Congenital and Hereditary Alopecias (including Congenital Alopecia Universalis)

Class of non-syndromic monogenic hypotrichoses and atrichias — atrichia with papular lesions and congenital alopecia universalis due to HR*, Marie Unna hypotrichosis, simple hypotrichoses, autosomal recessive localised hypotrichosis and woolly hair, dominant woolly hair, monilethrix and hypotrichosis with skin vesicles — together with the syndromic and acquired forms that enter the differential diagnosis.*

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

Core entities of the class. Vitamin D-dependent rickets type 2A, the ectodermal dysplasias, the CDH3 and TP63 disorders, trichothiodystrophy, Menkes disease, Woodhouse-Sakati syndrome and hypotrichosis-lymphoedema-telangiectasia syndrome enter only the differential diagnosis.

1. Introduction

1.1. Definition of the class

Congenital and hereditary alopecias, also called genotrichoses, are monogenic disorders in which the structure, growth or differentiation of hair is altered, producing hypotrichosis (reduced hair density or length) or atrichia (absence of hair). They may occur in isolation, when the defect is confined to the follicle and the shaft, or form part of broader conditions involving the skin, teeth, nails, sweat glands or other organs. A 2023 review counted 28 non-syndromic hair disorders, linked to 25 identified genes and 4 loci still without a gene, and found that about 30% of the genodermatoses discovered by next-generation sequencing (NGS) include hair abnormalities [77]. The “alopecia universalis” associated with the HR gene corresponds to atrichia with papular lesions (APL) and congenital alopecia universalis (ALUNC), two designations now understood as the same recessive allelic spectrum of HR [12]. APL shares its initial presentation and molecular diagnosis with the other non-syndromic monogenic hypotrichoses, which are therefore studied together.

1.2. From alopecia universalis to the first human hair gene

In 1998, Ahmad and colleagues, at Columbia University, studied a consanguineous Pakistani family with a recessive form of alopecia universalis and, by homozygosity mapping, established linkage to a 6-centimorgan interval at 8p12 (LOD 6.19). Within the interval they located the human homologue of the murine hairless gene and found a missense variant in the affected individuals; the protein, a putative transcription factor with a zinc finger, is expressed mainly in the brain and skin [8]. It was the first gene identified in a hereditary human alopecia. The missense variant of that family (Thr1022Ala, in OMIM numbering; = NM_005144.5:c.3064A>G p.(Thr1022Ala)) was later reclassified by OMIM as a variant of uncertain significance, and the causality of HR rests on the families described below [1]. The family was Pakistani, and in the same year Cichon and colleagues described HR variants in a Pakistani family studied since 1993 (LOD 7.90 at 8p22-p21), homozygous for the missense variant NM_005144.5:c.3407T>A p.(Val1136Asp), and in an Omani family with congenital alopecia universalis, homozygous for a splice donor site variant [1, 78]. Also in 1998, Zlotogorski and colleagues found the same 1-base-pair deletion (2417delC, historical nomenclature) in five Palestinian families with APL [1]. Also in 1998, another study from Ahmad's group found a missense variant in the zinc finger domain of HR in a large family of Irish Travellers, an ethnic minority of Ireland, with milia-like cysts on the knees and elbows, and proposed calling the disorder atrichia with papular lesions [79]. In 2001, Miller and colleagues described a patient with atrichia with papules and normal HR, but with biallelic variants of the vitamin D receptor (VDR) and vitamin D-resistant rickets: the alopecia was clinically and histologically indistinguishable from the HR form, which placed the two genes in the same pathway of the postnatal follicular cycle [5]. In 2002, Zlotogorski and colleagues proposed clinical diagnostic criteria for APL, described the hypopigmented whitish streaks on the scalp as a constant finding and stressed that the disorder is probably more frequent than published estimates, because it is confused with alopecia universalis of autoimmune origin [2]. In 2008, Yip and colleagues revised these criteria, noting the growing number of sporadic cases in unrelated individuals [3].

1.3. Marie Unna and translational control of HR

Marie Unna described in 1925 a large German family with congenital hypotrichosis of dominant transmission [11]; in 2011, Redler and colleagues found, in the great-granddaughter of a member of that original family, an HRURF initiation codon variant (3G>A in OMIM notation) that cosegregated with the disorder [9]. For eight decades the molecular basis remained unknown, until Wen and colleagues, in 2009, identified in a large Chinese family an initiation codon variant of U2HR, a small inhibitory upstream open reading frame (ORF) located in the 5′ untranslated region (5′UTR) of HR, which encodes a predicted peptide of 34 amino acids conserved in mammals; in 18 families of different origins they found loss-of-initiation, delayed-termination, nonsense and missense variants, all increasing translation of the main HR ORF [10]. U2HR is one of four upstream ORFs in the 5′UTR of HR and is now catalogued as a gene in its own right, HRURF (MIM 619257) [1, 9], and by 2025 at least 25 pathogenic variants had been published [11]. In 2012, Zhang and colleagues linked a second form of Marie Unna, mapped to 1p21.1-1q21.3, to the EPS8L3 gene [13].

1.4. The simple hypotrichoses and woolly hair

The term hereditary hypotrichosis simplex designates non-syndromic alopecias without a characteristic shaft abnormality, with diffuse and progressive hair loss from childhood [46, 48]. The first form with a gene was hypotrichosis simplex of the scalp, linked in 2003 to nonsense variants of CDSN, which encodes corneodesmosin [18]; APCDD1 followed in 2010 [16], RPL21 in 2011 [48], SNRPE in 2013 [46] and LSS in 2018 [53]. In parallel, autosomal recessive localised hypotrichosis (LAH, localized autosomal recessive hypotrichosis) and autosomal recessive woolly hair (ARWH, autosomal recessive woolly hair) proved to be the same family of disorders: DSG4 was identified in 2003 [27], LIPH in 2006 by screening about 350,000 people from the Volga-Ural region of Russia [31], LPAR6 (then P2RY5) in 2008 in six Pakistani families [36], KRT25 in 2015 [38] and C3orf52 in 2020 [41]. Woolly hair was first documented by Gossage in 1907 in a European family, and Hutchinson and colleagues in 1974 divided the non-syndromic forms into woolly hair naevus (non-hereditary), autosomal dominant woolly hair and autosomal recessive woolly hair [32]. The first gene for dominant woolly hair, KRT74, was described in 2010 [22], followed by KRT71 in 2012 [50] and ADAM17 in 2024 [57].

1.5. Monilethrix and hypotrichosis with vesicles

Monilethrix is a structural shaft abnormality, with elliptical nodes of normal thickness separated by constrictions (internodes) where the hair breaks. In 1997, Winter and colleagues identified the first variants in the hair cortex keratin hHb6 (KRT86) in a four-generation British family and in three isolated patients, the first direct evidence of hair keratin involvement in a human disease [59]; in the same year they described the first variant in hHb1 (KRT81) [80]. In 2006, Zlotogorski and colleagues showed that twelve Jewish families from Iraq, Iran and Morocco with monilethrix without vertical transmission had biallelic DSG4 variants, linking recessive monilethrix to LAH [28]. Hypotrichosis with recurrent skin vesicles was associated in 2009 with DSC3 in an Afghan family [65].

1.6. Current nomenclature and reclassifications

OMIM numbers the hypotrichoses from 1 to 16 and keeps separate series for woolly hair and monilethrix; several entries overlap, because the same gene received two names according to the predominant phenotype (for example, hypotrichosis 7 and AR woolly hair 2 are both LIPH, MIM 604379; hypotrichosis 8 and AR woolly hair 1 are both LPAR6, MIM 278150) [81, 82]. The most recent entries are hypotrichosis 15, due to C3orf52 (MIM 620177), and hypotrichosis 16, due to ADAM17 (MIM 621490) [42, 58]. The reference entry of the series (hypotrichosis 1, MIM 605389) defines hereditary hypotrichosis simplex as a non-syndromic hypotrichosis without a characteristic shaft abnormality, with normal hair at birth and loss and thinning from early childhood through follicular miniaturisation, in two forms, limited to the scalp (for example, CDSN) or generalised (for example, APCDD1), with dominant or recessive inheritance; the same entry separates it from congenital atrichia, in which absence of hair is total and permanent, and from Marie Unna, which has twisted shaft dystrophy [83]. Monilethrix now has three entries, one per keratin gene (MIM 158000 for KRT86, 621169 for KRT81 and 621170 for KRT83), and OMIM calls DSG4 hypotrichosis 6 autosomal recessive monilethrix, which it considers clinically more severe [61–63]. Three gene-phenotype relationships in the series rest on a single family and are flagged by OMIM as provisional: hypotrichosis 3 (KRT74), hypotrichosis 5 (EPS8L3) and hypotrichosis 13 (KRT71) [14, 24, 52]. In 2007, Wali and colleagues noted that three recessive hypotrichoses share normal beard in men and sparse eyebrows, eyelashes and body hair, and proposed designating them LAH1 (18q, DSG4, hypotrichosis 6), LAH2 (3q27, LIPH, hypotrichosis 7) and LAH3 (13q14, LPAR6, hypotrichosis 8) [29, 33, 37]. Alopecia-intellectual disability syndrome (APMR) is also an OMIM series: APMR1 due to AHSG (3q27.3, one Iranian family, provisional relationship), APMR2 (locus 3q26.2-q26.31, MIM 610422), APMR3 (locus 18q11.2-q12.2, MIM 613930) and APMR4 due to LSS (MIM 618840) [84, 85]. Orphanet groups the entities into "hypotrichosis simplex" (ORPHA:55654), "hypotrichosis simplex of the scalp" (ORPHA:90368), "woolly hair" (ORPHA:170), "monilethrix" (ORPHA:573), "Marie Unna hereditary hypotrichosis" (ORPHA:444) and "atrichia with papular lesions" (ORPHA:86819) [69–72, 86, 87]. The entry ORPHA:701 "alopecia universalis" brings together HR-related ALUNC with the alopecia areata loci (OMIM 104000 and 610753, the latter a susceptibility locus at 16q11-q22 identified by affected sib-pair analysis, without a gene) [88], and its prevalence (1–5/10,000 in Europe) therefore describes the autoimmune disorder [73]. For OMIM, ALUNC is a severe autosomal recessive alopecia with complete absence of hair development, distinct from alopecia areata of autoimmune basis (locus AA1, MIM 104000), and APL is distinguished from it by the diffuse papular eruption that appears years after hair loss [78, 79, 89]. At the border with the syndromic forms, a 2026 study applied the ClinGen lumping criteria to dominant SREBF1-related IFAP syndrome (ichthyosis follicularis, atrichia and photophobia) and to hereditary mucoepithelial dysplasia, which share the variant NM_004176.5:c.1579C>T, and proposed the unifying name "SREBF1-related syndromic disorder of epidermal differentiation" [90].

