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17 These authors contributed equally to this work.
Affiliations
Department of Pediatric Dermatology, University Children’s Hospital Zurich, Zurich, SwitzerlandEpidermolysis bullosa Centre, Department of Dermatology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
Fundación DEBRA Chile, Santiago, ChileFacultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, ChileDepartment of Cardiology, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
Department of Pediatric Dermatology, University Children’s Hospital Zurich, Zurich, SwitzerlandDepartment of Dermatology, University Hospital Zurich, Zurich, Switzerland
Department of Pediatric Dermatology, University Children’s Hospital Zurich, Zurich, SwitzerlandDepartment of Dermatology, University Hospital Zurich, Zurich, Switzerland
Fundación DEBRA Chile, Santiago, ChileFacultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, ChileDermatology Department, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
Inherited epidermolysis bullosa (EB) comprises rare heterogeneous disorders characterized by cutaneous and mucosal fragility. Most of the 20 proteins affected have structural functions. Recently, a previously undescribed type of EB simplex (EBS), caused by gain-of-function mutations in KLHL24, encoding KLHL24 has been identified (
). This protein seems to be involved in protein ubiquitination. Patients carrying monoallelic mutations in the translation initiation codon of KLHL24 have a characteristic clinical phenotype, showing skin defects and blistering at birth and unusual stellate scarring, skin fragility, and whorled or macular hyperpigmentation or hypopigmentation in childhood (Figure 1a–e ). Although skin fragility improves by adulthood, nail dystrophy, anetoderma, and hair loss may occur (Figure 1f–h).
Figure 1Cutaneous and cardiac features of EBS-KLHL24.(a) Congenital skin defects and blistering; (b) characteristic stellate scarring; (c–e) macular or whorled hypopigmentation and hyperpigmentation in children; and (f–h) mild skin fragility, anetoderma, diffuse alopecia, and nail dystrophy in adults. (i, j) Echocardiograph of patient 1: four-chamber view at (i) end-diastole and (j) end-systole with severe dilatation of LV and LA and severely impaired LV ejection fraction. (k, l) Magnetic resonance imaging (CMR): (k) cine sequence (end-diastole) in the short axis view at basal level and (l) wall thinning of inferoseptal and inferior LV wall segments (white arrows). Extensive late-gadolinium enhancement in all segments: transmural fibrosis, corresponding to the thinned inferior and inferolateral wall of the LV (small arrowheads), non-transmural mid-wall fibrosis visible in the septum (large arrowheads), and to a lesser extent, the lateral, anterior, and septal segments of the LV and diffuse fibrosis of the RV. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle.
Given that KLHL24 is widely expressed, we investigated extracutaneous features in a cohort comprising families from Chile, Germany, Italy, Switzerland, and the United States (see Supplementary Material online). Institutional approval for investigations and written informed consent were obtained, and patients gave permission to have their photographs and medical information published.
Eighteen patients with EBS-KLHL24 from nine families (nine males, nine females) were examined (Table 1). The mean patient age was 21.7 years, with nine children (2–13 years old) and nine adults (24–46 years old). Patients 1–10 have previously been described (
), and patients 11–18 are newly reported. Two additional individuals (patients 19 and 20) belong to family 9; they had skin fragility and died of dilated cardiomyopathy (DCM) at the ages of 39 and 54 years. In all examined patients, pathogenic variants in the translation initiation codon of KLHL24 were found (Table 1). Whole-exome sequencing and multigene panel data showed no pathogenic variants in genes known to be associated with DCM (
ECG: Nonspecific changes Echo: Severe biventricular DCM, EF = 27% MRI: Transmural fibrosis, corresponding to the thinned inferior and inferolateral wall of the LV Nontransmural mid-wall fibrosis in the septum; the lateral, anterior and septal segments of the LV show nontransmural fibrosis Diffuse fibrosis in the RV.
