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Short anagen syndrome: The long and short of it

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By Warren R. Heymann, MD, FAAD
Feb. 7, 2024
Vol. 6, No. 6

Dr. Warren Heymann photo
Have you ever encountered a patient who says that their hair does not grow very much and that they rarely need to cut their hair? I have, and I suppose you have, too. Although considered uncommon, short anagen syndrome (SAS) is probably underrecognized. When patients (or their parents) ask why this happens, I usually shrug my shoulders, telling them that I do not know but suspect that it reflects the genetic, biological spectrum of growth — perfectly healthy people can be 4'10'' or 7'2" tall. That answer is momentarily satisfying, but it is not enough. This commentary focuses on SAS and new information that offers a potential clue to SAS pathogenesis in some cases.

SAS was first conceptualized by Headington in his review of telogen effluvium, stating, “On the basis of clinical observation, but without good scientific evidence obtained by direct measurements, it appears probable that some individuals with a slight but persistent telogen effluvium of indefinite onset may experience increased shedding due to idiopathic shortening of anagen (a short anagen syndrome) that features increased shedding and decreased hair length.” (1) Shortly after that, cases appeared in the literature, the initial case being a 19-year-old woman who also had linear scleroderma and an occluded lacrimal duct. The term SAS came to my attention in the 2005 paper by Antaya et al., reporting the case of a 10-year-old girl with short, fine blond scalp hair that had not been cut since birth. She was otherwise healthy without any abnormalities of the skin, teeth, or nails to suggest an ectodermal dysplasia. The authors noted that SAS “is a condition that is unassociated with either scalp hair breakage, total hair loss, or usually with any serious association.” (2)

SAS is usually a disorder of childhood, with a reported female/male ratio of 10/1. Most cases have been reported in White patients but have also been observed in Asian (Indian, Korean, Taiwanese, Japanese), African, and Hispanic patients. (3) In their series of 8 SAS patients, Oberlin et al. note that SAS “clinically presents as diffuse short hair, often with low hair density but without discrete patches of alopecia. The anagen phase is short, lasting only approximately 4 to 10 months. Shortening the anagen phase produces synchronization of the hair cycle, with relapsing episodes of excessive hair shedding. The hair pull test is typically positive…with recurrent episodes of telogen effluvium…Microscopic examination of the hair reveals short telogen hairs with tapering tips indicating uncut hairs, confirming the diagnosis. Other features such as structure and strength are usually normal, without fragility, breakage, hair unruliness, or inflammation.” (4) Iorizzo and Starace endorse using the card test (placing the hairs on a white card and examining them with a dermatoscope), demonstrating pointed hair tips, confirming that the hairs have not been cut. (5) Electron microscopy and X-ray microanalysis demonstrated that SAS hairs are normal ultrastructurally and biochemically. (6)

Image for DWII on short anagen syndrome
Image from citation 11.
In their retrospective review of 25 cases of SAS (20 female, 5 male, median age 4 years), Starace et al. observed a mean anagen-to-telogen ratio of 66:34 (normal ratio 90:10), with 10-20% of hair shafts being < 60 μm thick on trichoscopy. Regarding the differential diagnosis, “The most difficult condition to differentiate is the loose anagen hair syndrome (LAHS). LAHS is a rare, benign, sporadic, or autosomal dominant disorder characterized by easy and painless extraction of hairs. It affects females more frequently than males, appearing from 2 to 6 years of age with increased hair loss, irregular alopecic areas, or lack of hair elongation. The pull test is positive for anagen roots without outer root sheaths, and the trichogram shows more than 70% anagen hairs, while trichoscopy shows the typical rectangular granular structures and solitary yellow dots of LAHS. This is in contrast to SAS which shows different features. The pull test in patients affected by SAS is negative or slightly positive, with conic-tipped short telogen hair. Trichoscopy reveals no specific features, only showing a thin hair diameter. The hair card test demonstrates short hairs with different lengths (less than 10 cm) and with a conical tip to demonstrate that it has never been cut. The trichogram reveals a high percentage of telogen hair with low percentage of anagen hair and a decreased A/T ratio (2:1).” Other considerations include diffuse alopecia areata, telogen effluvium, and ectodermal dysplasias. (7)