1.7. Operational classification

For clinical practice, the entities are organised into five groups by age at onset, shaft appearance and inheritance, which are the data available at the first visit: recessive atrichias with onset in infancy (APL/ALUNC due to HR); dominant congenital hypotrichosis with coarse hair (Marie Unna, HRURF and EPS8L3); simple hypotrichoses without shaft abnormality, dominant (APCDD1, CDSN, KRT74, SNRPE, RPL21) or recessive (LSS); recessive localised hypotrichosis and woolly hair of the lipid and desmosomal axis (LIPH, LPAR6, C3orf52, KRT25, DSG4) and dominant woolly hair (KRT74, KRT71, ADAM17); and structural shaft abnormalities with fragility (monilethrix due to KRT81/83/86 and DSG4) or with skin fragility (DSC3). This division is operational and combines the classifications of OMIM, Orphanet and the Japanese and Chinese reviews, which separate non-syndromic and syndromic forms [32, 91, 92].

2. Molecular Genetics and Pathophysiology

2.1. The follicular cycle as a common target

The hair follicle is a skin appendage that, after fetal morphogenesis, goes through cycles of growth (anagen), regression (catagen) and rest (telogen) throughout life [91]. The genes of this class act at distinct points of this cycle and of shaft structure: HR and VDR control re-entry into anagen after the first postnatal cycle [5]; HRURF regulates the amount of hairless protein [10]; the LIPH–C3orf52–LPAR6 axis produces and senses a lipid mediator required for differentiation of the inner root sheath [41, 82]; the inner root sheath keratins (KRT25, KRT71, KRT74) shape the shaft [22, 38, 50]; the cortex keratins (KRT81, KRT83, KRT86) give it mechanical strength [59, 80]; and the desmosomal cadherins (DSG4, DSC3) and corneodesmosin (CDSN) maintain adhesion between keratinocytes of the follicle and epidermis [18, 27, 65].

2.2. HR: atrichia with papular lesions and congenital alopecia universalis

HR (8p21.3; MANE Select transcript NM_005144.5) encodes the hairless protein, a JmjC-domain histone demethylase that removes methylation of lysine 9 of histone H3 (H3K9me1 and H3K9me2) [93]. It acts as a transcriptional corepressor of VDR, the thyroid hormone receptor and the retinoic acid-related orphan receptors [12]. Liu and colleagues showed that two missense variants from patients with APL abolish demethylase activity and identified by ChIP-Seq HR targets involved in epidermal development, neural function and transcriptional regulation [93]. In the absence of functional hairless, the follicle does not re-enter anagen after the first catagen: the dermal papilla loses contact with the epithelium, and what remains of the follicle turns into keratin-filled cysts, which correspond clinically to the papules [7, 12]. In the case described by Miller, the cyst epithelium expressed keratins 15 and 17, markers of the follicular bulge where the stem cells reside, indicating that the stem cell reserve persists but cannot regenerate the follicle [5].

Inheritance is autosomal recessive. More than 30 HR variants have been described, mostly in consanguineous families, but also in compound heterozygosity in unrelated families [4, 7, 94]. In a cohort of ten Pakistani families (nine consanguineous), Ullah and colleagues found seven novel variants — frameshift, nonsense and splicing (c.2203+5G>C and c.2776+5G>A) — and the recurrent variant NM_005144.5:c.1837C>T p.(Arg613Ter) [95, 96]. In two consanguineous families from Kashmir the recurrent variant NM_005144.5:c.2818C>T p.(Arg940Ter), in exon 13, was found [6, 96]. In a non-consanguineous Chinese family, the proband was compound heterozygous for a paternal nonsense variant and a maternal 2-base-pair deletion, one of them the first variant described in exon 10 [94]. The designation congenital alopecia universalis (OMIM 203655) and that of APL (OMIM 209500) refer to the same gene; Alibrahim and colleagues argue that ALUNC is distinguished by hair loss already at birth and by the absence of papules and cysts in the lower dermis [4], whereas genetic reviews treat them as a single allelic spectrum in which the appearance of papules depends on age and observation [12]. The family studied by Wang and colleagues showed phenotypic heterogeneity with the same variants, which the authors attribute to modifier genes [94]. In five consanguineous Pakistani families with APL, Kim and colleagues (2007) found three nonsense variants, and families with the same variant shared the same homozygous haplotype, indicating spread of ancestral alleles in the population rather than independent mutations; they observed no genotype-phenotype correlation [1]. In a large consanguineous Israeli Arab family, the deletion 3434delC (historical nomenclature), in exon 18, alters the conserved C-terminal region [1]. The hypothesis that common HR variants contribute to androgenetic alopecia did not survive correction for multiple comparisons and remains an unconfirmed association [1].

2.3. HRURF: Marie Unna hypotrichosis due to excess hairless

HRURF (NM_001394132.1) is the inhibitory ORF upstream of the main HR ORF, in the same transcript. Variants that eliminate the initiation codon, delay the termination codon, introduce premature termination codons or alter amino acids reduce the inhibition exerted on HR translation, and the result is an excess of normal hairless protein [10]. The mechanism is therefore the opposite of that of APL, and inheritance is dominant. The classic initiation codon variant NM_001394132.1:c.1A>G p.(Met1?) was identified in a five-generation Chinese family, in all affected members [96, 97]. In a Danish family, Holm and colleagues found NM_001394132.1:c.105G>T, which replaces the termination codon with a tyrosine codon, p.(Ter35TyrextTer?) in VariantValidator notation; the similar variant c.104A>G fuses the HRURF and HR reading frames in frame and increases expression of the fused protein [11, 96]. The level of hairless varies throughout the follicular cycle, and fine regulation is needed to restart growth [11]. In the 18 additional families studied by Wen and colleagues, 12 different heterozygous variants were found; the initiation codon variant 2T>C (OMIM notation) was later found in a four-generation Turkish family with sparse eyebrows, eyelashes and body hair but relatively normal scalp hair, which broadens the Marie Unna spectrum to forms with little scalp involvement [9].

The second form of Marie Unna was linked to EPS8L3 in a four-generation Chinese family: the variant NM_133181.4:c.22G>A p.(Ala8Thr) (MANE Select; = NM_024526.3:c.22G>A in the published transcript) was present in the eight affected and absent in the seven unaffected members, in 676 healthy controls and in 781 patients from another project [13]. The evidence rests on this family, and OMIM classifies the relationship as provisional; EPS8L3, unlike the paralogous proteins EPS8L1 and EPS8L2, has no guanine nucleotide exchange activity on RAC and does not restore actin remodelling in fibroblasts, so the mechanism in the follicle is unknown [14, 15]; in another large Chinese family with Marie Unna no EPS8L3 variants were found, and all affected members had the HRURF c.1A>G variant [97].

2.4. The LIPH–C3orf52–LPAR6 axis: recessive localised hypotrichosis and woolly hair

LIPH (3q27.2; NM_139248.3) encodes lipase H, a membrane-associated phosphatidic acid-selective phospholipase A1 that generates 2-acyl lysophosphatidic acid (LPA) [31, 32]. LPA binds to the G protein-coupled receptor encoded by LPAR6 (P2Y5), expressed in the Henle and Huxley layers of the inner root sheath; LPAR6 is a gene nested in intron 17 of RB1 [36]. C3orf52 encodes a transmembrane protein co-expressed with lipase H in the inner sheath, which interacts directly with it and is required for lipase H-mediated LPA synthesis [41]. Loss of function of any of the three reduces LIPH–LPA–LPAR6 signalling and transactivation of the epidermal growth factor receptor (EGFR), and the hair remains underdeveloped; the three disorders are therefore clinically indistinguishable [82]. Sentoku and colleagues (2026) showed that LIPH variants act through more than one route: three mutant proteins (p.W108R, p.H205R and p.V437Gfs4) are no longer secreted and induce more severe endoplasmic reticulum stress; only the C-terminal variant p.V437Gfs4 loses affinity for C3orf52, because the two proteins interact through their C-termini; C3orf52 anchors lipase H to the plasma membrane; and all variants tested reduce secretion of the effector TGF-α through the LPA6 receptor [98].

LIPH variants are well characterised by population. In the Volga-Ural region, the exon 4 deletion (c.527_628del), arising from recombination mediated by a SINE retrotransposon, is a founder variant [31, 32]. Rogaev and colleagues had found in 1999, among the Mari people, 21 families with 26 affected individuals and estimated the allele frequency at 1% or more; Kazantseva and colleagues identified the deletion (about 985 base pairs, including exon 4 and adjacent introns) in 14 Mari and 36 Chuvash families and, in 2292 chromosomes from population samples collected without regard to phenotype, measured an allele frequency of 0.033 in the Chuvash and 0.030 in the Mari, with no allele in other Finno-Ugric or Russian populations; from this they estimated more than 98,000 heterozygous carriers and about 1500 affected homozygotes in the populations of Mari and Chuvash ancestry, a model-based estimate rather than a count [33]. In Pakistan, all variants described are homozygous and more than half of the families with LIPH disease have c.659_660del, in exon 5 [32, 82]; VariantValidator describes the effect of this deletion as NM_139248.3:c.659_660del p.(Ile220ArgfsTer25), whereas the literature uses p.Ile220Argfs*29 [82, 96]. In Japan, 98.7% of families with ARWH have LIPH variants, mainly c.736T>A p.(Cys246Ser) and c.742C>A p.(His248Asn), both in exon 6 [82, 96]. In China, the 19 cases published up to 2024 were all due to LIPH, and 12 families had c.742C>A in homozygosity or compound heterozygosity [32]. In a 2025 Chinese series of six unrelated patients, three were homozygous for c.742C>A, one homozygous for c.454G>A p.(Gly152Arg) and two compound heterozygous; carriers of p.(Gly152Arg) had milder hair loss [96, 99]. The in-frame duplication c.280_369dup is recurrent in Pakistani, Israeli, Turkish, Arab and Jewish patients [32]. In two consanguineous Pakistani families, Petukhova and colleagues found two different alleles segregating in the same family (the deletion c.659_660del and a 90-base-pair duplication), with affected individuals homozygous for one or the other or compound heterozygous, and warned that, even in consanguineous families, homozygosity by common descent should not be assumed [33]. In 17 Pakistani families, Khan and colleagues (2011) found linkage to LIPH in nine and to LPAR6 in eight, with no difference in severity between genes or variants [33, 37]. By the end of 2024 more than 30 LIPH variants, more than 20 LPAR6 variants and two in each of the KRT25 and C3orf52 genes had been described [32].

In LPAR6, Azeem and colleagues described seven homozygous variants in 14 Pakistani families with LAH3, three of them already described in patients with woolly hair, although none of their patients had it, which shows that the same allele produces hypotrichosis or woolly hair; in a Turkish family, the homozygous missense Pro196Leu was associated with pitting and longitudinal ridging of the nails [37]. In a 15-year-old Pakistani boy, a homozygous LPAR6 missense variant (D63V in OMIM notation, which does not state the transcript) coexisted with incomplete achromatopsia due to a homozygous PDE6H variant, an example of dual diagnosis in a consanguineous family [37]. The recurrent variant c.436G>A p.(Gly146Arg) has the same numbering in the historical transcript NM_005767.6 and in the MANE transcript NM_001162498.3, according to VariantValidator [96, 100]. Khan and colleagues found it in four of five Pakistani families, and in the fifth a novel variant c.47A>T p.(Lys16Met), which structural modelling predicted to destabilise the receptor through loss of ionic interactions [100]. For C3orf52, homozygous loss-of-function variants have been described in four individuals with LAH [41], the nonsense variants c.492T>A p.(Tyr164Ter) in a Hispanic American patient and c.34G>T p.(Glu12Ter) in an American patient of Arab ancestry [32], and a homozygous frameshift (5-base-pair deletion) in a five-generation consanguineous family from Kashmir [43, 101]. The two original nonsense variants are homozygous in sib pairs from two families; p.(Tyr164Ter) was present in heterozygosity in 1 of 119,840 individuals in gnomAD, and the mutant proteins showed reduced expression, abnormal localisation and marked inhibition of lipase H-mediated LPA synthesis [43].

