Are You Confident of the Diagnosis?
What you should be alert for in the history
The typical patient with loose anagen hair syndrome is a young, healthy, fair-haired girl, seen with her parents regarding the concern that her hair “does not grow long” or “rarely needs to be cut” (Figure 1). Girls with the syndrome predominate over boys (6:1 to 36:1), and patients with blond and light brown hair predominate over those with dark-colored hair. Onset is typically between 3 and 6 years. However, affected individuals span a wide range of ages, including adults.
According to Olsen and colleagues, concerns about hair in this syndrome may follow 3 patterns: hair that is thin, sparse and fine (type A presentation), hair that is unmanageable and unruly (type B presentation), or hair that is shedding (type C presentation). Type A and type B presentations are most commonly seen in children, whereas the type C presentation is most commonly seen in adults.
Additional history may reveal that the child’s hair is painlessly extracted in clumps whenever it is inadvertently pulled by other children or siblings during normal playing. Furthermore, hair may be lost in the occipital scalp from rubbing the head on the pillow at night. The hair rapidly grows back in these areas, and permanently bald areas are not seen. Parents may also report that the child’s hair is dry, dull and lustreless. A family history of loose anagen hair syndrome may be present, but this is not common.
Characteristic findings on physical examination
Patients with loose anagen hair syndrome have a spectrum of findings on physical examination. The hair density may be reduced, either diffusely or in localized areas of the scalp. Completely bald areas, however, are not a feature of this syndrome. The vertex and occipital scalp are frequent sites of hair loss. Hair in the occiput may also be noted to be rough and sticky and not lie flat. The hairs may lack shine and the distal ends may be observed to be of uneven lengths.
There is no scalp inflammation or scarring. The eyebrows, eyelashes and body hair are typically normal. There is no hair fragility or hair breakage. The teeth, nails and skin are normal.
Expected results of diagnostic studies
A pull test is an essential component of the evaluation and should be performed from several areas of the scalp. Extracted hairs are examined further with light microscopy, and if necessary, also by electron microscopy. Normally, in healthy individuals who do not have the loose anagen hair syndrome, less than 5 telogen hairs and no anagen hairs are extracted by the pull test. In patients with the syndrome, a pull test results in the extraction of 3 to 20 abnormal-appearing anagen hairs and rarely a few telogen hairs as well (Figure 2, Figure 3).
The morphology of the extracted anagen hairs is abnormal. By light microscopy, the extracted anagen hairs lack both the internal and external root sheath and show a ruffled cuticle distal to the hair bulb. The appearance of the ruffled cuticle resembles a “crumpled sock” that falls down around one’s ankles (Figure 4). The appearance of the hair shaft resembles a “golf club” because the hair bulb frequently appears at an acute angle to the hair shaft rather than at the normal angle of 180 degrees.
Electron microscopy is not required for the diagnosis of loose anagen hair syndrome but will show that a proportion of the hair shafts have an abnormal shape with grooves, ridges and twisting. This leads to irregularly shaped hairs on cross-section. Many findings are similar to the changes seen in the uncombable hair syndrome. Mirmirani, Uno and Price identified several ultrastructural changes in the inner root sheath by electron microscopy, including intercellular edema in the Huxley layer and dyskeratosis of cells in the Henle layer and cuticle.
The hair pull test in a given patient with loose anagen hair syndrome may be negative on some occasions and positive on others. Therefore, a single negative pull test does not rule out the diagnosis of loose anagen hair syndrome. Furthermore, it is now recognized that extractable (loose) anagen hairs are not a pathognomonic feature of the loose anagen hair syndrome and can be found normally. Approximately 60% of children and 2% to 14% of adults normally have one to two extractable loose anagen hairs by the pull test.
As a result, Tosti and colleagues proposed that the diagnosis of the loose anagen syndrome should include extraction of more than 10 anagen hairs on the pull test. This cut-off may be overly restrictive and certainly any number of anagen hairs greater than three is abnormal. Scalp examination of adolescents and adults with the loose anagen hair syndrome may reveal thicker and longer hair than affected children. However, the pull test continues to show extractable loose angen hairs.
In addition to the pull test, the forced pluck (trichogram) technique is sometimes performed to provide additional diagnostic information. A trichogram is obtained by forcefully extracting 50 to 100 hairs using a rubber tipped clamp, or hemostat. In the loose anagen hair syndrome, the trichogram will show at least 70% to 80% loose anagen hairs and the proportion of anagen hairs is frequently closer to 100%. Obtaining a trichogram is painful, and therefore rarely performed in children.
