CASE REPORTS Pediatric Dermatology Vol. 32 No. 1 102–108, 2015
Early-Onset Heart Failure, Alopecia, and Cutaneous Abnormalities Associated with a Novel Compound Heterozygous Mutation in Desmoplakin Nina K. Antonov, B.S.,* Mina Y. Kingsbery, M.D.,† Luis O. Rohena, M.D.,‡ Teresa M. Lee, M.D.,§ Angela Christiano, Ph.D.,†,¶ Maria C. Garzon, M.D.,†,§ and Christine T. Lauren, M.D.†,§ *College of Physicians and Surgeons, Columbia University, New York, New York †Department of Dermatology, Columbia University Medical Center, New York, New York ‡San Antonio Military Medical Center, Fort Sam Houston, Texas Departments of §Pediatrics and ¶Genetics and Development, Columbia University Medical Center, New York, New York
Abstract: Mutations in the desmosomal protein desmoplakin have been associated with various conditions affecting the skin and heart. The prototype is Carvajal syndrome, characterized by cardiomyopathy, woolly hair, palmoplantar keratoderma (PPK), and skin fragility. We report the case of a 3-year-old boy presenting with severe left-sided heart failure with a preceding history of cutaneous abnormalities including congenital alopecia, PPK, nail dystrophy, and follicular hyperkeratosis on the extensor surfaces. Genetic testing revealed a novel combination of two heterozygous mutations in the DSP gene encoding desmoplakin: R1400X and R2284X. Both are predicted to be deleterious to protein function. This case adds to our understanding of the spectrum of clinical presentations of syndromes associated with desmoplakin mutations and highlights the need for cardiac examination in patients with characteristic cutaneous findings.
Desmosomes are intercellular junctions expressed in simple and stratified epithelium and the intercalated discs of cardiac myocytes. They play a role in cell adhesion and tissue integrity and may have secondary roles in cell signaling. Mutations in 10 different
desmosomal proteins have been discovered in recent years to be associated with clinical syndromes with varying involvement of the skin, hair, and heart (1). Mutations in desmoplakin, a component of the desmosome, have been associated with Carvajal
Address correspondence to Christine T. Lauren, M.D., Columbia University Department of Dermatology, 161 Fort Washington Avenue, 12th floor, New York, NY 10032, or e-mail: cat35@cumc. columbia.edu. DOI: 10.1111/pde.12484
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syndrome (2,3), striate palmoplantar keratoderma (PPK) (4), skin fragility–woolly hair syndrome (5), and lethal acantholytic epidermolysis bullosa (LAEB) (6), among other phenotypes. In this study we describe a previously unreported clinical presentation characterized by congenital alopecia, striate PPK, follicular hyperkeratosis with plugging on the extensor surfaces, nail dystrophy, and dilated cardiomyopathy associated with severe left ventricular dysfunction and dilation causing heart failure at age 3 years. DNA testing identified a novel combination of mutations in the DSP gene. CASE REPORT A 3-year-old boy presented to an outside hospital with a 1-week history of rhinorrhea, cough, abdominal pain and decreased appetite. On physical examination there was an intermittent gallop on cardiac auscultation and his liver was enlarged 2 cm below the costal margin. A chest radiograph showed an enlarged heart with evidence of pulmonary congestion; he was transferred to our center for management of heart failure. An electrocardiogram (ECG) was significant for left axis deviation, Q waves in the inferior and lateral leads, and low-voltage QRS with premature ventricular contractions. An echocardiogram was performed and revealed moderate left atrial dilation with a severely dilated left ventricle and severe globally decreased systolic function, with an ejection fraction of 24% (normal 54–75%) (Fig. 1). There was mild to moderate mitral regurgitation and a trivial pericardial effusion. Serum chemistry, complete blood count, and liver function tests were unremarkable. B-type natriuretic
Figure 1. Echocardiogram: two-dimensional apical four chamber view demonstrating severe dilation of the left ventricle and moderate dilation of the left atrium.
