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Morphological Approach to Hair Disorders

2003; Elsevier BV; Volume: 8; Issue: 1 Linguagem: Inglês

10.1046/j.1523-1747.2003.12172.x

1529-1774

Rodney Sinclair, D Jolley, Rica Mallari, Jill Magee, Antonellá Tosti, Bianca Maria Piracinni, Colombina Vincenzi, Rudolf Happle, Juan Ferrando, Ramón Grimalt, Leroy Thérèse, D. Van Neste, Abraham Zlotogorski, Angela M. Christiano, David Whiting,

Genetic and rare skin diseases.

The Workshop on the morphological approach to hair disorders brought together a group of clinicians involved in hair biology research. Six speakers spoke on a range of topics that can be grouped broadly into a central theme. It summarizes the evolution of medical research. The section by Tosti and coworkers describes a patient with a new unique syndrome. The section by Ferrando and colleagues provides a framework in which patients with rare hair disorders can be classified. The section by Whiting tries to define the normal anatomy of the hair follicle and both horizontal and vertical sections. It is only when normal anatomy has been absolutely defined that pathological deviations can be recognized. The section by Sinclair and coworkers attempts to estimate the reliability of histological diagnosis so that its true value of pathology can be recognized. The section by Zlotogorski and coworkers shows how accurate clinical and histological definition of disease acts as the cornerstone for gene discovery techniques. Once a causative mutation is found and a gene product identified, then the biological consequences of the altered protein product can be studied and the impact of the abnormal molecular function on hair biology can be understood. It is hoped that improved understanding of hair disease will then lead to useful therapeutic interventions. The final section by Leroy and Van Neste highlights the difficulties of evaluating therapeutic interventions in hair loss disease and proposes a new technique. The Workshop on the morphological approach to hair disorders brought together a group of clinicians involved in hair biology research. Six speakers spoke on a range of topics that can be grouped broadly into a central theme. It summarizes the evolution of medical research. The section by Tosti and coworkers describes a patient with a new unique syndrome. The section by Ferrando and colleagues provides a framework in which patients with rare hair disorders can be classified. The section by Whiting tries to define the normal anatomy of the hair follicle and both horizontal and vertical sections. It is only when normal anatomy has been absolutely defined that pathological deviations can be recognized. The section by Sinclair and coworkers attempts to estimate the reliability of histological diagnosis so that its true value of pathology can be recognized. The section by Zlotogorski and coworkers shows how accurate clinical and histological definition of disease acts as the cornerstone for gene discovery techniques. Once a causative mutation is found and a gene product identified, then the biological consequences of the altered protein product can be studied and the impact of the abnormal molecular function on hair biology can be understood. It is hoped that improved understanding of hair disease will then lead to useful therapeutic interventions. The final section by Leroy and Van Neste highlights the difficulties of evaluating therapeutic interventions in hair loss disease and proposes a new technique. androgenetic alopecia Atrichia with papular lesions contrast enhanced phototrichogram technique This sequence of papers tells a story. It is that medical research begins and ends with the patient. In all disciplines of medicine patients present to doctors who by careful observation of the signs and symptoms of their complaint establish a diagnosis. The needs of our patients motivates us to go into the laboratory and research their disease and find useful therapeutic interventions that we can then take back to the patient to alleviate morbidity. In our discipline, interaction between clinicians who are morphologists and diagnosticians and scientific researchers is pivotal in workshops such as this one help to increase the understanding between these two groups and foster closer collaboration. Tosti et al presented the case of a woman with a unique hair loss disorder. She presented with two areas of hypotrichosis on the scalp which had been present since childhood and were fixed. At the age of 1 the child had been noted to gradually develop linear hyperpigmentation on the head, neck, trunk and limbs. The hair on the left parietal region and on the occipital area stopped growing at this stage and remained short in contrast to the adjacent scalp hair. These patches had hair 3–5 cm in length that was pigmented and had a lanugo like texture (Figure 1). Scalp and skin biopsies were performed. The skin biopsy showed mild epidermal acanthosis with follicular plugging (Figure 2). Scalp biopsies were sectioned longitudinally