Both SAS and LAS may have a strong psychological impact on both patients and their caregivers, including low self-esteem, anxiety, depression, insecurity, worry, frustration, and body dysmorphia. In a total of 163 respondents to a questionnaire, negative psychologic symptoms were reported in 44.2% (38/89) of LAS patients, 48.3% (43/89) of LAS caregivers, 56.8% (42/74) of SAS patients, and 47.2% (35/74) of SAS caregivers. (8) Even though SAS usually resolves spontaneously after puberty, it is understandable why patients (or their parents) may desire treatment. Most reports focus on the use of oral biotin and topical minoxidil. (7,9)

The pathogenesis of SAS is enigmatic. Ultimate hair length is determined by the duration of anagen, which is under genetic control and is influenced by age, sex, and possibly other factors, including hormones. (7) Most cases are sporadic. A familial case in which the hair growth improved with the onset of puberty was consistent with autosomal dominant inheritance. (10) Doche et al. reported a case of SAS in a 3-year-old girl whose parents were cousins. (11)

Cesarato et al. recruited 48 patients diagnosed with “short anagen hair syndrome” (SAH, which I still call SAS) or who had short, non-growing hair resembling SAS and investigated them genetically. Exome sequencing was performed in the first cohort of 27 patients. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-colored hair and regression of the frontoparietal hairline. The most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with male pattern hair loss (MPHL). “Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.” (12)

In an editorial accompanying Cesarato et al., Onoufriadis notes that “WNT10A is a good candidate gene for hair disorders. Biallelic pathogenic variants in WNT10A have been identified in various autosomal recessive forms of ectodermal dysplasia (ED), including Schöpf–Schulz–Passarge syndrome, odonto-onychodermal dysplasia and hypohidrotic ectodermal dysplasia, all of which may feature hypotrichosis or other forms of abnormal hair growth. Heterozygous carriers of specific WNT10A variants may also display ectodermal derivative impairments, often involving hair (particularly in females).” He suggests that the genetic overlap between SAH and MPHL may provide insights into shared pathobiological mechanisms and possible common therapeutic approaches. (13)

These findings are fascinating and hopefully shed more light on SAHS, but as with any discovery, they also raise more questions. To my knowledge, frontotemporal regression, a characteristic of androgenetic alopecia, was not mentioned in any articles I reviewed about classic SAS. Was it present but mild enough to go unnoticed? Does this represent a distinct subset of patients with SAS, with most patients having undefined genetic predispositions? Why is SAS prevalent in girls with genetic variants linked to male pattern alopecia? Regardless of what further research reveals, Cesarato et al. should be applauded for their efforts to unravel the mysteries of SAS.

Point to Remember: Short anagen syndrome (SAS) is an underrecognized disorder usually observed in children and typically resolves after puberty. It may be accompanied by psychological distress. Topical minoxidil and oral biotin may help therapeutically. Novel research has associated WNT10A variants with SAS and male pattern alopecia, opening the door for new areas of investigation of pathogenesis and therapy. 

Our expert’s viewpoint

Gabriele Richard, MD, FACMG
GeneDx, Maryland

Over the past decades, the discovery of the genetic underpinnings of rare inherited Mendelian disorders has significantly furthered our understanding of the pathomechanisms of common, polygenic, and/or multifactorial traits. A prime example, to pick just one, was the discovery of mono- or biallelic pathogenic loss-of-function variants in the human profilaggrin gene (FLG) in patients with ichthyosis vulgaris. Resulting reduced or absent expression of profilaggrin in the upper epidermal layers perturbs epidermal cornification, increases transepidermal water loss and allows enhanced penetration of irritants and allergens, with subsequent inflammatory responses upon exposure. (14, 15) Subsequent research demonstrated compromised skin barrier integrity due to FLG deficiency in 10-40% of patients with atopic dermatitis (AD). (15) This makes filaggrin deficiency not only the single most significant risk factor for AD, but also for irritant contact dermatitis, nickel contact sensitization, and other multifactorial disorders of the atopic disease spectrum, such as allergic rhinitis, asthma, and food allergies, which currently affect up to 20% of the population worldwide (16). The FLG discovery opened the door to a deeper understanding of the complex interplay between epidermal barrier disruption, external insults on this barrier, a dysfunctional immune system in AD and atopic disease, and the vital importance of an early recovery of the skin barrier in preventing ensuing allergic disease. (15)