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peptide was high (2053.7 pg/mL). The patient was initially started on high-dose steroids because of concerns about myocarditis, given the low-voltage QRS complexes on ECG and C-reactive protein of 23.7 mg/L (normal ≤2.9 mg/L), but the infectious examination was negative, including all viral serologies and a respiratory virus polymerase chain reaction panel. The patient was started on a continuous milrinone infusion and listed as status 1a for heart transplantation. On hospital day 28 he underwent successful orthotropic heart transplantation. He had an uneventful postoperative recovery period and continues to do well 12 months after transplantation. Dermatology was consulted to evaluate multiple cutaneous findings. Examination revealed diffuse alopecia of the scalp, with areas of sparse short curly hair, and sparse eyebrows and eyelashes (Fig. 2A). Palmoplantar hyperkeratosis was present in a striate pattern on the palms (Fig. 2B) and at points of pressure on the soles (Fig. 2C). His toenails were thickened and discolored, with evidence of subungual debris (Fig. 2D); fungal culture of his toenails was negative. He had groups of follicular papules with plugging on his elbows, knees, and hips (Fig. 2E). He had perioral fissures and crusts. Dental examination was normal. His mother reported that he had had no hair on his scalp since birth. She also noted blisters and erosions, specifically at sites of friction, that started at approximately 2 years of age. An outside dermatologist had previously evaluated him for scalp bullae at 22 months of age; skin biopsy was nondiagnostic. MOLECULAR STUDIES The patient’s parents are both from the Dominican Republic. His mother denied a family history of skin or cardiac disease or consanguinity. The patient has a younger sister who is healthy, without similar skin findings or known cardiac disease. Genetic testing was performed in the patient and his mother. Direct sequencing revealed two heterozygous mutations in the DSP gene in our patient (Fig. 3). The first was a novel nonsense mutation c4198C>T in exon 23, resulting in substitution of a stop codon for an arginine residue at amino acid 1400 of the DSP protein (R1400X). The second was the mutation c6850C>T in exon 24, resulting in substitution of a stop codon in place of an arginine residue in position 2284 (R2284X). The mother was a heterozygous carrier of the mutation R2284X. The patient’s father was not available to provide a blood sample, nor was his clinical history
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Figure 2. Clinical features of our patient. (A) Diffuse alopecia of the scalp and sparse eyebrows and eyelashes. (B) Striate hyperkeratosis on the palms and (C) diffuse hyperkeratosis at pressure points on the soles. (D) Dystrophic toenails with subungual debris. (E) Follicular hyperkeratosis with plugging on the knees.
available. The mutation R1400X was presumably paternally inherited, although a de novo mutation cannot be excluded. Sequencing also revealed that the patient was heterozygous for c2636A>G in exon 16 of the DSC2 gene encoding desmocollin 2, representing the D879G variant of uncertain significance. DISCUSSION The first described mutation in desmoplakin was reported in association with Carvajal syndrome, presenting in several Ecuadorian families. This disorder is characterized by left ventricular dilated cardiomyopathy, striate PPK, woolly hair, and skin fragility associated with a homozygous mutation
(7901delG) in the C tail domain of desmoplakin (2,3). More than 40 different mutations in desmoplakin have been identified since, with the clinical phenotype depending on the nature and location of the mutation, isoform specificity, and the effect on interactions with other cytoskeletal components (1). The clinical features described in association with desmoplakin mutations are summarized in Table 1 and include hair findings; cutaneous involvement of the palms, soles, and extremities; nail findings; cardiac involvement; dental anomalies; and general skin fragility (Table 1). Alopecia of the scalp, eyebrows, and eyelashes is a highly distinctive feature of this case and contrasts with the woolly hair classically described in Carvajal
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Figure 3. DSP gene and DSP protein showing the relative locations of mutations found in our patient.
syndrome and other desmosomal genodermatoses. Transient alopecia has been occasionally reported in desmoplakin-associated syndromes (Table 1). This includes generalized alopecia during the first year of life and continued development of scalp blisters (5); sparse woolly scalp hair from birth that sheds, resulting in total alopecia after 1 year of life (7); and scalp alopecia since birth with near-total absence of scalp hair, eyebrows, and eyelashes by age 5 years (8). A new phenotype characterized by arrthymogenic right ventricular cardiomyopathy (ARVC), alopecia, and PPK was found to be associated with a novel mutation in the gene encoding plakoglobin (JUP), another desmosomal protein (9). As such, alopecia should be considered a feature seen in desmosomal cardiocutaneous syndromes. Nail involvement has been reported in association with desmoplakin mutations (Table 1). Fingernail clubbing was originally described in some patients with Carvajal syndrome (2). Other nail phenotypes include progressively worsening nail dystrophy (5), thickened nails and subungual hyperkeratosis and wedging (10), and easily detachable toenails in response to mechanical stress (11). Leukonychia has recently been reported in several patients with heterozygous missense mutations in desmoplakin (12,13). Our patient’s nail dystrophy with hyperkeratotic thickened nails and subungual debris is a striking clinical finding; this adds further support to the role of desmoplakin in nail development. Additional cutaneous findings noted in our patient included striate PPK on the palms, diffuse PPK on the soles, and follicular hyperkeratosis with plugging on the extensor surfaces. PPK is a classic feature of desmosomal genodermatoses and has been reported in many cases of desmoplakin mutations (Table 1). Linear and diffuse PPK of the palms and soles has