and horizontally. Longitudinal sections showed the presence of terminal follicles. Sebaceous glands were hyperplastic. Transverse sections showed a decreased follicular density with numerous vellus and intermediate follicles. A diagnosis of scalp mosaicism associated with widespread cutaneous mosaicism due to systematized sebaceous nevus was made. Treatment with 2% topical minoxidil twice a day produced gradual elongation and thickening of the affected hairs with considerable cosmetic improvement according to the patient. Alopecia due to scalp mosaicism is a feature of incontinentia pigmenti, where the areas of alopecia follow Blaschko's lines. Unlike this case, the involved areas are completely bald. In this case the scalp mosaicism produced a population of hair that differed from surrounding scalp because of the length and texture. The alopecic areas in fact represented short lanugo-like pigmented hair. The pathology confirmed the presence of terminal and intermediate follicles with mild reduction in hair density. The histological findings were consistent with a diagnosis of nevus sebaceous because of the hyperplasia of the epidermis, the increased number of large and piriform sebaceous glands and the presence of ectopic apocrine glands in the mid dermis. The authors were unable to find any comparable cases in the literature. This case points out that the presence of bands or patches of scalp hair of a different texture and length with respect to the surrounding scalp may indicate scalp mosaicism. Hair diseases represent a significant portion of cases seen by paediatric dermatologists. Many disorders of the hair can be studied with simple diagnostic techniques, as the hair is easily accessible to examination. While numerous techniques for examination of the hair are now available and include scanning electron microscopy, X-ray microanalysis of genetic hair disorders, in general, clinical observation and a microscopic examination of the hair shaft provide the greatest clues. Whilst X-ray microanalysis and chromatography of hair amino acids are useful in the diagnosis of trichothiodystrophy, this diagnosis can often also be made by polarized light microscopy. With light microscopy specific abnormalities are easily detected with careful observation. The range of abnormalities seen include periodic narrowing of hair (monilethrix), ringed hair (pili annulati), trichoschisis and “tiger tail” hair (trichothiodystrophy), pili torti, trichorrhexis invaginata (Netherton syndrome), bubble hair and “ruffling” (loose anagen hair). Whilst uncombable hair syndrome may be most easily diagnosed with scanning electron microscopy, clues are also obtained with light microscopic examination of hair shafts, in particular when they are examined in cross-section. Hair dysplasias in children can be oriented by clinical observation and microscopic examination of hair shafts. Numerous atlases are available to facilitate this diagnosis. (Ferrando and Grimalt, 2000Ferrando J. Grimalt R. Atlas of diagnosis in paediatric trichology.Madrid: MI&C. 2000Google Scholar). Established human scalp hair follicles cycle independently and continuously during their lifespan through stages of growth, rest and shedding (Montagna and Parakkal, 1974Montagna W. Parakkal P.F. The stucture and function of the skin,.3rd edn. New York, Academic Press1974: 172-258Google Scholar;Abell, 1994Abell E. Embryology and anatomy of the hair follicle.in: Olsen E.A. Disorders of Hair Growth, Diagnosis and Treatment. New York, McGraw-Hill1994: 1-19Google Scholar;Stenn et al., 1999Stenn K.S. Nixon A.J. Jahoda C.A.B. McKay I.A. Paus R. Controversies in experimental dermatology. What controls hair cycling?.Exp Dermatol. 1999; 8: 229-236Crossref PubMed Scopus (46) Google Scholar;Stenn and Paus, 2001Stenn K.S. Paus R. Controls of ahir follicle cycling.Physiol Rev. 2001; 81: 449-494Crossref PubMed Scopus (1119) Google Scholar). Scalp hairs comprise large terminal hairs and small vellus hairs. Terminal hairs are conspicuous and exceed 0.03 mm in diameter and 1 cm in length, and may be pigmented and medullated. The hair fiber diameter remains uniform during a single growth phase under normal conditions. Terminal hairs grow to a specific length, which varies with the individual. Hair length is determined by the rate and duration of the growth phase (Whiting, 2001Whiting D.A. Possible mechanisms of miniaturisation during androgenetic alopecia or pattern hair loss.J Am Acad Dermatol. 