Abnormal Sweat Chloride Research Articles

M292 CASE OF AN ADULT WITH RECURRENT INFECTIONS AND ELEVATED SWEAT CHLORIDE CONCENTRATIONS

Recurrent sinopulmonary infections and abnormal sweat chloride testing suggest a diagnosis of Cystic Fibrosis (CF). Without a CF transmembrane conductance regulator (CFTR) mutation, the diagnosis is less likely. Patients with negative CF genetic testing, positive sweat testing and diagnosed immunodeficiency have been reported, mainly in the pediatric literature. We present an adult patient with recurrent infections, elevated sweat chloride concentrations and negative CF genetic testing.

Reports of Three Cases of Atypical Cystic Fibrosis with Azoospermia

Cystic Fibrosis is the most common autosomal recessive genetic disease in Caucasian population. Extending knowledge about the molecular pathology on the one hand allows better delineation of the mutations in the CFTR gene and the other to dramatically increase the predictive power of molecular testing. This study wants to underline that the identification of individuals with atypical cystic fibrosis can sometimes present particular difficulties of interpretation. On that ground, if there is a strong clinical suspicion, it is always advisable the biochemical study by performing the sweat test, followed by sequencing of the CFTR gene. Not all patients with cystic fibrosis have abnormal sweat chloride levels, severe lung disease, or failure to thrive. These three cases remind us to think “outside the box.” For these reasons, in patients with idiopathic azoospermia, it is important to perform the sequencing of CFTR gene.

WS20.3 Acquired CFTR dysfunction in patients with primary ciliary dyskinesia (PCD)?

It has been shown that chronic bronchitis, cigarette smoke, hypoxia, and chronic airways inflammation are associated with reduced CFTR function. Primary ciliary dyskinesia (PCD) is characterized by chronic sino-pulmonary disease and chronic bronchiectasis. We have noticed that some patients with PCD have borderline or high sweat chloride test. This may suggest acquired CFTR dysfunction in these patients. Objectives To analyze CFTR function in a large cohort of PCD patients by measuring sweat chloride and nasal potential difference (NPD), and to compare the results with control individuals and patients with CF. Methods 30 PCD patients >6 years treated at our clinic performed sweat test and NPD. For all patients with above normal values in the sweat test and NPD tests, analysis for CFTR mutations or exome analysis was performed. Results The mean (±SD) value of sweat chloride of the 30 PCD patients was 51.5±18.6 mmol/L (normal 60 mmol/L) and 9/30 had normal values. 2/17 patients had abnormal NPD and genetically confirmed PCD. Conclusions PCD patients may have abnormal sweat chloride tests; therefore, it is important to perform NPD in patients with abnormal/borderline sweat test in order to differentiate between PCD and CF and to confirm the diagnosis with genetic analysis. It is suggested that PCD should be added to the list of diseases causing false-positive sweat tests. The significance of this reduced CFTR function needs further investigation since new therapies that augment CFTR function may be beneficial in these patients.

Inconclusive diagnosis of cystic fibrosis after newborn screening.

To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; "CF screen positive, inconclusive diagnosis" [CFSPID]) for disease manifestations. Infants with CFSPID and CF based on NBS from 8 CF centers were prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life. Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median [interquartile range]:77 [61-106] vs 144 [105-199] μg/L; P < .0001) than did subjects with CF. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did CFSPID→CFSPID patients. A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.

Exercise Intolerance, Malnutrition, Abnormal Sweat Chloride Levels, and Two CFTR Mutations: Is It Cystic Fibrosis?

Exercise Intolerance, Malnutrition, Abnormal Sweat Chloride Levels, and Two CFTR Mutations: Is It Cystic Fibrosis?

Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis?

BackgroundThe phenotypic spectrum of cystic fibrosis (CF) has expanded to include patients affected by single-organ diseases. Extensive genotyping and nasal potential difference (NPD) testing have been proposed to assist in...

