > 60 mEq/dL (diagnostic of CF) in seven patients (14%), and from 40 to 60 mEq/dL in eight patients (16%).
The frequency of CFTR mutations was elevated above that expected in the general population: heterozygous DeltaF508 (12% vs 3%), R75Q (14% vs 1%), and intron 8 5T (17% vs 5 to 10%).
1979 Soter NA, Mihm
MC, Colten HR. Cutaneous necrotising venulitis in patients with cystic fibrosis.
J Pediatr 1979; 95:197-201. [PubMed]
Two patients developed palpable purpura late in the course of their disease. Biopsies showed necrotising venulitis with perivenular infiltrate composed of neutrophils, fibrin hypogranulated mast cells and endothelial cell necrosis. Circulating immune complexes were detected. A variety of immunological abnormalities have been described in such patients. (Also Finnegan MJ et al, Quart J Med1989; 72:609-621.[PubMed]; Hodson ME. J R Soc Med 1992; 85 (Suppl 19):38-40.[PubMed]).
2010 Molyneux ID, Moon T, Webb AK, Morice AH. Treatment of cystic fibrosis associated cutaneous vasculitis with chloroquine. J Cyst Fibros 2010; 9:439-441. [PubMed]
Vasculitis is a well recognised complication of cystic fibrosis. Corticosteroids are the mainstay of treatment but some cases can be resistant and may require additional disease modifying agents. The authors describe a case of steroid resistant cutaneous vasculitis which was successfully treated with chloroquine in addition to corticosteroids and a subsequent relapse successfully treated with chloroquine alone.
2001 Saglani S,
Bush A. Cystic fibrosis and Down's syndrome: not always a poor prognosis. Pediatr
Pulmonol 2001; 31:321-322. [PubMed]
A child developed a bronchiolitis-like illness and was found to have mosaic Down's syndrome (diagnosed on karyotype) and also cystic fibrosis, diagnosed on the basis of a high sweat osmolality (247 mosmoles/kg sweat; normal, 62-137) and a homozygous delta F508 genotype. Despite two potentially life-threatening conditions, the child is doing well at the age of 7 years, despite pancreatic insufficiency.
2010 Guy EL, Peckham DG, Brownlee KG, Conway SP, Lee TW. Cystic fibrosis coexisting with trisomy 21. J Cyst Fibros 2010; 9:330-331. [PubMed]
Previous reports of children with coexistence of cystic fibrosis and full trisomy 21 died in infancy and the oldest reported survivor being 6 years of age. This report describes a young man with genetically confirmed trisomy 21 and homozygous for the F508del cystic fibrosis mutation. Despite the diagnosis of cystic fibrosis being delayed until the age of 2 years he has reached the age of 25 years. However he has poor lung function and a continuous ambulatory oxygen requirement.
The first report of CF in a patient with Down's syndrome was that of Milunsky A. Pediatrics 1968; 42:501-4.
Wang X. Moylan B. Leopold DA. Kim J. Rubenstein RC. Togias A. Proud D. Zeitlin PL. Cutting GR. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhino sinusitis in the general population. JAMA 2000; 284:1814-1819. [PubMed]
Eleven of 147 chronic rhino sinusitis (CRS) patients (7.5%) were found to have a CF mutation (DeltaF508, n = 9; G542X, n = 1; and N1303K, n = 1). Diagnostic testing excluded CF in 10 of these patients and led to CF diagnosis in 1. Excluding this patient from the analyses, the proportion of CRS patients who were found to have a CF mutation (7%) was significantly higher than in the control group (n = 2 [2%]; P =.04, both having DeltaF508 mutations). Furthermore, 9 of the 10 CF carriers had the polymorphism M470V, and M470V homozygotes were over represented in the remaining 136 CRS patients (P =.03).
These data indicate that mutations in the gene responsible for CF may be associated with the development of chronic rhinosinusitis in the general population. Another study suggesting that CF heterozygotes or even atypical patients with CF may be over represented in a condition with similar clinical features to CF.
2007 Basu AP. Kumar P. Devlin AM. O'Brien CJ. Cystic fibrosis presenting with bilateral facial palsy. Eur J Paediatr Neurol 2007; 11:240-242. [PubMed]
A 15-week old male infant presented with bilateral lower motor neuron facial palsy of unknown cause. Subsequently his growth deteriorated and he developed progressively worsening cough and wheeze. A diagnosis of cystic fibrosis was confirmed and hypovitaminosis A detected. Improvement of the facial palsy was noted following standard management of cystic fibrosis including vitamin A supplementation.