been reported in striate PPK (4,14) and in skin fragility–woolly hair syndrome (5). Several recent reports of desmoplakin mutations describe linear hyperkeratosis on the palms and a focal pattern at trauma-prone sites on the soles (Table 1), consistent with our patient’s clinical features. A distinctive pattern of follicular hyperkeratosis with plugging was noted on our patient’s elbows, hips, and knees. This has not been previously described in cases of desmosomal genodermatoses and adds to the phenotypic variability seen in these conditions. Cardiomyopathy associated with desmoplakin mutations may be dilated left ventricular cardiomyopathy, as in Carvajal syndrome (2), biventricular dilated cardiomyopathy, or ARVC (Table 1). It classically presents during adolescence or adulthood, but our patient rather unusually presented at age 3 years with decompensated heart failure. Two recent cases describe biventricular cardiomyopathy with symptoms of heart failure presenting at a young age, including 3 years (15) and in the first year of life (8). Our case of early-onset progressive heart failure is one of the youngest in the literature and highlights the need for cardiac examination in patients suspected of having a desmosomal genodermatosis. In the desmosome, desmoplakin links transmembrane cadherins through its N-terminal region to the cytoplasmic intermediate filament network through the C-terminal tail. R1400X and R2284X are damaging to the protein structure and function when analyzed by the SIFT (16) and Polyphen (17) algorithms. The nonsense mutation R1400X in the DSP gene causes loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The maternally inherited mutation R2284X is a nonsense mutation that occurs in the last exon and causes loss of normal protein function due
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TABLE 1. Clinical Features Reported in Cases of Desmoplakin Mutations Hair Alopecia Diffuse alopecia of the scalp since birth with history of scalp bullae (our case) Generalized alopecia in first year of life, continued development of blisters and alopecia on scalp (5) Reduced body hair (5) Near-absent eyelashes and eyebrows* (5,8,13), Sparse hairs in frontal scalp and high frontal hairline (11,13,20) Hair that shed at 1 year of life resulting in total alopecia (7) Universal alopecia (LAEB) (6,21,22) Woolly hair Lusterless, scant hair (10) Woolly and curly hair (3,5,12,13,15,20,23–27) Woolly hair that rarely grew longer than 10–15 cm (11) Long and curly eyelashes (11,27) Palms, soles, and extremities Palmoplantar keratoderma (5,10–13,15,24,26) Diffuse (25,27) Striate (3,13) Linear pattern of skin thickening on fingers and palms, circumscribed areas of skin thickening on the soles* (2–4,8,14,20), More pronounced friction-prone sites on the soles (2–4,7,8,11) Symmetric (8) or asymmetric (7) Associated with fissuring of the plantar epidermis (10,24,27) Dry, flaking skin on palms and soles with onset at age 20 years (4) Vesicular lesions on knees, palms, and soles with onset in childhood (23) Follicular keratosis on elbows and knees (2,3) Psoriasiform hyperkeratosis of knees, elbows, and shins with prominence around hair follicles (20) Follicular hyperkeratosis on wrists, elbows, ankles, and knees (8) Follicular hyperkeratosis with plugging on the knees, elbows, and hips* Focal hyperhidrosis of hands and feet (11) Nails Fingernail clubbing (2,3) Nail dystrophy (5,11,13,27) Toenails thickened and dystrophic with adjacent hyperkeratosis (8) Thickened nails with subungual hyperkeratosis and wedging (10) Dystrophic toenails with subungual debris* Neonatal nail loss (LAEB) (6,21,22) Toenails easily detachable in response to mechanical stress (11) Leukonychia On hands and feet (12) Bilateral of third and fourth toes (13) Heart Left ventricular dilated cardiomyopathy (3) Onset of heart failure often during adolescence (3) Left-sided ARVC with arrhythmia of LV origin (28) ARVD/C (12,29–31) Mild, moderate, and severe forms (29) ARVD with ventricular tachycardia originating in midseptal area (23) Causing heart failure at age 11 years (25) Biventricular dilated cardiomyopathy (13,20,24) Presenting at age 3 years* (15), Symptoms of heart failure within first year of life (8) Sudden death at age 14 years (11) With features of noncompaction cardiomyopathy, heart failure presenting at age 6 years and at age 10 years (26)
TABLE 1. Continued Other Cardiomyopathy leading to sudden death at age 9 years (7) Cardiomyopathy noted on 32-week ultrasound (LAEB) (21) Acute myocarditis (12) Severe right ventricular dilation and slight left ventricular enlargement, electrocardiographic abnormalities, episodes of syncope (13) Palpitations in 6 patients, cardiac arrest in 3, syncope in 1, chest pain with increased myocardial enzymes in 2, sudden death in 6 (32) Teeth Abnormally formed teeth (5) Enamel defects in deciduous and permanent teeth (11) Three triangular natal teeth in mandibula (LAEB) (6) Oligodontia (13) Absent molars and premolars (20) Only 4 permanent molars and several persisting primary teeth (24) Father with agenesis of 4 teeth, son with agenesis of 10 teeth (12) General skin Skin blistering and fragility (5,8,10,11) Onset in newborn period (5,11,27) and after age 1 year (7) Recurrent blistering particular on perioral areas, extremities, trunk (5) Tongue erosions, widespread bullae, some skin with leathery texture and fine scale (5) Spontaneous blisters on anterior leg and hands (7) Vesicular bullae not related to erosion or pressure (7) Blistering tendency diminished by age 6–8 years (11) Continued blistering at sites of friction (27) Exceptionally dry skin since birth (23) Severe fragility of skin and mucous membranes (LAEB) (6) Lethality in neonatal period (6), reported on day 1 of life (21) and day 26 of life (22) Extensive cutaneous erosions at birth, epithelial shedding covering >50% of body (21) Virtually total denudement of skin and mucosae, with reepithelialization but recurrent blistering (22) Pustules on face, hands, and hips at birth (10) LAEB, lethal acantholytic epidermolysis bullosa; ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy. *Denotes features seen in the case presented in this article.
