name: Hypotrichosis 4
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
description: >
  Hypotrichosis 4 (HYPT4; OMIM 146550), clinically known as Marie Unna hereditary
  hypotrichosis 1 (MUHH1), is a rare autosomal dominant hair disorder with a
  characteristic triphasic course: scalp hair, eyebrows and eyelashes are absent or
  scanty at birth, coarse and wiry hair grows in during childhood, and progressive
  scalp hair loss begins around puberty. Other ectodermal structures are essentially
  spared.

  The molecular lesion is unusual and is easy to state backwards. The disease variants
  do not lie in the coding sequence of the hairless gene (HR) at 8p21.3. They lie in
  HRURF (approved 2020; historically and still widely called U2HR), a small inhibitory
  upstream open reading frame embedded in the 5' untranslated region of the HR
  transcript, which encodes a conserved 34-amino-acid peptide and normally represses
  translation of the downstream main HR ORF. Loss-of-initiation, delayed-termination,
  nonsense and missense variants all abolish that repression, and functional assays
  show they converge on *increased* translation of the main HR ORF. The consequence for
  hairless is therefore overproduction of an otherwise wild-type corepressor - a
  dosage/gain-of-expression lesion - not loss of hairless function. This distinguishes
  HYPT4 sharply from the biallelic HR coding loss-of-function disorders (atrichia with
  papular lesions, alopecia universalis congenita), which are separate entities and are
  not curated here.

  What excess hairless then does to the follicle is established only in the mouse. The
  ENU-derived hairpoor mouse carries the orthologous uORF start-codon mutation, and in
  that model HR overexpression alters Wnt-pathway modulators and shortens the hair
  cycle. Those downstream steps have not been demonstrated in human MUHH1 scalp, and
  the two published mouse results point in opposite directions on Wnt activity; both
  points are recorded in `discussions`.
disease_term:
  preferred_term: hypotrichosis 4
  term:
    id: MONDO:0100522
    label: hypotrichosis 4
synonyms:
- MUHH1
- Marie Unna hereditary hypotrichosis 1
- Marie Unna congenital hypotrichosis
- hypotrichosis, Marie Unna type, 1
- HYPT4
parents:
- Hair Disorder
- Congenital Hypotrichosis
references:
- reference: DOI:10.1111/jocd.70382
  title: "Significant Hair Regrowth With 5% Topical Minoxidil in a Child With Marie Unna Hereditary Hypotrichosis Caused by a Recurrent <scp><i>HRURF</i></scp> Variant"
- reference: PMID:22584530
  title: "A newly identified missense mutation of the HR gene is associated with a novel, unusual phenotype of Marie Unna Hereditary Hypotrichosis 1 including limb deformities."
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018631
      label: Marie Unna hereditary hypotrichosis
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >
      MONDO:0018631 is the parent grouping concept "Marie Unna hereditary
      hypotrichosis". It has exactly two children in MONDO - MONDO:0100522
      (hypotrichosis 4 / MUHH1, causal gene HGNC:55085 HRURF) and MONDO:0013017
      (hypotrichosis 5 / MUHH2, attributed to EPS8L3). Because the parent spans two
      different causal loci it is a broader concept than this entry, not an exact
      match, and is recorded as a cross-reference only.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Heterozygous HRURF (U2HR) variants segregate with the phenotype in
    multigenerational families across several ancestries, including the original
    1925 German kindred. Sporadic (presumed de novo) cases are also reported.
    Penetrance and expressivity are left unset: no formal penetrance study was
    found, and although reports describe severity varying within families, no
    source was located that assesses expressivity as such.
  evidence:
  - reference: PMID:20659777
    reference_title: "Marie Unna hereditary hypotrichosis: identification of a U2HR mutation in the family from the original 1925 report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MUHH is an autosomal dominant disorder that is characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty."
    explanation: States the autosomal dominant inheritance pattern of MUHH alongside its defining clinical course.
  - reference: PMID:26269244
    reference_title: "Identification of mutations in U2HR in two Chinese families with Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both these mutations cosegregated with the disease phenotype in the two families."
    explanation: Cosegregation of heterozygous U2HR variants with the phenotype in two multigenerational families supports dominant transmission.
  - reference: PMID:37012647
    reference_title: "Identification of a novel sporadic U2HR pathogenic variant in a patient with Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a sporadic case of a 4-year-old boy with clinical features suggestive of MUHH, in whom we identified the new pathogenic variant c.67C>T; p.(Gln23*) in U2HR."
    explanation: Documents a sporadic presentation, so a negative family history does not exclude the diagnosis.
genetic:
- name: HRURF
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HRURF
    term:
      id: hgnc:55085
      label: HRURF
  notes: >
    HRURF (HGNC:55085, "HR upstream open reading frame", 8p21.3) was approved as a
    distinct HGNC gene record only in 2020, with U2HR retained as an alias. Every
    primary MUHH1 report from 2009 through at least 2023 attributes the variants to
    "U2HR", described as an inhibitory upstream ORF inside the 5' UTR of HR
    (HGNC:5172); reports from 2025 onward use HRURF and gloss it as "formerly known
    as U2HR". The two names denote the same element. MONDO records HRURF as the
    RO:0004003 causal gene for MONDO:0100522, which is why this entry uses the
    approved symbol while the cited snippets say U2HR.

    Reported variant classes are all confined to the 34-codon uORF: loss of the
    initiation codon (c.1A>T, c.2T>C, c.3G>A), delayed/read-through termination
    (c.104A>G, c.105G>T), nonsense (c.67C>T) and missense (c.74C>T, c.74C>G), with
    mutation hot spots at codons 1-7 and 24-28.
  evidence:
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR)."
    explanation: The founding report identifying U2HR/HRURF as the causal element and locating it in the 5' UTR of HR.
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations."
    explanation: Establishes the allelic spectrum within the uORF across 18 additional unrelated families.
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing confirmed a heterozygous pathogenic variant in the HRURF gene, associated with autosomal dominant Marie Unna Hereditary Hypotrichosis."
    explanation: A recent report using the approved HRURF symbol for the same causal element, confirming heterozygous variants in patients.
- name: HR
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HR
    term:
      id: hgnc:5172
      label: HR
  notes: >
    HR (HGNC:5172) is recorded here only to make the relationship explicit, not as a
    second causal gene for HYPT4. HRURF sits inside HR's 5' UTR and the disease acts
    through HR protein output, but the linkage-era studies that mapped MUHH to 8p21
    explicitly excluded the HR coding sequence, and that exclusion is what led to the
    uORF discovery.