2.5. Inner root sheath keratins: KRT25, KRT71 and KRT74

Keratins 25, 71 and 74 are epithelial keratins specific to the inner root sheath, which moulds the shaft and anchors it to the follicle [22, 50]. KRT25 (17q21.2; NM_181534.4) is a type I keratin; the variant c.950T>C p.(Leu317Pro), homozygous in two consanguineous Pakistani families (combined LOD 7.9), disrupts the second α-helical domain and heterodimerisation with type II keratins in the inner sheath and medulla [38, 96]. In the Volga-Ural region, Zernov and colleagues examined 119 people with hypotrichosis and separated two groups: one with the LIPH exon 4 deletion and another, with woolly hair, homozygous for KRT25 c.712G>T p.(Val238Leu), with a founder effect and disruption of intermediate filaments in HaCaT cells [39, 96]. In the Chuvash population, the allele frequency of p.(Val238Leu) was 0.015%, with a common haplotype suggesting a founder effect, and heterozygous carriers had no shaft abnormalities; the patients had hair of 5 to 15 cm, cut every 3 or 4 years, follicular density of 210/cm² in the occipital and 90/cm² in the frontotemporal region (normal 175–300/cm²), abnormalities in 70% of shafts and 25–30% of telogen hairs on the trichogram (normal 10–20%) [40]. In a six-generation Pakistani family, the homozygous missense Arg89His (OMIM numbering) caused light-brown woolly hair with frontal hairline recession, patchy loss from 2–3 years of age, sparse eyebrows and dental anomalies (mandibular crowding or maxillary diastemas) in all affected members, a feature not described in the other families [40]. There is also a report of dominant woolly hair due to a heterozygous KRT25 missense variant in the helix termination motif [12], which OMIM keeps as an association not yet confirmed and does not include in the gene-phenotype relationship [25]. In the mouse, the Rex phenotype, with curly fur and vibrissae, results from Krt25 missense variants in the helix termination motif, with abnormal distribution of keratin 71, its probable heterodimeric partner [40].

KRT74 (12q13.13; NM_175053.4) shows both inheritance patterns. In the dominant form, the variant NM_175053.4:c.444C>A p.(Asn148Lys), in the helix initiation motif, disorganises intermediate filaments in cultured cells through a dominant-negative effect [22, 96]; Wasif and colleagues described a splicing variant (c.IVS8-1G>A) in a family with ten individuals affected by woolly hair and a missense variant c.1444G>A p.(Asp482Asn) in a family with 14 individuals affected by scalp hypotrichosis, which corresponds to hypotrichosis 3 [23, 24]. In the recessive form, homozygosity for c.821T>C p.(Phe274Ser), in the coil 1B domain, caused pure hair and nail ectodermal dysplasia in a Pakistani family; the follicles and epidermis of the affected individual lacked keratin 74, indicating loss of function [102]. KRT71 (NM_033448.3) causes dominant woolly hair with hypotrichosis through missense variants in the helix initiation motif (c.422T>G p.(Phe141Cys), Japanese family) or termination motif (c.1295A>G p.(Tyr432Cys), Chinese family) [50, 51, 96], and an intronic variant that adds 12 nucleotides to the transcript and 4 amino acids to the tail domain was associated with loose anagen hair and woolly hair in a mother and daughter [103]. In mice, the dominant allele Caracul-like 4, with wavy fur, has a variant in Krt71, the gene that also harbours the Caracul and Reduced coat alleles and a variant associated with curly coat in dogs [22].

2.6. ADAM17 and hypotrichosis 16

Wang and colleagues (2024) described a dominant ADAM17 variant, p.D647N, causing hypotrichosis with woolly hair. Mice with the same variant reproduced the abnormality; the mutant protein binds more strongly to the E3 ubiquitin ligase TRIM47, is ubiquitinated and degraded, and reduced ADAM17 decreases Notch signalling, depleting follicular stem cells [57]. OMIM created the entry hypotrichosis 16 (MIM 621490) for this form [58].

2.7. Simple hypotrichoses without shaft abnormality: APCDD1, CDSN, SNRPE, RPL21 and LSS

APCDD1 (18p11.22; NM_153000.5) encodes a membrane glycoprotein abundant in the follicle that interacts with WNT3A and LRP5 and inhibits the Wnt pathway upstream of β-catenin. The variant NM_153000.5:c.26T>G p.(Leu9Arg), in the signal peptide, was found in three families; it disrupts transport from the endoplasmic reticulum to the membrane and probably acts through a dominant-negative effect on the normal protein, with follicular miniaturisation [16, 96]. The gene's name derives from its downregulation by APC in colorectal tumours, but a germline APCDD1 variant does not confer a risk of polyposis [12].

CDSN (6p21.33) causes two disorders with opposite molecular logic. Heterozygous nonsense variants produce a truncated corneodesmosin that retains the glycine- and serine-rich N-terminal domain, aggregates into amyloid fibrils around the follicles and in the papillary dermis and forms annular oligomers toxic to keratinocytes: hypotrichosis simplex of the scalp is thus a localised amyloidosis [18, 104]. Biallelic null variants or complete deletion of the gene cause peeling skin disease type 1 (peeling skin syndrome), autosomal recessive, with erythroderma and generalised superficial peeling [12]. In one family, a compound heterozygote had generalised peeling and the mother, carrying only the nonsense allele, had thin hair throughout life [12]. The two nonsense variants that defined hypotrichosis 2 were NM_001264.5:c.643C>T p.(Gln215Ter), in Israeli and Spanish families, with different haplotypes indicating independent origin, and NM_001264.5:c.598C>T p.(Gln200Ter), in a Danish family [19, 20]. Linkage to 6p21.3 was established in two Danish families and confirmed in the large eight-generation Spanish family described by Toribio and Quiñones in 1974, with a total LOD of 11.97 [19].

SNRPE (1q32.1; NM_003094.4) encodes the Sm-E protein, a core component of the small nuclear ribonucleoproteins (U snRNPs) of the spliceosome. Pasternack and colleagues found NM_003094.4:c.1A>G p.(Met1?) in a Spanish family and in an isolated case from the United Kingdom, and c.133G>A p.(Gly45Ser) in a Tunisian case; the initiation codon variant generates an N-terminally truncated protein, probably from an alternative initiation codon, which localises and is incorporated normally into U snRNPs, suggesting a defect in splicing activity rather than biogenesis [46, 96]. Additional causal variants have been described [105]: in three patients of different origins (Chinese, Spanish and Turkish), a splicing variant and a de novo missense variant and the recurrent initiation codon variant, which led the authors to consider SNRPE variants relatively frequent; the variant identified by Pasternack in one of the cases had also arisen de novo [47]. Why a ubiquitous spliceosome component produces a phenotype restricted to hair is unexplained [12]. Amudhavalli and colleagues described a patient with microcephaly, congenital atrichia and multiple congenital anomalies, with a de novo intronic deletion (c.82-28_82-16del) causing exon skipping, and proposed the name SNRPE-related syndromic microcephaly and hypotrichosis, bringing it closer to the craniofacial spliceosomopathies [106].

RPL21 (13q12.2; NM_000982.4) encodes ribosomal protein L21. The variant NM_000982.4:c.95G>A p.(Arg32Gln) cosegregated in a Chinese family with generalised dominant hypotrichosis simplex, was found in two patients from another Chinese family and was absent in 200 controls [48, 96]. The two families, from Inner Mongolia (17 affected among 52 members) and Shandong province (14 of 30, complete penetrance), did not share a haplotype, which excludes a founder effect [49]. Neither bone marrow failure nor anaemia has been described, unlike other ribosomopathies [12].

LSS (21q22.3) encodes lanosterol synthase, which cyclises (S)-2,3-epoxysqualene into lanosterol in cholesterol synthesis. Biallelic variants cause an autosomal recessive spectrum: congenital cataract, hypotrichosis simplex (hypotrichosis 14), alopecia-intellectual disability syndrome (APMR4) and palmoplantar keratoderma with congenital alopecia type 2 [12, 53, 54, 107]. Blood cholesterol and its precursors are normal [53, 54]; the mutant protein is partly located outside the endoplasmic reticulum [53]; and the epoxysqualene/lanosterol ratio in forehead sebum demonstrates the enzymatic block [108]. In mice, epidermal deletion of Lss caused neonatal death from dehydration, induced deletion in adults caused hypotrichosis and deletion in the lens caused cataract [108]. In the form with keratoderma, variants (NM_002340.6) such as c.3G>A (alternative initiation at Met81), c.1025T>G p.(Ile342Ser) and c.1522G>T p.(Gly508Trp) markedly reduced lanosterol in vitro, and the cornified envelope was abnormal [107]. In four Chinese families with recessive hypotrichosis simplex, a deep intronic variant (c.893-175G>A) was identified only by combining genome sequencing with RNA sequencing [109]. Romano and colleagues proposed a genotype-phenotype correlation by position: hypotrichosis variants cluster in the N-terminus of the enzyme, and those of congenital cataract 44 (MIM 616509), such as NM_002340.6:c.1762G>A p.(Gly588Ser) and c.1741T>C p.(Trp581Arg), in the C-terminal domain; a Chinese boy compound heterozygous for c.1025T>G p.(Ile342Ser) (N-terminal) and c.1887G>T p.(Trp629Cys) (C-terminal) had an intermediate phenotype, with cataract and hypotrichosis [55, 56].

2.8. Desmosomal cadherins: DSG4 and DSC3

Desmoglein 4 is expressed in the suprabasal epidermis and in the follicle and, in the follicle, coordinates the switch from proliferation to differentiation; DSG4 variants cause hereditary hypotrichosis in humans and the lanceolate hair phenotype in the mouse, and DSG4 is also an autoantigen in acquired pemphigus vulgaris [27]. In the Iraqi Jewish families with recessive monilethrix, all seven patients were homozygous for a common haplotype at 18q, absent in 20 controls (P<0.0001), and four DSG4 variants were found [28]. A recurrent intragenic deletion of about 5 kb, homozygous, explains LAH in five Pakistani families [12, 29]. In Chinese patients with recessive monilethrix, a homozygous deletion of 48,644 base pairs beginning in intron 1 of DSG4 and extending into the intergenic region between DSG4 and DSG3 has been described [29]. In a Japanese patient and in Jewish siblings of Iraqi and Iranian origin, all negative for the three keratins of dominant monilethrix, compound heterozygosity in DSG4 led the authors to conclude that LAH and monilethrix are not independent disorders but a spectrum of variable expressivity [29]. In two unrelated Muslim Arab children, the same homozygous 4-base-pair deletion produced hypotrichosis of the eyebrows and eyelashes with generalised follicular keratotic papules and normal scalp hair, which the authors likened to keratosis pilaris atrophicans [29]. Desmocollin 3, encoded by DSC3, is another desmosomal cadherin; loss of function reduces adhesion between keratinocytes (intraepidermal vesicles) and anchorage of the shaft [12, 65]. In the original Afghan family, the variant was NM_001941.5:c.2129T>G p.(Leu710Ter), homozygous in exon 14, in a region with a multipoint LOD of 3.30 at 18q12.1 [65, 96]; the second, Leu727Ter (OMIM numbering), was homozygous in an Egyptian boy born to consanguineous parents [67]; the third variant described, c.154G>C p.(Val52Leu), was found by genome sequencing in a Saudi boy [66]. In the Egyptian boy's skin, electron microscopy showed desmosomes of variable morphology, some small, with separation between cells mainly at the inner desmosomal plaques [67].

