Monilethrix

Monilethrix is a condition that produces a beaded appearance of the hair and the term comes from the Latin word for necklace (monile) and the Greek for hair (thrix).^10–12 Most families with monilethrix show an autosomal dominant inheritance pattern, but autosomal recessive forms also exist. The hair is usually normal at birth but is replaced within weeks by affected hairs that are dry, dull, and brittle, breaking spontaneously and leaving a stubble-like appearance (Fig. 31.1). The hairs may break almost flush with the scalp or may attain lengths of 0.5–2.5 cm, or occasionally longer. There may be spontaneous improvement with time, especially during puberty and pregnancy, but the condition never resolves completely. Follicular keratosis is commonly associated and may involve the scalp, face, and limbs. On microscopy, spindle-shaped ‘nodes’ separated by constricted internodes are seen (Fig. 31.2). The nodes have the diameter of normal hair and may be medullated, whereas the internodes are narrower and usually nonmedullated, and are the sites of fracture. In monilethrix the hair shaft fragility is due to structural weakness of the hair fiber that is caused by a genetic defect in keratin intermediate filament protein. Mutations in the hair cortex keratin genes KRT81 (hHB1), KRT83 (hHB3), and KRT86 (hHB6) have been identified in autosomal dominant monilethrix.¹⁵ An autosomal recessive form of monilethrix is caused by mutation in the DSG4 gene and presents with more extensive alopecia of the scalp, body, and limbs, and a papular rash involving the extremities and periumbilical region.¹⁶

This is characterized by groups of three or four regularly spaced twists of the hair shaft on its own axis (Fig. 31.3).^9,10 Microscopically, twists are seen, each 0.4–0.9 mm in width, occurring usually in groups of three or more at irregular intervals. Twists are almost always 180°, although some are 90° or 360°. The hair shaft is somewhat flattened. Pili torti may occur as an isolated phenomenon, with onset at birth or in the early months of life. The hair is usually fairer than expected and is spangled, dry, and brittle, breaking at different lengths (Fig. 31.4). It may stand out from the scalp and tends to be short, especially in areas subject to trauma.

Pili torti can occur alone or as a manifestation of defined syndromes, some of which are identifiable in the neonatal period. Menkes syndrome is an X-linked recessive condition caused by mutations in a gene encoding for a protein believed to be a copper-transporting P-type ATP-ase,¹⁷ and the multiple abnormalities are due to decreased bioavailability of copper, with resultant functional deficiencies of copper-dependent enzymes. In the early months of life, scalp and eyebrow hair becomes kinky, coarse, and sparse. Lax, pale skin, hypotonia, and early neurodegenerative changes may already be seen in the neonatal period. In Bazex syndrome, inherited as an X-linked dominant trait,¹⁸ congenital hypotrichosis with pili torti is associated with follicular atrophoderma and multiple facial milia, both of which may also be present from birth. These patients have an increased susceptibility to the development of basal cell carcinomas. In Björnstad syndrome, pili torti is associated with sensorineural deafness and occasionally mental retardation.¹⁹ In later childhood, normal hair may replace the affected hairs, with a considerable improvement in appearance. Both autosomal dominant and recessive inheritance patterns have been reported. Recently the gene for Björnstad syndrome has been mapped to chromosome 2 in a family with an autosomal recessive mode of inheritance (Fig. 31.5).¹⁹ Pili torti may occur also in Rapp–Hodgkin syndrome, although pili canaliculi is the more characteristic finding.

The term trichorrhexis nodosa (TN) refers to the light microscopic appearance of a fracture with splaying out and release of individual cortical cells from the main body of the hair shaft, producing an appearance suggestive of the ends of two brushes pushed together (Fig. 31.6).^10–12 When the break occurs, the brush-like end is clearly seen. Electron microscopy shows the disrupted cuticle and splaying of cortical cells. The defect renders the hair very fragile, and it breaks readily with trauma – or sometimes probably spontaneously. In congenital autosomal dominant TN, the hair is usually normal at birth but is replaced within a few months with abnormal, fragile hair. Trichorrhexis nodosa was found in eight of 25 children with mitochondrial disorders in the absence of skin manifestations, suggesting that hair examination may be a useful diagnostic tool when these disorders are suspected.²⁰ Trichorrhexis nodosa is also seen in trichohepatoenteric syndrome, a condition that includes intractable diarrhea of infancy, facial dysmorphism, developmental delay, and immunodepression.²¹

There is a growing list of conditions associated with trichorrhexis nodosa (Box 31.2).