Early acute pancreatitis in a child with compound heterozygosis ∆F508/R1438W/Y1032C cystic fibrosis: a case report

IntroductionRecent studies suggest an important role of the cystic fibrosis transmembrane conductance regulator gene in the development of pancreatitis. It occurs approximately in 20% of patients with cystic fibrosis and almost exclusively in pancreatic sufficient people. Newborn screening and improved panels of deoxyribonucleic acid mutation analysis techniques are revealing more rare and nonclassical pictures of the disease, generally associated with pancreatic sufficiency and with an increased risk of developing pancreatitis. Mutations R1438 and Y1032 are considered rare mutations, and, when singularly associated with ∆F508, lead to a mild phenotype with pancreatic sufficiency and no detectable respiratory involvement.Case presentationWe present the case of a Caucasian girl, aged six years, whose genotype was characterized by three different mutations ∆F508, R1438W and Y1032C, never reported, together, in the same patient. She presented with a positive immunoreactive trypsinogen screening, a borderline sweat test, and, in the first years, a favorable pulmonary course, and pancreatic sufficiency. At the age of six years, she presented with a sudden episode of acute abdominal pain, anorexia and fever. A diagnosis of pancreatitis was made after clinical and laboratory examinations. Venous rehydration, bowel rest and therapy with ursodeoxycholic acid resulted in complete remission.The treatment was successful, with normalization of her symptoms and laboratory parameters within four weeks.ConclusionThere has been a vast expansion in the understanding of the wide range of phenotypes associated with cystic fibrosis transmembrane conductance regulator dysfunction since the discovery of the cystic fibrosis transmembrane conductance regulator gene. The genotype-phenotype correlation in pancreatitis is rare compared to other organ manifestations, since this is seen almost exclusively among pancreatic sufficient patients with cystic fibrosis. Our study supports that compound heterozygosis ∆F508-R1438W/Y1032C is a 'cystic fibrosis-causing genotype' characterized by an immunoreactive trypsinogen positive screening, abnormal sweat chloride testing, and pancreatic sufficiency, with an increased risk of acute pancreatitis at an early age.

Novel splice‐site mutation in ATP8B1 results in atypical Progressive Familial Intrahepatic Cholestasis Type 1

Our objective was to identify the molecular genetic basis of an Alagille-like condition not linked to JAG1 or NOTCH2 in two related sibships. Because of common ancestry, and an autosomal recessive mode of inheritance, it was hypothesized that all affected and no unaffected individuals would be homozygous for the same haplotype in the region of the causative gene. Single nucleotide polymorphism arrays were therefore used to genotype 3 affected individuals from two sibships, their mothers and four unaffected siblings, to identify regions of homozygosity. Genes within the largest regions were prioritized and sequenced for mutations. Mutant RNA transcripts were also sequenced. A novel splice acceptor site mutation in the ATP8B1 gene was identified (a G-C preceding exon 16 resulting in a 4 bp deletion and frameshift from the 5' end of exon 16). This result was unexpected because ATP8B1 mutations are associated with progressive familial intrahepatic cholestasis type 1 (PFIC1). Intrahepatic bile duct paucity, cardiac anomalies, renal tubular acidosis and hypothyroidism led to an initial diagnosis of Alagille syndrome. However, in retrospect, abnormal sweat chloride, normal gamma-glutamyl transferase, normal to low cholesterol, and an autosomal recessive mode of inheritance were consistent with PFIC1. Renal tubular acidosis, hypothyroidism and cardiac anomalies have not previously been associated with PFIC1. This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community.

389 Prolonged Clostridium difficile associated diarrhoea in a cystic fibrosis patient precluding suitability for lung transplant: an important issue for patients awaiting transplantation

