Genetic Hair Disorders: A Review

Hypotrichosis Simplex

Hypotrichosis simplex (HS) (Mendelian Inheritance in Man (MIM) 146520, MIM 278150, MIM 146550, MIM 613981, and MIM 605389) [4] is a descriptive term for the clinical manifestations related to diffuse hair thinning without any morphological abnormalities of the hair shaft. Several hereditary hypotrichosis simplex (HHS) pedigrees have been published showing autosomal dominant inheritance, while others show autosomal recessive inheritance. Clinical variability can be observed on the basis of patient’s age of onset, as well as eyebrow and eyelash involvement [5]. Mutations in six genes have been identified for isolated HS, and mutations in three of them—CDSN (MIM 602593), APCDD1 (MIM 607479), and RPL21 (MIM 603636)—are responsible for autosomal dominant forms [4].

When the hypotrichosis simplex is only limited to the scalp, it is called hereditary hypotrichosis simplex of the scalp (HHSS) (MIM 146520), which is a rare non-syndromic autosomal dominant condition characterized by exclusively scalp hair loss, sparing other ectodermal structures and with no systemic abnormalities [6]. It is caused by nonsense mutations in the corneodesmosin gene (CDSN) which leads to expression of a truncated protein probably toxic to hair growth [7].

Patients present with normal hair at birth, then a gradually progressive scalp hair loss begins in the middle of the first decade ending with almost complete hair loss by the third decade. Eyebrows, eyelashes, and other body hair beside teeth and nails are completely normal. Developmental and intellectual development are normal [8]. Hypotrichosis simplex of the scalp was first described by Toribio and Quinones [9]. Males and females are affected equally [9].

Marine Unna Hypotrichosis

Marie Unna hypotrichosis, also known as Marie Unna hereditary hypotrichosis (MUHH) (OMIM ID #146550) is a rare autosomal dominant condition characterized by scalp hair that is sparse or absent at birth [10], with variable coarse, wiry hair regrowth in childhood, and potential loss again at puberty causing non-scarring alopecia [11]. It was first described by Marie-Unna in a German family, where individuals over seven generations were affected by a previously unreported type of congenital hypotrichosis. The exact mechanism of hair loss is not yet known, and genetic factors may play a role. There are hypotheses that might contribute to the pathogenesis including decreased number of functional follicles, altered hair shaft morphology, and abnormal follicle cycling [12]. Mutation of the U2HR gene, located in chromosome 8p21 is responsible for MUH. Several mutations in the U2HR gene that have been reported in the literature [10, 13, 14].

Patients have normal to adequate hair at birth and develop pattern alopecia resembling severe androgenetic alopecia at puberty [15]. Eyelashes, eyebrows, body hair, and secondary sexual hair are sparse or absent. Loss of eyebrows and presence of wiry, twisted scalp hair, resembling pili torti, is important for diagnosis [16]. Nails, teeth, and sweat glands are normal. Milia-like facial lesions can occur [17].

The hair shaft shows irregular twisting at odd angles and diameter variability along its length on light microscopy. Peeling of the cuticle and longitudinal grooves are noticeable on scanning electron microscopy [15]. Histologically, the number of hair follicles is decreased and there is a mild to moderate inflammatory infiltrate, but no fibrosis and scarring. The distinctive pattern of hair loss and twisted hair shaft provides a clue to the diagnosis of MUH. Unfortunately, there is no effective treatment available [17].