2.9. Cortex keratins: monilethrix due to KRT81, KRT83 and KRT86

The type II keratins hHb1 (KRT81), hHb3 (KRT83) and hHb6 (KRT86) form obligate heterodimers with type I keratins in the trichocytes of the cortex and constitute the intermediate filaments that give the shaft its strength [59, 80]. Variants of dominant monilethrix are heterozygous missense variants in the helix initiation and termination motifs, required for filament assembly; the incorporated mutant chain disorganises the filament (dominant-negative effect) [59, 110]. In historical protein nomenclature, the hHb6 substitution Glu410Lys was found in a four-generation British family and in three isolated patients, Glu410Asp in a French family with a milder phenotype, and Glu403Lys at the corresponding position of hHb1, which defines a shared hotspot [59, 80]; this old numbering has not been converted to the KRT86 MANE transcript (NM_001320198.2) and is retained as a historical designation. OMIM numbers the same substitutions differently, as E413K and E413D in KRT86 and E413K and E402K in KRT81, and describes as a hotspot the residue corresponding to Glu402 of hHb1 and hHb6 and to Glu407 of hHb3; these protein numberings are retained as OMIM designations, without conversion to HGVS, and OMIM does not state the correspondence with the numbering used in the original articles [61–63]. Other KRT86 variants in OMIM include Glu402Lys (de novo in an American man and in a Greek patient), Glu402Gln (Welsh patient), Asn114Asp (the first in the helix initiation motif, Swedish family), Ala118Glu (French family), Leu409Pro (Venezuelan family) and Leu410Pro (de novo in a French boy) [61]. In KRT83, Glu407Lys was found in a Dutch girl, her mother and grandmother and in a Belgian family, and Glu418Lys in a Dutch family; the latter occupies the position equivalent to Glu413Lys of KRT86 and KRT81 [63]. According to Winter and colleagues (1998), patients with the most frequent hHb6 variant (E413K in OMIM numbering) always develop dystrophic hypotrichosis and occipital and nuchal follicular hyperkeratosis in the first year, which persist into adulthood, whereas families with the other variants of the same residue or of KRT81 show wide intrafamilial variation [61]. In a family with linkage to 12q13, 4 of 12 affected members had only follicular keratosis of the neck, elbows and knees, without hair abnormality, and there was non-penetrance in an obligate carrier [61]. In a Tasmanian family with 120 members examined, the variant c.839C>T (A280V), in the coil 2A domain, was the first outside the initiation and termination motifs and was present in affected individuals and in clinically normal carriers, whose non-moniliform hairs had reduced elasticity [110]. In a Turkish family, the KRT86 nonsense variant c.1231G>T p.(Glu411*) was present in the three affected children and in the apparently unaffected mother, with a weaker signal; SNaPshot analysis confirmed maternal mosaicism, the first description of mosaicism in a monogenic hair loss disorder [111]. In a Venezuelan family a pathogenic KRT86 variant coexisted with a KRT81 variant of uncertain significance [60]. KRT83 illustrates the relationship between variant type and phenotype: heterozygous missense variants cause dominant monilethrix, whereas biallelic loss of function (c.811delA p.(Ser271fs), homozygous in a Pakistani family) causes progressive symmetric erythrokeratoderma, a disorder of the skin and not of the hair [112].

2.10. Table of normalised variants

2.11. Penetrance, expressivity and modifiers

In the recessive forms, heterozygous carriers have normal hair: the mother of Boisen's patient, heterozygous for an HR variant, had normal hair density [7]. In the dominant forms there is variable expressivity and, in monilethrix, incomplete penetrance and parental mosaicism [110, 111]. In Marie Unna, a Danish woman with the familial variant had increased hair in adolescence and, as an adult, hair of normal length and thickness but coarse, unlike the usual post-pubertal loss [11]. In the minoxidil trial in LIPH-related ARWH, the three patients from the same family all responded better than the others, which the authors interpreted as a possible effect of a genetic modifier [34]. In the Chinese series, the variant p.(Gly152Arg) was associated with a milder phenotype than p.(His248Asn) [99].

3. Clinical Spectrum and Manifestations by System

3.1. Features common to the non-syndromic forms

In the non-syndromic forms, the defect is confined to the hair and, in some, to the follicular skin. Growth, development, teeth, nails and sweating are normal, and it is precisely this normality that separates these disorders from the ectodermal dysplasias, which affect several appendages of ectodermal origin [4, 76]. The signs that guide identification of each group are the age at which hair fails (at birth, in the first months or during childhood), the extent (scalp only, or also eyebrows, eyelashes and body hair), the appearance of the shaft (normal, woolly, coarse or beaded) and the presence of follicular papules, cysts or vesicles. None of the sources consulted describes prospective natural history cohorts; the data come from family series and isolated cases.

3.2. Atrichia with papular lesions and congenital alopecia universalis (HR)

In APL, the newborn has hair, which may be normal or sparse and patchy, and loses it in the first months; the hair does not regrow [2, 7]. In the Syrian case published in 2026, shedding began at 2–3 months and alopecia was complete by 6 months [4]; in the American case of 2022, loss occurred between 6 and 12 months [7]. Loss affects the scalp, eyebrows, eyelashes and body hair; isolated hairs sometimes remain, and at puberty axillary and pubic hair is absent or reduced [3, 4]. The papules, which correspond to keratin-filled follicular cysts, are smooth, firm, whitish or skin-coloured, 1–3 mm, milia-like, and appear on the face (mainly the cheeks), scalp, limbs and trunk; they usually appear between 2 and 3 years of age and increase in number with age, although in the Syrian case they were noticed by the parents at 12–18 months [4, 7]. The hypopigmented whitish streaks on the scalp surface were described by Zlotogorski as a constant finding [2]. The skin is smooth and without scarring, and nails, teeth, sweating and growth are normal [4]. The alopecia is permanent and does not respond to the treatments used in alopecia areata [2, 4]. The American patient had global developmental delay without an identified genetic cause, which the authors did not attribute to APL [7]. In ALUNC, as defined by Alibrahim and colleagues, complete loss is present at birth or in the immediate neonatal period and papules are absent [4]. In the families described by OMIM, the Pakistani newborns had a few fine hairs on the vertex that fell out within weeks (or did not regrow after the ritual shaving of the first week), the Omani infants lost their fine hair by 2 months, and a 17-year-old Israeli Arab girl, with apparently unrelated parents, lost her normal hair by 4 months, without papules but with small keratinising cysts on biopsy [78]. In an Arab family from Upper Galilee with seven affected members over five generations, the papules covered the whole skin, predominantly on the cheeks, thighs and buttocks [79]. Heterozygotes have normal hair and, in a large consanguineous family, 31 healthy male relatives, carriers or not of the variant, had the same pattern of androgenetic alopecia [79]. OMIM draws attention to the fact that monilethrix may be labelled congenital alopecia universalis if the few existing hairs are not examined under the microscope [78].

3.3. Marie Unna hypotrichosis (HRURF, EPS8L3)

Scalp hair, eyebrows and eyelashes are absent or sparse at birth [113]; during childhood coarse, wiry, twisted hair that is difficult to comb grows, and after puberty progressive loss sets in, often with a pattern similar to that of androgenetic alopecia, with loss of eyebrows and eyelashes [10, 11, 13]. In the Danish family, the 4-year-old boy had blond, sparse, coarse, dry and wiry hair, a high and receding frontal hairline, absent eyebrows, and sparse eyelashes and body hair; his 8-year-old sister had unmanageable, frizzy, coarse hair that never grew past her shoulders; and their 42-year-old mother had very sparse hair at birth, short frizzy hair in childhood and scalp hair growth in adolescence, with hair of normal length but coarse as an adult, and onychoschizia [11]. Trichoscopy showed a scalp without inflammation and 1–2 hairs per follicle; light microscopy showed longitudinal grooves, variation in diameter and a frayed cuticle [11]. Twisted shaft dystrophy distinguishes Marie Unna from the simple hypotrichoses; the main manifestation is a progressive, patterned scalp alopecia, and a six-generation Italian family had 20 affected members [113]. A five-generation Chinese family combined HRURF-related Marie Unna with multiple trichoepitheliomas, without CYLD variants [97]. In the Chinese family with the EPS8L3 form, the 36-year-old proband had little or no hair at birth; in childhood the hair became wiry, irregular and difficult to comb, the frontal and parietal regions became bald or sparse and the eyebrows and eyelashes were always thin, with a normal vertex, pubic and axillary hair that did not develop, slight scarring and normal intellectual and sexual development; biopsy showed a marked reduction of mature follicles [14].

3.4. Simple hypotrichoses without shaft abnormality

In the APCDD1 forms, hair is normal at birth and thinning and loss begin in early childhood and worsen with age [12, 16]. In CDSN-related hypotrichosis simplex of the scalp and KRT74-related hypotrichosis 3, hair is normal in early childhood, loss limited to the scalp begins in the middle of the first decade and baldness is near-complete by the third, while body hair, beard, eyebrows, axillary hair, teeth and nails remain normal [12, 18, 23]. In the large eight-generation Spanish family in which scalp hypotrichosis was described, the children were normal at birth, growth slowed between 5 and 12 years and, between 20 and 25 years, all affected individuals, men and women, were left with only sparse, thin, short hairs; other families had hypotrichosis already present at birth or onset between 6 and 17 years [19]. Microscopy is normal in the early stages, and in advanced stages there are focal areas of defective cuticle [19]. In the Pakistani family with hypotrichosis 3, the 14 affected members were born with sparse hair, which regrew after ritual shaving but began to thin between 3 and 5 years of age, with normal eyebrows, eyelashes, beard and moustache [24]. In the SNRPE form, loss is present from birth or early childhood and varies greatly within and between families, from thinning of the scalp and axillae to complete loss of scalp and body hair, with sparse or absent eyebrows and pubic hair usually spared [12, 46]; in the original Spanish family the hair was light and fine, the 4-year-old child and the mother had diffuse absence of scalp hair and two cousins had had no hair since birth, and biopsy showed vellus-type follicles [47]. In the RPL21 form, density is normal at birth, loss begins in the first six months and progresses to near-total loss of scalp hair, with fine, dry and fragile residual hairs and sparse body hair, eyebrows and eyelashes [12, 48]; in the two Chinese families loss began between 2 and 6 months, without regrowth or shaft twisting, the beard was spared and biopsy showed smaller and fewer follicles [49]. In hypotrichoses 9 and 10, each known from one consanguineous Pakistani family, the hair was brown, fine and sparse from birth on the scalp, arms and legs, with normal eyebrows and eyelashes (hypotrichosis 9), or absent from the scalp at birth, with sparse eyebrows, eyelashes, beard and body hair and papules on the scalp where the shafts ended without crossing the skin (hypotrichosis 10) [44, 45]. In LSS-related hypotrichosis 14, scalp hair is sparse to absent and lanugo-like, with sparse and fragile eyebrows and sparse eyelashes and body hair [53]; histology showed a thickened epidermis, absence of follicles and sebaceous hyperplasia [109], and in 2026 dental dysplasia was proposed as an associated feature [114].