Background: At present more than 1800 mutations have been described in the CFTR-gene. Several rare mutations are believed to cause mild lung disease and late onset of symptoms. We present a 5 y old Belgian boy heterozygous for an atypical CFTR variant and a novel variant which was never described before. Case report: A 5 y old boy with recurrent bronchitis and chronic sinusitis was referred to our clinic with repeated abnormal sweat chloride (Cl) (right 70mEq/L; left 53mEq/L) and elevated sweat sodium values (right 86mEq/L; left 62mEq/L), performed by Gibson and Cooke gauze method. Chest CT scan showed bronchial wall thickening and mucous plugging, without bronchiectasis. He is pancreatic sufficient, without history of pancreatitis. By screening the coding region of CFTR, using sequencing and MLPA (Multiplex Ligation-dependent Probe Amplification), he was shown to be heterozygous for c.224G>A (p.Arg75Gln − legacy name: R75Q) and c.122C>G (p.Pro41Arg), a novel variant which was never described before. Analysis of the parents is ongoing to prove that both variants are on different alleles. Discussion: R75Q is described as a variant overrepresented in patients with atypical CF, sarcoidosis, COPD and chronic pancreatitis and rather influences bicarbonate conductance than Cl. Our young patient has already respiratory symptoms and abnormal sweat chloride values. To our knowledge CFTR p.Pro41Arg has never been described before and its clinical relevance is not clear. As this boy has signs and symptoms of CF disease in combination with an atypical CFTR mutation, this novel mutation might be involved. However, mutations outside the coding region cannot be excluded.

388 Detection of a novel CFTR mutation c.122C>G (p.Pro41Arg) in a young cystic fibrosis (CF) patient with recurrent respiratory symptoms

Background: At present more than 1800 mutations have been described in the CFTR-gene. Several rare mutations are believed to cause mild lung disease and late onset of symptoms. We present a 5 y old Belgian boy heterozygous for an atypical CFTR variant and a novel variant which was never described before. Case report: A 5 y old boy with recurrent bronchitis and chronic sinusitis was referred to our clinic with repeated abnormal sweat chloride (Cl) (right 70mEq/L; left 53mEq/L) and elevated sweat sodium values (right 86mEq/L; left 62mEq/L), performed by Gibson and Cooke gauze method. Chest CT scan showed bronchial wall thickening and mucous plugging, without bronchiectasis. He is pancreatic sufficient, without history of pancreatitis. By screening the coding region of CFTR, using sequencing and MLPA (Multiplex Ligation-dependent Probe Amplification), he was shown to be heterozygous for c.224G>A (p.Arg75Gln − legacy name: R75Q) and c.122C>G (p.Pro41Arg), a novel variant which was never described before. Analysis of the parents is ongoing to prove that both variants are on different alleles. Discussion: R75Q is described as a variant overrepresented in patients with atypical CF, sarcoidosis, COPD and chronic pancreatitis and rather influences bicarbonate conductance than Cl. Our young patient has already respiratory symptoms and abnormal sweat chloride values. To our knowledge CFTR p.Pro41Arg has never been described before and its clinical relevance is not clear. As this boy has signs and symptoms of CF disease in combination with an atypical CFTR mutation, this novel mutation might be involved. However, mutations outside the coding region cannot be excluded.

A need for quality improvement in sweat tests

With the nationwide introduction of newborn screening for cystic fibrosis, the number of infants being tested for cystic fibrosis by sweat testing has significantly increased. This group of patients is more challenging to test than older children, and there is a greater risk of having an inadequate amount of sweat for analysis. This issue was analyzed by LeGrys et al using data from national sources and from the states. They found that the rates of insufficient samples (QNS rates) were variable, especially in the national survey, and were sometimes as high as 40%. Given that high QNS rates often signify problems in sweat collection, these data point to the need for a national quality improvement process. Patients identified by newborn screening, even if they have documented cystic fibrosis causing mutations, are still tested by sweat testing to insure they have a clinical phenotype. New recommendations for sweat testing (J Pediatr 2008;153:S4-14) are more stringent because of the challenge presented by testing more infants, and the threshold for an abnormal sweat chloride in infancy is now 30 milliequivalents per liter.Article page 1035 ▸ With the nationwide introduction of newborn screening for cystic fibrosis, the number of infants being tested for cystic fibrosis by sweat testing has significantly increased. This group of patients is more challenging to test than older children, and there is a greater risk of having an inadequate amount of sweat for analysis. This issue was analyzed by LeGrys et al using data from national sources and from the states. They found that the rates of insufficient samples (QNS rates) were variable, especially in the national survey, and were sometimes as high as 40%. Given that high QNS rates often signify problems in sweat collection, these data point to the need for a national quality improvement process. Patients identified by newborn screening, even if they have documented cystic fibrosis causing mutations, are still tested by sweat testing to insure they have a clinical phenotype. New recommendations for sweat testing (J Pediatr 2008;153:S4-14) are more stringent because of the challenge presented by testing more infants, and the threshold for an abnormal sweat chloride in infancy is now 30 milliequivalents per liter. Article page 1035 ▸ The Need for Quality Improvement in Sweat Testing Infants after Newborn Screening for Cystic FibrosisThe Journal of PediatricsVol. 157Issue 6PreviewThe proportion of insufficient sweat tests after positive newborn screening for cystic fibrosis was determined. Infants ≤3 months old had a mean (±standard deviation) rate of 7.2% (±7.6) (range, 0% to 40%). Collection methods did not affect the rates. The high and variable rates indicate a need for quality improvement. Full-Text PDF