2001; 45: S87-S94Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Vellus hairs are inconspicuous and are 0.03 mm or less in diameter and less than 1 cm in length and lack melanin and medulla. Terminal hairs miniaturized to vellus hair proportions are termed vellus-like hairs. Terminal hairs are rooted in subcutaneous tissue or deep dermis. Vellus hairs are rooted in upper dermis. Termination of the growing or anagen phase is marked by the intermediate or catagen phase which lasts approximately 2 weeks. In catagen, the hair shaft retreats upward, and the outer root sheath shrinks. In catagen, the lower follicle disappears leaving an angiofibrotic strand or streamer (stela) indicating the former position of the anagen root. The ensuing telogen phase lasts an average of 3 months before a new anagen hair develops. In telogen, the resting club-shaped, depigmented root is situated at the bulge level where the arrector pili muscle inserts into the hair follicle. The telogen hair is shed during the exogen phase, which may not coincide with the new anagen phase. Assuming 100,000 scalp hairs with 10% in telogen, the average hair loss equals 100 per day. The next anagen cycle begins with enlargement of the dermal papilla at bulge level and formation of a new anagen bulb. The terminal anagen hair extends from its bulb in the subcutaneous tissue to its point of emergence from the epidermis through the follicular infundibulum (Montagna Solomon, 1994, andMontagna and Parakkal, 1974Montagna W. Parakkal P.F. The stucture and function of the skin,.3rd edn. New York, Academic Press1974: 172-258Google Scholar;Headington, 1984Headington J.T. Transverse microscopic anatomy of the human scalp: A basis for a morphometric approach to disorders of the hair follicle.Arch Dermatol. 1984; 120: 449-456Crossref PubMed Scopus (361) Google Scholar;Sperling, 1991Sperling L.D. Hair anatomy for the clinician.Am J Acad Dermatol. 1991; 25: 1-17Abstract Full Text PDF PubMed Scopus (116) Google Scholar;Abell, 1994Abell E. Embryology and anatomy of the hair follicle.in: Olsen E.A. Disorders of Hair Growth, Diagnosis and Treatment. New York, McGraw-Hill1994: 1-19Google Scholar;Soloman, 1994;Whiting, 2000Whiting D.A. Histology of Normal Hair.in: Hordinsky M. Sawaya M. Scher R. Atlas of Hair and Nails. Philadelphia, PA, Churchill Livingstone2000: 9-23Google Scholar). The root consists of the hair bulb, which surrounds the dermal papilla containing connective tissue cells and blood vessels (Figure 3). The papilla is surrounded by undifferentiated, actively dividing hair matrix cells. Melanocytes are usually present at the apex of the dermal papilla. Hair matrix cells in this vicinity give rise to hair medullary cells. Hair matrix cells around this central area produce elongated cortical cells which stream upward to form the developing hair shaft. Higher up in the keratogenous zone, these cells become compacted into hard keratin. The outer fringe of matrix cells forms the hair cuticle and the surrounding inner root sheath. The hair cuticle invests the hair fiber with 6–10 overlapping layers of cuticle cells. Cuticle cells keratinize and project outward and forward to interlock with the inwardly projecting cuticle cells of the inner root sheath. The inner root sheath surrounds the hair fiber and comprises 3 layers: The inner layer forms the cuticle of the inner root sheath comprising overlapping elongated cells which slant downward. The middle layer of Huxley comprises 3–4 layers of cuboidal cells. The outer layer of Henle comprises a single layer of elongated cells. The inner root sheath is surrounded by one or more layers of cells of the outer root sheath or trichilemma. The potential space between inner and outer root sheaths is named the companion layer and allows the inner root sheath to slide upward over the outer root sheath during hair growth. The outer root sheath is covered by the hyaline, or vitreous membrane, which is continuous with the epidermal basement membrane surrounding the dermal papilla. This in turn is surrounded by the connective tissue or fibrous sheath of the hair follicle that is continuous with the dermal papilla. A pad of elastic tissue, the Arao-Perkins body, may develop under the dermal papilla (Arao and Perkins, 1969Arao T. Perkins E.M. The interrelation of elastic tissue and human hair follicles.in: Montagna W. Dobson R.L. Advances in Biology of Skin, Vol. 9: Hair Growth. Oxford, Pargamon Press1969: 443Google Scholar). The central hair shaft grows upward through the lower and upper follicle. Proceeding from hair bulb up the lower follicle, the inner and outer root sheaths thicken and become well demarcated. Henle's layer keratinizes first with the appearance of trichohyaline granules near the bulb, forming a distinct pinkish keratinized band higher up from the bulb. The cuticle of the inner root sheath is the next to keratinize, synchronizing with keratinization of the cuticle of the hair shaft. Finally, trichohyaline granules appear in Huxley's layer, signaling impending keratinization. Keratinization of the inner root sheath is completed half way up the lower follicle (Figure 4). The keratinized inner root sheath occupies the upper half of the lower follicle. The lower follicle ends at the level of insertion of the arrector pili muscle, the so-called bulge area (Cotsarelis et al., 1990Cotsarelis G. Sun T. Lavker R.M. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implication for follicular stem cells, hair cycle and skin carcinogeneisis.Cell. 1990; 61: 1329-1337Abstract Full Text PDF PubMed Scopus (1898) Google Scholar). The isthmus extends upward from the bulge area to the level of entry of the sebaceous duct. The inner root sheath crumbles and disappears in the isthmus of the upper follicle (Figure 5). There it is replaced by trichilemmal keratin formed by the outer root sheath. Trichilemmal keratin lines the upper isthmus extending to the entry of the sebaceous duct at the base of the infundibulum. The infundibulum extends upward from the sebaceous duct level to surface epidermis. The infundibulum is lined by epidermis with a granular layer and basket-weave keratin which is continuous with skin surface epidermis. The hair shaft has no secure attachments to isthmus or infundibulum, which allows freedom of movement. Horizontal sections at the sebaceous duct level show up follicular units. Follicular units are hexagonal tissue packets surrounded by a loose collagen network containing several terminal and vellus follicles with sebaceous ducts and glands and arrector pili muscles. Vellus hairs are rooted in papillary or upper reticular dermis. Vellus hairs do not contain medullary cavity or melanin. Vellus hair diameter is less than the thickness of its inner root sheath. True vellus hairs have thin external root sheaths and stelae in the upper dermis. Vellus-like miniaturized hairs have thicker external root sheaths and long stelae extending into lower dermis or fat. Hairs are typically miniaturized by androgenetic alopecia or by alopecia areata. Follicular stelae, in upper dermis only, indicate vellus hairs. Follicular stelae in lower dermis indicate terminal, catagen, or telogen hairs or miniaturized, vellus-like hairs. When anagen ends, hair goes into catagen, the intermediate stage between growth and rest, for 10–14 days. As catagen begins, the hair shaft and bulb start retracting upward leaving behind an angiofibrotic streamer or stela linking the follicle to the site of the former anagen bulb. The hair shaft and inner root sheath slide upward together through outer root sheath leaving an elongated mass of trichilemmal outer root sheath below. Apoptosis or individual cell death of trichilemmal cells produces a volumetric shrinkage of the outer root sheath. Thickening and wrinkling of the surrounding hyaline layer occurs with this shrinkage of trichilemma. As the hair shaft retreats further upward, its base becomes club shaped and surrounded by a pocket of trichilemmal keratin. The vestigial bulb and dermal papilla trail beneath, linked to the follicular stela. As the telogen hair develops, it retracts to the level of the bulge at the insertion of the arrector pili muscle (Figure 6). Here a telogen germinal unit is formed below the telogen club. The telogen germinal unit consists of trichilemma that is somewhat convoluted and surrounded by palisading basaloid cells. The telogen germinal unit has a characteristic appearance and shows no obvious apoptosis. A central mass of trichilemmal keratin, star-shaped in horizontal section, surrounded by trichilemma and fibrous sheath, is present between the hair shaft and telogen germinal unit. Discrimination between terminal anagen, catagen, and telogen hairs is only possible when the lower follicle is examined below the bulge level for the presence of inner root sheath, apoptosis, or trichilemmal club, respectively. In the upper follicle only a keratinized hair shaft can be seen with no internal root sheath, so discrimination between anagen, catagen, or telogen hairs is not possible at this level. After 2–4 months of telogen, a new anagen hair bud develops beneath the telogen germinal units and grows down the existing follicular tract or stela to form an anagen hair. Subsequent hair cycling will continue throughout life for as long as that hair follicle is viable. Accurate counts of hair follicles are often useful in diagnosing different causes of hair loss (Whiting, 1998Whiting D.A. Scalp biopsy as a diagnostic and prognostic tool in androgenetic alopecia.Dermatol Ther. 1998; 8: 24-33Google Scholar). Detailed follicular data can be derived from examination of horizontal sections of scalp biopsies. All terminal and vellus hairs, follicular streamers (stelae), and follicular units should be counted. Anagen, catagen, and telogen terminal hairs can be distinguished. 4 mm punch biopsies, from the mid-scalp of normal controls, have shown a mean follicular count of 40 hairs comprising 35 terminal hairs and 5 vellus hairs (Whiting, 1998Whiting D.A. Scalp biopsy as a diagnostic and prognostic tool in androgenetic alopecia.Dermatol Ther. 1998; 8: 24-33Google Scholar); the terminal hairs comprised 93.5% anagen and 6.5% telogen hairs; the average follicular density was approximately 3 follicles/mm2. Visualizing the human hair follicle at different levels and in different points of the hair cycle should allow easy correlation between vertical and horizontal sections. Working knowledge of the normal three-dimensional appearance of the human hair follicle should assist in recognizing the various abnormalities that can occur in clinical or experimental situations.