to translation of an abnormal protein product. Truncating mutations and homozygous missense mutations in the C-terminal domain, such as R2284X, have been shown to predispose to cardiomyopathy (3,11). The mutation R2284X, when present alone, has been reported to be associated with ARVC (18). R1400X in exon 23 is a novel mutation and has not been reported in the literature. Mutations in the DSC2 gene encoding desmocollin 2 have been reported to be associated with autosomal dominant ARVC (19), but it is unclear as to the effect, if any, this variant has on our patient’s clinical phenotype. This boy with a novel compound heterozygous mutation in the DSP gene presented with severe dilated cardiomyopathy at age 3 years and a longstanding history of congenital alopecia, nail dystrophy, PPK, and follicular hyperkeratosis with plugging on the extensor surfaces. Unusual features of this case
Antonov et al: Heart Failure and Alopecia with DSP Mutation
include diffuse alopecia; a distinctive pattern of follicular hyperkeratosis with plugging on the elbows, knees, and hips; and cardiomyopathy with onset of heart failure at a young age. This case highlights the need for evaluation for mutations in the DSP gene in patients with cardiomyopathy and alopecia or other hair abnormalities. It also demonstrates the importance of evaluation for potential cardiomyopathy in children with unusual patterns of alopecia or alopecia together with PPK. ACKNOWLEDGMENTS We would like to thank the patient’s family for sharing medical records and photographs. REFERENCES 1. Petrof G, Mellerio JE, McGrath JA. Desmosomal genodermatoses. Br J Dermatol 2012;166:36–45. 2. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 1998;39:418–421. 3. Norgett EE, Hatsell SJ, Carvajal-Huerta L et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000;9:2761–2766. 4. Whittock NV, Ashton GH, Dopping-Hepenstal PJ et al. Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol 1999; 113:940–946. 5. Whittock NV, Wan H, Morley SM et al. Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Dermatol 2002;118:232–238. 6. Jonkman MF, Pasmooij AM, Pasmans SG et al. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 2005;77:653–660. 7. Asimaki A, Syrris P, Ward D et al. Unique epidermolytic bullous dermatosis with associated lethal cardiomyopathy related to novel desmoplakin mutations. J Cutan Pathol 2009;36:553–559. 8. Tanaka A, Lai-Cheong JE, Cafe ME et al. Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families. Br J Dermatol 2009;160:692–697. 9. Erken H, Yariz KO, Duman D et al. Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation. Br J Dermatol 2011; 165:917–921. 10. Al-OwainM,WakilS,ShareefFet al.Novelhomozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes. Clin Genet 2011;80:50–58. 11. Mahoney MG, Sadowski S, Brennan D et al. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol 2010;130:968–978.
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12. Boule S, Fressart V, Laux D et al. Expanding the phenotype associated with a desmoplakin dominant mutation: Carvajal/Naxos syndrome associated with leukonychia and oligodontia. Int J Cardiol 2012;161:50–52. 13. Keller DI, Stepowski D, Balmer C et al. De novo heterozygous desmoplakin mutations leading to NaxosCarvajal disease. Swiss Med Wkly 2012;142:w13670. 14. Armstrong DK, McKenna KE, Purkis PE et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet 1999;8:143–148. 15. Uzumcu A, Norgett EE, Dindar A et al. Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet 2006;43:e5. 16. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–1081. 17. Adzhubei IA, Schmidt S, Peshkin L et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–249. 18. Fressart V, Duthoit G, Donal E et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace 2010;12:861– 868. 19. McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. In: Pagon RA, Adam MP, Bird TD et al, eds. GeneReviews [online]. Seattle, WA: University of Washington, Seattle, 1993–2014. Available at http://www.ncbi.nlm.nih.gov/books/NBK1131. Accessed February 2, 2014. 20. Norgett EE, Lucke TW, Bowers B et al. Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin. J Invest Dermatol 2006;126:1651–1654. 21. Bolling MC, Veenstra MJ, Jonkman MF et al. Lethal acantholytic epidermolysis bullosa due to a novel homozygous deletion in DSP: expanding the phenotype and implications for desmoplakin function in skin and heart. Br J Dermatol 2010;162:1388–1394. 22. Hobbs RP, Han SY, van der Zwaag PA et al. Insights from a desmoplakin mutation identified in lethal acantholytic epidermolysis bullosa. J Invest Dermatol 2010;130:2680–2683. 23. Alcalai R, Metzger S, Rosenheck S et al. A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol 2003;42:319–327. 24. Chalabreysse L, Senni F, Bruyere P et al. A new hypo/ oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations. J Dent Res 2011;90:58–64. 25. Krishnamurthy S, Adhisivam B, Hamilton RM et al. Arrhythmogenic dilated cardiomyopathy due to a novel mutation in the desmoplakin gene. Indian J Pediatr 2011;78:866–869. 26. Williams T, Machann W, K€ uhler L et al. Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and
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acantholytic palmoplantar keratoderma. Clin Res Cardiol 2011;100:1087–1093. 27. Smith FJ, Wilson NJ, Moss C et al. Compound heterozygous mutations in desmoplakin cause skin fragility and woolly hair. Br J Dermatol 2012;166:894–896. 28. Norman M, Simpson M, Mogensen J et al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005;112: 636–642. 29. Rampazzo A, Nava A, Malacrida S et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002; 71:1200–1206.
