Outcomes of Cystic Fibrosis Screening–Positive Infants With Inconclusive Diagnosis at School Age

BACKGROUND AND OBJECTIVES Cystic fibrosis (CF) screen–positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children. METHODS Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive–screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes. RESULTS The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls. CONCLUSIONS Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Orthostatism, Constipation, and Early Satiety

A 65-year-old woman with a history of Graves disease, status post radioactive iodine therapy, and a biopsy-proven benign calcified breast nodule sought care for evaluation of multiple symptoms. She had constipation for 8 years, with prior fecal urgency, and intermittent diarrhea for the previous year. She was diagnosed with irritable bowel syndrome. Her weight remained stable until 1 1/2 years earlier, and she had lost 6.8 kg. For the previous 3 years, the patient had experienced multiple urinary symptoms including hesitancy, urgency, incontinence, and retention. She was diagnosed with a cystocele, the correction of which did not help. She had noted difficulty focusing her eyes when moving from a dark to a well-lit environment, or vice versa. She also reported orthostatic light-headedness for 1½years, which worsened on exposure to a hot environment. Neurologic examination showed abnormally dilated pupils with prominently sluggish constriction in response to light. Autonomic reflex screening indicated patchy postganglionic sympathetic sudomotor, marked cardiovagal, and cardiovascular adrenergic failure, with neurogenic orthostatic hypotension. Thermoregulatory sweat testing showed 82% anhidrosis. A nuclear medicine gastric-emptying study indicated delayed gastric emptying and colonic hypomotility. Serum testing was markedly positive for ganglionic (alpha 3) acetylcholine receptor autoantibodies. The patient was diagnosed with autoimmune autonomic ganglionopathy. The patient received intravenous immunoglobulin. She returned and reported 80% improvement in all symptoms, and neurologic examination showed normal pupillary response to light. Autonomic reflex screening indicated improvement of her adrenergic function, and thermoregulatory sweat testing showed an impressive improvement of her sudomotor function. Her postganglionic sympathetic sudomotor and cardiovagal function remained impaired. Gastric emptying remained mildly delayed. She was maintained on intravenous immunoglobulin, which was later tapered after azathioprine was started. Autoimmune autonomic ganglionopathy usually presents subacutely, much like other autoimmune neurologic diseases. Typical features of this disorder are the impaired pupillary reaction to light and prominent sicca symptoms, indicating prominent cranial parasympathetic (cholinergic) impairment. Also consistent with this diagnosis are the prominent gastrointestinal tract symptoms. Prominent cholinergic failure helps distinguish autoimmune autonomic ganglionopathy from peripheral autonomic neuropathy or neurodegenerative disorders such as pure autonomic failure.

Constipation and Syncope

A 43-year-old woman sought care for severe constipation associated with syncopal episodes. Her constipation alternated with explosive diarrhea. Chronic left-sided abdominal pain and severe bloating developed after eating. She was diagnosed with irritable bowel syndrome. After the initial onset of symptoms, nausea, bloating, and intractable vomiting developed. Symptoms were exacerbated by food and were partially relieved with vomiting. She had multiple episodes of bilious, undigested emesis per day. Trials of antiemetics and motility agents provided no substantial relief. She adopted a liquid diet, avoided solid foods, and eventually had a gastrostomy tube placed. She lost at least 15.9 kg over 2 years. Review of systems was significant for generalized fatigue and a burning sensation in her hands and feet. Her medical history was pertinent for Graves disease previously treated with remote thyroid radioablation, and she was now taking thyroid hormone replacement therapy. Neurologic examination findings were normal except for unreactive pupillary light reflexes. A gastrointestinal tract transit study showed persistently delayed colonic transit with mildly delayed gastric emptying. Autonomic reflex screening showed diffuse postganglionic sympathetic sudomotor, severe cardiovagal, and severe cardiovascular adrenergic impairment. Thermoregulatory sweat testing showed diffuse anhidrosis. Creatinine value was mildly increased. The serum was strongly positive for ganglionic (alpha 3) acetylcholine receptor-immunoglobulin G. The findings strongly suggested an autonomic autoimmune polyganglionopathy, with autoimmune gastrointestinal dysmotility as the predominant phenotype. She received intravenous immunoglobulin. She had complete resolution of her previous constipation, nausea, and vomiting. She regained 22.7 kg. Her gastrostomy tube was removed. Repeated gastrointestinal tract transit studies approached normal findings. Repeated autonomic testing and thermoregulatory sweat testing showed improvement. Over several months, the intravenous immunoglobulin dose was tapered. The patient remained asymptomatic for 8 years on long-term immunosuppression with azathioprine, she had a recurrence of her previous symptoms. Repeated gastrointestinal tract transit studies again showed delayed gastrointestinal tract emptying. Another intravenous immunoglobulin course controlled her symptoms, with normalization of gastrointestinal tract transit studies. Autoimmune gastrointestinal dysmotility can manifest as either hypomotility or hypermotility but most often presents as gastroparesis or pseudo-obstruction. Symptoms include nausea, vomiting, bloating, early satiety, diarrhea, constipation, and involuntary weight loss. It can be idiopathic or paraneoplastic. Risk factors for idiopathic cases include personal or family histories of autoimmunity.

Cystic Fibrosis in two Ghanaian Children

Cystic fibrosis (CF) is a severe life-limiting genetic disorder resulting from mutations in the cystic fibrosis transmembrane regulator gene and is reported to be more prevalent among Caucasians than people of African descent. The past three decades have seen a gradual increase in the reporting of CF in non-European populations with CF in all regions including Africa. We report on the first two known Ghanaian children diagnosed with CF presenting early in infancy. The first patient presented with severe acute malnutrition and persistent diarrhea resulting from severe exocrine pancreatic insufficiency. In the second patient, there were recurrent wheeze and recurrent pneumonia, severe dehydration with metabolic alkalosis. Diagnosis of CF in Ghana is challenging due to the absence of diagnostic tools such as sweat testing equipment. In the first patient, sweat testing and genetic testing were done in South Africa. In the second patient, sweat testing was not done but diagnosis was confirmed by genetic testing. Both patients presented with classical CF symptoms including Pseudomonas aeruginosa airway infection before age 6 months. Both children are currently alive and healthy on appropriate treatment. These case reports highlight the growing evidence of CF occurring in people of African descent and the diagnostic challenges faced in Africa.

Outcomes of early repeat sweat testing in infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID)

Background: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat sweat testing in the first year of life. Methods: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018 and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat sweat testing in the first year of life. Results: Fifty subjects (median age at end of follow-up, 16 months [range, 7–21 months]) were enrolled. Forty-one (82%) had the first sweat chloride in the intermediate range. During follow up, 150 sweat tests were performed (range, 1–7/infant). After a median follow-up of 8.5 months (range 1–16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n=2 [4%]) at 2 and 5 months, respectively; healthy carrier (n=8 [16%]), at a median age of 4 months (range 2–8 months); and healthy (n=1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants. Conclusions: Early repeat sweat testing in the first year of life can shorten the time to definitive diagnosis in screening positive subjects with initial sweat chloride levels in the intermediate range.

Sweat Testing and Recent Advances

Cystic fibrosis (CF) is the most common fatal genetic disease of the Caucasian population. Sweat testing is the principal diagnostic test for CF, and it is used for the evaluation of infants with positive CF newborn screening (NBS) and in patients with clinical findings suggesting CF. This article describes the classical sweat test method in detail and also provides an overwiew of recent advances.