3.5. The LSS spectrum beyond hair

LSS illustrates the transition from an isolated hypotrichosis to syndromic forms in the same gene. Extensive congenital cataract was the first phenotype described; alopecia-intellectual disability syndrome (APMR4) combines hypotrichosis with intellectual disability or developmental delay, often with early-onset epilepsy, in ten individuals from six families [54]; also counting a patient with a single variant and allelic imbalance, OMIM summarises 11 patients from seven families, all with complete alopecia at birth, eight with ichthyosis and/or erythroderma, eight with epilepsy with onset between birth and 10 weeks, nine with absent or very limited speech, seven with hypotonia and delayed or absent walking, three with microcephaly, genital abnormalities in four of six boys, brain magnetic resonance imaging with non-specific changes in seven of nine and normal cholesterol in four of five [85]; two patients with palmoplantar keratoderma and congenital alopecia also had early cataract, pseudo-ainhum and agenesis of the corpus callosum [107]; and two Japanese patients had congenital hypotrichosis and midline anomalies without cataract [108]. In the Swiss siblings described by Romano, intellectual disability was initially considered coincidental, but Besnard's series, in which all patients had it, does not support this interpretation [85]. The non-syndromic forms (hypotrichosis 14) were described in two Arab sisters, with lanugo-like hair and short, fragile eyelashes at birth and marked loss in primary school, and in an Afghan family with four affected members, with sparse pubic hair and absence of axillary hair [55]. A 2025 case with a variant of EBP, another cholesterol synthesis gene, with congenital alopecia and cataracts, was presented as a phenocopy of LSS deficiency [115].

3.6. Recessive localised hypotrichosis and woolly hair (LIPH, LPAR6, KRT25, C3orf52, DSG4)

In recessive woolly hair, the hair is abnormal from birth or the first months: fine, sparse, tightly curled, with spiral curls or waves resembling sheep's wool, dry and dull, fragile and sometimes less pigmented; it grows slowly and stops growing at a few centimetres, rarely beyond 12 cm [32, 82]. Most patients have normal eyebrows, eyelashes, beard, axillary and pubic hair, nails, teeth and sweating, although eyebrows and eyelashes may be sparse; palmoplantar keratoderma or perifollicular keratosis is rare [32]. In LPAR6 disease, some patients have hyperkeratotic follicular papules, erythema and pruritus [12]. The degree of hypotrichosis ranges from mild to total alopecia, and the hair may improve or worsen with age [32]. In the Pakistani families, hair present at birth regrows sparse after the ritual shaving of the first week, and affected men have normal beard and moustache despite sparse or absent eyebrows, eyelashes, axillary and body hair; woolly hair and hypotrichosis may coexist within the same family, and the feature common to all is woolly hair at birth or in early childhood with growth that stops at a few centimetres [33, 37]. Among the Mari, eyebrows and eyelashes disappeared after the first year and pubic and axillary hair was practically absent [33]. Scalp biopsy showed, for LIPH and LPAR6, absence of normal follicular structures, replaced by comedo-like follicular remnants with hyperkeratinised infundibula and sebaceous glands disconnected from the follicles; in the Japanese patients there were diffuse pale follicular papules, dilated infundibula with keratin plugs and miniaturised bulbs [33, 37]. In KRT25-related woolly hair, the hair may be soft, short and sparse in the first years and only curl at about 4 years of age [40]. In C3orf52 disease, alopecia is focal, mainly parietal or on the eyebrows, without generalised woolly hair [32, 41]. In DSG4-related LAH, the hair is short, fragile and sparse on the scalp, trunk and limbs, with thin, atrophic shafts, frequent follicular papules and pruritus, onset in infancy and highly variable expressivity within the same family; some patients have beaded shafts and congenital scalp erosions [12, 28]. In the 12 Jewish families, all patients had generalised scalp alopecia in the first days of life, with a "black dots" appearance, and hyperkeratotic follicular papules with erythema, scaling and pruritus in infancy; the hair improved at the end of the second year, leaving patchy or extensive alopecia, mainly posterior, and some hairs reached 10 to 20 cm; the papules predominated on the back of the scalp and the nape, with variable numbers on the extensor surfaces of the arms and thighs and in the periumbilical region, and the eyebrows and eyelashes were sparse, with pubic hair spared [29]. In a large Pakistani family, severity varied between siblings unrelated to age, from mild forms sparing eyebrows and eyelashes to a 13-year-old boy almost without hair [29]. Shaft beading is best seen by dermoscopy of short, fine hairs and may be absent in long terminal hairs obtained by pulling or cutting, and one Chinese patient also had enamel hypoplasia [29, 61].

3.7. Dominant woolly hair (KRT74, KRT71, ADAM17)

In dominant woolly hair, the hair is tightly curled over the whole scalp and often on the eyebrows, persists into adulthood and is rarely accompanied by severe hypotrichosis; density is often normal and the problem is mainly one of texture [32]. In the Pakistani KRT74 family, the hair of the whole scalp was coarse, dull, dry and tightly curled from birth, with normal density, slow growth to a few centimetres, dystrophic anagen hairs with twists, knots and tapered ends on microscopy, and normal eyebrows, eyelashes and beard [25]. In a family described in 1987, normal and woolly hairs were intermixed over the whole scalp, with 20–38% abnormal hairs [25]. The KRT71 and ADAM17 families had associated hypotrichosis [50, 57]; in the Japanese KRT71 family, the 5-year-old child had tightly curled hair since birth, short, without fragility or papules, with reduced density of the scalp, eyebrows and eyelashes and longitudinal grooves on electron microscopy, while the father and grandfather had improved with age until left only with woolly hair of near-normal density [52], and in the family with the KRT71 intronic variant the hair was also poorly anchored (loose anagen hair) [103].

3.8. Monilethrix (KRT81, KRT83, KRT86, DSG4)

Monilethrix causes dystrophic-type alopecia: the shafts break at the constrictions, and the result is short, fragile hair, with diffuse occipital or temporal alopecia and follicular hyperkeratosis of the occipital region, the nape and the extensor surfaces of the limbs [60, 111]. The scalp is usually the only site affected, but in severe forms the secondary sexual hair, eyebrows, eyelashes and nails are affected [12]. Intra- and interfamilial variability is wide [111], there are carriers with apparently normal but less elastic hairs [110], and mosaic patients have mild manifestations [111]. Van Steensel and colleagues consider the disorder under-reported because of the mild forms [60]. The nodes are about 0.7 mm apart, the periodicity is neither diurnal nor synchronous between follicles, and in mild forms a few beaded hairs must be sought carefully [61]. In the four-generation British family, the hair was normal at birth, erythema and follicular hyperkeratosis of the occipital region and nape appeared in the first months and the hair then broke, leaving a stubble of 1–2 cm over the whole scalp [61]. Loss may persist throughout life, or the hair may regrow apparently normal in adolescence or, temporarily, in pregnancy, and some families have nail abnormalities [61]. In a French family with a KRT81 variant, a 4-year-old girl had dystrophic alopecia and obvious moniliform hair, her 1-year-old brother had changes only on electron microscopy, and the mother, without signs as an adult, had kept hairs from childhood with typical beading, the first demonstration of a moniliform phenotype that improves until it becomes undetectable [62]. In patients with KRT83 variants, loss was concentrated in the occipital region and worsened with friction, such as wearing a cap, and a 27-year-old patient had had "rough skin" since childhood due to follicular hyperkeratosis of the neck, arms, elbows and thighs; one patient's grandmother had scarring on the vertex [63]. The recessive DSG4 form overlaps clinically with LAH [28].

3.9. Hypotrichosis with recurrent skin vesicles (DSC3)

In the Afghan family, the four affected members had sparse and fragile scalp hair, absent eyebrows and eyelashes and vesicles filled with watery fluid on the scalp and most of the skin; biopsy showed mild follicular plugging [65]. The 4-year-old Saudi boy had, since birth, diffuse non-scarring alopecia of the scalp and recurrent intraepidermal blisters localised to the extremities, with post-inflammatory hyperpigmented macules and follicular hyperkeratosis [66]. In the Afghan family, hair present at birth regrew after ritual shaving but was fragile and began to fall out at 2–3 months; the vesicles, under 1 cm, disappeared and reappeared, ruptured with release of fluid and left scars that took 3–4 months to heal, without mucosal involvement, and the electrocardiogram and immunoglobulins IgA, IgE and IgD were normal [67]. A published comment questioned whether the lesions photographed were vesicles or keratosis pilaris, because the biopsy showed follicular plugging without a blister, and the authors maintained their description [67]. The Egyptian boy with the second nonsense variant had no hair at birth, later had hair that was always sparse and easy to pull out and, from 4 years of age, blisters on the hands, feet and knees and at sites of trauma, with follicular hyperkeratosis, dry skin, angular cheilitis, leukonychia with thin, brittle nails and irregular grooves in the dental enamel; trauma-induced skin fragility was the main difference from the Afghan siblings [67].

3.10. Treated disease

None of the entities has a treatment that alters the natural history. Treated-disease data are limited to improvements in density and shaft diameter with topical minoxidil in patients with LIPH variants [34], responses described with minoxidil in monilethrix [64] and a pilot study of topical gentamicin in CDSN-related hypotrichosis [21], detailed in section 7.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Total or near-total alopecia beginning in the first months of life, without inflammation, with eyebrows and eyelashes also lost, should suggest APL before alopecia areata, especially in children of consanguineous parents or with affected siblings [3, 4]. The later appearance of milia-like papules on the face and scalp strengthens the suspicion [7]. A child born with little hair who develops coarse, unmanageable hair in childhood, with a parent with a similar history and early baldness, suggests Marie Unna [11]. Hair that never grows beyond a few centimetres, tightly curled from birth, suggests recessive woolly hair, especially in families of Pakistani, Japanese, Chinese or Volga-Ural origin [32, 82]. A child with normal hair who progressively loses scalp hair from 5–10 years of age, with eyebrows and body spared, and with vertical transmission, suggests hypotrichosis simplex of the scalp [12, 18]. Short hairs that break, with follicular papules on the nape, suggest monilethrix [111].

4.2. Signs indicating a syndromic form

The presence of any of the following shifts the diagnosis towards a syndromic or metabolic form: rickets, hypocalcaemia or seizures in a child with total alopecia (VDR-related vitamin D-resistant rickets) [5]; developmental delay, epilepsy or cataract (LSS spectrum, alopecia-intellectual disability syndromes) [54]; hypodontia, conical teeth or heat intolerance (ectodermal dysplasias) [76]; palmoplantar keratoderma with woolly hair (desmosomal cardiomyopathies) [81]; severe infections in infancy (FOXN1 deficiency) [12]; ichthyosis, photophobia or keratosis follicularis spinulosa (IFAP) [116]; failure to thrive, periorificial rash, hypotonia or hearing loss (biotinidase deficiency and other inborn errors) [117, 118]; growth deficiency and failure of tooth eruption (GAPO) [119]; and hypogonadism at puberty with dystonia (Woodhouse-Sakati syndrome) [68].