Hyperchlorhidrosis Caused by Homozygous Mutation in CA12, Encoding Carbonic Anhydrase XII

Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO₂ hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).

Detection of Large Rearrangements in the Cystic Fibrosis Transmembrane Conductance Regulator Gene by Multiplex Ligation-Dependent Probe Amplification Assay When Sequencing Fails to Detect Two Disease-Causing Mutations

Most of the over 1600 mutations and sequence variants identified to date in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are point mutations or small deletions/insertions detectable by conventional sequencing. However, large rearrangements (deletions, duplications, or insertion/deletion mutations) have recently been reported to constitute 1-2% of CFTR mutations. The CFTR sequencing protocol at ARUP Laboratories interrogates the coding regions of all 27 exons and all intron/exon boundaries of the gene. This study was undertaken to determine whether testing for large gene rearrangements could improve the mutation detection rate. Nine cases with abnormal quantitative pilocarpine iontophoresis sweat chloride (SC) values (>60 mEq/L) and 20 cases with borderline SC levels (40-60 mEq/L) with only one or no mutations detected by the ARUP 32 mutation panel, including the 23 mutations recommended by American College of Medical Genetics (ACMG) for carrier screening, followed by sequencing, were tested using a multiplex ligation-dependent probe amplification (MLPA) assay. MLPA analysis identified one deletion among nine patients with SC >60 who had previously been tested with sequencing. None of the cases with borderline SC levels showed rearrangements. The MLPA assay for detection of large rearrangements may be valuable in individuals with positive SC levels where one or no mutations have been identified by sequencing.

Volumetric Capnography for the Evaluation of Pulmonary Disease in Adult Patients with Cystic Fibrosis and Noncystic Fibrosis Bronchiectasis

This study was designed to use volumetric capnography to evaluate the breathing pattern and ventilation inhomogeneities in patients with chronic sputum production and bronchiectasis and to correlate the phase 3 slope of the capnographic curve to spirometric measurements. Twenty-four patients with cystic fibrosis (CF) and 21 patients with noncystic fibrosis idiopathic bronchiectasis (BC) were serially enrolled. The diagnosis of cystic fibrosis was based on the finding of at least two abnormal sweat chloride concentrations (iontophoresis sweat test). The diagnosis of bronchiectasis was made when the patient had a complaint of chronic sputum production and compatible findings at high-resolution computed tomography (HRCT) scan of the thorax. Spirometric tests and volumetric capnography were performed. The 114 subjects of the control group for capnographic variables were nonsmoker volunteers, who had no respiratory symptoms whatsoever and no past or present history of lung disease. Compared with controls, patients in CF group had lower SpO(2) (P < 0.0001), higher respiratory rates (RR) (P < 0.0001), smaller expiratory volumes normalized for weight (V(E)/kg) (P < 0.028), smaller expiratory times (Te) (P < 0.0001), and greater phase 3 Slopes normalized for tidal volume (P3Slp/V(E)) (P < 0.0001). Compared with controls, patients in the BC group had lower SpO(2) (P < 0.0001), higher RR (P < 0.004), smaller V(E)/kg (P < 0.04), smaller Te (P < 0.007), greater P3Slp/V(E) (P < 0.0001), and smaller VCO(2) (P < 0.0002). The pooled data from the two patient groups compared with controls showed that the patients had lower SpO(2) (P < 0.0001), higher RR (P < 0.0001), smaller V(E)/kg (P < 0.05), smaller Te (P < 0.0001), greater P3Slp/V(E) (P < 0.0001), and smaller VCO(2) (P < 0.0003). All of the capnographic and spirometric variables evaluated showed no significant differences between CF and BC patients. Spirometric data in this study reveals that the patients had obstructive defects with concomitant low vital capacities and both groups had very similar abnormalities. The capnographic variables in the patient group suggest a restrictive respiratory pattern (greater respiratory rates, smaller expiratory times and expiratory volumes, normal peak expiratory flows). Both groups of patients showed increased phase III slopes compared with controls, which probably indicates the presence of diffuse disease of small airways in both conditions leading to inhomogeneities of ventilation.

Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco

Three siblings from Morocco consanguineous family presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction. Photosensitivity and blistering improved with age. Atrophic scars were prominent on the limbs. Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia. Several broncho-pulmonary infectious episodes complicated the evolution, and cystic fibrosis was first considered on the basis of repeated abnormal sweat chloride tests but not confirmed by molecular analyses. This autosomal recessive disorder matches that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians (OMIM 604173). It is discussed within the group of the major hereditary poikiloderma disorders, that is, Rothmund-Thomson syndrome, dyskeratosis congenita, and Kindler syndrome.

Could a defective epithelial sodium channel lead to bronchiectasis

BackgroundBronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation/infection. In 50% of cases, no etiology can be identified. Recently, the role of the epithelial sodium channel ENaC has been pointed out in the pathophysiology of cystic fibrosis, a disease due to mutations in the CFTR gene and causing bronchiectasis in the airways. Moreover, it was found that transgenic mice overexpressing ENaCβ present cystic fibrosis-like lung disease symptoms. Our aim was to evaluate if a defective ENaC protein could be involved in the development of bronchiectasis.MethodsWe extensively analysed ENaCβ and γ genes in 55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of CFTR. Thirty-eight patients presented functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride concentration or nasal potential difference measurement), and 17 had no such evidence.ResultsSequencing of the exons and flanking introns of the ENaCβ and γ gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in ENaCβ ; and p.Gly183Ser, p.Glu197Lys in ENaCγ) in heterozygous state in 8 patients. The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a CFTR mutation or variant (1 p.F508del, 1 IVS8-5T, and 1 IVS8-5T:1716G>A (p.E528E)). The other mutations were found in patients without CFTR mutation, the p.Glu197Lys mutation in 2 patients and the other variants in single patients. Among the 8 patients bearing an ENaC mutation, 5 had functional abnormalities suggesting impaired sodium transport.ConclusionOur results suggest that several variants in ENaCβ and γ genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for ENaCβ/CFTR mutations or variants.

155* Noninvasive evaluation of pulmonary disease using volumetric capnography in adult patients with cystic fibrosis

Volumetric capnography is a technique that analyses the pattern of CO2 elimination as a function of expired volume. Expired gas receives CO2 from three sequential compartments forming three recognizible phases on the capnogram. Phase 1 contains gas from proximal conducting airways. Phase 2 represents the transitional region characterized by an increasing CO2 concentration, and phase 3 represents alveolar gas (alveolar plateau). Here we present the results of volumetric capnography in 114 normal controls (Group 1) and 11 adult patients with cystic fibrosis (Group 2) with two abnormal sweat chloride concentrations. Age was 33.6±11.4 (1) and 34.3±11.7 (2). All patients had severe pulmonary involvement: FVC= 57.9±25.9; FEV1= 41.9±23.4; FEV1%=58.4±10.6. All of them had diffuse bronchiolitis and bronchiectasis on HRCT. Capnography revealed in Groups 1 and 2, respectively: respiratory rate (RR) = 12.9±3.5 and 20.6±8.4, p = 0.001; expiratory volume (Ve): 693.2±245.9 and 537.1±151.5, p = 0.03. Peak expiratory flow (PEF): 26.5±8.9 and 30.1±7.8, p = 0.11. Phase3 slope (P3Slp): 7.80±2.36 and 43.56±31.95, p< 0.001. P3Slp/Ve = 0.014±0.007 and 0.124±0.144, p< 0.001. Expiratory time (Te): 3.1±1.1 and 2.1±1.5, p< 0.001. Patients had obstructive defects with concomitant low vital capacities. Values of capnography in patients suggest a restrictive respiratory pattern. A large phase 3 slope was found in patients. Gas transport by diffusion is the dominant mechanism in acinar spaces. Steepened phase 3 slopes may represent increased diffusional resistance in peripheral lung. Small tidal volumes also produce steeper slopes. Phase 3 slope/Ve was still significantly greater in patients. These alterations can be expected in lungs with diffuse bronchiectasis. Supported by: UNICAMP.