Presentations due to the manifestations of vitamin deficiency, particularly of vitamin A, are well documented. A similar case in a 10 week old infant was reported with low vitamin A levels and bilateral facial nerve paralysis (Cameron C et al. J Cyst Fibros 2007; 6:241-243. [PubMed]).
2011 Horsley A, Helm J, Brennan A, Bright-Thomas R, Webb K, Jones A. Gout and hyperuricaemia in adults with cystic fibrosis. J R Soc Med 2011; 104 Suppl 1:S36-9.[PubMed]
Gout has not been described previously as a complication in cystic fibrosis (CF). Nine CF patients presented with symptoms of acute gout - an estimated prevalence of around 2.5% in the adult CF clinic population, compared to a previously described prevalence in the non-CF population of just over 1%. Serum urate is measured routinely at the annual review in this unit. Mean (SD) serum urate was 0.40 (0.09) mmol/L in male CF patients (n = 108) and 0.31 (0.08) mmol/L in female patients (n = 74). This was significantly greater than in historical controls. Thirty-seven percent of male CF patients and 36% of female patients had serum urate levels above the upper limit of normal.
Although hyperuricemia has been described by a number of authors in people with CF since 1978 (Davidson GP et al, J Pediatr 1978; 93:976-8. [PubMed] ; Sack J et al, 1980 Isr J Med Sci 1980: 417-9. [PubMed]) perhaps surprisingly, these authors did not report having observed any individuals with clinical gout. This is in marked contrast to the nine affected patients in the present report. Much of the previous discussion has concerned the possible renal effects. It was usually considered that the older less refined pancreatic enzyme preparations were more likely to cause problems, however these patients were receiving Creon - perhaps other factors in their treatment or lifestyle (diet, alcohol, medical treatment, etc) were contributory.
2011 Obeid M, Price J, Sun L, Scantlebury MH, Overby P, Sidhu R, Chiriboga CA, Quittell LM. Facial palsy and idiopathic intracranial hypertension in twins with cystic fibrosis and hypovitaminosis A. Pediatr Neurol 2011; 44:150-152. [PubMed]
10-week-old monozygotic twins, diagnosed with cystic fibrosis by newborn screening, developed facial palsy and increased intracranial pressure. Cranial imaging and cerebrospinal fluid analysis produced normal results. Levels of serum vitamin A were below the normal range. Low levels of vitamin A are associated with facial nerve paralysis, and are at least partly implicated in the development of increased intracranial pressure in infants with cystic fibrosis.
Facial palsy is a well documented as associated with low vitamin A levels in CF infants (Keating JP, Feigin RD. Increased intracranial pressure associated with probable vitamin A deficiency in cystic fibrosis. Pediatrics 1970; 46:41-46.[PubMed]); Silman JS et al. Arch Otolarygol 1985; 111:822-825. [PubMed]) ;Cameron C et al. J Cyst Fibros 2007; 6:241-243 [PubMed]); Basu AP et al. Eur J Paediatr Neurol 2007; 11:240-242. [PubMed]).
1959 Brown NM, Smith AN. Kartagener's syndrome with cystic fibrosis. BMJ 1959; 2(5154):725-728 [PubMed]
Fig. 1: An example of Kartagener's syndrome and CF from a later paper (Burnell & Robertson, 1974 below).
A man aged 20 years from Glasgow had appendicitis and was found to have CF proven by extensive investigation including a sweat chloride of 135-150 meq/l and sodium of 155-165 meq/l. He had suffered chronic ill health from childhood with poor growth and bronchiectasis, situs invertus and sinusitis – a syndrome described by Kartagener in 1933 (Kartagener M. Beitr Klin Tuberk 1933; 83:489) .
