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Naxos disease(NXD)

MedGen UID:
321991
Concept ID:
C1832600
Disease or Syndrome
Synonyms: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant; CARDIOMYOPATHY, ARRHYTHMOGENIC RIGHT VENTRICULAR, WITH SKIN, HAIR, AND NAIL ABNORMALITIES; Keratosis palmoplantaris arrythmogenic cardiomyopathy woolly hair; KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY; Mal de Naxos; NXD; PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR; Woolly hair palmoplantar keratoderma cardiac abnormalities; WOOLLY HAIR, PALMOPLANTAR KERATODERMA, AND CARDIAC ABNORMALITIES
SNOMED CT: Naxos disease (715535009); Keratoderma with wooly hair type I (715535009); Keratosis palmoplantaris and arrhythmogenic cardiomyopathy syndrome (715535009); Palmoplantar hyperkeratosis with arrhythmogenic cardiomyopathy (715535009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): JUP (17q21.2)
 
Monarch Initiative: MONDO:0011017
OMIM®: 601214
Orphanet: ORPHA34217

Definition

Naxos disease (NXD) is characterized by arrhythmogenic right ventricular cardiomyopathy associated with abnormalities of the skin, hair, and nails. The ectodermal features are evident from birth or early childhood, whereas the cardiac symptoms develop in young adulthood or later. Clinical variability of ectodermal features has been observed, with hair anomalies ranging from woolly hair to alopecia, and skin abnormalities ranging from mild focal palmoplantar keratoderma to generalized skin fragility or even lethal neonatal epidermolysis bullosa (Protonotarios et al., 1986; Cabral et al., 2010; Pigors et al., 2011; Erken et al., 2011; Sen-Chowdhry and McKenna, 2014). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (DCWHK; 605676) is caused by mutation in the desmoplakin gene (DSP; 125647). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645). [from OMIM]

Additional description

From MedlinePlus Genetics
Keratoderma with woolly hair is a group of related conditions that affect the skin and hair and in many cases increase the risk of potentially life-threatening heart problems. People with these conditions have hair that is unusually coarse, dry, fine, and tightly curled. In some cases, the hair is also sparse. The woolly hair texture typically affects only scalp hair and is present from birth. Starting early in life, affected individuals also develop palmoplantar keratoderma, a condition that causes skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused.

Keratoderma with woolly hair comprises several related conditions with overlapping signs and symptoms. Researchers have recently proposed classifying keratoderma with woolly hair into four types, based on the underlying genetic cause. Type I, also known as Naxos disease, is characterized by palmoplantar keratoderma, woolly hair, and a form of cardiomyopathy called arrhythmogenic right ventricular cardiomyopathy (ARVC). Type II, also known as Carvajal syndrome, has hair and skin abnormalities similar to type I but features a different form of cardiomyopathy, called dilated left ventricular cardiomyopathy. Type III also has signs and symptoms similar to those of type I, including ARVC, although the hair and skin abnormalities are often milder. Type IV is characterized by palmoplantar keratoderma and woolly and sparse hair, as well as abnormal fingernails and toenails. Type IV does not appear to cause cardiomyopathy.

Cardiomyopathy, which is a disease of the heart muscle, is a life-threatening health problem that can develop in people with keratoderma with woolly hair. Unlike the other features of this condition, signs and symptoms of cardiomyopathy may not appear until adolescence or later. Complications of cardiomyopathy can include an abnormal heartbeat (arrhythmia), heart failure, and sudden death.  https://medlineplus.gov/genetics/condition/keratoderma-with-woolly-hair

