Trichorrhexis nodosa (TN) is an inherited or acquired fragile hair shaft disorder characterized by hair breakage that occurs as a result of damage to hair cuticles.¹ The disease can have a more proximal or distal distribution along the hair shaft. There is a wide age range at presentation. Acquired TN is common in patients of African descent (proximal type) and Caucasian and Asian descent (distal type).

Acquired TN can be the result of physical trauma including excessive brushing, heat, pulling, or twisting.² It can also be the result of chemical trauma including permanent straightening or waving. Inherited TN can be caused by arginosuccinic aciduria, a rare metabolic disorder of the urea cycle causing hyperammonemia.³ If undiagnosed in infancy, neonates can present with failure to feed leading to lethargy and coma in some instances. Congenital TN can also be an incidental finding in patients with other hair shaft disorders including pili torti, monilethrix, and trichothiodystrophy.

TN may present with small, white, or gray flecks on the hair shafts. Hair damage is usually noticed as a change in the quality of the hair or as “dry ends” or “flyaway hair” and may have a “shaggy” or “skimpy” appearance (Figure 14-1).

Hair breakage can result in focal or diffuse alopecia depending on the extent of scalp involvement. A tug test, in which a swatch of hair is held in one hand and the proximal end of the hair is tugged with the other hand, will lead to fragments of shortened hairs that are easily broken off.

Each node is formed by cortical fiber separation and fraying of the hair shaft in a manner analogous to the bristles of two paint brushes being pushed together (Figure 14-2).

Monilethrix is a hair shaft disorder characterized by brittle, beaded hairs that emanate from keratotic, follicular papules.⁴ The condition usually manifests in the neonatal period or early childhood. In rare instances, babies are born
bald with beaded hairs appearing later in life. The course can be seasonal and is variable with some affected patients improving in adulthood, whereas in others it can worsen.

Monilethrix is usually inherited in an autosomal dominant fashion with high penetrance and variable expressivity. In the autosomal dominant variant, mutations in 3 type II basic hair keratin genes, hHb1, hHb3, and hHb6 (chromosome 12q13) have been described, with the latter being the most commonly altered.⁵,⁶,⁷,⁸,⁹ An autosomal recessive variant has been reported and is caused by a mutation in desmoglein 4.¹⁰,¹¹ Desmoglein 4 is a transmembrane cell adhesion molecule expressed in the hair cortex and upper cuticle, which is also associated with localized autosomal recessive hypotrichosis.⁸

Hair shafts rarely grow more than 2 to 3 cm. The hairs break easily, resulting in severe alopecia (Figure 14-3). In severe variants, the affected hair can involve the entire scalp, secondary sexual hair, eyebrows, and eyelashes.¹² Neonates who develop monilethrix initially present with normal lanugo hair and later have characteristic findings when they grow terminal hair. Follicular hyperkeratosis may also be found on the body. Other features may include koilonychia, mental retardation (rare), syndactyly, cataracts, as well as tooth and other nail abnormalities.¹³

Hair shafts show regularly spaced, elliptical nodes that are roughly 0.7 to 1.1 mm apart. The nodes are of normal caliber and have a typical air-filled medulla, whereas the areas of constriction show an absence of medulla (Figure 14-4).

Trichorrhexis invaginata is a rare congenital hair shaft abnormality characterized by short, brittle hairs that manifests in patients with Netherton syndrome (NS). NS, and thus trichorrhexis invaginata, affects children. Progressive alopecia and atopic eczema are present at a young age.

NS is an autosomal recessive disorder caused by mutations in the SPINK5 gene, which encodes the serine protease inhibitor LEKTI.¹⁴,¹⁵ LEKTI is necessary for proper skin barrier function and desquamation.¹⁶ Although its function in the follicle is not well characterized, LEKTI appears to be highly expressed in sites of keratinization such as the inner root sheath and upper infundibulum.¹⁷

NS is characterized by the triad of trichorrhexis invaginata, ichthyosis linearis circumflexa, and atopic diathesis.¹⁸ Patients are born with congenital ichthyosiform erythroderma,¹⁹ neonatal dehydration, failure to thrive, and recurrent infections.²⁰ Ichthyosis linearis circumflexa consists of migratory polycyclic erythematous patches with surrounding serpiginous double-edged scale.²¹ An atopic diathesis may include eczema-like eruptions, atopic dermatitis, asthma, pruritus, allergic rhinitis, angioedema, urticaria, elevated serum IgE, and/or hypereosinophilia.²⁰ The hair findings in NS, including TN, are not present in every hair. Multiple hairs should be tested, and the most high-yield location to pluck and examine is reported to be the lateral eyebrows.²²

In trichorrhexis invaginata, nodes appear at irregular intervals and are composed of a distal portion of the hair shaft that has sunken into the proximal portion creating a “ball-and-socket” appearance²² (Figure 14-5). Nascent nodes form under torsion, and the distal aspect of the hair shaft undergoes intussusception into the proximal aspect.²³

Pili torti is a hair shaft defect characterized by short, brittle, and spangled hairs and is associated with various syndromes, including Menkes disease, Björnstad syndrome, and p63 mutation-associated ectodermal dysplasia syndromes (referred to in the literature by multiple monikers such as ectrodactyly, ectodermal dysplasia, and cleft lip;
Rapp-Hodgkin syndrome; and ankyloblepharon ectodermal dysplasia cleft lip/palate syndrome/Hay Wells Syndrome). Pili torti usually presents in early childhood, but can sometimes occur at birth or arise after puberty.