Similarly, Cesarato et al. (12) initially focused on the rare genetic hair disorder, short anagen hair syndrome (SAH), and identified causal variants in the WNT10A gene in 40% of patients. WNT10A encodes a secreted signaling molecule in the canonical WNT pathway critically important for multiple processes during embryonic development and homeostasis of ectodermal epithelia. Biallelic pathogenic variants in WNT10A have been previously implicated in a broad continuum of phenotypes ranging from isolated severe oligodontia to odonto-onycho-dermal dysplasia, hypo/anhidrotic ED, and Schöpf–Schulz–Passarge syndrome. Individuals with monoallelic (heterozygous) variants are either unaffected or may have milder features in one or two ectodermal tissues. The characteristic feature is non-syndromic agenesis or hypoplasia of permanent teeth, which predominantly affects males. (17) Two WNT10A variants, p.(Phe228Ile) and p.(Cys107*), are commonly associated with tooth abnormalities or other ED features, while the p.(Phe228Ile) variant is also found in about 2.5% of the general population (gnomAD v4). (18) Considering the function of WNT10A and its expression pattern in ectodermal tissues including hair follicles, the finding of WNT10 variants as molecular cause of SAH is consistent; however, the observed sex-bias of the non-syndromic hair phenotype in female children versus non-syndromic tooth abnormalities in males is intriguing and begs further research into its underlying factors. Fifteen of 20 SAH patients carried at least one of the common two WNT10A variants involved in EDs, highlighting their phenotypic heterogeneity. And as three of four SAH patients with these variants on both alleles also showed involvement of teeth and nails consistent with ED, the SAH findings further extend the broad clinical spectrum of WNT10A-associatedED.

An exciting and potentially far-reaching outcome of Cesarato et al.’s study is building a link between the WNT10A gene and SAH to multifactorial male pattern hair loss (MPHL) via a shared pathomechanism (shortened anagen phase of the hair follicles) and unmasking at least two SAH and ED-associated WNT10A variants (p.(Phe228Ile) and p.(Cys107*)) as potential risk alleles for MPHL. (12) These results may pave the way for further explorations of the role of WNT10A variants and altered Wnt signaling and downstream pathways in predisposing to MPHL, for assessing variants in other ED genes with (MPHL-reminiscent) hair involvement as risk alleles for MPHL, and for identifying specific mechanisms and modifiers, which ultimately contribute to the diverse clinical presentations caused by WNT10A variants, including the noteworthy sex-bias of monoallelic variants.

  1. Headington JT. Telogen effluvium. New concepts and review. Arch Dermatol. 1993 Mar;129(3):356-63. doi: 10.1001/archderm.129.3.356. PMID: 8447677.

  2. Antaya RJ, Sideridou E, Olsen EA. Short anagen syndrome. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 1):S130-4. doi: 10.1016/j.jaad.2004.12.029. PMID: 16021162.

  3. Segawa Y, Yamasaki K, Otake E, Kikuchi K, Aiba S. Short anagen syndrome: A unique short hair syndrome without any characteristic hair morphological abnormality. J Dermatol. 2020 Oct;47(10):e349-e351. doi: 10.1111/1346-8138.15494. Epub 2020 Jul 12. PMID: 32656876.