    One outlier exists: a single Hungarian patient with alopecia universalis and
    four-limb deformities was reported with a heterozygous HR exon-3 missense variant
    (c.974G>A, p.Gly325Asp) under the label MUHH1 (PMID:22584530). That report is not
    cited as evidence anywhere in this entry. The authors themselves wrote that
    further studies are needed to establish a role for the variant, only one
    unaffected relative was available, the phenotype (alopecia universalis plus limb
    deformity) is not the MUHH1 triphasic course, and no subsequent family has
    replicated a coding-HR cause of MUHH1. Biallelic HR coding loss-of-function
    causes atrichia with papular lesions and alopecia universalis congenita, which
    are recessive and separate entities - see `differential_diagnoses`.
pathophysiology:
- name: HRURF Upstream Open Reading Frame Disruption
  biological_scale: MOLECULAR
  description: >
    A heterozygous germline variant disrupts the 34-codon inhibitory upstream open
    reading frame HRURF (U2HR) in the 5' untranslated region of the HR transcript.
    Loss-of-initiation, delayed-termination, nonsense and missense changes all
    destroy the uORF peptide's normal function. The variant is loss-of-function
    *for the uORF*; its effect on hairless is the opposite (see the next node).
  genetic_context:
    gene:
      preferred_term: HRURF
      term:
        id: hgnc:55085
        label: HRURF
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >
      The category applies to HRURF, whose repressive uORF function is abolished. The
      downstream consequence for HR is increased protein output, which is a different
      claim about a different gene product and is modeled as a separate node.
  biological_processes:
  - preferred_term: uORF-mediated repression of translational initiation at the main HR ORF
    term:
      id: GO:0045947
      label: negative regulation of translational initiation
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations."
    explanation: Defines the classes of uORF-disrupting variants that constitute the initiating lesion.
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "U2HR is predicted to encode a 34-amino acid peptide that is highly conserved among mammals."
    explanation: The uORF peptide length and its mammalian conservation are a sequence prediction, not an experimental measurement, and are graded accordingly.
  - reference: PMID:20163456
    reference_title: "Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript were found as the cause for autosomal dominant Marie Unna hereditary hypotrichosis."
    explanation: Independently states that the causal lesion is loss of function of the inhibitory uORF, not of the hairless coding sequence.
  downstream:
  - target: Translational De-repression of the Main HR Open Reading Frame
    causal_link_type: DIRECT
    description: >
      Destroying the uORF removes the translational brake it imposes on the
      downstream main HR ORF.
    evidence:
    - reference: PMID:19122663
      reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF."
      explanation: Reporter assays link each class of uORF defect directly to increased translation of the main HR ORF, which is the edge asserted here.
- name: Translational De-repression of the Main HR Open Reading Frame
  biological_scale: MOLECULAR
  description: >
    With the inhibitory uORF disabled, ribosomes translate the downstream main HR
    open reading frame more efficiently. This is the pivotal direction in the entry:
    translation of HR goes *up*, not down.
  biological_processes:
  - preferred_term: translation of the main HR open reading frame
    term:
      id: GO:0006412
      label: translation
    modifier: INCREASED
  evidence:
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF."
    explanation: Directly states the increased-translation direction for every reported class of uORF variant.
  - reference: PMID:20163456
    reference_title: "Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional assays confirmed that this mutation led to increased translation of the main HR ORF."
    explanation: An independent laboratory reproduces the increased-translation result for a further missense uORF variant.
  downstream:
  - target: Hairless Corepressor Protein Overexpression
    causal_link_type: DIRECT
    description: More efficient translation of the main ORF raises HR protein levels.
    evidence:
    - reference: PMID:19897589
      reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway."
      explanation: States the derepression-to-overexpression step explicitly in the mouse carrying the orthologous uORF mutation.
- name: Hairless Corepressor Protein Overexpression
  biological_scale: MOLECULAR
  description: >
    Hairless is a nuclear-receptor transcriptional corepressor expressed mainly in
    skin and brain that governs hair-follicle morphogenesis and cycling. In MUHH1 the
    protein itself is structurally normal; there is simply too much of it. Because HR
    acts by repressing transcription, excess HR means excess corepression at its
    target genes. Hair growth depends on HR being present in the right amount rather
    than merely present, which is why both loss and gain of HR produce alopecia.
  biological_processes:
  - preferred_term: hairless-mediated transcriptional corepression at nuclear-receptor target genes
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: INCREASED
  cell_types:
  - preferred_term: hair follicle keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  evidence:
  - reference: PMID:24447645
    reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Hairless (Hr), a transcriptional corepressor expressed mainly in the skin, regulates hair follicle (HF) morphogenesis and hair cycling."
    explanation: Establishes what the overproduced protein does - transcriptional corepression governing follicle morphogenesis and cycling.
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "show that fine-tuning of HR protein levels is important in control of hair growth"
    explanation: States that the quantity of HR protein, not its presence or absence, is the controlled variable in hair growth - the dosage framing of this node.
  - reference: PMID:19897589
    reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway."
    explanation: States that gain, not loss, of HR causes the alopecia in this model - the direction this entry curates.
  downstream:
  - target: Dysregulated Wnt Pathway Modulation in the Hair Follicle
    causal_link_type: DIRECT
    description: >
      Excess HR corepressor alters transcription of Wnt-pathway modulator genes in
      follicular skin. Demonstrated in the hairpoor mouse only.
    evidence:
    - reference: PMID:19897589
      reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway."
      explanation: Links HR overexpression to reduced expression of the Wnt inhibitor Sfrp2, the edge asserted here.
    - reference: PMID:24447645
      reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Dkk1 expression was increased in the skin of (+)/Hr(HP) and Hr(Hp)/Hr(Hp) mice, as well as in Hr-overexpressing mouse keratinocytes."
      explanation: An independent Wnt modulator, Dkk1, is also altered by HR overexpression, including in HR-overexpressing keratinocytes.
  - target: Abnormal Hair Shaft Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The coarse, twisted, variable-calibre shafts of MUHH1 arise in follicles
      operating under excess HR corepression. The intervening steps between HR dosage
      and shaft geometry are not established; the link is recorded as indirect and
      the specific cellular step is flagged in `discussions`.