The twisted appearance may be caused by mitochondrial dysfunction and the buildup of reactive oxygen species particularly in the inner root sheath.²⁴ Menkes disease is caused by a mutation in the X-linked ATP7A gene, which encodes a copper-transporting ATPase.²⁵,²⁶,²⁷,²⁸,²⁹,³⁰ Defects in this protein may account for hair twisting by defective incorporation of copper into keratin disulfide bonds and/or by the aforementioned mitochondrial dysfunction mechanism. Mutations in the BCS1L gene underlie the phenotype of Björnstad syndrome.²⁴,³¹ Hay-Wells and/Rapp Hodgkins syndromes are caused by mutations in the TP63 gene, which is expressed by many ectodermally derived structures such as the hair follicle.³²

Variable hair fragility manifests as patchy alopecia, with coarse stubble predominantly seen in the temporal and/or occipital areas presumably due to friction, with areas of hairs of up to 5 cm of length (Figure 14-6). The hairs of the eyelashes and eyebrows can also be involved. In addition to pili torti, patients with Menkes disease have severe developmental and neurologic impairment, connectivetissue abnormalities, and tortuous blood vessels.²⁵ After lanugo hair is shed, infants develop stubbly, sparse, hypopigmented hair that has been described as “steel wool” in appearance and texture because it is difficult to comb and fractures with friction.³³ In Björnstad syndrome, pili torti and bilateral sensorineural loss usually manifest before the age of two.³⁴ The degree of hair shaft fragility correlates to the severity of hearing loss.³⁴ TP63 gene mutation-related
ectodermal dysplasias have variable expressivity, but features can include irregular strands of tissue connecting the upper and lower eyelids, termed ankyloblepharon filiforme adnatum, hypohidrosis, erythroderma, palmoplantar keratoderma, and cleft lip, cleft palate, or both. There is often also a severe and recalcitrant scalp dermatitis in these patients.³⁵

Affected hairs are flattened and twisted on the horizontal axis typically by 180β turns. Usually runs of 3 to 10 twists are present at irregular intervals along the hair shaft (Figure 14-7).

Pili bifurcati is a rare hair shaft disorder characterized by thin, short fragile hairs eventuating in diffuse alopecia. Pili bifurcati affects patients in childhood.

The underlying pathogenic defect is unknown.

Pili bifurcati usually manifests in children with short fragile hair on the scalp, which can lead to diffuse alopecia.³⁶ Other sites include the eyelashes and eyebrows.³⁷

The affected hairs show bifurcated hair shafts. On scanning electron microscopy, a single hair shaft splits into two smaller shafts, which then fuse downstream to again form a single hair shaft.³⁸ The two bifurcated hair shafts are completely covered by their own cuticles.

Trichothiodystrophy is a hair shaft abnormality characterized by brittle hairs and is associated with neuroectodermal disorders. Trichothiodystrophy presents at birth.

Trichothiodystrophy is caused by mutations in xeroderma pigmentosum-B, xeroderma pigmentosum-D, and p8/TTDA helicase/ATPase subunits of the DNA repair/basal transcription factor IIH, which are three genes involved in transcription initiation and nucleotide excision repair.³⁹ The gene defects result in hair with a significant reduction in sulfur-rich cysteine matrix proteins. Alterations in these genes also give rise to xeroderma pigmentosum and Cockayne syndrome.

Depending on the specific gene mutation, patients with trichothiodystrophy can present with a complex, sometimes referred by the acronym PIBIDS: photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature, or IBIDS, when photosensitivity is not present. The hair findings include short, brittle hairs of varying length on the scalp, eyebrows, and eyelashes.³⁹,⁴⁰

Affected hairs show a clean transverse break through the hair shaft and an absence of cuticle cells at the fracture site, a defect termed trichoschisis (Figure 14-8). Hairs may be focally flattened or ribbon-like⁴¹ (Figure 14-9). When viewed under polarized light in the dark or “extinguished” position, an alternating light and dark banding pattern (tiger tail banding) can be seen⁴²,⁴³ (Figure 14-10).

Marie-Unna hereditary hypotrichosis (MUHH) is a hair shaft abnormality characterized by coarse, unruly hair, and progressive hair loss. The disorder usually presents in childhood.