Clinical features

From HPO
Sudden death
MedGen UID:
8257
Concept ID:
C0011071
Pathologic Function
Rapid and unexpected death.
Sudden cardiac death
MedGen UID:
38841
Concept ID:
C0085298
Pathologic Function
The heart suddenly and unexpectedly stops beating resulting in death within a short time period (generally within 1 h of symptom onset).
Diffuse palmoplantar hyperkeratosis
MedGen UID:
7201
Concept ID:
C0022584
Disease or Syndrome
Diffuse abnormal thickening of the skin on the palms and soles.
Palmoplantar keratoderma
MedGen UID:
1635750
Concept ID:
C4551675
Disease or Syndrome
Abnormal thickening of the skin of the palms of the hands and the soles of the feet.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Abnormal heart morphology
MedGen UID:
6748
Concept ID:
C0018798
Congenital Abnormality
Any structural anomaly of the heart.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Palpitations
MedGen UID:
14579
Concept ID:
C0030252
Finding
A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.
Paroxysmal ventricular tachycardia
MedGen UID:
18315
Concept ID:
C0030591
Disease or Syndrome
Episodes of ventricular tachycardia that have a sudden onset and ending.
Syncope
MedGen UID:
21443
Concept ID:
C0039070
Sign or Symptom
Syncope is a syndrome in which loss of consciousness is of relatively sudden onset, temporary (usually less than 1 to 2 minutes), self-terminating, and of usually rapid recovery. Syncope leads to a generalized weakness of muscles with loss of postural tone, inability to stand upright, and loss of consciousness. Once the patient is in a horizontal position, blood flow to the brain is no longer hindered by gravitation and consciousness is regained. Unconsciousness usually lasts for seconds to minutes. Headache and drowsiness (which usually follow seizures) do not follow a syncopal attack. Syncope results from a sudden impairment of brain metabolism usually due to a reduction in cerebral blood flow.
Ventricular arrhythmia
MedGen UID:
39082
Concept ID:
C0085612
Disease or Syndrome
A disorder characterized by an electrocardiographic finding of an atypical cardiac rhythm resulting from a pathologic process in the cardiac ventricles.
Right bundle branch block
MedGen UID:
88445
Concept ID:
C0085615
Disease or Syndrome
A conduction block of the right branch of the bundle of His. This manifests as a prolongation of the QRS complex (greater than 0.12 s) with delayed activation of the right ventricle and terminal delay on the EKG.
Premature ventricular contraction
MedGen UID:
56236
Concept ID:
C0151636
Disease or Syndrome
Premature ventricular contractions (PVC) or ventricular extrasystoles are premature contractions of the heart that arise in response to an impulse in the ventricles rather than the normal impulse from the sinoatrial (SA) node.
Prolonged QRS complex
MedGen UID:
489828
Concept ID:
C0235475
Finding
Increased time for the complex comprised of the Q wave, R wave, and S wave as measured by the electrocardiogram (EKG).. In adults, normal values are 0.06 - 0.10 sec.
T-wave inversion
MedGen UID:
105467
Concept ID:
C0520888
Finding
An inversion of the T-wave (which is normally positive).
Right ventricular cardiomyopathy
MedGen UID:
384481
Concept ID:
C2063326
Disease or Syndrome
Right ventricular dysfunction (global or regional) with functional and morphological right ventricular abnormalities, with or without left ventricular disease.
Abnormal morphology of right ventricular trabeculae
MedGen UID:
1615024
Concept ID:
C4531287
Anatomical Abnormality
Any structural anomaly of the muscular columns which project from the inner surface of the right ventricle of the heart (cardiac trabeculae, trabeculae carneae).
Sparse eyebrow
MedGen UID:
371332
Concept ID:
C1832446
Finding
Decreased density/number of eyebrow hairs.
Acantholysis
MedGen UID:
1687
Concept ID:
C0000887
Pathologic Function
The loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes.
Subungual hyperkeratosis
MedGen UID:
21379
Concept ID:
C0038605
Finding
A thickening of the stratum corneum in the region beneath the nails.
Onycholysis
MedGen UID:
39324
Concept ID:
C0085661
Disease or Syndrome
Detachment of the nail from the nail bed.
Nail dystrophy
MedGen UID:
66368
Concept ID:
C0221260
Disease or Syndrome
Onychodystrophy (nail dystrophy) refers to nail changes apart from changes of the color (nail dyschromia) and involves partial or complete disruption of the various keratinous layers of the nail plate.
Epidermal acanthosis
MedGen UID:
65136
Concept ID:
C0221270
Finding
Diffuse hypertrophy or thickening of the stratum spinosum of the epidermis (prickle cell layer of the skin).
Fragile skin
MedGen UID:
66826
Concept ID:
C0241181
Finding
Skin that splits easily with minimal injury.
Wooly hair
MedGen UID:
87469
Concept ID:
C0343073
Finding
The term wooly hair refers to an abnormal variant of hair that is fine, with tightly coiled curls, and often hypopigmented. Optical microscopy may reveal the presence of tight spirals and a clear diameter reduction as compared with normal hair. Electron microscopy may show flat, oval hair shafts with reduced transversal diameter.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Sparse body hair
MedGen UID:
350775
Concept ID:
C1862863
Finding
Sparseness of the body hair.
Abnormal blistering of the skin
MedGen UID:
412159
Concept ID:
C2132198
Finding
The presence of one or more bullae on the skin, defined as fluid-filled blisters more than 5 mm in diameter with thin walls.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNaxos disease
Follow this link to review classifications for Naxos disease in Orphanet.