A biopsy is not required for the diagnosis but will show a non-inflammatory, non-scarring alopecia. Examination of histologic sections using light and electron microscopy show lack of cohesion between various layers of the hair follicle as well as within layers of the inner root sheath and outer root sheath.
A characteristic finding is the premature keratinization of the inner root sheath in the Henle and Huxley layers. This is proposed to lead to abnormal adhesion between the cuticle of the inner root sheath and the cuticle of the hair shaft and in turn formation of a cleft between the two areas. There is also cellular discohesion and cleft formation within the outer root sheath and between the outer and inner root sheath.
Loose anagen syndrome may be mistaken for alopecia areata, trichotillomania, telogen effluvium and rarely other causes such as short anagen syndrome and toxic ingestion. A carefully obtained history along with scalp dermoscopy and examination of hairs extracted from the pull test will help to distinguish these conditions.
Alopecia areata can present as diffuse hair thinning that mimics loose anagen hair syndrome or it may present as circumscribed areas of complete hair loss. The pull test in areas of active alopecia areata will show telogen hairs as well as dystrophic anagen hairs containing a root sheath. Dermoscopy may reveal exclamation mark hairs, yellow dots, black dots, and vellus hairs.
A punch biopsy of early alopecia areata may reveal peribulbar inflammation, which is not found in the non-inflammatory biopsies from patients with loose anagen hair syndrome. In addition, some forms of alopecia areata show completely hairless areas, which are not a feature of loose anagen hair syndrome.
In trichotillomania, the pull test is negative for anagen hairs and the trichogram shows inner root sheaths around extracted anagen hairs. Dermoscopic features of trichotillomania, such as fractured hairs and black dots, are not seen in loose anagen hair syndrome.
In telogen effluvium, extracted hairs from a pull test are telogen hairs, rather than dystrophic anagen hairs.
Patients with the short anagen syndrome also have difficulty growing long hair and seldom need a haircut. However, dystrophic (loose) anagen hairs are not present in the short anagen syndrome.
Toxic ingestion in children must also be considered in the differential diagnosis, especially if hair loss is accompanied by other signs or symptoms such as abdominal pain, weight loss, irritability or learning difficulties or behavioral changes. A carefully obtained history will be helpful to evaluate exposure to toxic substances. Although drug overdose may lead to an acute illness and possibly a subsequent telogen effluvium, chronic high level exposure to metals such as lead or arsenic may also cause hair loss. Elevated levels of these metals may be detected in the serum
Who is at Risk for Developing this Disease?
Loose anagen hair syndrome is likely underdiagnosed and underreported. Sinclair and colleagues estimated the annual incidence to be approximately two cases per million individuals, but the true incidence may be higher. Several studies indicate a mean age of onset of 3 to 6 years. Although girls are more commonly affected than boys, (ratio 6:1 to 36:1), the syndrome may be underdiagnosed in boys because of their traditionally shorter hairstyles.
Other risk factors include Caucasian background and light colored hair, especially blonde and light brown. Because some cases are inherited in an autosomal dominant pattern with variable penetrance, children of adults with loose anagen syndrome are also at risk for developing this condition.
What is the Cause of the Disease?
The exact cause remains unknown. There is defective anchoring of anagen hairs, which causes them to be easily and painlessly extracted from the scalp. The defective anchoring occurs due to abnormal adhesion between the hair shaft and the inner root sheath. Defective adhesion between the outer root sheath and inner root sheath may also be contributory in some patients.
One of the most consistent findings is abnormal, premature keratinization of the inner root sheath. This leads to poor cohesion between hair shaft and the inner root sheath. The cuticle itself is ruffled, and this results in defective interlocking between the hair shaft and inner root sheath. The syndrome may be cyclical in activity because normal and abnormal regions of the hair follicle can been seen in the same patient.
Cytokeratin mutations in the inner or outer root sheath may contribute to the pathogenesis of loose anagen hair syndrome. Mutations in the K6HF gene, found in the outer root sheath companion layer, were identified in 3 of 9 families with loose anagen hair syndrome. Other keratin mutations, including the K6IRS1 gene located in the inner root sheath, could also play a role.
The poor adherence of the hair follicle to the inner root sheath may lead to a shortened duration of anagen phase. Clinically, this may lead to the inability to grow long hair. The actual growth rate of hairs may be normal but this remains to be fully evaluated.