The term ‘trichothiodystrophy’ refers to the sulfur-deficient brittle hair that is a marker for a neuroectodermal symptom complex occurring in a group of autosomal recessive genetic disorders.²² There is considerable genetic heterogeneity in trichothiodystrophy.²³ Named syndromes that fit into this spectrum include: Tay, Pollitt, Sabinas brittle hair, and Marinesco–Sjögren syndromes. The major clinical features seen in this group of conditions are photosensitivity with a DNA repair defect (due to mutations in the XPD ECCR2 DNA repair/transcription gene), ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature,^24–26 and osteosclerosis. Some authors use mnemonic acronyms including PIBIDS, IBIDS, and BIDS to identify patients by these key clinical characteristics (see also Chapter 19).²³ Features that may be evident in the neonatal period are intrauterine growth retardation, severe infections, congenital cataracts, nail dystrophy, facial dysmorphism, a collodion baby phenotype, and the characteristic fragile, dull, short, disordered hair involving the scalp hair, eyebrows, and eyelashes (Fig. 31.7).^27,28 On light microscopy the hair has a wavy, irregular outline and a flattened shaft, in which twists like a folded ribbon occur. Two types of fracture are seen: an atypical trichorrhexis nodosa and trichoschisis, a clean, transverse fracture (Fig. 31.8A). Using crossed polarizers, light and dark bands are seen when the hair is aligned in one of the polarizer directions – the so-called tiger-tail appearance (Fig. 31.8B). This may be absent at birth and is not fully developed until 3 months of age.²⁹ Scanning electron microscopy shows irregular ridging and fluting and a disordered, reduced, or absent cuticle scale pattern.

Several families have been reported in which some affected individuals exhibit features of hypotrichosis while others have woolly scalp hair.³⁰

Clinically, WH can be divided into syndromic and non-syndromic forms. The syndromic form includes Naxos disease, cardiofaciocutaneous syndrome and Carvajal syndrome.

Naxos disease is an autosomal recessive disorder that combines palmoplantar keratoderma and other ectodermal features with arrhythmogenic right ventricular dysplasia/cardiomyopathy. It was first reported in families on the Greek island of Naxos and is associated with a deletion in the plakoglobin gene. Cardiofaciocutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects, and mental retardation and is caused by heterozygous gain-of-function mutations in one of four different genes: KRAS, BRAF, MEK1, or MEK2. Some patients have associated woolly hair. In Carvajal syndrome, patients present with epidermolytic palmoplantar keratoderma, woolly hair, and dilated cardiomyopathy. Carvajal syndrome can be caused by mutations in the gene encoding desmoplakin.^31–36

Non-syndromic forms of hereditary woolly hair present as autosomal dominant (ADWH) or autosomal recessive (ARWH). Dominant forms of WH have been linked to mutations in the helix initiation motif of KRT74. Recessive forms of WH have been linked to mutations in the LIPH and the LPAR6/P2RY5 genes, both expressed in the inner root sheath of the hair follicle.

Localized and sporadic woolly hair (the woolly hair nevus) (Fig. 31.9) can also occur.