Professional guidelines

PubMed

Dri E, Leontsinis I, Tsiamis E, Dilaveris P, Latsios G, Aggeli C, Tousoulis D, Tsioufis C
Hellenic J Cardiol 2021 Nov-Dec;62(6):485-487. Epub 2021 Jan 13 doi: 10.1016/j.hjc.2021.01.002. PMID: 33450353
Tsatsopoulou AA, Protonotarios NI, McKenna WJ
Heart 2006 Dec;92(12):1720-3. Epub 2006 May 12 doi: 10.1136/hrt.2005.081679. PMID: 16698823Free PMC Article
Protonotarios N, Tsatsopoulou A, Anastasakis A, Sevdalis E, McKoy G, Stratos K, Gatzoulis K, Tentolouris K, Spiliopoulou C, Panagiotakos D, McKenna W, Toutouzas P
J Am Coll Cardiol 2001 Nov 1;38(5):1477-84. doi: 10.1016/s0735-1097(01)01568-6. PMID: 11691526

Recent clinical studies

Etiology

Tsatsopoulou A, Protonotarios I, Xylouri Z, Papagiannis I, Anastasakis A, Germanakis I, Patrianakos A, Nyktari E, Gavras C, Papadopoulos G, Meditskou S, Lazarou E, Miliou A, Lazaros G
Hellenic J Cardiol 2023 Jul-Aug;72:43-56. Epub 2023 Mar 3 doi: 10.1016/j.hjc.2023.02.007. PMID: 36870438
Protonotarios I, Asimaki A, Xylouri Z, Protonotarios A, Tsatsopoulou A
Heart Fail Clin 2022 Jan;18(1):89-99. Epub 2021 Oct 22 doi: 10.1016/j.hfc.2021.07.010. PMID: 34776086
Leopoulou M, Mattsson G, LeQuang JA, Pergolizzi JV, Varrassi G, Wallhagen M, Magnusson P
Expert Rev Cardiovasc Ther 2020 Nov;18(11):801-808. Epub 2020 Oct 8 doi: 10.1080/14779072.2020.1828064. PMID: 32966140
Hamada T, Tsuruta D, Fukuda S, Ishii N, Teye K, Numata S, Dainichi T, Karashima T, Ohata C, Furumura M, Hashimoto T
Exp Dermatol 2013 Feb;22(2):83-7. Epub 2012 Oct 8 doi: 10.1111/exd.12021. PMID: 23039137
Rickelt S, Pieperhoff S
Cell Tissue Res 2012 May;348(2):325-33. Epub 2012 Mar 27 doi: 10.1007/s00441-012-1365-0. PMID: 22450909Free PMC Article