  4. Oberlin KE, Maddy AJ, Martínez-Velasco MA, Vázquez-Herrera NE, Schachner LA, Tosti A. Short anagen syndrome: Case series and literature review. Pediatr Dermatol. 2018 May;35(3):388-391. doi: 10.1111/pde.13478. Epub 2018 Mar 26. PMID: 29582461.

  5. Iorizzo M, Starace M. Card Test as a Simple Method to Diagnose Short Anagen Syndrome. Dermatol Pract Concept. 2022 Apr 1;12(2):e2022059. doi: 10.5826/dpc.1202a59. PMID: 35646465; PMCID: PMC9116543.

  6. Martin JM, Montesinos E, Sanchez S, Torres C, Ramon D. Clinical, Microscopic and Ultrastructural Findings in a Case of Short Anagen Syndrome. Pediatr Dermatol. 2017 Jul;34(4):e221-e222. doi: 10.1111/pde.13175. Epub 2017 May 23. PMID: 28544234.

  7. Starace M, Gurioli C, Carpanese MA, Bruni F, Piraccini BM, Patrizi A, Alessandrini A. Short anagen syndrome: A case series and algorithm for diagnosis. Pediatr Dermatol. 2021 Sep;38(5):1157-1161. doi: 10.1111/pde.14750. Epub 2021 Aug 18. PMID: 34409646.

  8. Randolph MJ, Gwillim EC, Nguyen B, Tosti A. The psychologic impact of loose anagen syndrome and short anagen syndrome. Pediatr Dermatol. 2022 Jul;39(4):567-569. doi: 10.1111/pde.15002. Epub 2022 Apr 16. PMID: 35429064; PMCID: PMC9539961.

  9. Cheng YP, Chen YS, Lin SJ, Hsiao CH, Chiu HC, Chan JL. Minoxidil improved hair density in an Asian girl with short anagen syndrome: a case report and review of literature. Int J Dermatol. 2016 Nov;55(11):1268-1271. doi: 10.1111/ijd.12150. PMID: 27420346.

  10. Barraud-Klenovsek MM, Trüeb RM. Congenital hypotrichosis due to short anagen. Br J Dermatol. 2000 Sep;143(3):612-7. doi: 10.1111/j.1365-2133.2000.03720.x. PMID: 10971339.

  11. Doche I, Donati A, Valente NS, Romiti R, Hordinsky MK. Short anagen syndrome in a girl with curly dark hair and consanguineous parents. J Am Acad Dermatol. 2012 Dec;67(6):e279-80. doi: 10.1016/j.jaad.2012.06.012. PMID: 23158639.

  12. Cesarato N, Schwieger-Briel A, Gossmann Y, Henne SK, Hillmann K, Frommherz LH, Wehner M, Xiong X, Thiele H, Oji V, Milani D, Tantcheva-Poor I, Giehl K, Fölster-Holst R, Teichler A, Braeckmans D, Hoeger PH, Jones G, Frank J, Weibel L, Blume-Peytavi U, Hamm H, Nöthen MM, Geyer M, Heilmann-Heimbach S, Basmanav FB, Betz RC. Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss. Br J Dermatol. 2023 Nov 16;189(6):741-749. doi: 10.1093/bjd/ljad314. PMID: 37671665.

  13. Onoufriadis A. WNT10A gene variants at the root of short anagen hair syndrome. Br J Dermatol. 2023 Nov 16;189(6):653-654. doi: 10.1093/bjd/ljad377. PMID: 37768102.

  14. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006 Apr 38(4):441-6. PMID 16550169

  15. Drislane C and Irvine AD. The role of filaggrin in atopic dermatitis and allergic disease. Ann Allergy Asthma Immunol. 2020 Jan 124(1):36-43. PMID 31622670

  16. Zheng T, Yu J, Oh MH, Zhu Z. The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3:67–73. PMID: 25419479

  17. Bohring A, Stamm T, Spaich C, et al. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am J Hum Genet. 2009 Jul 85(1):97-105. PMID 19559398

  18. Chen S, Francioli LC, Goodrich JK et al., A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92–100 (2024). PMID 38057664

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