Autosomal Recessive Wooly Hair/Hypotrichosis Simplex (ARWH/H) or Familial Woolly Hair (WFH)

Autosomal recessive woolly hair/hypotrichosis simplex (ARWH/H) (OMIM ID #604379) is rare disorder characterized by tightly curled hair with variable light color (woolly hair) since infancy and variable degree of hypotrichosis [18]. It is caused by a mutation in P2RY5 or lipase membrane H gene (LIPH) [18]. LIPH encodes PA-PLA1a, a phospholipase A1 family member that produces lysophosphatidic acid (LPA) from phosphatidic acid, and plays a crucial role in hair growth in humans. LPA is an extracellular mediator that has many biological functions [19]. A mutation in P2RY5 gene (which is expressed in both Henle’s and Huxley’s layers of the inner root sheath of the hair follicle) had been identified in six consanguineous Pakistani families [20]. Patients have sparse, coarse, dry, and tightly curled hair, usually blond or lighter than other family members [21, 22] (Fig. 1).

Hypotrichosis with Juvenile Macular Dystrophy

Congenital hypotrichosis associated with juvenile macular dystrophy (MIM 601553) is a rare autosomal recessive disorder characterized by early hair loss, heralding progressive degeneration of the retinal macula leading to early blindness during the second to third decade of life [23, 24]. HJMD prevalence is unknown and has only been reported in approximately 30 patients [25–30].

Sprecher et al. [23] used mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin, which is expressed in the hair follicles and retinal pigment epithelium. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3. These findings establish for the first time the molecular etiology of HJMD and link a cadherin molecule in the pathogenesis of this hair and retinal disorder [23]. Furthermore, Indelman et al. reported another four members of a consanguineous family with HJMD. Light and scanning electron microscopy of the hair shaft revealed pili torti. Fundus examination of the eyes showed marked degeneration of the macular pigment epithelium. DNA analysis of the entire coding sequence of CDH3 revealed, in all affected individuals, a homozygous missense mutation resulting in a single amino acid substitution at position 503 of P-cadherin sequence (R503H). This is considered the first missense mutation reported in CDH3 and second mutation found to underlie HJMD [31].

Additionally, Indelman and his colleagues assessed nine patients belonging to five families to further characterize the CDH3 mutation spectrum and delineate possible phenotype–genotype correlations. Significant inter- and intrafamilial differences in hair morphology were found, as well as differences in associated skin findings, severity, and age of onset of visual disability [32]. It has been recommended that all patients with congenital hypotrichosis should undergo a thorough fundus examination [26, 27, 33, 33]. A therapeutic window for gene augmentation therapy to preserve visual acuity was suggested. More novel mutations in the CDH3 gene in HJMD have been reported afterwards [25, 28–30, 35–40].

Therapy for Hypotrichosis

The treatment of this type of alopecia is unsatisfactory. Topical minoxidil can improve the hair density and texture but for most patients wearing a wig is the best option [7].

Hair Shaft Disorders with Increased Fragility

Hair Shaft Disorders Without Hair Fragility

Pili Trianguli et Canaliculi, “Uncombable Hair Syndrome” or “Spun Glass Hair Syndrome”

Pili trianguli et canaliculi most often presents in infancy or early childhood, with spun-glass-appearing scalp hairs that are dry, curly, blond, and totally resist all efforts of styling [109]. Hair is not fragile and grows normally [110]. Most reported cases are sporadic, but autosomal dominant and autosomal recessive inheritance has been described [111]. Mutations are located in three genes involving PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) [112]. Electron microscopy reveals irregularly shaped triangular shafts on cross section, which are areas of the internal root sheath that have been abnormally keratinized. Several conditions have been reported in association with uncombable hair, such as ectodermal dysplasia, retinal dysplasia/pigmentary dystrophy, juvenile cataract, tooth enamel anomalies, oligodontia, digit abnormalities, and phalangoepiphyseal dysplasia [109].

In most cases of uncombable hair syndrome, the hair texture and manageability improve with ageing [111].