30. Yang Z, Bowles NE, Scherer SE et al. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res 2006;99:646–655. 31. den Haan AD, Tan BY, Zikusoka MN et al. Comprehensive desmosome mutation analysis in North Americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet 2009; 2:428–435. 32. Bauce B, Basso C, Rampazzo A et al. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J 2005;26:1666–1675.
Early-Onset Heart Failure, Alopecia, and Cutaneous Abnormalities Associated with a Novel Compound Heterozygous Mutation in Desmoplakin Nina K. Antonov, B.S.,* Mina Y. Kingsbery, M.D.,† Luis O. Rohena, M.D.,‡ Teresa M. Lee, M.D.,§ Angela Christiano, Ph.D.,†,¶ Maria C. Garzon, M.D.,†,§ and Christine T. Lauren, M.D.†,§ *College of Physicians and Surgeons, Columbia University, New York, New York †Department of Dermatology, Columbia University Medical Center, New York, New York ‡San Antonio Military Medical Center, Fort Sam Houston, Texas Departments of §Pediatrics and ¶Genetics and Development, Columbia University Medical Center, New York, New York
Abstract: Mutations in the desmosomal protein desmoplakin have been associated with various conditions affecting the skin and heart. The prototype is Carvajal syndrome, characterized by cardiomyopathy, woolly hair, palmoplantar keratoderma (PPK), and skin fragility. We report the case of a 3-year-old boy presenting with severe left-sided heart failure with a preceding history of cutaneous abnormalities including congenital alopecia, PPK, nail dystrophy, and follicular hyperkeratosis on the extensor surfaces. Genetic testing revealed a novel combination of two heterozygous mutations in the DSP gene encoding desmoplakin: R1400X and R2284X. Both are predicted to be deleterious to protein function. This case adds to our understanding of the spectrum of clinical presentations of syndromes associated with desmoplakin mutations and highlights the need for cardiac examination in patients with characteristic cutaneous findings.
Desmosomes are intercellular junctions expressed in simple and stratified epithelium and the intercalated discs of cardiac myocytes. They play a role in cell adhesion and tissue integrity and may have secondary roles in cell signaling. Mutations in 10 different
desmosomal proteins have been discovered in recent years to be associated with clinical syndromes with varying involvement of the skin, hair, and heart (1). Mutations in desmoplakin, a component of the desmosome, have been associated with Carvajal
Address correspondence to Christine T. Lauren, M.D., Columbia University Department of Dermatology, 161 Fort Washington Avenue, 12th floor, New York, NY 10032, or e-mail: cat35@cumc. columbia.edu. DOI: 10.1111/pde.12484
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syndrome (2,3), striate palmoplantar keratoderma (PPK) (4), skin fragility–woolly hair syndrome (5), and lethal acantholytic epidermolysis bullosa (LAEB) (6), among other phenotypes. In this study we describe a previously unreported clinical presentation characterized by congenital alopecia, striate PPK, follicular hyperkeratosis with plugging on the extensor surfaces, nail dystrophy, and dilated cardiomyopathy associated with severe left ventricular dysfunction and dilation causing heart failure at age 3 years. DNA testing identified a novel combination of mutations in the DSP gene. CASE REPORT A 3-year-old boy presented to an outside hospital with a 1-week history of rhinorrhea, cough, abdominal pain and decreased appetite. On physical examination there was an intermittent gallop on cardiac auscultation and his liver was enlarged 2 cm below the costal margin. A chest radiograph showed an enlarged heart with evidence of pulmonary congestion; he was transferred to our center for management of heart failure. An electrocardiogram (ECG) was significant for left axis deviation, Q waves in the inferior and lateral leads, and low-voltage QRS with premature ventricular contractions. An echocardiogram was performed and revealed moderate left atrial dilation with a severely dilated left ventricle and severe globally decreased systolic function, with an ejection fraction of 24% (normal 54–75%) (Fig. 1). There was mild to moderate mitral regurgitation and a trivial pericardial effusion. Serum chemistry, complete blood count, and liver function tests were unremarkable. B-type natriuretic
Figure 1. Echocardiogram: two-dimensional apical four chamber view demonstrating severe dilation of the left ventricle and moderate dilation of the left atrium.