- name: Dysregulated Wnt Pathway Modulation in the Hair Follicle
  biological_scale: CELLULAR
  description: >
    In the hairpoor mouse, HR overexpression changes the expression of secreted Wnt
    inhibitors in follicular skin. The two published results are not concordant in
    sign: Sfrp2 falls (which the authors read as excess Wnt activation), while Dkk1
    rises (a Wnt inhibitor and catagen inducer). The node therefore records the
    pathway as dysregulated rather than asserting a direction, and the discrepancy is
    tracked as an open controversy. Nothing here has been shown in human MUHH1 skin.
  biological_processes:
  - preferred_term: Wnt signaling pathway modulation in follicular skin
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DYSREGULATED
  - preferred_term: secreted Wnt-inhibitor (Sfrp2, Dkk1) expression
    term:
      id: GO:0030178
      label: negative regulation of Wnt signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:19897589
    reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study indicates that the gain in function of HR also results in alopecia, as seen with the loss of function of HR, via abnormal upregulation of the Wnt signaling pathway."
    explanation: Reports abnormal upregulation of Wnt signaling downstream of HR gain in the hairpoor mouse.
  - reference: PMID:24447645
    reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One of the Wnt inhibitors, Dickkopf (Dkk), inhibits hair growth during the hair cycle as a catagen inducer of apoptosis, resulting in HF reductions."
    explanation: Establishes Dkk1's role as a Wnt inhibitor and catagen inducer, the axis the same group found upregulated by HR - the reason this node is labelled dysregulated rather than uniformly activated.
  downstream:
  - target: Premature Catagen Entry and Hair Follicle Shortening
    causal_link_type: DIRECT
    description: >
      Upregulation of the catagen-inducing Wnt inhibitor Dkk1 accompanies early
      catagen entry and shorter follicles in heterozygous hairpoor mice.
    evidence:
    - reference: PMID:24447645
      reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings also indicated that alteration of the hair cycle in (+)/Hr(HP) mice was related to the up-regulation of Dkk1 by HR."
      explanation: The authors attribute the altered hair cycle in the heterozygous model to HR-driven Dkk1 upregulation, which is this edge.
- name: Premature Catagen Entry and Hair Follicle Shortening
  biological_scale: TISSUE
  description: >
    Heterozygous hairpoor mice enter catagen earlier and grow shorter hair follicles
    than wild type. This is the mechanistic proposal for why MUHH1 hair is short and
    why follicles progressively fail; it is a mouse result and has not been shown in
    human MUHH1 scalp.
  biological_processes:
  - preferred_term: hair cycle (anagen-catagen transition)
    term:
      id: GO:0042633
      label: hair cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24447645
    reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Additionally, an earlier entrance of HFs into catagen and shortened HF length in (+)/Hr(HP) mice compared to wild-type mice was observed."
    explanation: Directly measures earlier catagen entry and shortened follicles in the heterozygous model of MUHH1.
  downstream:
  - target: Progressive Loss of Hair Follicle Density
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Repeated cycles truncated at catagen are the proposed route to permanent
      follicle loss. The step is inferred: no study follows individual human MUHH1
      follicles from shortened cycling to loss.
- name: Progressive Loss of Hair Follicle Density
  biological_scale: TISSUE
  description: >
    Scalp biopsy in MUHH1 shows a markedly reduced number of follicles per unit area
    with only a mild to moderate inflammatory infiltrate, little fibrosis and no
    scarring - a non-scarring alopecia. The mechanism by which follicles are lost was
    explicitly stated as unknown in the largest histopathological pedigree study and
    remains so.
  cell_types:
  - preferred_term: hair follicle keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  biological_processes:
  - preferred_term: hair follicle development and maintenance
    term:
      id: GO:0001942
      label: hair follicle development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologically, there are dramatically reduced numbers of follicles per unit area, averaging nine total hairs per 4 mm cross-section as compared with a normal of 40."
    explanation: Quantifies the loss of follicle density in affected human scalp.
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of progressive hair loss is unknown."
    explanation: The authors state directly that the mechanism of follicle loss was not established, which is why this node carries no asserted cellular mechanism.
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic factors, altered hair shaft morphology, a decreased number of functional follicles, and abnormal follicle cycling have been suggested as contributors to the disease pathogenesis, with mutations in the U2HR gene, located on chromosome 8p21, identified as the underlying cause."
    explanation: A recent molecularly confirmed case series names reduced functional follicle number and abnormal follicle cycling as the proposed contributors, matching this node and the one above it.
  downstream:
  - target: Progressive Scalp Hair Loss After Puberty
    causal_link_type: DIRECT
    description: Loss of follicles is what the patterned post-pubertal alopecia consists of.
- name: Abnormal Hair Shaft Formation
  biological_scale: TISSUE
  description: >
    The hair that does grow is structurally abnormal: shafts of uniformly increased
    and variable diameter (up to 0.12 mm), deeply pigmented, twisted, bent at odd
    angles, longitudinally grooved on scanning electron microscopy, and irregular in
    cross-section. Dermoscopy shows pili torti. This produces the coarse, wiry,
    unruly hair of the childhood phase.
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual hair shafts are deeply pigmented, variable in diameter, twisted, and bent at odd angles; some have a longitudinal groove visible on scanning electron microscopy."
    explanation: Structural characterization of the abnormal shaft by light and scanning electron microscopy.
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The hair shafts are uniformly increased in diameter, measuring up to 0.12 mm."
    explanation: Quantifies the increased shaft calibre that gives the hair its coarse quality.
  downstream:
  - target: Coarse Wiry Scalp Hair in Childhood
    causal_link_type: DIRECT
    description: The altered shaft geometry is what makes the hair coarse, wiry and unruly.
  - target: Pili Torti
    causal_link_type: DIRECT
    description: Twisting of the shaft on its own axis is seen dermoscopically as pili torti.
phenotypes:
- category: Cutaneous
  name: Sparse Scalp Hair at Birth
  description: >
    Scalp hair is absent or scanty at birth and through early infancy. Note that this
    is not universal: the six-generation pedigree of Roberts et al. described affected
    individuals as born with adequate, normal to coarse hair, so the congenital phase
    varies between families.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:20659777
    reference_title: "Marie Unna hereditary hypotrichosis: identification of a U2HR mutation in the family from the original 1925 report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MUHH is an autosomal dominant disorder that is characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty."
    explanation: Defines absent or scanty scalp hair at birth as a characteristic feature.