1974 Burnell RH,
Robertson EF. Cystic fibrosis in a patient with Kartageners Syndrome. Am J Dis
Child 1974; 127:746-747. [PubMed]
A report from Adelaide Children’s Hospital, Australia. Said to be the third report of this combination with Kartageners syndrome of situs inversus totalis, bronchiectasis, and recurrent sinusitis with or without nasal polyps (figure 1). A white boy aged six months had “bronchopneumonia and neglect”. The lowest sweat electrolyte values were sodium 96 and chloride 80 meq/l. The duodenal biopsy showing partial villous atrophy which was rather puzzling and not discussed by the authors. The similarity of the symptoms of the two conditions, CF and Kartagener’s, is discussed. The two previous cases were doubtful. The authors advise excluding CF in all people with Kartagener’s syndrome. (Also Brown & Smith, 1959 above),
1993 Phillips RJ,
Crock CM, Dillon MJ, Clayton PT, Curran A, Harper JI. Cystic fibrosis presenting
as kwashiorkor with florid skin rash. Arch Dis Child 1993; 69:446-448. [PubMed]
Two infants with a florid erythematous rash and generalised oedema, hypoalbuminaemia, and anaemia were found to have cystic fibrosis. This rare presentation is associated with false negative sweat tests, delays in diagnosis, and a considerable mortality. The authors suggested that this presentation represents a manifestation of kwashiorkor secondary to intestinal malabsorption.
1986 Orenstein DM,
Wasserman AL. Munchausen syndrome by proxy simulating cystic fibrosis. Pediatrics
1986; 78:621-624. [PubMed]
Professor Sir Roy Meadow described Munchausen by proxy in 1977 (Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet 1977; ii: 343-345.[PubMed] & Meadow R. Munchausen syndrome by proxy. Arch Dis Child 1982; 57:92-98.[PubMed]).
This is the first report where CF was the falsified disorder. The mother falsified
the history of her child, cunningly altered sweat tests and stool fat analyses
and stole sputum from patients with CF to make her child appear to have cystic
fibrosis. Previous reports of the syndrome had concerned single signs or symptoms
but the present case involved the complex features of a multisystem genetic
Subsequently ten further reports of Munchausen or Munchausen by proxy with CF of the falsified disorder appeared in the literature up to 2008.
2001 Kanagasundaram SA, Lane LJ, Cavalletto BP, Keneally JP, Cooper MG. Efficacy and safety of nitrous oxide in alleviating pain and anxiety during painful procedures. Arch Dis Child 2001; 84:492-495. [PubMed]
The repeated need for venous access is a major problem for a significant proportion of children with CF – in some amounting to severe needle phobia. Another simple method of improving their quality of life was to use inhaled nitrous oxide before venepuncture. The technique was already used successfully in Belfast (Mills et al. 2001 below) and subsequently elsewhere for children with CF undergoing painful procedures (Williams V et al. Paediatr Nurse; 2006:18:31-33)).
This seemed an excellent form of treatment for children having distressing procedures and is obviously used successfully in a number of CF centres by experienced clinicians (Mills & Redmond, 2001 below). The method is now used in many CF Centres in the UK.
2001 Mills HL, Redmond AOB. Cystic fibrosis patients' view of self administered nitrous oxide (Entonox) during insertion of epicutaneo-cava catheters (long lines). 24th ECFS Conference Vienna 2001. Poster 291.
The distress of some children at even the thought of an intravenous injection or insertion of a venous catheter, when they have had many such insertions before, has to be seen to be believed. It is distressing not only for the unfortunate patient and the parents but also for the unfortunate doctor inserting the needle! The use of nitrous oxide is a great idea and appears very acceptable to most people. (The method was first published by Kanagasundaram et al, 2001 above).
2005 Koh JL, Harrison
D, Palermo TM, Turner H, McGraw T. Assessment of acute and chronic pain symptoms
in children with cystic fibrosis. Pediatr Pulmonol 2005; 40:330-335.[PubMed]
The aims of this study were to: 1) assess acute and chronic pain symptoms as reported by children with CF, and 2) examine the relationship between pain symptoms and disease severity as measured by percentage of forced expired volume in 1 sec (FEV1%). Forty-six children completed a self-report questionnaire assessing characteristics of chronic disease-related pain (frequency, intensity, duration, associated emotional upset, and location of pain). Forty-six percent of the sample described pain occurring at least once per week. A small subgroup of children reported longer-lasting and moderately intense pain. Children with chest pain were found to be particularly at risk for experiencing more functional limitations and a significantly lower FEV1% compared to children without chest pain. Disease-related pain is common for children and adolescents with CF, suggesting that pain assessment should be a routine part of their clinical care.
Pain appears to be a common problem in people with CF and definitely related to the disease severity. This article provides a useful up to date review of the subject which is of importance for many people with CF.