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peptide was high (2053.7 pg/mL). The patient was initially started on high-dose steroids because of concerns about myocarditis, given the low-voltage QRS complexes on ECG and C-reactive protein of 23.7 mg/L (normal ≤2.9 mg/L), but the infectious examination was negative, including all viral serologies and a respiratory virus polymerase chain reaction panel. The patient was started on a continuous milrinone infusion and listed as status 1a for heart transplantation. On hospital day 28 he underwent successful orthotropic heart transplantation. He had an uneventful postoperative recovery period and continues to do well 12 months after transplantation. Dermatology was consulted to evaluate multiple cutaneous findings. Examination revealed diffuse alopecia of the scalp, with areas of sparse short curly hair, and sparse eyebrows and eyelashes (Fig. 2A). Palmoplantar hyperkeratosis was present in a striate pattern on the palms (Fig. 2B) and at points of pressure on the soles (Fig. 2C). His toenails were thickened and discolored, with evidence of subungual debris (Fig. 2D); fungal culture of his toenails was negative. He had groups of follicular papules with plugging on his elbows, knees, and hips (Fig. 2E). He had perioral fissures and crusts. Dental examination was normal. His mother reported that he had had no hair on his scalp since birth. She also noted blisters and erosions, specifically at sites of friction, that started at approximately 2 years of age. An outside dermatologist had previously evaluated him for scalp bullae at 22 months of age; skin biopsy was nondiagnostic. MOLECULAR STUDIES The patient’s parents are both from the Dominican Republic. His mother denied a family history of skin or cardiac disease or consanguinity. The patient has a younger sister who is healthy, without similar skin findings or known cardiac disease. Genetic testing was performed in the patient and his mother. Direct sequencing revealed two heterozygous mutations in the DSP gene in our patient (Fig. 3). The first was a novel nonsense mutation c4198C>T in exon 23, resulting in substitution of a stop codon for an arginine residue at amino acid 1400 of the DSP protein (R1400X). The second was the mutation c6850C>T in exon 24, resulting in substitution of a stop codon in place of an arginine residue in position 2284 (R2284X). The mother was a heterozygous carrier of the mutation R2284X. The patient’s father was not available to provide a blood sample, nor was his clinical history
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Figure 2. Clinical features of our patient. (A) Diffuse alopecia of the scalp and sparse eyebrows and eyelashes. (B) Striate hyperkeratosis on the palms and (C) diffuse hyperkeratosis at pressure points on the soles. (D) Dystrophic toenails with subungual debris. (E) Follicular hyperkeratosis with plugging on the knees.
available. The mutation R1400X was presumably paternally inherited, although a de novo mutation cannot be excluded. Sequencing also revealed that the patient was heterozygous for c2636A>G in exon 16 of the DSC2 gene encoding desmocollin 2, representing the D879G variant of uncertain significance. DISCUSSION The first described mutation in desmoplakin was reported in association with Carvajal syndrome, presenting in several Ecuadorian families. This disorder is characterized by left ventricular dilated cardiomyopathy, striate PPK, woolly hair, and skin fragility associated with a homozygous mutation
(7901delG) in the C tail domain of desmoplakin (2,3). More than 40 different mutations in desmoplakin have been identified since, with the clinical phenotype depending on the nature and location of the mutation, isoform specificity, and the effect on interactions with other cytoskeletal components (1). The clinical features described in association with desmoplakin mutations are summarized in Table 1 and include hair findings; cutaneous involvement of the palms, soles, and extremities; nail findings; cardiac involvement; dental anomalies; and general skin fragility (Table 1). Alopecia of the scalp, eyebrows, and eyelashes is a highly distinctive feature of this case and contrasts with the woolly hair classically described in Carvajal
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Figure 3. DSP gene and DSP protein showing the relative locations of mutations found in our patient.
