Unusual phenotype of cystic fibrosis patient, compound-heterozygous for 2789+5G→A/ΔF508 mutations
Article Outline
Abbreviatons: CF, cystic fibrosis, TR, transmembrane receptor, FEV1, forced expiratory volume in 1
s, FVC, forced vital capacity, CFTR, cystic fibrosis transmembrane receptor, CAVD, congenital absence of vas deferens
Keywords: Cystic fibrosis, Mild phenotype, Mutations 2789+5G→A/ΔF508
Introduction
Cystic fibrosis (CF) is a monogenic inherited disease characterized by irreversible chronic lung obstruction, pancreatic involvement and altered sweat electrolyte level.1 In the last 10 years more than 1300 different mutations of cystic fibrosis transmembrane receptor (CFTR) have been reported, each associated with a characteristic phenotype.2, 3, 4
Here we describe the peculiar phenotype of a cystic fibrosis patient with a rare “mild” CFTR mutation, known as 2789+5G→A, and 2789+5G→A/ΔF508 genotype. Clinical history is reported in detail and compared with phenotypes of patients compound-heterozygous for the same mutations (2789+5G→A/ΔF508).
Case report
A 39-year-old male, in good clinical condition, was referred to us with obstructive azoospermic sterility. Imaging revealed bilateral absence of the vas deferens. Genetic molecular analysis for common CFTR gene mutations in DNA of peripheral leucocytes showed a rare genotype, 2789+5G→A/ΔF508, suggesting cystic fibrosis. Medical history revealed hospitalization for acute episodes of severe weakness, profuse sweating, vomiting, myalgia and polyuria at 18 and 20 years of age. Hypokalemia, metabolic alkalosis and mild hyperglycaemia were found. The patient was discharged with a suggested diagnosis of periodic hypokalemic paralysis. Hiatal hernia and gastroesophageal reflux were also detected. Hydration and potassium supplementation in summer prevented further episodes. At 30 years of age, the patient was diagnosed with poorly controlled diabetes mellitus and treated with oral therapy. On referral, the patient complained of gastroesophageal reflux; he had no respiratory symptoms, recurrent respiratory infections or nasal polyps.
Physical examination was normal; nutritional status and respiratory and abdominal examinations were within normal limits. Routine laboratory tests showed increased glycate haemoglobin levels. The sweat chloride test showed very high sweat chloride values (109.25meqL−1). Lung function tests showed absence of obstructive deficit (FEV1 107.9%; FVC 117.9%; TLCO 82.1%). The 6-min walking test on room air excluded desaturation; Borg scale was zero before and after the test. Blood gas analysis was normal with PaO2 of 98mmHg. High resolution CT scan of the chest excluded lung involvement; CT scan of the abdomen revealed reduced pancreatic volume and many surface microcysts. Liver cirrhosis and gastrointestinal obstructive syndrome were excluded.
The patient was counselled about his genetic disease and advised to undergo complete regular follow-up in a centre specialized in cystic fibrosis.
Discussion
This communication describes the phenotype of a CF patient compound-heterozygous for 2789+5G→A/ΔF508 mutations. The first report of splice site mutation 2789+5G→A (a G–A substitution at nucleotide 2789 in intron 14b) associated with mild cystic fibrosis, concerned a group of related subjects.5 It was recently estimated that this mutation accounts for 0.1% of CF chromosomes in the world6 and has different frequencies in different geographic areas.7, 8 Mutation 2789+5G→A was subsequently reported in homozygotes and compound-heterozygotes with CFTR “mild” mutations and congenital absence of vas deferens (CAVD).9
A feature of our case was unusual presentation of the disease. In most CF patients, onset is associated with respiratory or gastrointestinal symptoms. In our patient the first signs were hypokalemia and electrolyte abnormalities, which were not recognized by the doctors. Dave et al. and Bates et al. reported two cases of CF in which diagnosis was based on severe hypokalemia, metabolic alkalosis, high chloride levels in sweat and sodium loss as presenting symptoms; they concluded that it was advisable to consider CF, especially in young subjects with hypokalemia and alkalosis and no history of renal or gastrointestinal diseases.
In 2005, Dugueperoux et al. studied the French CF Registry and matched the phenotype of a group of CF patients, compound-heterozygous for 2789+5G→A/ΔF508 mutations, with the clinical features of ΔF508 homozygotes. They concluded that CF heterozygotes had a milder phenotype than homozygous patients, as well as higher age at diagnosis, lower frequency of pancreatic insufficiency, better anthropometric measures and no meconium ileus because the splice site 2789+5G→A mutation is associated with partially defective receptor production and small amounts of normal CFTR. Increased sweat chloride values and respiratory involvement were common features of both groups of CF patients. When we compared the clinical findings of our patient with those of heterozygous CF patients reported by Dugueperoux et al., some differences emerged: age at diagnosis (our patient was much older: 39 versus 16.6±12.7 years), absence of respiratory involvement and presence of diabetes mellitus (never reported in heterozygous CF patients and very frequent in homozygotes for the ΔF508 mutation). Moreover, our patient had CAVD which was why molecular analysis of the CFTR gene was done. This anomaly was not found in Dugueperoux's population of heterozygotes. The main similarities between the phenotype of our patient and those already reported by Dugueperoux included high sweat concentrations of chloride, gastroesophageal reflux, normal body mass index.
In conclusion, although the phenotype of our CF patient, compound-heterozygous for 2789+5G→A/ΔF508 mutations, may be associated with a milder course of the disease, it has the unusual features of CAVD, pancreatic involvement and diabetes mellitus, rather than respiratory involvement. The clinical presentation of our case was also unusual, underlining the importance of considering the possibility of CF in apparently healthy persons with episodes of severe hypokalemia and metabolic alkalosis. The expression of clinical phenotype in our patient may be the result of different penetrance of the two mutations and/or the effect of modifying genes.
Conflict of interest
All authors declare that there are no financial and personal relationships with other people or organizations that could inappropriately influence (bias) this work. No employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding have been received. None of the authors have a conflict of interest to declare in relation to this work.
References
- Recommendations for quality improvement in genetic testing for cystic fibrosis European Concerted Action on Cystic Fibrosis. Eur J Hum Genet. 2000;8:S2–S24
- Complete detection of mutations in cystic fibrosis of Native American origin. Hum Genet. 1994;94:629–632
- Identification of the cystic fibrosis gene: clonino and characterization of complementary DNA. Science. 1989;245:1066–1073
- . Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am J Hum Genet. 1997;60:1122–1127
- Identification of a splice site mutation (2789+5G→A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis. Hum Mutat. 1997;9:332–338
- . Mutation Analysis Consortium. Geographic distribution and regional origin of 272 cystic fibrosis mutations in European population. Hum Mutat. 1997;10:135–154
- . An unusual presentation of CF in an adult. Am J Kidney Dis. 2005;45:41–44
- . Cystic fibrosis presenting with hypokalemia and metabolic alkalosis in a previously healthy adolescent. J Am Soc Nephrol. 1997;8:352–355
- . The CFTR 3849+10kbC→T and 2789+5G→A alleles are associated with a mild CF phenotype. Eur Respir J. 2005;25:468–473
PII: S1755-0017(07)00018-8
doi:10.1016/j.rmedc.2007.10.009
© 2007 Elsevier Ltd. All rights reserved.