Hypohidrotic Ectodermal Dysplasia (Christ–Siemens–Touraine Syndrome)

Hypohidrotic ectodermal dysplasia (HED) is an ectodermal dysplasia which principally causes sparse hair, the inability to sweat, and abnormal or missing teeth (Fig. 8). The X-linked form is the most common, occurring in approximately 1 in 17,000 live births [117]. Males are disproportionately affected by the X-linked HED; however, approximately one-third of cases are inherited in either an autosomal recessive or autosomal dominant pattern, of which males and females are affected equally [114]. Approximately 90% of cases are due to mutations in the EDA1, EDAR, EDARADD, or WNT10A genes [118]. These genes encode for proteins utilized in the tumor necrosis factor α (TNFα) signaling pathway [117]. These mutations disrupt communication between surface epithelial cells and the underlying mesenchyme during embryonic development, thereby impairing the development of skin appendages [119].

Hypohidrosis due to hypoplasia of sweat glands leads to fevers as a child and heat intolerance throughout life, especially during exercise [120]. Hypodontia is seen with an average of nine permanent teeth in patients with HED, which are frequently smaller than normal and with altered shape [121]. Patients with HED exhibit a typical facies with prominent forehead, thick lips, and a flattened nasal bridge [122].

Scalp hair is thin, sparse, slow-growing, and lightly pigmented, though secondary sexual hair can be normal [122]. In microscopic hair analysis of 22 patients with HED, investigators found an increased incidence of variable shaft thickness, trichorrhexis nodosa, and pili torti compared to normal controls [123]. Phototrichogram analysis in a control-matched group of 12 patients with HED showed significantly decreased number of terminal hairs, decreased number of follicular units, decreased number of hairs per follicular unit, decreased terminal hair width, and decreased hair growth rate [124].

No specific guidelines for diagnosing HED have been published. Individuals are typically diagnosed during infancy as a result of the characteristic features of hypotrichosis, hypohidrosis, and hypodontia and typical facies [122]. Hypohidrosis can be confirmed with the starch–iodine test.

Biopsy is not routinely performed; however, horizontally sectioned 4-mm punch biopsy specimens of the scalp or palms that lack eccrine structures are diagnostic of HED; scalp biopsy is much more sensitive than palmar biopsy [123].

Genetic testing for mutations in the EDAR, EDARADD, or WNT10A genes can be done to confirm diagnosis.

There is currently no cure for HED, so treatment is focused on managing symptoms. It is important for HED patients to control their exposure to heat in light of their hypohidrosis. During hot weather, they should have access to a cool environment and plenty of water. A dentist can help treat the patient’s dental symptoms.

There is some promising data regarding EDA-A1 replacement protein that binds to the EDA-A1 receptor (EDAR) called EDI200 developed by Edimer Pharmaceuticals. EDI200 is a targeted therapy that has been shown to be effective in preventing manifestation of the disease when administered to newborn X-linked HED dog and mouse animal models [125]. These benefits persisted through adulthood in these animals. However, a phase II clinical trial (ClinicalTrials.gov Identifier NCT01775462) showed inconclusive results in humans [122].

Management of hair symptoms is discussed below.

Hidrotic Ectodermal Dysplasia (Clouston Syndrome)

Hidrotic ectodermal dysplasia (Clouston syndrome) is a rare autosomal dominant disorder characterized by nail thickening/shortening, palmoplantar keratoderma, and short, thin sparse hair. It is caused by different missense mutations in the gap junction β6 gene (GJB6), which encodes for connexin-30 [126]. The disease is most frequently associated with those of French–Canadian descent [127], but has been seen in other ethnicities. Unlike hypohidrotic ectodermal dysplasia, patients with Clouston syndrome have the ability to sweat and have normal dentition.

Patients with Clouston exhibit pale-colored, patchy, wiry, and brittle scalp hair during infancy, with progressive hair loss typically leading to total alopecia by puberty. Eyebrows, axillary, and pubic hair are sparse or absent, and eyelashes are short and sparse [128]. Hair abnormalities under light microscopy include trichorrhexis nodosa, trichoptilosis, pili bifurcati, variable diameter, damaged cuticles, and irregular helical twists [129, 130]. Electron microscopy of the abnormal hair shows a square shape in transverse section and longitudinal grooving [131].