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals are born with adequate, normal to coarse hair."
    explanation: In this large pedigree the neonatal hair was adequate rather than sparse, contradicting the claim that sparse hair at birth is universal.
- category: Cutaneous
  name: Coarse Wiry Scalp Hair in Childhood
  description: >
    During early infancy and childhood the scalp hair becomes coarse, wiry and unruly,
    standing out from the head. This is the most distinctive phase of the disease.
  phenotype_term:
    preferred_term: Coarse hair
    term:
      id: HP:0002208
      label: Coarse hair
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During early infancy the scalp hair becomes more coarse and wiry and stands out from the head."
    explanation: Direct clinical description of the coarse, wiry childhood hair.
  - reference: PMID:26269244
    reference_title: "Identification of mutations in U2HR in two Chinese families with Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant genodermatosis characterized by coarse, wiry, twisted hair developing during early childhood, with subsequent progressive hair loss."
    explanation: Confirms coarse, wiry, twisted childhood hair as the defining feature in molecularly confirmed families.
  sequelae:
  - target: Progressive Scalp Hair Loss After Puberty
    description: The coarse childhood hair is subsequently lost from around puberty.
- category: Cutaneous
  name: Progressive Scalp Hair Loss After Puberty
  description: >
    From around puberty, scalp hair is progressively lost in a patterned distribution
    that can mimic androgenetic or female-pattern hair loss, in the most advanced
    cases leaving only a sparse fringe in the tonsorial distribution.
  phenotype_term:
    preferred_term: Progressive alopecia
    term:
      id: HP:0002287
      label: Progressive alopecia
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In some individuals, scalp hair is progressively lost beginning at puberty or beyond, until only a sparse fringe in the tonsorial distribution remains."
    explanation: Describes the post-pubertal progressive, patterned scalp hair loss and its endpoint.
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study describes two cases from different unrelated families presenting with recalcitrant alopecia resembling female pattern hair loss, with dermoscopic findings consistent with pili torti and yellow dots."
    explanation: Documents that the adult hair loss can present as, and be mistaken for, female pattern hair loss.
- category: Cutaneous
  name: Sparse Eyebrows
  description: >
    Eyebrows are sparse to absent from early life. Eyebrow loss is a useful
    discriminator from androgenetic alopecia in an adult presenting with patterned
    scalp thinning.
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals have sparse to absent eyebrows, eyelashes and body hair including secondary sexual hair."
    explanation: Reports sparse to absent eyebrows in all affected members of a 16-affected pedigree.
  - reference: PMID:20814945
    reference_title: "Marie Unna hereditary hypotrichosis: a Turkish family with loss of eyebrows and a U2HR mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We concluded that there may be considerable clinical variations in MUHH, and that eyebrow loss is an important clue for accurate diagnosis."
    explanation: A U2HR-confirmed Turkish family in which eyebrow loss was the diagnostic clue.
- category: Cutaneous
  name: Sparse Eyelashes
  description: Eyelashes are sparse to absent from early life.
  phenotype_term:
    preferred_term: Sparse eyelashes
    term:
      id: HP:0000653
      label: Sparse eyelashes
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals have sparse to absent eyebrows, eyelashes and body hair including secondary sexual hair."
    explanation: Reports sparse to absent eyelashes in all affected individuals of the pedigree.
- category: Cutaneous
  name: Sparse Body Hair
  description: >
    Body hair, including secondary sexual hair, is sparse to absent, so the
    peripubertal development of axillary, pubic and beard hair is deficient.
  phenotype_term:
    preferred_term: Sparse body hair
    term:
      id: HP:0002231
      label: Sparse body hair
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals have sparse to absent eyebrows, eyelashes and body hair including secondary sexual hair."
    explanation: Documents sparse to absent body hair including secondary sexual hair.
- category: Cutaneous
  name: Pili Torti
  description: >
    Dermoscopy of the scalp in molecularly confirmed MUHH1 shows pili torti (hairs
    twisted about their long axis) together with yellow dots.
  phenotype_term:
    preferred_term: Pili torti
    term:
      id: HP:0003777
      label: Pili torti
  evidence:
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study describes two cases from different unrelated families presenting with recalcitrant alopecia resembling female pattern hair loss, with dermoscopic findings consistent with pili torti and yellow dots."
    explanation: First published dermoscopic description of MUHH, in patients with a confirmed HRURF variant.
- category: Cutaneous
  name: Abnormal Hair Shaft Morphology
  description: >
    Light and scanning electron microscopy show shafts of increased and variable
    diameter, deeply pigmented, twisted, bent at odd angles, longitudinally grooved,
    with variable and irregular oval to reniform cross-sections.
  phenotype_term:
    preferred_term: Abnormal hairshaft morphology
    term:
      id: HP:0003328
      label: Abnormal hairshaft morphology
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cross-sectional shapes are variable and irregular, exhibiting oval, angular to reniform shapes."
    explanation: Documents the irregular hair-shaft cross-sectional morphology.
- category: Dental
  name: Widely Spaced Upper Incisors
  description: >
    Other ectodermal structures are essentially spared, with the reported exception of
    exceptionally widely spaced upper incisor teeth in half the affected individuals
    of one large pedigree. This has not been systematically confirmed in other
    families and should not be treated as an established feature of MUHH1.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Widely-spaced incisors
    term:
      id: HP:0006304
      label: Widely-spaced incisors
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other ectodermal structures are unaffected except for exceptionally widely spaced upper incisor teeth seen in 50% of affected individuals."
    explanation: Reports widely spaced upper incisors in 50% of affected individuals, supporting both the finding and its FREQUENT band, while confirming that other ectodermal structures are spared.
histopathology:
- name: Reduced Follicular Density on Scalp Biopsy
  description: >
    Horizontal sections show a dramatic reduction in the number of follicles per unit
    area - about nine total hairs per 4 mm cross-section against a normal of 40.
  diagnostic: true
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologically, there are dramatically reduced numbers of follicles per unit area, averaging nine total hairs per 4 mm cross-section as compared with a normal of 40."
    explanation: The quantitative histopathological finding on scalp biopsy.
- name: Mild Inflammatory Infiltrate Without Scarring
  description: >
    A mild to moderate inflammatory infiltrate is present, but there is little
    fibrosis and no scarring - MUHH1 is a non-scarring alopecia, which separates it
    from the cicatricial alopecias.