Systemic Implications and Complications
Loose anagen hair syndrome is usually an isolated phenomenon occurring in healthy children with normal growth and development. However, the syndrome has been reported in association with several hereditary and developmental disorders including Noonan-like syndrome, ocular coloboma syndrome, trichorhinophalangeal syndrome, alopecia areata, nail patella syndrome, hypohidrotic ectodermal dysplasia, ectrodactyly-ectodermal dysplasia clefting syndrome, acquired immunodeficiency syndrome, diffuse or partial wooly hair syndrome, colobomas with dysmorphic facial features, uncombable hair syndrome and neurofibromatosis.
It is possible that some of these associations are coincidental. However, for some, such as Noonan-like syndrome with loose anagen hair, specific gene mutations (ie, SHOC2) have been consistently identified in affected patients.
Treatment options for loose anagen syndrome are summarized in the Table I.
|Medical Treatments – Topical||Minoxidil|
|Medical Treatments – Systemic||None|
Optimal Therapeutic Approach for this Disease
At present, there is no cure for loose anagen hair syndrome, and it is not known if any treatment can alter the course. Reassurance and education is an essential component of patient management.
Patients should be advised that hair length, thickness, strength and density generally improve over time, and this is accompanied by darkening of the hair. Many patients show improvement by 8 or 9 years of age. Despite this, many patients continue to have easily extractable hair into adulthood albeit to a lesser degree than found in childhood.
Patients should be advised to be gentle when shampooing and grooming to avoid extracting hairs. Patients should also be counseled to avoid traumatic hair care practices, such as excessive braiding. Twice daily topical application of 5% minoxidil is often used in the treatment of loose anagen hair syndrome given its theoretical ability to prolong hair cycling in the anagen phase. The evidence for its effectiveness in this condition is weak but it may help a proportion of individuals.
Reassurance is the most important aspect of patient management. Patients and parents should be reassured that there is usually some degree of cosmetically significant improvement over time.
Unusual Clinical Scenarios to Consider in Patient Management
Although most cases are unassociated with other anomalies, the loose anagen syndrome has been reported as part of many genetic syndromes including Noonan-like syndrome, ocular coloboma syndrome, trichorhinophalangeal syndrome, nail patella syndrome, hypohidrotic ectodermal dysplasia, ectrodactyly-ectodermal dysplasia clefting syndrome, diffuse or partial wooly hair syndrome, colobomas with dysmorphic facial features, uncombable hair syndrome and neurofibromatosis. A genetic consultation may be appropriate for any such cases.
What is the Evidence?
Baden, HP, Kvedar, JC, Magro, CM. “Loose anagen hair as a cause of hereditary hair loss in children”. Arch Dermatol. vol. 128. 1992. pp. 1349-53. (Fourteen patients with loose anagen syndrome across three families were studied. Using light and electron microscopy, the authors showed there was disadhesion between all layers of the hair follicle as well as within some of the layers. Premature keratinization of the inner root sheath was observed. The authors postulated that loose anagen hair syndrome has an autosomal dominant inheritance with variable expression. They proposed that the syndrome was cyclical in activity since normal and abnormal regions of the hair shaft could be seen in the same hair follicle.)
Chapalain, V, Winter, H, Langbein, L, Le Roy, JM, Labrèze, C, Nikolic, M. “Is loose anagen hair syndrome a keratin disorder? A clinical and molecular study”. Arch Dermatol. vol. 138. 2002. pp. 501-6. (The authors showed that companion layer keratin, K6HF, was mutated in 3 of 9 patients with loose anagen hair syndrome. This study provided some of the first genetic evidence as to a possible contributing cause for loose anagen hair syndrome. The authors also reported that minoxidil 5% lotion was helpful in 7 of 11 patients when used for 1 to 12 months.)
Cordeddu, V, Di Schiavi, E, Pennacchio, LA, Ma’ayan, A, Sarkozy, A, Fodale, V. “Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair”. Nat Genet. vol. 41. 2009. pp. 1022-6. (Although systemic associations among patients with loose anagen syndrome are not common, Noonan-like syndrome with loose anagen hair is among the most commonly reported systemic associations. The authors studied 25 patients with Noonan-like syndrome with loose anagen hair and showed that a single missense mutation in SHOC2 was associated with the syndrome. The mutation introduces an N-myristoylation site into SHOC2, which in turn targets it to the plasma membrane. This may facilitate activation of the mitogen-activated protein kinase signal transduction pathway.)