A 5-month-old boy with recurrent respiratory infections, failure to thrive, and borderline elevated sweat chloride levels

Both severe combined immunodeficiency (SCID) and cystic fibrosis (CF) may present in infancy with a history of respiratory infections and failure to thrive. Elevated sweat chloride levels on multiple sweat tests is diagnostic of CF; transient elevation of sweat chloride has been reported in patients with hypogammaglobulinemia and antibody deficiency without CF. This article presents a case report of a 5-month-old boy with recurrent respiratory infections, failure to thrive, and two borderline elevated sweat test levels. Laboratory evaluation including testing for CF as well as immune deficiency was performed in this patient. Two borderline abnormal sweat chloride tests together with isolation of Pseudomonas from the airway caused clinicians initially to suspect CF; however, mutation in gene coding for the gamma-chain of the IL-2 receptor and a negative CF genetic mutation analysis ultimately led to the final diagnosis of SCID. It is essential to make the diagnosis of SCID as early as possible because infants with SCID who do not undergo reconstitution of their immune system universally die in infancy because of infection. Early diagnosis and intervention can lead to an excellent prognosis in a previously fatal disease.

Detection of an Apparent Homozygous 3120G>A Cystic Fibrosis Mutation on a Routine Carrier Screen

A 28-year-old Caucasian female with no personal or family history of cystic fibrosis (CF) presented for preconception counseling and screening. Cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis using the Inno-LiPa CFTR assay revealed lack of hybridization for both the wild-type and mutant oligonucleotides for 3120+1G>A. This region was sequenced, and an apparent homozygous 3120G>A mutation was detected. Additional testing revealed an abnormal sweat chloride (77 mmol/L). Review of systems was essentially unremarkable with an absence of sinus symptoms, occasional nonproductive cough, and no features of malabsorption. Physical examination, chest X-ray, and pulmonary function tests were within normal limits. Only two other patients (siblings) with homozygous 3120G>A mutations have been reported (http://www.genet.sickkids.on.ca/cftr/). Both siblings had pancreatic insufficiency, mild pulmonary symptoms, and abnormal sweat chloride levels. Our findings suggest that a homozygous mutation of a G>A conversion at 3120 is associated with abnormal CFTR function and either a mild form of CF or no overt symptoms of disease, emphasizing the difficulties in assigning genotype/phenotype correlation.

Congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis transmembrane regulator (CFTR): correlation between genotype and phenotype.

To assess better the link between congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis (CF), we compared sweat chloride values, analysis of the CFTR intron 8 poly(T) tract length and analysis of 10 exons in a population of 38 patients with CBAVD. The data indicate that this population can be divided into three groups of patients. In the first group of 15 patients with abnormal sweat chloride (> 60 mmol/l), the frequency of CF mutations is high. In the second group of 18 patients with equivocal sweat chloride (between 40 and 60 mmol/l), the frequency of the 5T variant is high; 6 patients have a delta F508 mutation and a 5T variant and 1 patient is homozygous for the 5T variant; a 5T variant has been detected in 3 other patients, and a delta F508 mutation in another patient. A third group of 5 patients is probably not related to CF: these patients have other congenital abnormalities of the urogenital tract, low chloride values (< 40 mmol/l) and apparently no abnormality of the CF gene.