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mild to moderate inflammatory infiltrate is present, but little fibrosis and no scarring."
    explanation: Establishes the non-scarring character of the alopecia and the presence of only a modest infiltrate.
diagnosis:
- name: HRURF (U2HR) Sequencing
  description: >
    Diagnosis is confirmed by sequencing the small HRURF/U2HR upstream open reading
    frame in the 5' UTR of HR. This is a clinically important pitfall: the element is
    non-coding with respect to HR, so an HR coding-exon panel, or an exome pipeline
    that does not annotate this UTR-embedded ORF, will miss the causal variant. That
    is exactly why linkage mapped MUHH to 8p21 in 2000 but the causal element was not
    found until 2009.
  markers: Heterozygous pathogenic variant within the 34-codon HRURF (U2HR) upstream open reading frame in the 5' UTR of HR at 8p21.3.
  results: >
    A heterozygous loss-of-initiation, delayed-termination, nonsense or missense HRURF
    variant in a patient with the characteristic hair phenotype confirms MUHH1.
  evidence:
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR)."
    explanation: Identifies the region that must be sequenced to make the molecular diagnosis.
  - reference: PMID:20659777
    reference_title: "Marie Unna hereditary hypotrichosis: identification of a U2HR mutation in the family from the original 1925 report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct sequencing of U2HR was performed."
    explanation: Direct sequencing of the U2HR element is the method used to make the molecular diagnosis in practice.
  - reference: PMID:30809827
    reference_title: "Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that the c.1A>G mutation in an inhibitory upstream open-reading frame of HR (U2HR) was present in all MUHH patients"
    explanation: Sanger sequencing of the U2HR element identified the causal variant in every affected family member.
  diagnosis_term:
    preferred_term: HRURF (U2HR) sequencing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
- name: Trichoscopy and Hair Shaft Microscopy
  description: >
    Clinical diagnosis rests on the triphasic history plus examination of the hair
    itself. Trichoscopy shows pili torti and yellow dots; light microscopy and
    scanning electron microscopy of plucked shafts show increased and variable
    diameter, twisting, angular bending, longitudinal grooving and irregular
    cross-sections. These findings support the diagnosis but are not specific enough
    to replace HRURF sequencing.
  markers: Pili torti and yellow dots on trichoscopy; twisted, longitudinally grooved hair shafts of increased and variable diameter on microscopy.
  evidence:
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study describes two cases from different unrelated families presenting with recalcitrant alopecia resembling female pattern hair loss, with dermoscopic findings consistent with pili torti and yellow dots."
    explanation: Provides the dermoscopic (trichoscopic) findings used to support the diagnosis.
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual hair shafts are deeply pigmented, variable in diameter, twisted, and bent at odd angles; some have a longitudinal groove visible on scanning electron microscopy."
    explanation: Describes what hair-shaft light and scanning electron microscopy show in this disease.
  diagnosis_term:
    preferred_term: trichoscopy and hair shaft microscopy
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
differential_diagnoses:
- name: Atrichia with papular lesions / alopecia universalis congenita
  description: >
    Caused by biallelic loss-of-function variants in the HR *coding* sequence -
    the opposite direction of HR dysfunction from MUHH1, and recessive rather than
    dominant. Presents as complete, permanent alopecia from infancy with papular
    lesions, without the coarse-wiry childhood phase. Conflating these entities with
    MUHH1 because both involve HR is the main naming hazard around this locus.
  distinguishing_features:
  - Autosomal recessive rather than dominant
  - Biallelic loss-of-function variants in the HR coding sequence, not in the HRURF uORF
  - Total irreversible alopecia from infancy with papular lesions
  - No coarse, wiry childhood hair phase
  evidence:
  - reference: PMID:24898506
    reference_title: "[Alopecia and hypotrichosis in childhood: clinical features and diagnosis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the genes DSG4, LIPH and LPAR6 for the autosomal recessive forms of hypotrichosis as well as U2HR for hypotrichosis type Marie Unna"
    explanation: A clinical review separating the causal genes of the isolated alopecias, listing the HR gene for atrichia congenita and U2HR for Marie Unna type hypotrichosis as distinct entries.
- name: Hypotrichosis 5 (MUHH2)
  description: >
    The sibling MONDO concept under the same parent grouping. Exome sequencing in a
    single four-generation Chinese family mapped to 1p21.1-1q21.3 identified a
    heterozygous EPS8L3 missense variant. It is phenotypically overlapping but
    genetically distinct, and is a separate disease entry, not a subtype of HYPT4.
    Support rests on one family; subsequent MUHH cohorts have not replicated it.
  disease_term:
    preferred_term: hypotrichosis 5
    term:
      id: MONDO:0013017
      label: hypotrichosis 5
  distinguishing_features:
  - Maps to 1p21.1-1q21.3 rather than to 8p21.3
  - Attributed to EPS8L3 rather than to HRURF
  - No HRURF/U2HR variant identified in the reported family
  evidence:
  - reference: PMID:23099647
    reference_title: "Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3."
    explanation: Identifies a different gene at a different locus in a family with a MUHH phenotype, establishing the entity as genetically distinct from HYPT4.
- name: Autosomal recessive woolly hair / hypotrichosis
  description: >
    Biallelic LIPH or LPAR6 variants disrupt the LIPH-LPA-LPAR6 axis, giving tightly
    curled woolly hair with hypotrichosis from birth. Recessive, and the hair is
    kinky/woolly rather than the coarse wiry hair of MUHH1.
  distinguishing_features:
  - Autosomal recessive, frequently in consanguineous families
  - Tightly curled woolly hair from birth
  - No triphasic sparse-then-coarse-then-lost natural history
  evidence:
  - reference: PMID:24898506
    reference_title: "[Alopecia and hypotrichosis in childhood: clinical features and diagnosis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the genes DSG4, LIPH and LPAR6 for the autosomal recessive forms of hypotrichosis as well as U2HR for hypotrichosis type Marie Unna"
    explanation: Places LIPH and LPAR6 in the recessive hypotrichosis group, distinct from the U2HR-related Marie Unna type.