4.3. Diagnostic pitfalls

The best-documented pitfall is a diagnosis of alopecia areata universalis in a child with APL, followed by topical and systemic corticosteroids and other immunosuppressants without response [4, 7]. In the Syrian case, the child was diagnosed with alopecia areata between 2 and 3 years of age and received several treatments before the correct diagnosis at 4 years [4]. The second is to consider that an exome or panel with negative HR excludes Marie Unna, when the variant lies in the 5′UTR, outside the coding sequence [11, 12]. The third is to attribute early total alopecia to an HR defect without excluding VDR-related rickets, whose alopecia is identical [5].

4.4. Emergency signs and newborn screening

The non-syndromic forms have no emergency signs. Emergencies arise in the differentials: hypocalcaemia with seizures in vitamin D-resistant rickets [5], severe infections in FOXN1 athymia, whose neonatal T lymphopenia can be detected by low TRECs (T-cell receptor excision circles) on newborn screening [12], and metabolic decompensation in biotinidase deficiency, in which delayed diagnosis leads to irreversible neurological damage [117]. None of the non-syndromic monogenic hypotrichoses is part of newborn screening programmes.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria for APL

Only APL has formal clinical criteria. Zlotogorski and colleagues proposed them in 2002 [2] and Yip and colleagues revised them in 2008 [3]; the revised version, as summarised by Alibrahim and colleagues, has five major and five minor criteria, and the diagnosis is considered highly probable with at least four major criteria [4].

Source: Yip and colleagues, in the version summarised by Alibrahim and colleagues [3, 4].

5.2. Clinical evaluation and first-line investigations

Evaluation begins with a three-generation history, with specific questions about hair, teeth, nails, skin, sweating, deaths in childhood and orofacial clefts; a description of the hair in the neonatal period, whether it has ever been cut, whether it breaks easily and its colour; and the age at tooth eruption [76]. Examination includes hair colour, texture and length, broken ends, tooth count (20 deciduous and 32 permanent), nails, skin and a search for associated anomalies [76]. The pull test and trichoscopy indicate the nature of the defect: in the Danish Marie Unna family trichoscopy was normal, without scaling or perifollicular inflammation, with 1–2 hairs per follicle, and the pull test was negative [11]; in recessive woolly hair trichoscopy shows highly wavy serpiginous hairs, breaks and black dots [32]; in one case of APL a "star cluster" pattern was described [4]. Light microscopy of the shaft identifies monilethrix (nodes and internodes) and distinguishes it from the hypotrichoses without structural abnormality [12, 60]. In every child with early total alopecia, serum calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, with radiographs when indicated, exclude vitamin D-resistant rickets [5, 12]. In the Syrian case, the values were calcium 9.8 mg/dL, phosphorus 4.2 mg/dL, alkaline phosphatase 256 U/L and 25-hydroxyvitamin D 32 ng/mL; full blood count, liver, renal and thyroid function and serum zinc were normal [4].

5.3. Histology

Scalp biopsy (4 mm punch) in APL shows a thinned epidermis, absence of mature terminal follicles and sebaceous glands, and multiple keratin-filled follicular cysts in the upper and mid dermis, lined by stratified squamous epithelium, without inflammatory infiltrate or fibrosis [4]. This absence of inflammation separates APL from alopecia areata, with its peribulbar lymphocytic infiltrate [12]. Histology does not distinguish APL from ALUNC or from the alopecia of vitamin D-resistant rickets: in all three there are empty infundibula, absence of the lower two thirds of the follicle, irregular epithelial structures and keratinising cysts at all levels of the dermis, and the cysts may be present histologically without being visible on the skin (comparative study by Bergman and colleagues, cited by Boisen) [7]. In early or atypical APL the biopsy may be normal or inconclusive [4]. In CDSN-related hypotrichosis simplex of the scalp, the biopsy shows perifollicular and papillary dermal deposits that stain with Congo red and thioflavin T [12, 104].

5.4. Genetic testing

Genetic testing is the reference standard for definitive diagnosis, genotype-phenotype correlation and counselling [4, 7]. Because HR is a large gene, gene-by-gene Sanger sequencing is costly and slow, and Ali and colleagues recommend exome sequencing with priority analysis of the known genes [6]. A panel for hair disorders and ectodermal dysplasias, or targeted analysis of an exome or genome, should include at least HR and the 5′UTR/HRURF, EPS8L3, APCDD1, CDSN, KRT74, KRT71, KRT25, SNRPE, RPL21, LSS, LIPH, LPAR6, C3orf52, DSG4, DSC3, ADAM17, KRT81, KRT83, KRT86 and VDR, because the phenotype does not distinguish the lipid-axis genes from one another, nor the monilethrix keratins from one another [12, 32]. The choice of a panel rather than a single gene also follows from population distribution: among Pakistani families with recessive woolly hair, 52.8% had LPAR6 variants and 47.2% LIPH variants, whereas in Japan 98.7% had LIPH variants [82]. In the Danish family with Marie Unna, the HRURF variant was found by genome sequencing with analysis of a panel of ectodermal dysplasias and differentials [11].

5.5. Limitations of testing

A negative result does not exclude the diagnosis. Marie Unna type 1 results from variants in the 5′UTR of HR, outside the coding sequence, and an exome limited to coding regions or a panel covering only the HR coding sequence will not detect it; the request must mention HRURF [11, 12]. Deep splicing variants, such as the LSS intronic variant c.893-175G>A, have been identified only with genome and RNA sequencing [109]. The LIPH exon 4 deletion, a founder variant in the Volga-Ural region, and the intragenic DSG4 deletions (of about 5 kb in Pakistan and of 48,644 base pairs, from intron 1 into the DSG4–DSG3 intergenic region, in a Chinese patient) require methods that detect copy number variants [12, 29, 31]. In consanguineous families, analysis should not stop at a search for homozygosity: in LIPH, compound heterozygous affected individuals have been described within consanguineous families, with linkage to the locus but without homozygosity [33]. Low-level mosaicism in a parent may go unnoticed on conventional sequencing, as shown by the weaker signal of the KRT86 variant in the mother of the Turkish family, confirmed by SNaPshot [111]. Keratin genes form clusters at 12q13 and 17q21 with very similar paralogues, and the report should confirm in which gene the variant lies [12]. About half of the hypotrichosis simplex cases studied up to 2018 had no identified genetic cause [53], and there are still two hypotrichosis loci (9 and 10) without a gene, in which sequencing of the coding and splicing regions of the candidate genes in each interval found no variants [44, 45].

5.6. Report content and interpretation

The report should state the gene, the transcript with version (for HRURF, NM_001394132.1), HGVS nomenclature, zygosity and class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [11, 96]. Zygosity is decisive in CDSN: a heterozygous nonsense variant indicates dominant scalp hypotrichosis, two null variants indicate recessive peeling skin disease [12]. In KRT83, a heterozygous missense variant predicts monilethrix, and biallelic loss of function predicts skin disease [112]. In KRT74, heterozygosity is associated with dominant woolly hair or hypotrichosis and homozygosity with pure hair and nail ectodermal dysplasia [102]. A variant of uncertain significance in a keratin gene, such as the KRT81 variant coexisting with a pathogenic KRT86 variant in the Venezuelan family, should be interpreted by segregation [60]. Protein notation should follow VariantValidator when it differs from the published notation, as for the LIPH deletion c.659_660del [96].

5.7. Algorithm

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis is possible when the familial variants are known [76], and molecular results can be used for prenatal diagnosis, carrier testing and counselling in populations with recurrent variants, such as the Kashmiri families with APL [6]. The sources consulted do not describe use of preimplantation genetic testing in these disorders; technically it applies to any known familial variant. The decision should take into account that these are disorders limited to the hair, without systemic involvement [4].

6. Differential Diagnosis

6.1. Comparative table

6.2. Alopecia areata

Alopecia areata universalis is the diagnosis that most often wrongly replaces APL, and Zlotogorski and colleagues consider that this confusion explains the low published prevalence of APL [2]. The distinction rests on age at onset (APL begins in the first months and alopecia areata rarely does), on the papules and streaks, on histology without inflammation and on genetic testing [3, 4]. The distinction has therapeutic consequences: severe alopecia areata now has approved Janus kinase (JAK) inhibitors, such as ritlecitinib (LITFULO®, approved by the FDA for adults and adolescents aged 12 years and over and in the European Union on 15 September 2023) and baricitinib (Olumiant®, with severe alopecia areata in adults among its indications in the European Union) [120, 130, 131], whereas in APL there is no inflammation to treat and corticosteroids and immunomodulators are ineffective and cause exposure to adverse effects [4, 7].

6.3. Vitamin D-resistant rickets type 2A

Alopecia due to biallelic VDR variants is clinically and histologically a phenocopy of APL, including the cysts [5]. Patients are born with hair and lose it in the first months, and may have milia-like cysts [7]; the atlas of skeletal dysplasias states that alopecia may be present at birth and that presentation varies widely, sometimes only in adulthood with short stature and deformities [122]. In a consanguineous Bedouin family, the 6-year-old proband had had alopecia and rickets since infancy, mild sensorineural hearing loss and an asymptomatic papular eruption of the face and scalp since 2 years of age, a cutaneous picture superimposable on that of APL [121]. Not all patients with VDR-related rickets have alopecia: all variants described in the DNA-binding domain were associated with alopecia, but about a third of the ligand-binding domain variants (7 of 21) were not; patients with alopecia were diagnosed earlier (0.9 versus 3.3 years) and responded less well to calciferol, and in a child whose rickets responded to 1-alpha-hydroxycolecalciferol the alopecia did not regress [121]. Only the rickets and the calcium and vitamin D abnormalities separate the two disorders, and biochemistry is therefore mandatory before HR testing [5, 12].