Clouston syndrome should be suspected in individuals with nail dystrophy, hypotrichosis, and palmoplantar hyperkeratosis starting early in life [128]. The diagnosis can be confirmed by genetic analysis. The best initial genetic test is targeted analysis for the four known GJB6 pathogenic variants, and if initial testing is inconclusive, sequence analysis can be done [126].

There is no cure for Clouston disease; its treatment involves management of symptoms. Artificial nails may be used to improve appearance of nails. Skin emollients may improve palmoplantar hyperkeratosis [128].

Management of hair symptoms is discussed below.

AEC Syndrome/Rapp–Hodgkin Syndrome

AEC syndrome is an ectodermal dysplasia characterized by ankyloblepharon (partial or complete fusion of the eyelids), ectodermal defects, and cleft lip/palate. Rapp–Hodgkin syndrome is distinguished from AEC syndrome by the absence of ankyloblepharon [132]. Once thought to be separate disorders, the two diseases are now considered to be varying presentations of the same genetic disease [132–135]. AEC syndrome is due to a mutation in the TP63 gene, coding for the p63 protein, which is involved in epidermal differentiation [136]. The disease has an autosomal dominant pattern of inheritance, though approximately 70% of mutations arise de novo [137]. Additional symptoms include dental hypoplasia, nail dysplasia, decreased sweating, and hair symptoms described below [137].

Virtually 100% of newborns with AEC syndrome have skin erosions of the scalp of varying severity, with severe erosions leading to scarring alopecia and hypotrichosis (Fig. 9) [137]. In a review of 72 cases of Rapp–Hodgkin syndrome, 82% of cases exhibited hair described as dry, wiry, and sparse; 36% showed pili torti et canaliculi, 24% had hypopigmented hair, 21% had scalp dermatitis, and 18% had a prominent forehead or high frontal hairline [138]. Scalp hair loss frequently begins at puberty and continues through the 20s and 30s, and typically affects the frontal hairline to the crown, with relative sparing of the occipital and temporal regions, but often leads to almost complete hair loss [138]. Absence or thinning of eyebrows and eyelashes is common, and body hair is usually sparse. Varying severity of Rapp–Hodgkin syndrome can manifest with different degrees of hair symptoms.

Diagnosis can be suspected owing to the characteristic clinical features described above, and can be confirmed with sequence analysis of the TP63 gene [137].

Treatment focuses on management of symptoms. Neonatal scalp skin erosions should be treatment with dilute bleach soaks in order to prevent secondary infection [137], perhaps decreasing incidence of scarring alopecia after healing. Cleft lip and palate can be corrected by surgery, and ankyloblepharon typically resolves on its own but may be corrected by an ophthalmologist if necessary [137].

Management of hair symptoms is discussed below.

Managing Hair Symptoms of Ectodermal Dysplasias

The use of topical minoxidil has been proposed and its effectiveness in certain types of epidermal dysplasia is supported by isolated case reports, used either on its own [139] or in combination with topical tretinoin [140]. Using only topical minoxidil is probably the safer option due to possibility of side effects when used in combination with tretinoin, such as eruptive pyogenic granuloma [141]. The cases supporting the effectiveness of minoxidil involved HED and Clouston syndrome [142]; it is unknown whether minoxidil’s effectiveness is generalizable to other forms of ectodermal dysplasia.

Some surgical techniques have been used with success. Patients are generally poor candidates for hair transplant because of lack of sufficient donor sites [143]. However, autologous hair transplantation has been used to replace eyebrows in a patient with ectodermal dysplasia [144]. Tissue expansion surgery has been successfully used to correct areas of alopecia in a patient with hypohidrotic ectodermal dysplasia [145].

Patients may opt for use of a wig. A great resource for education and support meant for patients with ectodermal dysplasia is The National Foundation for Ectodermal Dysplasias (http://www.NFED.org).