Taking woolly hair to heart

By Warren R. Heymann, MD, FAAD
October 27, 2021
Vol. 3, No. 43

Woolly hair (WH) appears as strongly coiled hair — it may be localized or diffuse, with the latter often associated with syndromes affecting the heart, gastrointestinal tract, or central nervous system.

This commentary will briefly touch on localized disease and new information regarding autosomal recessive wooly hair/hypotrichosis. The focus, however, will be on recognizing WH syndromes with cardiac involvement — which could prove lifesaving.

The term woolly hair nevus (WHN) describes WH restricted to a limited area of the scalp. WHN has been classified into three types: Type I is not associated with any other cutaneous or scalp problems; Type 2 is associated with a linear verrucous epidermal nevus; and Type 3 is acquired progressive kinking of the hair. (1) Approximately half of WHN are type 2, associated with an ipsilateral verrucous epidermal nevus, which may be considered as a mosaic RASopathy caused by an HRAS p.G12S mutation. WHN have been associated with ophthalmologic, auditory, dental, skeletal, and renal anomalies. (2)

Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is a rare form of congenital alopecia, which can be caused by mutations in lipase H (LIPH), lysophosphatidic acid receptor 6 (LPAR6/P2RY5), or keratin 25 (KRT25) genes. Lysophosphatidic acid (LPA) is an extracellular molecule that binds to its G protein-coupled receptor in the inner root sheath of hair follicles. LIPH encodes for the membrane-associated phosphatidic acid-preferring phospholipase A1, which breaks down phosphatidic acid into LPA. (3) LPA bind the P2Y5 receptor in the hair follicle epithelium and activates hair growth. In ARWH due to LIPH pathogenic variants, loss-of-function variants in LIPH lead to a deficiency of lysophosphatidic acid and insufficient activation of P2Y5. Taki et al demonstrated that topical minoxidil resulted in improvement of hypotrichosis in 8 patients (3 from one family) with LIPH variants of ARWH/H. (4) Topical minoxidil, however, was not effective in 6-year-old dizygotic twins (boy and girl) with ARWH/H due to novel variants of the LPAR6 gene. (5)

As aptly stated by Ramot, “It is not very common for the dermatologist to be the one who saves the lives of patients. However, such is the case when examining patients that present with the combination of woolly hair and palmoplantar keratoderma. This combination can herald the presence of a lethal arrhythmogenic cardiomyopathy due to mutations in genes that encode desmosomal proteins.” Early diagnosis of these cutaneous features is crucial because their appearance precedes the cardiac manifestations. Rendering these diagnoses allows for life-saving implantation of cardioverters. Whole exome sequencing will increasingly allow prompt diagnosis. (6) Most of these conditions are inherited in an autosomal recessive manner and can be divided into three syndromes: Keratoderma with woolly hair (KWWH) type I: caused by mutations in JUP, which encodes plakoglobin (Naxos disease — causing a right ventricular cardiomyopathy); KWWH type II: caused by mutations in DSP, which encodes desmoplakin (Carvajal disease — associated with a left ventricular cardiomyopathy of early onset) (6,7); and KWWH type III: caused by mutations in DSC2, which encodes desmocollin 2 — associated with a right ventricular cardiomyopathy. (6,8)

According to Maruthappu et al, arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disorder that may cause sudden cardiac death in young patients (<35 years old), making early diagnosis essential. The genetic basis of AC in the majority of cases is linked to a mutation in a component of the desmosome, a key electromechanical adhesion complex between cardiomyocytes. AC associated mutations have been reported to occur in five desmosomal genes: plakoglobin, desmoplakin, plakophilin 2, desmoglein 2, and desmocollin 2. Importantly, the authors were able to perform detailed cutaneous and cardiac phenotyping of 38 carriers (in 6 families) of a dominant loss-of-function mutation in desmoplakin with AC. All carriers had curly hair, but non-carrier offspring in the family did not. The palmoplantar keratoderma was more variable. The expression of connexin 43 (Cx43) appeared reduced in the basal epidermis from affected patient skin. This particular junctional component is critical for electrical conduction in the cardiac intercalate disc. (9)

When observing WH, clinicians should quickly determine if the condition is localized, generalized, or syndromal. If a keratoderma appreciated (even a mild form), referral to cardiologist and geneticist is warranted.

Point to Remember: Recognition of rare woolly hair syndromes may be lifesaving because the cutaneous features of wooly hair and keratoderma precede the presentation of the arrhythmogenic cardiomyopathy.

