A new wrinkle in the diagnosis of cystic fibrosis?
By Warren R. Heymann, MD, FAAD
March 23, 2022
Vol. 4, No. 12
Sir, - I have observed that the skin of children with cystic fibrosis wrinkles excessively early when soaked with tap water. The physical sign is highly reliable irrespective of the degree of nutrition of the patient…It is possible that the disorder of salt flux in cystic fibrosis is connected with the apparent excessive hypertonic reactivity of the skin. Three minutes and a bowl of water might provide a cheap screening test for this condition. – R.B. Elliott (1)
Cystic fibrosis (CF) is an autosomal recessive disorder of exocrine gland function that most commonly affects those of Northern European descent at a rate of 1:3500. Clinically, it is manifested by chronic sinopulmonary infections and pancreatic insufficiency. The most common cause of death is end-stage lung disease. CF is caused by a genetic mutation on chromosome 7 that codes for transmembrane conductance regulator (CFTR) protein, which functions as a transmembrane cAMP-activated chloride channel. The most common mutation is delta F508, which is found in two-thirds of all cases worldwide. Despite the new class of medications known as CTFR modulators, most patients succumb to end-stage lung disease around the fourth decade of life. Dermatological features of CF include “salty sweat” and acrodermatitis enteropathica secondary to zinc deficiency due to malabsorption from pancreatic insufficiency. (2,3)
In the United States, newborns are screened for CF as part of a newborn screening panel for genetic disease. According to the Cystic Fibrosis Foundation: “Every state’s CF newborn screening program begins with a blood test from the baby to check the levels of a chemical made by the pancreas called immunoreactive trypsinogen, or IRT. Some states only test IRT levels on the first blood test. These are called IRT-only states. Other states conduct both an IRT and a DNA test. These are called IRT-DNA states.” (4) Confirmatory sweat chloride tests demonstrate an elevated sweat chloride > 60 mEq/L. (1) Although newborn screening for CF has improved the outcome for those with a ‘classical’ CF phenotype, there are limitations because of the many mutations of the CTFR gene that yield different phenotypes. According to Course and Hanks, “as our understanding of the CFTR gene has evolved, correlating some genotypes to clinical outcomes has become more challenging. It is now becoming clear that there are some CFTR mutations, such as those termed CF-SPID [cystic fibrosis – screen positive inconclusive diagnosis], and particularly p.[Arg117His;7T], that may result in minimal or no disease burden, and could form part of the ‘normal variation’ in CFTR genotype.” (5)
According to Arkin et al, the first to describe the rapid appearance of transient white papules and plaques was Elliott in 1974. (6) In 1996, English and McCollough described the case of a 20-year-old woman with a few years history of transient nonpruritic symmetrical thickening on the palms and lateral fingers that developed with a whitish discoloration after exposure to water. The authors named the condition “transient reactive papulotranslucent acrokeratoderma.” (7) Subsequently, Yan et al reported three patients with a striking similarity to those with transient reactive papulotranslucent acrokeratoderma. All three patients manifested the “hand-in-the-bucket” sign, having presented to a physician with a hand immersed in a bucket of water to more promptly demonstrate the physical findings. The authors labeled the disorder “aquagenic palmoplantar keratoderma.” (8)
This phenomenon has been reported with a variety of names, all reflecting the same process. The literature seems to be settling on the term “aquagenic wrinkling of the palms” (AWP — which will be used for the rest of this commentary), but readers should also be familiar with the previously mentioned terms in addition to aquagenic syringeal acrokeratoderma and aquagenic (pseudo) keratoderma.
The etiology of AWP is unknown but has been associated with abnormal transepidermal water loss (4), aberrant aquaporin 5 expression (aquaporins are membrane proteins generally responsible for rapid osmotic water movement across the plasma membrane). (8) Histologic features are apparent after the skin is immersed in water (do not biopsy dry skin) and may reveal dilated acrosyringia, hyperplasia of eccrine glands with clear cell change, vacuolization, and an increased number of capillaries around and adjacent to the eccrine coils at the dermal-hypodermal junction. (9)
There appear to be three general settings for the appearance of AWP: sporadic cases, mostly in young women, often resolving within a few years; cases associated with CF; and, drug-associated or induced (notably NSAIDS — especially COX-2 inhibitors — tobramycin, clarithromycin, gabapentin, spironolactone, and isotretinoin). (10,11) Therapy of AWP has been inconsistent with use of topical and systemic antiperspirants, keratolytics, and anti-inflammatory agents. (10)
Regarding the use of AWP as a screening test for CF, Singh et al observed that a three-minute cut-off for development of AWP was applied to 54 children referred for a sweat test. Twenty children had sweat chloride values of ≥60 mEq/l and were diagnosed as CF — 15 of these developed AWP at ≤3 minutes, giving a sensitivity of 75%. The authors concluded that in children with phenotypes compatible with CF who develop AWP in 3 minutes may be diagnosed as probable cystic fibrosis and referred for confirmation by sweat test analysis. (12) Alexopoulos et al measured AWP in CF patients, CF-heterozygotes (CF-het) and normal controls after a 3-minute brief immersion in water (BIW). A total of 250 individuals (100 CF patients, their 50 CF-het parents, 100 healthy controls) were analyzed. The rate of positives for AWP at 3 min among CF patients, CF-het and controls was 68%, 8% and 0%, respectively (P < 0.01). The best diagnostic performance in detecting between CF patients and non-CF was achieved by the presence of papules and wrinkling at 7 minutes. The authors concluded that AWP after BIW could be elicited easily and potentially could be used as an initial screening tool for CF. (13)
Grimalt et al, in an editorial accompanying Alexopoulos et al, opine: “The conclusions from the paper are clear: There is a strong association between AWP and CF. AWP after BIW could be easily used as a screening tool to assess if an individual with symptoms and signs that raise the likelihood of CF is a CF patient. Brief immersion to water could be implemented in resource-limited scenarios, as a quick and easy, low-cost, risk-free test for initial screening that could guide further clinical decisions for confirmatory tests like sweat test and/or molecular DNA analysis.” (14)
On a personal note, I recall raising the diagnosis of AWP (using another term) when one of the patients in the article by Yan et al (8) was presented at the Duhring conference at the University of Pennsylvania. It is gratifying to know that rendering this diagnosis may assist in confirming the diagnosis of CF, allowing these patients earlier access to treatment.