Diagnosis

Tsatsopoulou A, Protonotarios I, Xylouri Z, Papagiannis I, Anastasakis A, Germanakis I, Patrianakos A, Nyktari E, Gavras C, Papadopoulos G, Meditskou S, Lazarou E, Miliou A, Lazaros G
Hellenic J Cardiol 2023 Jul-Aug;72:43-56. Epub 2023 Mar 3 doi: 10.1016/j.hjc.2023.02.007. PMID: 36870438
Protonotarios I, Asimaki A, Xylouri Z, Protonotarios A, Tsatsopoulou A
Heart Fail Clin 2022 Jan;18(1):89-99. Epub 2021 Oct 22 doi: 10.1016/j.hfc.2021.07.010. PMID: 34776086
Bolling MC, Jonkman MF
Exp Dermatol 2009 Aug;18(8):658-68. Epub 2009 Jun 23 doi: 10.1111/j.1600-0625.2009.00908.x. PMID: 19558499
Adhisivam B, Mahadevan S
Indian J Pediatr 2006 Apr;73(4):359-60. doi: 10.1007/BF02825834. PMID: 16816500
Protonotarios N, Tsatsopoulou A
Orphanet J Rare Dis 2006 Mar 13;1:4. doi: 10.1186/1750-1172-1-4. PMID: 16722579Free PMC Article

Therapy

Gultekin N, Kucukates E
Acta Cardiol 2013 Aug;68(4):433-7. doi: 10.1080/ac.68.4.2988900. PMID: 24187773
Sajeev CG, Francis J, Sankar V, Vasudev B, Venugopal K
Circulation 2006 Jul 25;114(4):e60-1. doi: 10.1161/CIRCULATIONAHA.105.562835. PMID: 16864732

Prognosis

Leopoulou M, Mattsson G, LeQuang JA, Pergolizzi JV, Varrassi G, Wallhagen M, Magnusson P
Expert Rev Cardiovasc Ther 2020 Nov;18(11):801-808. Epub 2020 Oct 8 doi: 10.1080/14779072.2020.1828064. PMID: 32966140
Chalabreysse L, Senni F, Bruyère P, Aime B, Ollagnier C, Bozio A, Bouvagnet P
J Dent Res 2011 Jan;90(1):58-64. Epub 2010 Oct 12 doi: 10.1177/0022034510383984. PMID: 20940358
Antoniades L, Tsatsopoulou A, Anastasakis A, Syrris P, Asimaki A, Panagiotakos D, Zambartas C, Stefanadis C, McKenna WJ, Protonotarios N
Eur Heart J 2006 Sep;27(18):2208-16. Epub 2006 Aug 7 doi: 10.1093/eurheartj/ehl184. PMID: 16893920
Adhisivam B, Mahadevan S
Indian J Pediatr 2006 Apr;73(4):359-60. doi: 10.1007/BF02825834. PMID: 16816500
Protonotarios N, Tsatsopoulou A
Orphanet J Rare Dis 2006 Mar 13;1:4. doi: 10.1186/1750-1172-1-4. PMID: 16722579Free PMC Article

Clinical prediction guides

Saravanan RR, Amuthan V, Janarthanan RA, Balasubramanian S, Mohamed SN
Indian Heart J 2012 Jan-Feb;64(1):84-7. Epub 2012 Mar 26 doi: 10.1016/S0019-4832(12)60017-0. PMID: 22572432Free PMC Article
Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ
Am J Hum Genet 2007 Nov;81(5):964-73. Epub 2007 Sep 28 doi: 10.1086/521633. PMID: 17924338Free PMC Article
Antoniades L, Tsatsopoulou A, Anastasakis A, Syrris P, Asimaki A, Panagiotakos D, Zambartas C, Stefanadis C, McKenna WJ, Protonotarios N
Eur Heart J 2006 Sep;27(18):2208-16. Epub 2006 Aug 7 doi: 10.1093/eurheartj/ehl184. PMID: 16893920
Protonotarios N, Tsatsopoulou A, Anastasakis A, Sevdalis E, McKoy G, Stratos K, Gatzoulis K, Tentolouris K, Spiliopoulou C, Panagiotakos D, McKenna W, Toutouzas P
J Am Coll Cardiol 2001 Nov 1;38(5):1477-84. doi: 10.1016/s0735-1097(01)01568-6. PMID: 11691526
Coonar AS, Protonotarios N, Tsatsopoulou A, Needham EW, Houlston RS, Cliff S, Otter MI, Murday VA, Mattu RK, McKenna WJ
Circulation 1998 May 26;97(20):2049-58. doi: 10.1161/01.cir.97.20.2049. PMID: 9610536

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