Uncombable hair is a relatively rare anomaly of the hair shaft that results in a disorganized, unruly hair pattern that is impossible to comb flat.^11,13,37 Synonyms are spun-glass hair, pili canaliculi, and pili trianguli et canaliculi. In the classic clinical form, the hair is a light silvery-blond, paler than expected. It is frizzy, stands away from the scalp, and cannot be combed flat. It is often ‘spangled’ or glistening (Fig. 31.10). It is usually normal in length, quantity, and tensile strength. The onset may be with the first terminal growth or later. Eyebrows, lashes, and body hair are normal. Most cases improve with the onset of puberty. There are reports suggesting both dominant and recessive inheritance patterns. Scanning electron microscopy best demonstrates the characteristic shallow grooving or flattening of the surface.³⁷ These areas are often discontinuous and change orientation many times along the length of the hair, occurring on different planes of the hair at different points. Cross-sectional microscopy shows triangular, reniform, and other unusual shapes. Most children with uncombable hair are otherwise normal; the findings have been demonstrated in a variety of other syndromes with congenital onset, including progeria, Marie Unna hypotrichosis,³⁸ Rapp–Hodgkin syndrome,³⁹ orofacial digital syndrome type I,⁴⁰ ectrodactyly ectodermal dysplasia and clefting syndrome,⁴⁰ and hypohidrotic ectodermal dysplasia.³⁹ The classic clinical appearance of spun-glass or uncombable hair would seem to depend on the proportion of abnormal hairs.

This hair shaft abnormality, which may be present at birth, does not result in significant hair fragility. The hair looks pleasantly shiny, and on close observation alternating bright and dark bands are seen.⁴¹ There are usually no associated abnormalities. The condition may be sporadic or inherited, usually as a dominant characteristic. The bright areas are due to light scattered from clusters of air-filled cavities within the cortex, and in a hair mount, viewed with transmitted light, the light areas appear as dark patches. Scanning electron microscopy shows longitudinal wrinkling and folding in bands corresponding to the abnormal areas, possibly due to the evaporation of air in the spaces when the hair is coated in the vacuum. Transmission electron microscopy demonstrates multiple holes within the cortex. Recently, a locus for pili annulati was mapped to Ch12q24.32–24.33.⁴²

Trichorrhexis invaginata

This is the characteristic hair shaft abnormality of Netherton syndrome, an autosomal recessive condition due to mutations in the SPINK5 gene, which encodes for the serine protease inhibitor LEKTI (see also Chapter 19).⁴³ Although the severity varies considerably, the clinical and microscopic findings are present from birth. In the severely affected neonate, the hair may be extremely sparse or even absent altogether (Fig. 31.11). What hair is present is short and dull and breaks easily. The changes may affect eyebrows, eyelashes, and general body hair.¹³

Hair mount demonstrates a ball-and-socket configuration with various patterns seen (Fig. 31.12). The classic ‘bamboo hair’ occurs when the soft abnormal hair shaft wraps around a firmer distal shaft, producing the appearance of a shallow invagination of the distal into the proximal shaft. There is a tulip-like form with a deeper invagination and longer sides of the ‘cup.’¹¹ Circumferential strictures may be found, representing the earliest stage of the invagination. The term ‘golf-tee hair’ has been given to the expanded proximal end of an invaginate node after a break has occurred. Thin vellus hairs may show multiple invaginations, the so-called ‘canestick hairs.’⁴⁴ A helical pattern of twisting with obliquely running parallel invaginations has recently been described.⁴⁵

There appear to be several distinct genotypes within this group, with recessive, dominant, and X-linked inheritance patterns being represented.^46,47

Those with recessive inheritance are in general the most severe and congenital in onset. In some pedigrees, there is a total absence of hair (congenital atrichia, atrichia congenita, alopecia universalis congenita) and on biopsy no hair follicles are found. Mutations in the hairless gene on chromosome 8 have been demonstrated in some families.⁴⁶

In some dominant pedigrees, the hair is present but extremely sparse (congenital hypotrichosis, hypotrichosis simplex), with biopsy demonstrating a few scattered, miniaturized follicles occurring in decreased numbers; only the scalp is involved, the hair elsewhere being normal. In some of these pedigrees mutations have been found in corneodesmosin, a keratinocyte adhesion molecule.⁴⁸

Marie-unna hypotrichosis

The hair in this autosomal dominant condition is usually sparse or absent at birth, but it is not until early childhood that the characteristic coarse, wiry hair appears, showing flattening and irregularly distributed twisting on microscopy.^49,50 The condition has been mapped to a mutation in the inhibitory upstream open reading frame of the hairless gene on chromosome 8p21.^51,52