Point to Remember: Aquagenic wrinkling of the palm may be sporadic, drug-associated (or induced), or be associated with cystic fibrosis. If there is clinical suspicion for CF, patients should be referred for a sweat test and/or molecular DNA analysis.
Our experts’ viewpoints
Howard B. Pride, MD, FAAD
This is a superlative review of aquagenic wrinkling of the palms (AWP). The quoted study from Alexopoulos et al. (13) is a very well-done, controlled trial of aquagenic wrinkling in patients with known cystic fibrosis (CF), known carriers of the CF gene and normal controls, 4% of which would be predicted to be CF gene carriers given the gene’s incidence in the general population. The observer was not blinded, but the results are still compelling; AWP after seven minutes of room temperature water immersion was a highly sensitive and specific discerner of those with and without CF. Unfortunately, there was no measure that accurately discerned carriers from non-carriers, the specificity being high (positive test is predictive of being a carrier) but the sensitivity being very low (negative test does not rule out the carrier state).
Where does this leave us? There are CF patients who sneak undetected through the newborn screening process who present to our primary care and pulmonary colleagues with respiratory and/or gastrointestinal symptoms suggestive of CF. According to our pulmonologist, “This is rare because the newborn screen is quite comprehensive and getting more comprehensive with time.” I can’t think of a quicker and easier, in-office screen than to place a patient’s hands in water for seven minutes and observe the results. Would this circumvent sweat testing and genetic analysis? In resource-rich settings like the United States, certainly not, but in resource-poor countries, this could be a very helpful tool.
It is hard for me to imagine a young man, down on one knee, diamond ring in hand only to be told that first, both partners need to immerse their hands in water to assure that the chance mating of two CF carriers will not occur. In fact, the negative predictive value of AWP testing is very poor and will not be of value in pre-conception counseling.
How about the most likely scenario for us as dermatologists? A patient presents with a history of painful, pruritic papules and hyper wrinkling after water immersion. Could they have latent, atypical CF? A pertinent review of signs and symptoms is presented in the table below. Positive findings would prompt me to refer to a pulmonologist for further evaluation and testing. The odds are that our patient will be otherwise completely well, so do we have a difficult conversation regarding the possibility of being a CF carrier? While studies have looked at carriers to see the incidence of AWP, the reverse has not been done. The odds are that this patient has greater than the baseline 4% chance of being a carrier, but how much more is open to speculation. We are currently left to our own best judgement as to whether a carrier state conversation is informative or unduly anxiety-inducing for our patient.
Affected systems and symptoms in atypical cystic fibrosis (15)
Respiratory: chronic sinusitis, nasal polyposis, poorly controlled obstructive lung disease, recurrent pneumonia, digital clubbing
Gastrointestinal: meconium ileus, rectal prolapse, atypical acute pancreatitis or chronic pancreatitis, diarrhea, constipation, weight loss or poor weight gain, nutritional deficiency
Endocrine and metabolic: diabetes mellitus, hypochloremia, hypokalemia, metabolic alkalosis
Genitourinary: azoospermia in men, reduced fertility in women
Albert C. Yan, MD, FAAP, FAAD
Professor, Pediatrics and Dermatology
Perelman School of Medicine at the University of Pennsylvania
As with many clinical pearls that are based on expert judgment, the “three-minute” time I had recommended originally for the “hand-in-the-bucket” test was based on the gestalt of how long it took patients to elicit their findings during the patient's initial visits. There were a minority of patients, however, who demonstrated evidence of early changes, but who needed more time than the usual 3 minutes. It is therefore enlightening to have had these investigators rigorously evaluate the actual time needed to elicit these findings.
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Singh A, Lodha R, Shastri S, Sethuraman G, Sreedevi KN, Kabra M, Kabra SK. Aquagenic Wrinkling of Skin: A Screening Test for Cystic Fibrosis. Indian Pediatr. 2019 Feb 15;56(2):109-113. PMID: 30819988.
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