6.4. Syndromic and metabolic forms

The ectodermal dysplasias are distinguished by involvement of more than one appendage: teeth, nails and sweat glands [76]. Focal congenital alopecia also has syndromic causes: in incontinentia pigmenti (IKBKG, X-linked dominant, lethal in most boys) there is patchy atrophic alopecia, mainly on the posterior vertex, with dull and coarse or fine and sparse hair in early childhood [132]; in encephalocraniocutaneous lipomatosis, due to mosaic activating variants of FGFR1 or KRAS, naevus psiloliparus (hairless lipomatous naevus of the scalp, usually unilateral and frontotemporal) is associated with intellectual disability in 30% and seizures in 50% [133]. GAPO syndrome combines postnatal growth deficiency visible between 6 months and 1 year, reduced hair from 2–3 months with total alopecia by 2–3 years, failure of eruption of the deciduous and permanent dentition and progressive optic atrophy in about a third [119]; a review of 105 cases published since 1947 describes a multisystem disorder with excessive extracellular matrix deposition due to loss of function of ANTXR1 [134]; optic atrophy is not constant [125]. IFAP syndrome combines ichthyosis follicularis, atrichia and photophobia; the X-linked form results from MBTPS2 variants and the dominant form from SREBF1 variants, both in the SREBP pathway of cholesterol regulation, with a normal serum lipid profile [116]. In the X-linked form, boys have the full picture, ranging from congenital atrichia to alopecia established at 18 months after normal hair at birth, and carriers may have atrophoderma and ichthyotic lesions along Blaschko's lines, due to functional X-chromosome mosaicism; the BRESHECK variant adds brain malformations, intellectual disability, Hirschsprung disease, corneal opacities, renal dysplasia, cryptorchidism, cleft palate and vertebral malformations [127]. A 5-month-old Portuguese infant with severe IFAP/BRESHECK, with ichthyosis follicularis, atrichia, photophobia, brain malformations, global delay, hypotonia, Hirschsprung disease and renal hypoplasia, had the recurrent MBTPS2 variant NM_015884.4:c.1286G>A p.(Arg429His) [127]. GAPO syndrome, the MBTPS2 and SREBF1 spectra, alopecia-intellectual disability syndrome and FOXN1 deficiency belong to the congenital alopecia syndromes with systemic involvement. Palmoplantar keratoderma with congenital alopecia type 1, due to a heterozygous GJA1 missense variant (NM_000165.5:c.23G>T p.(Gly8Val)), combines alopecia or hypotrichosis from birth with total leukonychia, diffuse keratosis pilaris and hyperkeratotic plaques at friction sites beginning at about 2 years of age [128]. In alopecia-intellectual disability syndrome type 1, described in consanguineous families from the Middle East and Pakistan, alopecia is total from birth and affects all hair-bearing areas, with moderate to severe intellectual disability (intelligence quotient of 40 to 54 in the Iranian family with the AHSG variant) and, in one sibship, deafness [84]; an estimate cited by OMIM, based on about 14 published patients, proposes a worldwide prevalence of 1 per million, a value derived from case counts and not from a population study [84]. Among inborn errors of metabolism, alopecia occurs mainly in the neonatal period and in infancy, in zinc deficiency and acrodermatitis enteropathica, biotin-responsive multiple carboxylase deficiency, defects of calciferol metabolism, essential fatty acid deficiency, Menkes disease, methylmalonic and propionic acidurias, ornithine aminotransferase deficiency and the porphyrias; many of these causes are treatable [118]. In biotinidase deficiency, rash and alopecia are hallmarks of the disease but may appear late or not at all, and all patients respond to oral biotin [117]. Woolly hair with palmoplantar keratoderma requires cardiac evaluation, because the desmosomal disorders due to JUP (Naxos disease) and DSP (dilated cardiomyopathy with woolly hair and keratoderma) cause cardiomyopathy [81]; a 2025 review attributes Naxos disease to DSG2 and Carvajal syndrome to DSC2 [32], which diverges from the OMIM entries and should not be followed [81]. Other signs accompanying syndromic woolly hair are skin fragility and cheilitis (PKP1), dental anomalies and cranial sclerosis (tricho-dento-osseous syndrome, DLX3) and the RASopathies (Noonan, cardiofaciocutaneous, Costello) [32].

6.5. Shaft abnormalities

Monilethrix is distinguished by periodic constrictions and by perifollicular papules and erythema, absent in woolly hair; pili torti have milder 90–360° twists that are irregularly spaced; trichorrhexis nodosa produces a longitudinal brush-like fracture; and pseudo-pili annulati result from invagination of the shaft [32]. Trichorrhexis nodosa and tapered ends are also seen in woolly hair [12]. In the variant forms of argininosuccinic aciduria, trichorrhexis nodosa is characteristic: from a distance the child may appear hairless, but there is always a short down; the hair is dry, short and very fragile, and under the microscope the shaft has small nodules where breakage occurs [135].

7. Treatments and Risk Management Strategies

7.1. Principles and absence of guidelines

There is no guideline or scientific society consensus for the hereditary hypotrichoses and atrichias; searches of the literature and the European networks identified no such document, and the available recommendations come from diagnostic criteria, reviews and case series [3, 32, 82]. No drug has an approved indication for any of the core entities [12]. The first therapeutic measure is the correct diagnosis, which spares the child with APL futile and potentially harmful treatments, such as systemic corticosteroids or disease-modifying antirheumatic drugs [4, 7]. Management is supportive: sun protection of the hairless scalp, wigs and other forms of camouflage, treatment of symptomatic follicular cysts, genetic counselling and psychological support [4, 12]. The 2025 review of recessive woolly hair describes current treatments as "symptomatic trials" without standardised evidence-based regimens [32].

7.2. Atrichia with papular lesions and Marie Unna

In APL, alopecia is irreversible and no treatment restores the hair; alopecia areata treatments, including topical and systemic corticosteroids, were ineffective in the published cases [4, 7, 12]. For the milia-like papules, Boisen's patient received tretinoin 0.05% cream, stopped after two months because of skin irritation; the authors note that the results of topical tretinoin in eruptive milia are variable [7]. The Syrian family received counselling on the irreversibility of the disorder and psychological support [4]. In Marie Unna, management likewise consists of camouflage and counselling [12]. The JAK inhibitors approved for severe alopecia areata have no rationale in APL, which is not inflammatory [4, 120].

7.3. Minoxidil in LIPH-related recessive woolly hair

Minoxidil is a peripheral vasodilator; applied to the scalp it causes dilatation of the local microcirculation with a dose-response relationship [136]. The only prospective evidence in this class is the study by Taki and colleagues, an open-label, non-randomised, two-arm, single-centre trial in Nagoya lasting one year: eight Japanese patients with LIPH-related recessive woolly hair (four men and four women, 4–38 years; three compound heterozygous c.736T>A/c.742C>A and five homozygous c.736T>A, three of them from the same family) applied minoxidil 1% solution, 2 mL twice daily over the whole scalp, for one year; a 31-year-old woman with trichorhinophalangeal syndrome type 1 received the same treatment [34]. Hypotrichosis improved in the eight patients with LIPH variants, measured by the percentage of hair-covered area on standardised photographs, and shaft diameter increased significantly (P<0.01) in the temporal region in seven patients and in the occipital region in seven; the patient with trichorhinophalangeal syndrome did not improve [34]. The response was binary: some patients ended with a hair-covered area above 80% and began to need haircuts, others remained below 50%, and the three relatives were all in the first group [34]. One patient withdrew on day 196 because his hair was too long and he wanted to cut it, and another worsened during a period in which he applied the product only once daily [34]. There were no serious adverse effects; mild ones were dry scalp skin, trichiasis and mild body hypertrichosis [34]. The solution was supplied by the manufacturer [34]. Outside this trial, four Japanese patients with LIPH variants had significant growth with minoxidil 1% or 5% for 6 months to 3 years [32]. There are no studies in patients with LPAR6, KRT25 or C3orf52 variants [12, 82]. Use is off-label [32].

7.4. Minoxidil in monilethrix and other hypotrichoses

A systematic review of 24 studies on monilethrix (16 paediatric only, 3 mixed, 3 adult only and 2 with unspecified age) identified topical and oral minoxidil as the most effective therapies, with variable efficacy of oral retinoids and other treatments, and concluded that paediatric studies are needed to assess long-term outcomes [64]. A 2026 report describes a response to sublingual minoxidil in a congenital hypotrichosis with ectodermal features of hair and teeth [137]. The sources consulted do not provide a dose of oral minoxidil for hair disorders; the only oral minoxidil label in Portugal is for severe hypertension, and it should not be used as a dose reference for this purpose [138].

7.5. Minoxidil dosing: reference study and comparison labels

The dose in the Taki trial (1% solution, 4 mL/day) differs from the European label in concentration and volume: the label uses 2% and 5% solutions with a maximum of 2 mL per day and excludes children and adolescents, so the trial regimen lies outside the label conditions in age, indication and volume [34, 136]. The American over-the-counter label is even more restrictive in indication (vertex, adult men) [140].

7.6. Topical gentamicin in CDSN-related hypotrichosis simplex of the scalp

Gentamicin, an aminoglycoside, can induce read-through of premature termination codons. Peled and colleagues showed, in a reporter system and in a patient's primary keratinocytes, that gentamicin induced read-through of a recurrent CDSN nonsense variant and restored synthesis of full-length corneodesmosin; in a pilot trial, four patients applied topical gentamicin to the scalp for six months, with significant improvement in the SALT score (Severity of Alopecia Tool) [21]. The concentration and regimen are not given in the abstract, and the full text was not accessible. The theoretical extension to other nonsense variants, such as those of recessive woolly hair, has no clinical data [32].

7.7. Other treatments described

The 2025 review lists as emerging or experimental options platelet-rich plasma, follicular stem cells, microneedling, low-level laser and traditional Chinese medicine preparations, all with evidence from small case numbers and without controlled studies [32]. The authors consider that drugs targeting the LIPH/LPA/P2Y5 pathway may become options [32]; Malki and colleagues stressed that phosphatidic acid and LPA promote follicle formation in the mouse [32].

7.8. Regulatory status

7.9. Trials and therapeutic studies

None of these studies has a randomised comparison group, and numbers are small; the Taki trial does not report confidence intervals, and its design (open-label, with product supplied by the manufacturer) limits interpretation [34]. The systematic review on monilethrix brings together mainly case reports, subject to publication bias [64]. A ClinicalTrials.gov search in October 2026 using the terms hypotrichosis, atrichia, monilethrix, woolly hair and Marie Unna returned only studies of acquired alopecias (androgenetic, areata, chemotherapy), with no trial directed at the hereditary forms [141].

7.10. Developments in the last 12 months

Between November 2025 and October 2026 there were no authorisations, regulatory applications or drug trials for these disorders. The developments are genetic and mechanistic: functional characterisation of five LIPH variants and of the role of C3orf52 as a membrane anchor for lipase H (preclinical study, August 2026) [98]; new biallelic LSS variants, including a deep intronic variant detected by genome and RNA sequencing (December 2025) and two novel variants in Chinese children (June 2026) [109, 114]; a series of six Chinese patients with LIPH variants and the first proposed genotype-phenotype correlation for p.(Gly152Arg) (November 2025) [99]; a review on the diagnosis and treatment of recessive woolly hair (December 2025) [32]; a Japanese case of HRURF-related Marie Unna (2026) [142]; a case of APL in Syrian siblings with a proposal for clinicopathological diagnosis in low-resource settings (May 2026) [4]; a report of response to sublingual minoxidil (September 2026) [137]; the proposal to unify SREBF1-related IFAP and hereditary mucoepithelial dysplasia (2026) [90]; an EBP phenocopy of LSS deficiency (November 2025) [115]; and brief reviews on congenital atrichia and monilethrix (September 2026) [143, 144].