- name: Androgenetic / female pattern hair loss
  description: >
    The adult MUHH1 phenotype can closely mimic patterned hair loss and has been
    misdiagnosed as recalcitrant female pattern hair loss. The congenital and
    childhood phases, sparse eyebrows and eyelashes, and abnormal hair shafts
    distinguish it.
  distinguishing_features:
  - No congenital sparse-hair phase and no coarse, wiry childhood hair
  - Eyebrows, eyelashes and body hair are normal
  - Hair shafts are structurally normal on microscopy
  evidence:
  - reference: PMID:39872230
    reference_title: "Recalcitrant Female Pattern Hair Loss Like Alopecia Unveils Unexpected Rare Entity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study describes two cases from different unrelated families presenting with recalcitrant alopecia resembling female pattern hair loss, with dermoscopic findings consistent with pili torti and yellow dots."
    explanation: Documents MUHH1 presenting as, and being mistaken for, recalcitrant female pattern hair loss.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No numeric prevalence or incidence estimate for HYPT4/MUHH1 was found. Sources
    describe the disease only qualitatively as rare; the measure they intend is not
    stated, so `measure_type` is UNKNOWN and no rate is recorded. Orphanet does index
    the parent concept Marie Unna hereditary hypotrichosis as ORPHA:444, but that code
    is not present in the Orphadata leaf-disorder bulk file this repository caches, so
    no ORPHA-quoted epidemiology row could be curated.
  evidence:
  - reference: PMID:26269244
    reference_title: "Identification of mutations in U2HR in two Chinese families with Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant genodermatosis characterized by coarse, wiry, twisted hair developing during early childhood, with subsequent progressive hair loss."
    explanation: Characterizes the disease as rare, which is the only occurrence claim the literature supports.
progression:
- phase: Congenital and infantile
  notes: >
    Scalp hair, eyebrows and eyelashes are absent or scanty at birth in most reported
    families, although one large pedigree described normal to coarse neonatal hair.
  evidence:
  - reference: PMID:40433810
    reference_title: "Clinical Presentation of a Family Diagnosed With Marie Unna Hereditary Hypotrichosis 1 Caused by a Novel Variant in HRURF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marie Unna hereditary hypotrichosis 1 (MUHH1) is a rare autosomal dominant condition characterized by the absence or scarcity of hair at birth with the growth of coarse, wiry, and unruly hair during childhood and progressive hair loss after puberty."
    explanation: States the congenital phase of the natural history in a recent HRURF-confirmed family.
- phase: Childhood
  notes: >
    Coarse, wiry, unruly hair grows in and stands out from the head. Hair shafts are
    thick, twisted, grooved and irregular in cross-section.
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During early infancy the scalp hair becomes more coarse and wiry and stands out from the head."
    explanation: Describes the childhood phase of the natural history.
- phase: Post-pubertal
  notes: >
    Progressive patterned scalp hair loss begins around puberty and continues into
    adulthood, in some individuals leaving only a tonsorial fringe. At least one
    family member has been reported with the opposite course - progressive scalp hair
    growth during adulthood - so the post-pubertal trajectory is not uniform.
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In some individuals, scalp hair is progressively lost beginning at puberty or beyond, until only a sparse fringe in the tonsorial distribution remains."
    explanation: Describes the post-pubertal progressive loss and its most advanced endpoint.
  - reference: PMID:40433810
    reference_title: "Clinical Presentation of a Family Diagnosed With Marie Unna Hereditary Hypotrichosis 1 Caused by a Novel Variant in HRURF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case report describes the clinical presentation of three Danish family members with congenital hypotrichosis with a new phenotypic variation marked by progressive scalp hair growth during adulthood in one of the members."
    explanation: Documents a family member whose adult course was hair growth rather than loss, supporting the statement that the post-pubertal trajectory is not uniform.
treatments:
- name: Genetic Counseling and Supportive Hair Care
  description: >
    There is no disease-modifying therapy. Management is genetic counseling for the
    50% transmission risk of a dominant trait, molecular confirmation of the family
    variant, and cosmetic/supportive measures (gentle hair care, camouflage, wigs).
    This entry states that plainly rather than listing aspirational options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:24898506
    reference_title: "[Alopecia and hypotrichosis in childhood: clinical features and diagnosis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy does not exist for these rare forms of alopecia. However, molecular genetic diagnosis is possible for the identification of the genetic causes and for the specification of the recurrence risk."
    explanation: States both halves of current management - no therapy exists, and molecular diagnosis serves recurrence-risk counseling.
- name: Topical Minoxidil
  description: >
    A single 2025 case report describes significant hair regrowth on once-daily 5%
    topical minoxidil in a child with a recurrent HRURF variant. This is one patient
    and is not established therapy for MUHH1; it is recorded so the lead is
    discoverable, not as a recommendation.
  treatment_term:
    preferred_term: topical pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: minoxidil
      term:
        id: CHEBI:6942
        label: minoxidil
  therapeutic_modality: SMALL_MOLECULE
  notes: >
    Deliberately carries no evidence item. The source is Cui et al., J Cosmet Dermatol
    2025, DOI:10.1111/jocd.70382 (PMC12340736), listed in the top-level `references:`
    block. The local DOI_10.1111_jocd.70382.md cache contains bibliographic metadata
    without an abstract or full text. Europe PMC indexes the letter as PMC12340736
    without a PMID and provides open full text; the missing local body does not mean
    that the source has no quotable text. The claim remains unevidenced here pending
    retrieval and verification of a substantive passage from that full text.
animal_models:
- name: Hairpoor mouse (Hr^Hp)
  species: Mouse
  genotype: Hr^Hp/+ heterozygous and Hr^Hp/Hr^Hp homozygous; T-to-A transversion at nucleotide 403 abolishing the uATG of the second uORF in the Hr 5' UTR
  category: Genetic
  publication: PMID:19513791
  description: >
    An ENU-derived mouse carrying the mutation orthologous to human MUHH1 variants -
    in the start codon of the second uORF in the Hr 5' UTR. It is the only in vivo
    model of the uORF-dosage mechanism, and every downstream mechanistic claim in this
    entry beyond "translation of HR increases" comes from it.
  genes:
  - preferred_term: Hr
    term:
      id: hgnc:5172
      label: HR
  evidence:
  - reference: PMID:19513791
    reference_title: "A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both mutations were in the uATG codon of the second uORF in the 5' UTR and corresponded to the mutations identified in Marie Unna Hereditary Hypotrichosis (MUHH) patients."
    explanation: Establishes that the mouse lesion is at the same uORF start codon as the human MUHH variants, which is what makes the model mechanism-matched.
  modeled_mechanisms:
  - target: Translational De-repression of the Main HR Open Reading Frame
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >
      The mouse uATG mutation abolishes the same uORF and produces HR overexpression
      by translational derepression, the same molecular event as in human MUHH1.
    limitations: >
      The allele behaves as semidominant in the mouse - homozygotes are completely
      bald with cyst-like follicles, a state with no human counterpart, since human
      MUHH1 is described only in heterozygotes. Several mechanistic results in this
      model were obtained from homozygotes or from HR-overexpressing keratinocytes
      rather than from the heterozygote that corresponds to the human genotype.
    evidence:
    - reference: PMID:19897589
      reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway."
      explanation: Shows the model reproduces translational derepression and HR overexpression, the node it is linked to.
