OTHER CONDITIONS

1959 Brown NM, Smith AN. Kartagener’s syndrome with cystic fibrosis. BMJ 1959; 2(5154): 725-728. [PubMed]

Figure 23: 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) (figure 23).

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 Bromptom 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).

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 12). 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),

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).

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; Hodson ME. J R Soc Med 1992; 85 (Suppl 19):38-40).

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 and others have been reported subsequently. Often the renal or thyroid problems are associated.

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. & Meadow R. Munchausen syndrome by proxy. Arch Dis Child 1982; 57:92-98). 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 disorder.
Subsequently nine further reports of Munchausen or Munchausen by proxy with CF of the falsified disorder appeared in the literature up to 2005.

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.

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).

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 desiminated 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, 1995. [PubMed]). 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])

2001 Cornacchia 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.

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.

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 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.

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).

Fig. 39: Armmani Prasad
Fig. 40: Dr Peter Bye
Fig. 41: Mark Elkins

Armmani Prasad (figure 39) is the senior Physiotherapist at the CF Unit Great Ormond Street Hospital for Children, London and one the leading CF physiotherapists in the UK and internationally. She has written extensively on CF and also been an invited speaker at many conferences both in the UK and abroad and regularly advises the CF Trust on matters relating to CF care.

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%).

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

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. [PubMed]. 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.

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 reserveations regarding liver toxicity.

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