Chronic proteinuria and hematuria Xerosis cutis, palmoplantar keratoderma, nail dystrophy
2
1
6 (F)
Switzerland-Italy
c.[1A>G]
None
121 (<147)
2.3 (<6)
333 (<390)
ECG: n/d Echo: Normal results
Diffuse alopecia, nail dystrophy, xerosis cutis Speech delay
3
1
9 (F)
Switzerland-Italy
c.[1A>G]
None
526 (<147)
23.7 (<6)
874 (<390)
ECG: n/d Echo: Normal results
Mild diffuse alopecia, xerosis cutis, palmoplantar keratoderma, nail dystrophy
4
2
6 (M)
Switzerland-Germany
c.[2T>C]
Tachycardia, extrasystoles
182 (<168)
7.7 (<6)
82 (<390)
ECG: Normal results Echo: Normal results
Developmental and fine motor skill delay
5
3
46 (F)
Germany
c.[1A>G]
None
66 (<170)
15 (<25)
695.7 (<169)
ECG: Nonspecific changes Echo: Mild systolic dysfunction with dilatation of left ventricle
Complete scalp and body hair loss
6
3
6 (F)
Germany
c.[1A>G]
None
95 (<149)
64.9 (<24)
60.1 (<40)
ECG: n/d Echo: n/d
7
4
36 (F)
Germany
c.[1A>G]
None
74 (<168)
19 (<25)
170 (<125)
ECG: n/d Echo: n/d
Complete scalp and body hair loss.
8
5
12 (M)
Germany
c.[1A>G]
None
74 (<152)
30 (<25, 40.5% of CK)
186.7 (<186)
ECG: n/d Echo: n/d
9
6
39 (M)
Italy
c.[1A>G]
Occasional chest pain at night (2014), improved with medication
n/d
n/d
n/d
ECG: Mean = 50 b.p.m. (bradycardia), sporadic ventricular extrasystoles Echo 2014: LV dilatation, EF = 43%. Echo 2018: EF = 43% by Simpson method, global hypokinesia
10
6
13 (M)
Italy
c.[1A>G]
None
209 (≤200)
5.0 (≤5)
125.6 (<125)
ECG: Normal results Echo: Normal results
11
7
35 (F)
United States
c.[1A>G]
None, but episode with loss of consciousness
n/d
n/d
n/d
ECG: Normal results Echo: Normal results
Hair thinning in early adulthood, progressive hair loss Seizure disorder of unknown origin
12
8
28 (F)
Chile
c.[1A>G]
None Normal
60
14 (<25)
43 (<125)
ECG: Normal results Echo: Normal results
Moderate alopecia since 11 years of age Fine and dry hair
13
9
4 (M)
Chile
c.[2T>G]
None/Normal
129 (<308)
31 (<25)
89 (<125)
ECG: n/d Echo: Normal results
Fine and dry hair Mild follicular atrophoderma on arms
14
9
33 (M)
Chile
c.[2T>G]
Heart murmur (I/IV)
75 (<308)
11 (<25)
926 (<125)
ECG: Electric axis diverted to the left. Normal headsets, ventricular complexes and AV conduction Intraventricular conduction altered by anterior left hemiblock. Echo: Severe DCM, diagnosed 2016 LV severely dilated in systole (83ml/m2) and diastole (112ml/m2), diffuse hypokinesia and severely depressed systolic function (LVEF = 26%)
Mild alopecia, dry hair Moderate follicular atrophoderma on cheeks, arms and thighs
15
9
25 (M)
Chile
c.[2T>G]
Heart murmur (II/IV), extrasystoles
85 (<308)
13 (<25)
638 (<125)
ECG: Isolated ventricular extrasystoles Nonspecific alteration of ventricular repolarization Echo: LV severely dilated, moderate to severe systolic dysfunction (LVEF 30%), mild to moderate functional mitral insufficiency, Carpentier III
Mild alopecia Fine and dry hair Mild follicular atrophoderma on thighs
16
9
33 (F)
Chile
c.[2T>G]
Heart murmur (I/VI)
104 (<308)
10 (<25)
258 (<125)
ECG: Normal Echo: Mild systolic dysfunction of LV, LVEF = 40% normal left atrium and right chambers
Moderate alopecia Fine and dry hair Moderate follicular atrophoderma on thighs and arms Hip dysplasia and scoliosis
17
9
24 (F)
Chile
c.[2T>G]
None/normal
101 (<308)
9 (<25)
152 (<125)
ECG: n/d Echo: Normal with normal/low systolic function
Dry hair and moderate alopecia since 13 years of age Mild follicular atrophoderma on arms and thighs
18
9
2 (M)
Chile
c.[2T>G]
None
141 (<308)
40 (<25)
210 (<125)
ECG: n/d Echo: Normal
Mild alopecia, dry hair
19
9
Death at age 39 (M)
Chile
c.[2T>G]
Cardiac death
—
—
—
DCM from history only
—
20
9
Death at age 54 (F)
Chile
c.[2T>G]
Cardiac death
—
—
—
DCM from history only
—
Abbreviations: AV, atrioventricular; BP, blood pressure; CK, creatine kinase; CKMB, CK muscle band; DCM, dilated cardiomyopathy; ECG, electrocardiography; Echo, echocardiography; EF, ejection fraction; F, female; LV, left ventricle; LVEF, left ventricular ejection fraction; M, male; MRI, magnetic resonance imaging; n/d, not done; RV, right ventricle.