2006 Williams V, Riley A, Rayner R, Richardson K. Inhaled nitrous oxide during painful procedures: a satisfaction survey. Paediatric Nursing 2006; 18:31-33. [PubMed]
Inhaled nitrous oxide was safe and effective in reducing trauma and the effects of needle phobia and being offered to children with CF for procedural pain in the district general hospital at Wolverhampton
2009 Flume PA, Ciolino
J, Gray S, Lester MK. Patient-reported pain and impaired sleep quality in adult
patients with cystic fibrosis. J Cyst Fibros 2009; 8:321-325.[PubMed]
.Sleep impairment has been described in patients with cystic fibrosis (CF). Pain is a known cause of sleep disturbance and as pain is commonly reported in patients with CF, we sought to find an association between impaired sleep quality and pain. Fifty adult CF patients completed surveys of pain and sleep quality. We found that pain and poor sleep quality are reported in a majority of adult CF patients and there is a strong correlation between the two. This will have important clinical implications in the evaluation and treatment of adult patients.
There are more reports and attention paid to chronic pain which is very common in people with CF. In this study from the USA the pain was contributing significantly to sleep disturbance in many patients
2013 Wilson K, Jamersom PA. Comparison of central venous catheter and peripheral vein samples of antibiotics in children with cystic fibrosis. J Spec Pediatr Nurs 2013; 18:33-41. [PubMed]
A trial to determine if accurate serum antibiotic levels can be obtained from central venous catheters (CVCs) in pediatric patients with cystic fibrosis. Fifty paired CVC-peripheral vancomycin or tobramycin specimens were collected within 5 min of each other following a 5-ml flush and discard. Specimen samples were randomized by first site drawn. Central venous catheter and peripheral antibiotic levels were highly correlated (r =.97, p <.001), with no statistically significant difference (t = 1.18, p =.25).
So accurate antibiotic concentrations can be obtained from CVCs, reducing pediatric patient trauma and stress. A practical very useful study of great relevance to child patients!
Primary Sclerosing Chiolangitis
Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003; 113:286-292. [PubMed].
This complex study concludes that the data indicate that there is an increased prevalence of CFTR abnormalities in primary sclerosing cholangitis (PSC) as demonstrated by molecular and functional analyses and that these abnormalities may contribute to the development of PSC in a subset of patients with inflammatory bowel disease.
2013 Anand A. Tullis E. Stephenson A. Nickel JC. Leveridge MJ. Pseudomonas aeruginosa bacteremia and prostatitis in a patient with cystic fibrosis. Canadian Urological Association Journal. 2013; 7:E1-3. [PubMed]
Patients with cystic fibrosis commonly suffer chronic respiratory infections, although systemic dissemination is relatively rare. Acute bacterial prostatitis presents dramatically and is believed to be mostly caused by local migration (with or without instrumentation) of the lower urinary tract and presents with a predictable microbial aetiology. The authors report a case of a 26-year-old man who has CF presenting with acute Pseudomonas aeruginosa bacterial prostatitis due to haematogenous propagation from a chronic pulmonary infection.
2000 Bombieri C, Luisetti M, Belpinati F, Zuliani E, Beretta A, Baccheschi J, Casali L, Pignatti PF. Increased frequency of CFTR gene mutations in sarcoidosis: a case/control association study. Eur J Hum Genet 2000; 8:717-720.[PubMed]
A complete screening of the CFTR gene by DGGE and DNA sequencing was performed in patients with sarcoidosis. In 8/26 cases, missense and splicing CFTR gene mutations were found, a significant difference over controls (9/89) from the same population. A trend towards disease progression was observed in patients with CFTR gene mutations compared to patients without mutations.
These data suggest that CFTR gene mutations predispose to the development of sarcoidosis.
2005 Burton CM, Pressler T, Milman N. Pulmonary sarcoidosis in a child with cystic fibrosis. Pediatr Pulmonol 2005; 39:473-7. [PubMed]
A 13-year-old girl with known CF (homozygous delta F508 defect) presented with a sudden decline in lung function. FEV1 decreased from 80% to 64% predicted, and FVC from 90% to 80% predicted. Diffusion capacity for carbon monoxide (D(L)CO) was 92% predicted. There was no history of cough, dyspnea, or reduced exercise tolerance, but she had arthralgia of the knee- and ankle-joints. A chest radiograph and CT scan of the thorax demonstrated pronounced bilateral hilar and mediastinal lymphadenopathy, compatible with pulmonary sarcoidosis. Histological examination of lymph node biopsy specimens obtained at mediastinoscopy demonstrated noncaseating epithelioid-cell granuloma. The majority of lymphocytes were CD4+ T lymphocytes, with a CD4+/CD8+ ratio of 5:1. The patient showed a prompt response to treatment with oral corticosteroids, and lung function returned to baseline levels. Subsequent radiographic appearances showed almost complete regression of mediastinal lymphadenopathy.