syndrome and other desmosomal genodermatoses. Transient alopecia has been occasionally reported in desmoplakin-associated syndromes (Table 1). This includes generalized alopecia during the first year of life and continued development of scalp blisters (5); sparse woolly scalp hair from birth that sheds, resulting in total alopecia after 1 year of life (7); and scalp alopecia since birth with near-total absence of scalp hair, eyebrows, and eyelashes by age 5 years (8). A new phenotype characterized by arrthymogenic right ventricular cardiomyopathy (ARVC), alopecia, and PPK was found to be associated with a novel mutation in the gene encoding plakoglobin (JUP), another desmosomal protein (9). As such, alopecia should be considered a feature seen in desmosomal cardiocutaneous syndromes. Nail involvement has been reported in association with desmoplakin mutations (Table 1). Fingernail clubbing was originally described in some patients with Carvajal syndrome (2). Other nail phenotypes include progressively worsening nail dystrophy (5), thickened nails and subungual hyperkeratosis and wedging (10), and easily detachable toenails in response to mechanical stress (11). Leukonychia has recently been reported in several patients with heterozygous missense mutations in desmoplakin (12,13). Our patient’s nail dystrophy with hyperkeratotic thickened nails and subungual debris is a striking clinical finding; this adds further support to the role of desmoplakin in nail development. Additional cutaneous findings noted in our patient included striate PPK on the palms, diffuse PPK on the soles, and follicular hyperkeratosis with plugging on the extensor surfaces. PPK is a classic feature of desmosomal genodermatoses and has been reported in many cases of desmoplakin mutations (Table 1). Linear and diffuse PPK of the palms and soles has
been reported in striate PPK (4,14) and in skin fragility–woolly hair syndrome (5). Several recent reports of desmoplakin mutations describe linear hyperkeratosis on the palms and a focal pattern at trauma-prone sites on the soles (Table 1), consistent with our patient’s clinical features. A distinctive pattern of follicular hyperkeratosis with plugging was noted on our patient’s elbows, hips, and knees. This has not been previously described in cases of desmosomal genodermatoses and adds to the phenotypic variability seen in these conditions. Cardiomyopathy associated with desmoplakin mutations may be dilated left ventricular cardiomyopathy, as in Carvajal syndrome (2), biventricular dilated cardiomyopathy, or ARVC (Table 1). It classically presents during adolescence or adulthood, but our patient rather unusually presented at age 3 years with decompensated heart failure. Two recent cases describe biventricular cardiomyopathy with symptoms of heart failure presenting at a young age, including 3 years (15) and in the first year of life (8). Our case of early-onset progressive heart failure is one of the youngest in the literature and highlights the need for cardiac examination in patients suspected of having a desmosomal genodermatosis. In the desmosome, desmoplakin links transmembrane cadherins through its N-terminal region to the cytoplasmic intermediate filament network through the C-terminal tail. R1400X and R2284X are damaging to the protein structure and function when analyzed by the SIFT (16) and Polyphen (17) algorithms. The nonsense mutation R1400X in the DSP gene causes loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The maternally inherited mutation R2284X is a nonsense mutation that occurs in the last exon and causes loss of normal protein function due
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TABLE 1. Clinical Features Reported in Cases of Desmoplakin Mutations Hair Alopecia Diffuse alopecia of the scalp since birth with history of scalp bullae (our case) Generalized alopecia in first year of life, continued development of blisters and alopecia on scalp (5) Reduced body hair (5) Near-absent eyelashes and eyebrows* (5,8,13), Sparse hairs in frontal scalp and high frontal hairline (11,13,20) Hair that shed at 1 year of life resulting in total alopecia (7) Universal alopecia (LAEB) (6,21,22) Woolly hair Lusterless, scant hair (10) Woolly and curly hair (3,5,12,13,15,20,23–27) Woolly hair that rarely grew longer than 10–15 cm (11) Long and curly eyelashes (11,27) Palms, soles, and extremities Palmoplantar keratoderma (5,10–13,15,24,26) Diffuse (25,27) Striate (3,13) Linear pattern of skin thickening on fingers and palms, circumscribed areas of skin thickening on the soles* (2–4,8,14,20), More pronounced friction-prone sites on the soles (2–4,7,8,11) Symmetric (8) or asymmetric (7) Associated with fissuring of the plantar epidermis (10,24,27) Dry, flaking skin on palms and soles with onset at age 20 years (4) Vesicular lesions on knees, palms, and soles with onset in childhood (23) Follicular keratosis on elbows and knees (2,3) Psoriasiform hyperkeratosis of knees, elbows, and shins with prominence around hair follicles (20) Follicular hyperkeratosis on wrists, elbows, ankles, and knees (8) Follicular hyperkeratosis with plugging on the knees, elbows, and hips* Focal hyperhidrosis of hands and feet (11) Nails Fingernail clubbing (2,3) Nail dystrophy (5,11,13,27) Toenails thickened and dystrophic with adjacent hyperkeratosis (8) Thickened nails with subungual hyperkeratosis and wedging (10) Dystrophic toenails with subungual debris* Neonatal nail loss (LAEB) (6,21,22) Toenails easily detachable in response to mechanical stress (11) Leukonychia On hands and feet (12) Bilateral of third and fourth toes (13) Heart Left ventricular dilated cardiomyopathy (3) Onset of heart failure often during adolescence (3) Left-sided ARVC with arrhythmia of LV origin (28) ARVD/C (12,29–31) Mild, moderate, and severe forms (29) ARVD with ventricular tachycardia originating in midseptal area (23) Causing heart failure at age 11 years (25) Biventricular dilated cardiomyopathy (13,20,24) Presenting at age 3 years* (15), Symptoms of heart failure within first year of life (8) Sudden death at age 14 years (11) With features of noncompaction cardiomyopathy, heart failure presenting at age 6 years and at age 10 years (26)