Two examined patients had been diagnosed with DCM before our study (patients 9 and 14). The latter had a positive family history with cardiac death of a brother and mother, both of whom also had skin fragility (patients 19 and 20).
Three unrelated patients had neurological involvement: patient 4 with delay of cognitive and motor development, patient 2 with speech delay, and patient 11 with seizures of unknown origin (Table 1). Because missense and pathologic in frame mutations of KLHL24 were recently linked to neurological disease (
). was increased. All adult patients with more than 2-fold elevated NT-pro-BNP levels (n = 5) had significant dysfunction on echocardiography and/or cardiac magnetic resonance imaging (Figure 1i–l). Creatine kinase muscle band was elevated in 7 of the 16 patients. Fifteen patients were evaluated by cardiology, of whom six were diagnosed with DCM (40%); the youngest was 25 years old (patient 15). None of the newly diagnosed patients (patients 1, 5, 15, and 16) had reported cardiac symptoms (Table 1).
Taken together, in this cohort of 20 patients with EBS-KLHL24, 17 (85%) had evidence of cardiac involvement with either elevated cardiac biomarkers or documented DCM (8/20 patients [40%]), leading to death at an early age in two of them.
DCM is defined as ventricular dilatation with impaired ventricular systolic function (left ventricular ejection fraction < 50%) in the absence of features of different phenotypes of cardiomyopathy or evidence of acquired heart disease (e.g., coronary artery disease). Early, even presymptomatic intervention improves outcome (
DCM occurs as a familial disease in 20%–35% of cases with more than 30 genes identified. Onset of familial DCM tends to be earlier in life than average. There is significant variability explained by modifying genetic and acquired risk factors (
). KLHL24 is expressed at similar levels in keratinocytes and cardiomyocytes (see Supplementary Figure S1 online). As in the skin, cardiac KLHL24 may regulate the degradation of structural cytoskeletal proteins involved in mechanical resilience. KLHL24 was also identified as interacting with components of the COP9 signalosome, a critical regulator of the cullin-RING family of ubiquitin ligases activity (
Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice.
Here, we provide evidence that patients with EBS-KLHL24 display potentially life-threatening DCM in early adulthood. Although dilated cardiomyopathy may be a final common pathway of a variety of acquired and inherited cardiac conditions, none of our patients with DCM showed a different cardiac phenotype (e.g., hypertrophic cardiomyopathy or restrictive cardiomyopathy) or heart disease (e.g., coronary artery disease, cardiac arrhythmias).
Our data are supported by two other reports. Recently, severe cardiomyopathy was reported in a single case of EBS-KLHL24 (
), and homozygous KLHL24 loss-of-function mutations were found in two siblings with hypertrophic cardiomyopathy with glycogen accumulation in cardiomyocytes (
DCM in EBS-KLHL24 may be missed because skin fragility and blistering improve with age, leading to infrequent follow-up evaluations. Moreover, because of reduced physical activity because of skin fragility and slow development of DCM, patients may not experience early cardiac symptoms. Thus, regular screening for cardiac involvement to identify presymptomatic DCM is required. Given its high sensitivity, serial measurements of NT-pro-BNP levels along with careful history taking may be the optimal screening tool (
). In the case of cardiomyopathy, timely implementation of preventive measures, such as heart failure medication or device therapy, may likely improve outcomes. This study was likely crucial for the survival of patient 1, who initially refused echocardiogram for lack of clinical symptoms. His ejection fraction turned out to be 27%. If EBS-KLHL24 is clinically suspected, genetic testing and cardiac monitoring are mandatory.
Conflict of Interest
The authors state no conflict of interest.
Acknowledgments
We thank the patients and their families for participation in this study. Gabriele Grüninger is acknowledged for expert technical assistance. Most of this study was supported by Debra International (HAS 1 CH) and the Chilean whole-exome sequencing data analysis by the CONICYT FONDEQUIP EQM150093 and EQM140157.
Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice.
KLHL24 mutations have recently been associated with epidermolysis bullosa simplex. Initial studies focused on skin fragility. However, the picture of KLHL24 mutations causing extracutaneous human disease is emerging, with dilated cardiomyopathy as a strong association. In addition, neurological disease is suspected as well. Careful clinical follow-up and functional studies of (mutated) KLHL24 in these tissues are needed.
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