The probability that CF and sarcoidosis would coexist by chance in a Danish child of this age is approximately 1:10(9). The collective incidence and geographic distribution of previously described patients with coexistent CF and sarcoidosis lend support to an association between the two diseases.
1974 Fluge G, Aarskog
D. Silver-Russell dwarfism and cystic fibrosis. Am J Dis Child 1974; 127:760-761. [PubMed]
A Norwegian girl aged seven years with CF and the typical features of Silver-Russell dwarfism. Intestinal malabsorption was documented at two years and no effect noted from a gluten free diet. Full investigation at six years showed positive sweat tests (Cl 77-114 & Na 82-137 meq/l) diagnostic of CF and confirmed the features of S-R dwarfism. A previous example of this association had been published by Taussig (Am J Dis Child 1973; 125:495-503).
2006 Hayes D Jr.
Obstructive sleep apnea syndrome: a potential cause of lower airway obstruction
in cystic fibrosis. Sleep Medicine 2006; 7:73-75.[PubMed]
A six-year-old healthy female with cystic fibrosis (CF) and pancreatic sufficiency presented with cough, weight loss, and lung function decline. Further history suggested obstructive sleep apnea, and nocturnal polysomnography (NPSG) confirmed this. Adenotonsillectomy resulted in resolution of clinical symptoms with return of normal lung function. This case establishes that obstructive sleep apnea syndrome (OSAS) may be a potential cause of lower airway inflammation and resulting weight loss in the young CF population.
It is useful to remember that increase in respiratory symptoms and signs in CF may be related to the upper respiratory tract which may be obstructed by the huge tonsils and adenoids. In such cases adenotonsillectomy may be followed by dramatic improvement even in young children not only in overnight oxygen saturations but also in weight increase and general wellbeing.
M, Zenorini A, Perobelli S, Zanolla L, Mastella G, Braggion C. Prevalence of
urinary incontinence in women with cystic fibrosis. BJU Internat 2001; 88: 44-48. [PubMed]
Of 176 women with CF, 35% were occasionally incontinent of urine but 24% were regularly incontinent. As urine loss is likely to be an under-reported problem, particularly in a CF clinic devoted to mainly chest problems, the authors suggest that women with CF should be asked directly about urinary incontinence as part of their routine follow-up. Pelvic floor muscle exercises were said to help. Also there was a similar report from Manchester Adult CF clinic (Orr A et al. BMJ 2001; 322:1521[PubMed]) and a further one showing some response to pelvic floor muscle exercises (McVean RJ et al. J Cyst Fibros 2003; 2:171-176.[PubMed]).
These are really important reports which would improve the recognition of a distressing and relatively common symptom in women with CF which may go unreported and cause considerable distress for many years.
2006 Prasad SA,
Balfour-Lynn IM, Carr SB, Madge SL. A comparison of prevalence of urinary incontinence
in girls with cystic fibrosis, asthma and healthy controls. Pediatr Pulmonol
2006; 41:1065-1068. [PubMed]
Another study on urinary incontinence - this time on younger patients. In recent years the physiotherapists have taken an increasing interest in bladder dysfunction in CF. Girls with CF aged 11 to 17 years were studied and urinary incontinence was reported by 17/51 (33%) girls, compared with only 4/25 (16%) of those with asthma and 2/27 (7%) healthy controls. The problem was associated with increasing severity of lung disease. (also described in adults with CF by Cornacchia et al, 2001 above; Orr A et al. BMJ; 322:1521).
1994 Sawyer S, Bowes
G, Phelan PD. Vulvovaginal candidiasis in young women with cystic fibrosis.
BMJ 1994; 308:1609. [PubMed]
Vulvovaginal candidiasis was more common in 55 women with CF than in controls (13 vs.4) and more difficult to treat. Many women with CF had recognized the association of the Candida infection with their use of antibiotics. The authors suggested women with CF should be given routine advice about the possibility of candidiasis.
This was an important paper as it is unlikely that women would be asked about such problems in a busy CF clinic for adults which are often “chest orientated” – yet adequate treatment of the candidiasis would significantly improve the patient’s quality of life. Somewhat analogous to this problem was the later recognition of the increased incidence of urinary incontinence in women with CF (see Cornacchia et al, 2001).