A subset of patients with MUHH have mutations in the U2HR locus, an upstream regulator of the Hr gene, but the exact mechanism of the disease is not known.⁴⁴ Mutations in the epidermal growth factor receptor kinase substrate 8-like protein 3 have also been associated with MUHH.⁴⁵

MUHH can present as an isolated phenomenon or as part of an autosomal dominant inherited syndrome. Typically, patients are born with normal-appearing to slightly coarse hair, although there are cases with sparse to no hair.⁴⁶,⁴⁷ Over time, hair is progressively lost and becomes coarse and wiry. In addition to the scalp, hair can be lost from the eyebrows, eyelashes, and the body. By puberty, a nonscarring alopecia is present, with the vertex and scalp margins being the most affected sites.⁴⁸

Affected hairs are deeply pigmented, are of varying caliber, and may be twisted or bent.⁴⁹

Also called “ringed hair,” pili annulati is a rare hair shaft disorder characterized by light and dark bands within the hair shaft, leading to a “shiny,” “spangled,” or “sandy” appearance.

The disorder is present at birth or arises during infancy.

Pili annulati is inherited in an autosomal dominant fashion. The disease-causing locus has been mapped to the telomeric region on chromosome 12q.⁵⁰

The hairs in pili annulati show alternating light and dark banding along the hair shaft with a variable number of hairs affected, often imparting a shiny appearance to the hair (Figure 14-11). It can affect the entire scalp hair or be patchy and can also involve the axillae, beard, and pubic region.⁵¹,⁵² Hair growth is normal and hairs are typically pliable and strong, but there may be some degree of hair fragility. TN-like fractures may be induced in the dark bands.

The clinically apparent light bands appear as dark bands on hair mount because of the inverse effects of reflected and transmitted light (Figures 14-12 and 14-13). The bands correspond to air-filled cavities within the hair shaft that can be appreciated on electron microscopy.⁵³,⁵⁴,⁵⁵

Woolly hair is a hair shaft disorder characterized by fine, tightly wound hairs that may be associated with other disorders or syndromes. The disorder usually presents in childhood.

Mutations that underlie the autosomal recessive presentations of wooly hair affect P2RY5 gene⁵⁶,⁵⁷ and lipase H gene.⁵⁸,⁵⁹ The P2RY5 gene encodes a G protein-coupled receptor that is expressed in Henle and Huxley layers of the inner root sheath of the hair follicle. Lipase H gene mutations are also present in isolated hypotrichosis and likely plays a role in hair follicle growth⁵⁸,⁵⁹ Somatic mosaic HRAS mutations can cause the association of woolly hair and epidermal nevi.⁶⁰

Woolly hair can present in isolation on the scalp in a partial or focal manner, such as in the wooly hair nevus, or in a syndromic manner⁶¹,⁶² (Figure 14-14). Associated findings and syndromes include palmoplantar keratoderma,⁶³ keratosis pilaris atrophicans fasciei,⁶⁴ Noonan syndrome,⁶⁵ Carvajal syndrome,⁶⁶ cardiofaciocutaneous syndrome,⁶⁷ Naxos disease,⁶⁸ keratosis follicularis spinulosa decalvans,⁶⁹ and epidermal nevi.⁶⁰

Naxos disease is an autosomal recessive disorder characterized by wooly hair from birth, diffuse nonepidermolytic palmoplantar keratoderma, and arrhythmogenic right ventricular dysplasia/cardiomyopathy.⁷⁰,⁷¹ The latter tends to present in late puberty. In contrast, patients with Carvajal syndrome exhibit epidermolytic palmoplantar keratoderma in addition to wooly hair and cardiac defects.⁶⁶,⁷²

There are no specific pathologic findings on hair mount.

Acquired progressive kinking of the hair (APKH) is a rare disorder characterized by a rapid onset of curly, unruly hair. The disorder presents in children and young adults with a peak in adolescence.

The underlying pathogenic defect is unknown.

APKH presents as ill-defined patches of frizzy and kinky hairs typically on the frontal, temporal, and vertex of the scalp.⁷³,⁷⁴ Hairs can be hypopigmented, hyperpigmented, or of normal color compared with the surrounding unaffected hairs.⁷⁵

Hairs are apparently normal on light microscopy, but partial twisting along the long axis of the hair shaft and shallow canalicular grooves can be seen on scanning electron microscopy.⁷⁶,⁷⁷

Uncombable hair syndrome is a hair shaft disorder characterized by unruly hair that is difficult to style. The condition is also known as pili trianguli et canaliculi, and spun glass hair. The disorder usually manifests in childhood, but acquired cases that present later in life have been reported.

Uncombable hair syndrome is caused by mutations in peptidylarginine deiminase 3 (PADI3), transglutaminase 3 (TGM3), and trichohyalin (TCHH). PADI3 and TGM3 mediate posttranslational modification of TCHH, and all three
genes are involved in the formation of the hair shaft.⁷⁸ An autosomal recessive inheritance pattern is implicated in the majority of cases.

The hair is usually blonde to light brown with a frizzy, spangled texture, and projects outward from the scalp⁷⁹,⁸⁰ (Figure 14-15).