Our expert’s viewpoint

Yuval Ramot, MD, MSc, IFAAD
Associate Professor of Dermatology
Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine
Jerusalem, Israel

Woolly hair is a rather remarkable phenotype for the dermatologist to encounter (6, 10). It is characterized by tightly curled hair, which is difficult to comb, that appears shortly after birth. The first distinction that the dermatologist should make is whether the woolly hair phenotype is localized or diffuse (11). If it is localized the diagnosis is probably woolly hair nevus, but if it is diffuse and involves the entire scalp, a syndromic form of woolly hair should be considered. In such cases, it is essential to examine the palms and soles of the patient, since if the patients also present with palmoplantar keratoderma, the patients have keratoderma with woolly hair (KWWH), a syndrome that can also cause lethal arrhythmogenic cardiomyopathy (12, 13). Since the symptoms of the heart anomalies appear only later in life (usually at adolescence), by making the right diagnosis early, it is possible to provide the patients with a life-saving intervention, i.e. implantation of a defibrillator.

Although the clinical evaluation of patients is always important, in the case of KWWH it is essential to perform a detailed genetic evaluation, for several reasons: (6) It is the only way to ascertain the diagnosis of the patient; (10) it will provide information on the cardiac risk (there are genetic syndromes where the patients have KWWH without heart involvement) (14); (11) genetic testing of all family members will discover asymptomatic or pauci symptomatic patients; (12) eventually, it can be used for genetic counseling of all family members for future pregnancies. Nowadays, when modern genetic analyses tools are widely available (e.g. whole exome sequencing) and relatively accessible, such tools should be utilized as part of the evaluation of the patients.

Keratoderma and woolly hair are not the only skin phenotypes that herald the presence of heart disease. For example, the presence of hyperpigmented and indurated plaques on the inner thighs is a pathognomonic sign for H syndrome, which can also involve the heart (15). Therefore, knowledge on such cutaneous signs is important for the practicing dermatologist (16) (see The H syndrome – Understanding Y).

1. Taj FT, Kologi S. Woolly Hair Nevus Type 2: Rare Entity. Int J Trichology. 2019 Jan-Feb;11(1):38-40.

2. Gomes TF, Guiote V, Henrique M. Woolly hair nevus: case report and review of literature. Dermatol Online J. 2020 Jan 15;26(1):13030.

3. Lv H, Li M, Cheng R. Novel small-insertion mutation in the LIPH gene in a patient with autosomal recessive woolly hair/hypotrichosis. J Dermatol. 2020 Sep 9. doi: 10.1111/1346-8138.15581. Epub ahead of print.

4. Taki T, Tanahashi K, Takeichi T, Yoshikawa T, Murase Y, Sugiura K, Akiyama M. Association of topical minoxidil with autosomal recessive woolly hair/hypotrichosis caused by LIPH pathogenic variants. JAMA Dermatol. 2020; 156: 1132-1134.

5. Piquer-García J, Torres-Navarro I, Martínez-Castellano F, Évole-Buselli M. Autosomal recessive woolly hair and hypotrichosis in two Caucasian dizygotic twins. Description of a novel biallelic mutation in the LPAR6 gene. Int J Dermatol. 2020 Oct 5. doi: 10.1111/ijd.15207. Epub ahead of print.

6. Ramot Y. Keratoderma and woolly hair: an important clue for the presence of cardiac pathology. Br J Dermatol. 2019 May;180(5):983-984.

7. Pavone P, Falsaperla R, Barbagallo M, Polizzi A, Praticò AD, Ruggieri M. Clinical spectrum of woolly hair: indications for cerebral involvement. Ital J Pediatr. 2017 Nov 2;43(1):99.

8. Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, McKenna WJ, Behr ER, Crosby AH. Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology. 2009;113(1):28-34.

9. Maruthappu T, Posafalvi A, Castelletti S, Delaney PJ, Syrris P, O'Toole EA, Green KJ, Elliott PM, Lambiase PD, Tinker A, McKenna WJ, Kelsell DP. Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype. Br J Dermatol. 2019 May;180(5):1114-1122.

10. Ramot Y, Zlotogorski A. Molecular genetics of alopecias. Curr Probl Dermatol. 2015;47:87-96.

11. Ramot Y, Zlotogorski A. The twisting tale of woolly hair: a trait with many causes. J Med Genet. 2015;52(4):217-23.

12. Horev L, Babay S, Ramot Y, Saad-Edin B, Moorad S, Ingber A, et al. Mutations in two genes on chromosome 13 resulting in a complex hair and skin phenotype due to two rare genodermatoses: KLICK and autosomal recessive woolly hair/hypotrichosis simplex. Br J Dermatol. 2011;164(5):1113-6.

13. Molho-Pessach V, Sheffer S, Siam R, Tams S, Siam I, Awwad R, et al. Two Novel Homozygous Desmoplakin Mutations in Carvajal Syndrome. Pediatr Dermatol. 2015;32(5):641-6.

14. Ramot Y, Molho-Pessach V, Meir T, Alper-Pinus R, Siam I, Tams S, et al. Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair. J Med Genet. 2014;51(6):388-94.

15. Molho-Pessach V, Ramot Y, Camille F, Doviner V, Babay S, Luis SJ, et al. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70(1):80-8.

16. O'Neill JL, Narahari S, Sane DC, Yosipovitch G. Cardiac manifestations of cutaneous disorders. J Am Acad Dermatol. 2013;68(1):156-66.

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