Atrichia with papular lesions

This is a distinctive association of congenital atrichia and tiny, white papules.⁵³ Atrichia of the scalp may be present from birth or appear in early childhood. In most cases, fetal hair is shed in the first 3 months of life and never replaced; eyebrows and eyelashes may or may not be involved (Fig. 31.13). The papular lesions, which occur diffusely but predominate on the face and scalp, are not present in the neonatal period. Histopathology shows the papules to represent keratin-filled follicular cysts in contact with the overlying epidermis. Recent work has demonstrated mutations in the hairless gene on chromosome 8, as seen also in alopecia universalis congenita.⁴⁷

Vitamin D-dependent rickets type 2A (VDDR2A) can present with alopecia that is clinically and pathologically indistinguishable from that seen in atrichia with papular lesions.⁵⁴

Congenital hypotrichosis and milia

In this condition, which bears some clinical similarity to atrichia with papular lesions, there is hypotrichosis with sparse, coarse hair, and multiple milia are present at birth on the face and sometimes also the limbs and trunk. Study of a large pedigree suggests X-linked dominant inheritance.⁵⁵

Hypotrichosis with juvenile macular dystrophy

Hair that is short and sparse from birth is a feature of this rare autosomal recessive disorder in which progressive macular degeneration can lead to blindness during the first to fourth decades. The hair may be morphologically normal or show a variety of nonspecific shaft abnormalities. The disease results from mutations in CDH3 encoding P-cadherin.⁵⁶

Hypotrichosis–lymphedema–telangiectasia syndrome

Congenital hypotrichosis is a feature of this condition, accompanied later in life by lymphedema and telangiectasia. Mutations have been found in the transcription factor gene SOX18.⁵⁷

Hypotrichosis associated with ectodermal dysplasias

Hypotrichosis (see also Chapter 29) is an important feature in many ectodermal dysplasias,⁵⁸ but often becomes obvious only after the neonatal period. A selection of conditions in which there may be congenital or early-onset severe hypotrichosis or atrichia will be considered here.

Ankyloblepharon, ectodermal dysplasia and clefting syndrome, and Rapp–Hodgkin syndrome

At birth in the ankyloblepharon, ectodermal dysplasia and clefting syndrome (AEC, Hay–Wells), the scalp is usually red and scaly with extensive erosions and crusts, and there is a severe hypotrichosis (Fig. 31.14).⁶⁴ Other neonatal features include a generalized erythroderma with or without erosive lesions, ankyloblepharon filiforme, lacrimal duct atresia, cleft palate and lip, and hypoplastic nails. Both Rapp–Hodgkin and AEC syndromes have mutations in 3q27 which encodes the p63 gene. As such, they are currently viewed as related disorders, with reported cases of Rapp–Hodgkin syndrome sharing all the features of AEC apart from the ankyloblepharon.^58,65

In this group of conditions (see also Chapter 19), which includes autosomal recessive and autosomal dominant forms of lamellar ichthyosis, congenital ichthyosiform erythroderma, and lamellar ichthyosis of the newborn (self-healing collodion baby), the hair is often either absent or shed in the early weeks of life with the collodion scale (Fig. 31.15).

Keratitis, ichthyosis, and deafness (KID) syndrome

Severe hypotrichosis of scalp, eyebrows, and eyelashes may be evident at birth (Fig. 31.16). Other congenital features include spiny follicular plugs, perioral furrowing, reticulate hyperkeratosis of the palms and soles, widespread thickened erythematous plaques, and hearing loss. The condition is usually caused by mutations in GJB2, encoding connexin 26.^48,59

Hypotrichosis with hereditary mucoepithelial dysplasia

Hereditary mucoepithelial dysplasia is a dominantly inherited disease characterized by congenital nonscarring hypotrichosis with coarse abnormal hair, gingival erythema, severe keratitis, follicular keratotic papules, and periorificial psoriasiform plaques.⁷¹ It has been suggested that this and IFAP may be the same condition, but there are sufficiently different features to make it likely they are separate entities. Searches for abnormal expression of gap junction and desmosomal proteins have so far been unrewarding.⁷¹

Hypotrichosis with premature aging syndromes

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