7.11. Agents to avoid, pregnancy and special populations

In APL, systemic corticosteroids and disease-modifying antirheumatic drugs should be avoided, as they are ineffective and cause exposure to adverse effects [4, 7]. Topical minoxidil is contraindicated in pregnancy and breastfeeding and in people with hypertension or cardiovascular disease [136]. Relatives who apply minoxidil should avoid contact with small children, because of the hypertrichosis described after inadvertent exposure [136]. In the transition to adulthood, Marie Unna may worsen after puberty [11], and the psychosocial impact justifies ongoing support [4, 76].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by inheritance pattern

8.2. Genes with two inheritance patterns

In four genes, the inheritance pattern depends on variant type and zygosity, and counselling has to start from the genotype and not only from the gene. In CDSN, a heterozygous nonsense variant causes dominant scalp hypotrichosis, and two null variants cause recessive peeling skin disease; a couple in which one partner has CDSN-related hypotrichosis and the other carries a null variant may have children with either disorder [12]. In KRT74, heterozygosity is associated with dominant woolly hair or hypotrichosis and homozygosity with pure hair and nail ectodermal dysplasia [23, 102]. In KRT83, heterozygous missense variants cause monilethrix and biallelic loss of function causes erythrokeratoderma [112]. In KRT25 the established inheritance is recessive; association with a dominant family has been described, but OMIM still treats it as unconfirmed [12, 25, 38, 40]. In monilethrix, the absence of vertical transmission should lead to consideration of both recessive DSG4 disease and dominant KRT86 disease with incomplete penetrance or mosaicism in a parent [28, 110, 111].

8.3. Cascade testing, carriers and mosaicism

When the familial variant is known, carrier testing in relatives, prenatal diagnosis and targeted screening in high-risk consanguineous families become possible [4, 6, 76]. In populations with founder variants (the LIPH exon 4 deletion in the Volga-Ural region, c.659_660del in Pakistan, c.736T>A and c.742C>A in Japan and China), targeted testing for these variants is an efficient first step [32, 82]. In the dominant disorders, a clinically normal parent may be a mosaic carrier, as in the Turkish monilethrix family in which the mother had the variant at a lower proportion [111]. Younger siblings of a case of APL can be followed clinically from birth, as in the Syrian family in which the 2-month-old sister began to lose hair before having papules [4].

8.4. Prenatal and preimplantation diagnosis and minors

Prenatal diagnosis is technically possible when the familial variant is known [6, 76]. The decision on prenatal or preimplantation diagnosis in disorders limited to the hair involves ethical considerations and should be discussed in the genetics clinic, taking into account the absence of systemic involvement in the non-syndromic forms [4]. Testing of asymptomatic minors is justified only when it alters surveillance, as in the syndromic differentials (for example, siblings of patients with Woodhouse-Sakati syndrome, to identify hypogonadism in time) [68].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

There are no population prevalence studies for any of the core entities. Orphanet classifies the prevalence of Marie Unna, hypotrichosis simplex of the scalp, woolly hair and monilethrix as unknown; hypotrichosis simplex as a whole is in the class <1/1,000,000, with 38 cases recorded; pure hair and nail ectodermal dysplasia is in the same class, with 20 cases; and alopecia-intellectual disability syndrome has 15 families recorded [69–72, 86, 129, 145]. These figures count published cases and do not measure true frequency. The prevalence of 1–5/10,000 in Europe assigned to "alopecia universalis" (ORPHA:701) refers to alopecia areata universalis [73]. For APL, the authors who proposed criteria consider the disorder underdiagnosed, because it is confused with alopecia areata [2, 3], and monilethrix is considered under-reported because of the mild forms [60]. In Japan, LIPH-related recessive woolly hair is described as the most prevalent hereditary hair disorder [91].

9.2. Founder populations and geographical distribution

The sources consulted contain no data from Portugal on the core entities; the only Portuguese case found is a syndromic differential, an infant with MBTPS2-related IFAP/BRESHECK [127]. From Brazil there is only the record of an LPAR6 variant in recessive woolly hair [32]. The absence of data does not mean the absence of patients.

9.3. Consanguinity and low-resource settings

Most families with APL, LAH and ARWH are consanguineous [4, 82, 95], and diagnosis depends on tests that are not always accessible. Alibrahim and colleagues, in Syria, could not perform HR testing because of financial constraints and advocated a high-probability diagnosis based on clinical criteria, histology and biochemical exclusion, with targeted screening in high-risk consanguineous families [4].

9.4. European networks and patient associations

The relevant European Reference Network is ERN-Skin, dedicated to rare and complex skin diseases [74]. Associations with information on disorders of hair and appendages include the National Foundation for Ectodermal Dysplasias, in the USA, and the Ectodermal Dysplasia Society, in the United Kingdom [75, 76]. In Japan, several syndromic hereditary hair disorders are recognised as designated intractable diseases, with support from the Ministry of Health [91].

10. Illustrative Clinical Case

10.1. Genetically confirmed atrichia with papular lesions

Boisen, Lewis and Hendrick (2022) described a 5-year-old girl, in the USA, seen for congenital absence of most of her hair and hair loss [7]. At birth she had small amounts of black hair in patches, almost all of which she lost between 6 and 12 months of age, without regrowth. On examination there was a single terminal hair on the vertex and complete absence of the rest of the scalp hair, with many 1–2 mm skin-coloured to whitish papules on the scalp; the eyebrows and eyelashes were sparse [7]. Previous genetic testing had identified biallelic likely pathogenic HR variants, described by the authors as c.3515G>A and p.W1172X; the mother was heterozygous and had hair of normal density, and the parents were related (the biological father was a maternal cousin of the mother) [7]. The patient also had global developmental delay without an identified genetic cause. With the diagnosis confirmed, biopsy was not needed; tretinoin 0.05% cream was proposed for the milia-like lesions, which the family stopped after two months because of skin irritation [7]. The figures show the left lateral scalp with absence of hair, papules and a sparse eyebrow (https://pmc.ncbi.nlm.nih.gov/articles/PMC9840447/figure/FIG1/) and the top view of the scalp (https://pmc.ncbi.nlm.nih.gov/articles/PMC9840447/figure/FIG2/). The variants were not normalised because the publication does not state the transcript; topical tretinoin is a symptomatic attempt and not an established treatment.

10.2. Atrichia with papular lesions in siblings, clinicopathological diagnosis

Alibrahim and colleagues (2026) described a 4-year-old Syrian boy, the son of first cousins, born at term weighing 3.2 kg and with normal development [4]. His hair was normal at birth, began to fall out at 2–3 months and alopecia was complete by 6 months; the parents noticed keratotic papules at 12–18 months. Between 2 and 3 years of age he was diagnosed with alopecia areata and received topical and systemic corticosteroids and other treatments, without response. At 4 years he had no scalp hair, eyebrows or eyelashes, with smooth skin without scarring, centroparietal sparing and numerous firm, painless, whitish 2–3 mm papules on the scalp and cheeks; nails, teeth, sweating, growth and neurological examination were normal. Biochemistry, including calcium, phosphorus, alkaline phosphatase and 25-hydroxyvitamin D, was normal. The 4 mm biopsy of the vertex showed a thinned epidermis, absence of mature terminal follicles and sebaceous glands and multiple keratinised follicular cysts without inflammation or fibrosis. His sister, aged 2 months, was born with normal hair and was beginning to lose hair in patches, without papules [4]. HR testing was recommended but not performed because of financial constraints, and the diagnosis was of high probability by Yip's criteria; the family received counselling on irreversibility, psychological support and three-monthly follow-up [4]. The figures show the sister at 2 months (https://pmc.ncbi.nlm.nih.gov/articles/PMC13167302/figure/fig1-03000605261446471/), the boy at 4 years with the scalp and cheek papules (https://pmc.ncbi.nlm.nih.gov/articles/PMC13167302/figure/fig2-03000605261446471/) and the histology (https://pmc.ncbi.nlm.nih.gov/articles/PMC13167302/figure/fig3-03000605261446471/). The case shows the cost of diagnostic error (two years of ineffective treatments) and the value of clinical criteria when testing is not available, but without molecular confirmation it does not exclude other causes of atrichia.

10.3. Marie Unna in a Danish family

Holm and colleagues (2025) studied a 4-year-old boy with diffuse congenital hypotrichosis, blond, sparse, coarse and wiry hair, a high frontal hairline, absent eyebrows and sparse eyelashes and body hair, without signs of hypohidrosis or systemic involvement [11]. Genome sequencing, with analysis of an ectodermal dysplasia panel, identified NM_001394132.1:c.105G>T in HRURF, absent from gnomAD 4.1 and classified as likely pathogenic, also present in the affected mother and sister and absent in the unaffected maternal grandparents [11, 96]. The mother had hair growth in adolescence and, as an adult, hair of normal length but coarse, a course different from the usual post-pubertal loss [11]. The figures (pde15982-fig-0001 to fig-0005) are at https://pmc.ncbi.nlm.nih.gov/articles/PMC12646977/.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The non-syndromic hypotrichoses do not reduce life expectancy or compromise organs; their burden is aesthetic and psychosocial [4, 12]. In APL, alopecia is permanent and the papules increase with age [3, 4]. In Marie Unna, loss usually worsens after puberty, with individual variation [11]. In the dominant simple hypotrichoses, scalp baldness is near-complete by the third decade in the CDSN and KRT74 forms [12, 23]. In recessive woolly hair, the hair may improve or worsen with age, and topical minoxidil improved density in the patients studied with LIPH variants, with loss of benefit when application was reduced [32, 34]. With topical minoxidil, the labels state regression to baseline 3–4 months after stopping [136]. In monilethrix, expression is variable and may be mild [60, 111]. In the forms of the LSS spectrum with cataract or intellectual disability, prognosis depends on these manifestations [54]. Stigmatisation and impact on quality of life have been described in the ectodermal disorders, and many patients develop effective coping strategies [76].

11.2. Surveillance

There is no published surveillance schedule for the non-syndromic hypotrichoses; the intervals in the table derive from the sources indicated and from the practice described in the cases, not from a guideline.

12. Summary and Final Considerations

Congenital and hereditary alopecias form a class of monogenic disorders in which the defect is confined to the follicle and the shaft, unlike the ectodermal dysplasias and the syndromes with alopecia. Atrichia with papular lesions, caused by biallelic HR variants, begins with hair loss in the first months and adds, during childhood, papules that correspond to follicular cysts; it is permanent, non-inflammatory and frequently treated as alopecia areata. The alopecia of VDR-related vitamin D-resistant rickets is identical, and calcium-phosphate biochemistry is mandatory before genetic testing. Marie Unna hypotrichosis depends on variants in the small HRURF ORF in the 5′UTR of HR, which increase the amount of hairless and escape tests limited to coding regions. The simple hypotrichoses (APCDD1, CDSN, KRT74, SNRPE, RPL21, LSS) differ in age at onset and inheritance, and LSS and SNRPE show that a gene for isolated hypotrichosis can also cause syndromic forms. Recessive localised hypotrichosis and woolly hair converge on the LIPH–C3orf52–LPAR6 lipid pathway, with founder variants in the Volga-Ural region, Pakistan, Japan and China, and dominant woolly hair involves inner sheath keratins and ADAM17. Monilethrix results from cortex keratins, with incomplete penetrance and mosaicism that complicate counselling, and from a recessive form due to DSG4. None of these disorders has an approved treatment or a guideline; topical minoxidil improved density in an open-label trial in patients with LIPH variants and is the most cited treatment in monilethrix, always off-label, and topical gentamicin is an experimental approach for CDSN nonsense variants. Management rests on molecular diagnosis with panels that include non-coding regions, counselling based on zygosity and variant type, discontinuation of ineffective treatments and psychosocial support.

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