  - target: Dysregulated Wnt Pathway Modulation in the Hair Follicle
    relationship: MEASURES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >
      This model is the sole source of the Wnt-modulation claim; it measures Sfrp2 and
      Dkk1 transcript and protein levels in mutant skin.
    limitations: >
      The link extrapolates upward: the measurements are transcript and protein levels
      in mouse skin, while the node asserts a cell-level change in Wnt pathway
      activity in the hair follicle. No Wnt pathway readout has been reported in human
      MUHH1 scalp at all, and the two reported modulator changes point in opposite
      directions on net Wnt activity.
    readouts:
    - name: Sfrp2 expression in mutant skin
      target: Dysregulated Wnt Pathway Modulation in the Hair Follicle
      direction: DECREASED
      interpretation: Reduced secreted Wnt inhibitor, read by the authors as excess Wnt activation.
      evidence:
      - reference: PMID:19897589
        reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway."
        explanation: Reports the direction of the Sfrp2 measurement in this model.
    - name: Dkk1 expression in mutant skin and HR-overexpressing keratinocytes
      target: Dysregulated Wnt Pathway Modulation in the Hair Follicle
      direction: INCREASED
      interpretation: >
        Increased secreted Wnt inhibitor and catagen inducer - the opposite sign from
        the Sfrp2 result.
      evidence:
      - reference: PMID:24447645
        reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Dkk1 expression was increased in the skin of (+)/Hr(HP) and Hr(Hp)/Hr(Hp) mice, as well as in Hr-overexpressing mouse keratinocytes."
        explanation: Reports the direction of the Dkk1 measurement in this model.
  - target: Premature Catagen Entry and Hair Follicle Shortening
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >
      Heterozygous hairpoor mice enter catagen earlier and have shorter follicles than
      wild type, measured directly by hair-cycle staging and follicle length.
    limitations: >
      Premature catagen entry has never been demonstrated in human MUHH1 scalp; the
      only human histopathology available is a cross-sectional follicle count. The
      mouse hair cycle is synchronized and wave-like whereas the human scalp cycles
      asynchronously, so timing results do not transfer directly.
    readouts:
    - name: Hair follicle length and hair-cycle stage
      target: Premature Catagen Entry and Hair Follicle Shortening
      direction: DECREASED
      interpretation: Shorter follicles and earlier catagen entry in heterozygous mutants.
      evidence:
      - reference: PMID:24447645
        reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Additionally, an earlier entrance of HFs into catagen and shortened HF length in (+)/Hr(HP) mice compared to wild-type mice was observed."
        explanation: The direct measurement of follicle length and catagen timing in this model.
    evidence:
    - reference: PMID:19513791
      reference_title: "A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hair follicles (HFs) of Hr(Hp)/+ mice underwent normal cycling and appeared normal, although smaller than those of the wild-type mice."
      explanation: Independently reports smaller follicles in the heterozygote, the genotype that corresponds to human MUHH1.
  - target: Progressive Loss of Hair Follicle Density
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >
      Heterozygous mutants have sparse, short hair progressing towards near alopecia,
      broadly paralleling the human progressive loss.
    limitations: >
      The mouse phenotype is not the human natural history. Human MUHH1 is triphasic -
      sparse at birth, coarse and wiry in childhood, then patterned loss from puberty -
      and the model has no counterpart to the childhood coarse-wiry phase or to the
      pubertal inflection point. No follicle-density quantification in the mutant was
      reported for comparison with the human count of nine hairs per 4 mm section.
    evidence:
    - reference: PMID:19513791
      reference_title: "A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice display sparse and short hair in the Hr(Hp)/+ heterozygous state and complete baldness in the Hr(Hp)/Hr(Hp) homozygous state."
      explanation: Describes both the partial resemblance in the heterozygote and the homozygous phenotype that has no human counterpart.
    - reference: PMID:19897589
      reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hairpoor mouse mutants display partial hair loss at an early age and progress to near alopecia, which resembles the MUHH phenotype."
      explanation: The authors' own assessment of how far the model resembles the human phenotype.
discussions:
- discussion_id: muhh1_wnt_direction
  kind: CONTROVERSY
  status: OPEN
  prompt: >
    Does hairless overexpression in MUHH1 raise or lower net Wnt/beta-catenin activity
    in the hair follicle?
  attaches_to:
  - pathophysiology#Dysregulated Wnt Pathway Modulation in the Hair Follicle
  rationale: >
    Both published answers come from the same group working in the same hairpoor
    mouse, and they point in opposite directions. In 2010 they reported that HR
    overexpression decreases Sfrp2, a secreted Wnt inhibitor, and concluded that
    alopecia follows from abnormal upregulation of Wnt signaling. In 2014 they
    reported that HR overexpression increases Dkk1, also a secreted Wnt inhibitor and
    a catagen inducer, and concluded that Dkk1 upregulation drives the follicular
    abnormality. Increasing one Wnt inhibitor while decreasing another does not yield
    a single net direction, and no study measures a direct Wnt/beta-catenin pathway
    output such as nuclear beta-catenin or Axin2/Lef1 transcription in the mutant
    follicle. Until such a readout exists the pathway node is curated as DYSREGULATED
    rather than INCREASED, and any downstream reasoning that assumes "excess Wnt" in
    MUHH1 is running ahead of the data.
  evidence:
  - reference: PMID:19897589
    reference_title: "Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This mutation conferred overexpression of HR through translational derepression and, in turn, decreased the expression of Sfrp2, an inhibitor of the Wnt signaling pathway."
    explanation: The result read as increased Wnt activity - one side of the discrepancy.