Hamm, H, Traupe, H. “Loose anagen hair of childhood: the phenomenon of easily pluckable hair”. J Am Acad Dermatol. vol. 20. 1989. pp. 242-8. (The authors describe two boys, age 4 and 9 years, with loose anagen hair syndrome. Because the syndrome had only been observed in children when the article was published, the authors proposed the name loose anagen hair of childhood. The results of this early study confirmed those of others, namely a predominance of anagen hairs (98% to 100 %) on the trichogram. The authors showed longitudinal depressions, and twisting of the hair fibers were observed using light and electron microscopy.)
Mirmirani, P, Uno, H, Price, V. “Abnormal inner root sheath of the hair follicle in loose anagen syndrome. An ultrastructural study”. J Am Acad Dermatol. vol. 64. 2011. pp. 129-34. (The authors performed light and electron microscopy on biopsy samples from four patients with loose anagen syndrome. The major pathologic changes were identified in the inner root sheath.)
Nodl, F, Zaun, H, Zinn, KH. “Gesteigerte Epilierbarkeit von Anagenhaaren bei Kindern als Folge eines Reifungsdefekts der Follikel mit gestorter Verhaftung von Haarschaft und Wurzelscheiden”. Das Phanomen der leicht ausziehbaren Haare. Akt Dermatol. vol. 12. 1986. pp. 55-7. (Along with the observations of Price and Gummer, and Hamm and Traupe, this was one of the earliest descriptions of loose anagen hair syndrome. The German authors named the condition the phenomenon of “leicht ausziehbaren Haare” or “easily extractable hair.” Similar to Price and Gummer, these authors also showed premature keratinization of the inner root sheath in biopsies of affected patients.)
Olsen, EA, Bettencourt, MS, Cote, NL. “The presence of loose anagen hairs obtained by hair pull in the normal population”. J Investig Dermatol Symp Proc. vol. 4. 1999. pp. 258-60. (The authors evaluated the results of hair pull tests in 110 normal subjects ranging in age from 6 months to 83 years. Loose anagen hairs were present in 61% of healthy children under the age of 10 years. However, the total number of loose anagen hairs obtained by pull test was considerably less than the number of hairs extracted in patients with the loose anagen hair syndrome. Olsen and colleagues defined the three clinical presentations of loose anagen hair syndrome: type A [thin, sparse and fine hair], type B [unruly and unmanageable hair], and type C [shedding hair].)
Price, VH, Gummer, CL. “Loose anagen syndrome”. J Am Acad Dermatol. vol. 20. 1989. pp. 249-56. (The clinical features of 27 patients [22 children and 5 adults] with loose anagen hair syndrome were described with attention to differences between children and adults. The authors also showed using light and electron microscopy that the distorted [loose] anagen hairs lacked inner and outer root sheaths. By histology, they showed that there was premature keratinization in the inner root sheath and hypothesized that this contributed to the abnormal cohesion between the inner root sheath and hair shaft. The syndrome was proposed to be inherited in some cases.)
Sinclair, R, Cargnello, J, Chow, CW. “Loose anagen syndrome”. Exp Dermatol. vol. 8. 1999. pp. 297-8. (The study consisted of a retrospective review of 43 cases of loose anagen syndrome seen over a 4-year period. Based on their referral patterns, the authors estimated the incidence of the loose anagen hair syndrome to be 2 to 2.5 cases per million per year. In this study, the female-to-male ratio was 6:1 and the mean age of presentation was 6.24 years. Of 29 patients studied in detail, 24 had blond hair, 4 had light brown and 1 had black. Follow-up of 24 patients for a mean of 2.6 years showed that many improved by the age of 8 years.)
Tosti, A, Peluso, AM, Misciali, C, Venturo, N, Patrizi, A, Fanti, PA. “Loose anagen hair”. Arch Dermatol. vol. 133. 1997. pp. 1089-93. (Fourteen children and five adults with loose anagen syndrome were evaluated over a 7-year period. The authors defined loose anagen syndrome by the presence of more than 10 anagen hairs on a pull test and more than 80% extractable anagen hairs on the trichogram.)
Zaun, H. “Syndrome of loosely attached hair in childhood”. Pediatric dermatology: advances in diagnosis and treatment. 1984. pp. 64-5. (The author provided the first description of loose anagen hair syndrome in a 6-year-old fair-haired girl who presented with hair thinning.)
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