TABLE 1. Continued Other Cardiomyopathy leading to sudden death at age 9 years (7) Cardiomyopathy noted on 32-week ultrasound (LAEB) (21) Acute myocarditis (12) Severe right ventricular dilation and slight left ventricular enlargement, electrocardiographic abnormalities, episodes of syncope (13) Palpitations in 6 patients, cardiac arrest in 3, syncope in 1, chest pain with increased myocardial enzymes in 2, sudden death in 6 (32) Teeth Abnormally formed teeth (5) Enamel defects in deciduous and permanent teeth (11) Three triangular natal teeth in mandibula (LAEB) (6) Oligodontia (13) Absent molars and premolars (20) Only 4 permanent molars and several persisting primary teeth (24) Father with agenesis of 4 teeth, son with agenesis of 10 teeth (12) General skin Skin blistering and fragility (5,8,10,11) Onset in newborn period (5,11,27) and after age 1 year (7) Recurrent blistering particular on perioral areas, extremities, trunk (5) Tongue erosions, widespread bullae, some skin with leathery texture and fine scale (5) Spontaneous blisters on anterior leg and hands (7) Vesicular bullae not related to erosion or pressure (7) Blistering tendency diminished by age 6–8 years (11) Continued blistering at sites of friction (27) Exceptionally dry skin since birth (23) Severe fragility of skin and mucous membranes (LAEB) (6) Lethality in neonatal period (6), reported on day 1 of life (21) and day 26 of life (22) Extensive cutaneous erosions at birth, epithelial shedding covering >50% of body (21) Virtually total denudement of skin and mucosae, with reepithelialization but recurrent blistering (22) Pustules on face, hands, and hips at birth (10) LAEB, lethal acantholytic epidermolysis bullosa; ARVD/C, arrhythmogenic right ventricular dysplasia/cardiomyopathy. *Denotes features seen in the case presented in this article.
to translation of an abnormal protein product. Truncating mutations and homozygous missense mutations in the C-terminal domain, such as R2284X, have been shown to predispose to cardiomyopathy (3,11). The mutation R2284X, when present alone, has been reported to be associated with ARVC (18). R1400X in exon 23 is a novel mutation and has not been reported in the literature. Mutations in the DSC2 gene encoding desmocollin 2 have been reported to be associated with autosomal dominant ARVC (19), but it is unclear as to the effect, if any, this variant has on our patient’s clinical phenotype. This boy with a novel compound heterozygous mutation in the DSP gene presented with severe dilated cardiomyopathy at age 3 years and a longstanding history of congenital alopecia, nail dystrophy, PPK, and follicular hyperkeratosis with plugging on the extensor surfaces. Unusual features of this case
Antonov et al: Heart Failure and Alopecia with DSP Mutation
include diffuse alopecia; a distinctive pattern of follicular hyperkeratosis with plugging on the elbows, knees, and hips; and cardiomyopathy with onset of heart failure at a young age. This case highlights the need for evaluation for mutations in the DSP gene in patients with cardiomyopathy and alopecia or other hair abnormalities. It also demonstrates the importance of evaluation for potential cardiomyopathy in children with unusual patterns of alopecia or alopecia together with PPK. ACKNOWLEDGMENTS We would like to thank the patient’s family for sharing medical records and photographs. REFERENCES 1. Petrof G, Mellerio JE, McGrath JA. Desmosomal genodermatoses. Br J Dermatol 2012;166:36–45. 2. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 1998;39:418–421. 3. Norgett EE, Hatsell SJ, Carvajal-Huerta L et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000;9:2761–2766. 4. Whittock NV, Ashton GH, Dopping-Hepenstal PJ et al. Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol 1999; 113:940–946. 5. Whittock NV, Wan H, Morley SM et al. Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. J Invest Dermatol 2002;118:232–238. 6. Jonkman MF, Pasmooij AM, Pasmans SG et al. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 2005;77:653–660. 7. Asimaki A, Syrris P, Ward D et al. Unique epidermolytic bullous dermatosis with associated lethal cardiomyopathy related to novel desmoplakin mutations. J Cutan Pathol 2009;36:553–559. 8. Tanaka A, Lai-Cheong JE, Cafe ME et al. Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families. Br J Dermatol 2009;160:692–697. 9. Erken H, Yariz KO, Duman D et al. Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation. Br J Dermatol 2011; 165:917–921. 10. Al-OwainM,WakilS,ShareefFet al.Novelhomozygous mutation in DSP causing skin fragility-woolly hair syndrome: report of a large family and review of the desmoplakin-related phenotypes. Clin Genet 2011;80:50–58. 11. Mahoney MG, Sadowski S, Brennan D et al. Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol 2010;130:968–978.
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