  - reference: PMID:24447645
    reference_title: "Increased expression of Dkk1 by HR is associated with alteration of hair cycle in hairpoor mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dkk1 expression was increased in the skin of (+)/Hr(HP) and Hr(Hp)/Hr(Hp) mice, as well as in Hr-overexpressing mouse keratinocytes."
    explanation: The result pointing the other way - a second Wnt inhibitor going up rather than down.
- discussion_id: muhh1_human_mechanism_gap
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Does anything downstream of increased HR translation - Wnt modulator change,
    premature catagen, follicle shortening - actually occur in human MUHH1 scalp?
  attaches_to:
  - pathophysiology#Dysregulated Wnt Pathway Modulation in the Hair Follicle
  - pathophysiology#Premature Catagen Entry and Hair Follicle Shortening
  rationale: >
    The human evidence stops early. Increased translation of the main HR ORF is shown
    in human reporter assays, and reduced follicle density is shown in human scalp
    biopsy. Everything in between - the Wnt modulator changes, earlier catagen entry,
    and follicle shortening - comes from the hairpoor mouse alone, and that model is
    semidominant with a homozygous phenotype (complete baldness, cystic follicles)
    that has no human counterpart. The largest human histopathological study states
    outright that the mechanism of progressive hair loss is unknown, and no
    transcriptomic, proteomic or single-cell dataset from MUHH1 follicles was found.
    So the entry's middle nodes are model-derived and should be read that way. The
    resolving experiments would be a scalp-biopsy hair-cycle and Wnt-target readout in
    genotyped MUHH1 patients, and a heterozygous knock-in of a human HRURF variant.
  evidence:
  - reference: PMID:10674378
    reference_title: "Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of progressive hair loss is unknown."
    explanation: The human histopathological study explicitly leaves the follicle-loss mechanism open, which is the gap this discussion records.
  - reference: PMID:19513791
    reference_title: "A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice display sparse and short hair in the Hr(Hp)/+ heterozygous state and complete baldness in the Hr(Hp)/Hr(Hp) homozygous state."
    explanation: Shows the model's semidominant behaviour, the specific respect in which it diverges from the human heterozygous-only disease.
- discussion_id: muhh1_gene_symbol_attribution
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    Should MUHH1 variants be attributed to HRURF as a gene, or to a regulatory element
    of HR?
  attaches_to:
  - genetic#HRURF
  - genetic#HR
  rationale: >
    Every primary report from 2009 to 2023 describes the lesion as being in "U2HR, an
    inhibitory upstream open reading frame in the 5' UTR of the human hairless gene" -
    that is, as a regulatory element of HR, not as a separate gene. HGNC approved
    HRURF as its own protein-coding gene record only in 2020, and reports from 2025
    onward use that symbol while glossing it as "formerly U2HR". MONDO records
    HGNC:55085 as the causal gene for MONDO:0100522, and this entry follows that. The
    open question is practical rather than nomenclatural: variant-calling pipelines and
    gene panels built around HR coding exons do not report this element, which is why
    the causal variant escaped detection for nine years after the locus was mapped, and
    a panel that lists "HR" is not necessarily testing HRURF.
  evidence:
  - reference: PMID:19122663
    reference_title: "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR)."
    explanation: The founding paper describes the element as a uORF within HR's 5' UTR, using the U2HR name.
  - reference: PMID:40433810
    reference_title: "Clinical Presentation of a Family Diagnosed With Marie Unna Hereditary Hypotrichosis 1 Caused by a Novel Variant in HRURF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel likely pathogenic variant c.105G>T (p.(*35Tyrext*?)) in HRURF, formerly known as U2HR, causing MUHH1 was identified."
    explanation: A recent report using the approved HRURF symbol and stating explicitly that it is the former U2HR, confirming the two names denote one element.
notes: >
  Lump/split. MONDO:0100522 is curated here as a disease, not as a subtype or a
  grouping. Its MONDO parent, MONDO:0018631 "Marie Unna hereditary hypotrichosis",
  has exactly two children - this concept (MUHH1, causal gene HGNC:55085 HRURF at
  8p21.3) and MONDO:0013017 hypotrichosis 5 (MUHH2, attributed to EPS8L3 at
  1p21.1-1q21.3). Two different loci with different causal genes make those siblings,
  not subtypes of one another, and make the parent a union of two diseases rather than
  a disease itself. MUHH2 is therefore recorded under `differential_diagnoses`, not
  under `has_subtypes`, and the parent is recorded as a `skos:broadMatch`
  cross-reference. If MONDO:0018631 is ever curated it belongs in `kb/groupings/`.

  No `conforms_to` module target was found. There is no hair-follicle-cycle or
  hair-follicle-morphogenesis module in `kb/modules/`. The nearest candidates were
  checked and rejected: `eda_edar_nfkb_ectodermal_appendage` scopes itself to the
  EDA-EDAR-EDARADD-NF-kappaB pathway ectodermal dysplasias, and MUHH1 involves no part
  of that pathway; `keratin_intermediate_filament_fragility` requires a keratin variant
  and there is none here.

  Claims found in sources but not curated. A single Hungarian patient with alopecia
  universalis and four-limb deformities was reported with a heterozygous HR exon-3
  missense variant under the MUHH1 label (PMID:22584530); the authors called for
  further study, the phenotype is not the MUHH1 course, and no family has replicated
  it, so it is described in `genetic` notes rather than curated as a mechanism. A
  five-generation Chinese family had MUHH co-occurring with multiple familial
  trichoepithelioma, but the authors concluded the accompanying FABP12 variant was
  probably coincidental (PMID:30809827), so no comorbidity is asserted. Follicular
  hyperkeratosis with milia-like facial papules is mentioned in secondary sources as a
  variable accessory feature; no cached source stated it in quotable form, so it is
  not curated.

  Deep research. The committed report is a `claude_code` report
  (`research/Hypotrichosis_4-deep-research-claude_code.md`). Falcon returns HTTP 402
  and openscientist was timing out server-side at the time of curation, so neither was
  used. `just preflight-dr` returned WARN because HR is mentioned more often than
  HRURF; that is intrinsic to a disease whose causal element sits inside another
  gene's 5' UTR, and disease identity was confirmed independently - MONDO:0100522
  carries OMIM:146550 and RO:0004003 HGNC:55085, both matching the report.