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Inheritance

1

Autosomal recessive HP:0000007

The single reported ECTD7 family segregates a homozygous KRT74 missense variant across four affected siblings; unaffected relatives are heterozygous or wild type. Heterozygosity for this allele produced no hair or nail phenotype in that family, which is the observation that separates ECTD7 from the dominant KRT74 woolly-hair phenotype caused by other alleles.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family."

Documents homozygous segregation of the causal allele with autosomal recessive PHNED in the reported family.

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Pathophysiology

2

Keratin-74 Intermediate Filament Instability

KRT74 encodes a type II keratin that heterodimerizes with a type I partner to build intermediate filaments in the hair follicle inner root sheath and in nail-forming epithelium. The p.Phe274Ser substitution alters a conserved residue in the coil 1B rod domain required for long-range keratin dimerization, destabilizing filament assembly. In patient tissue the protein is undetectable, so the operative lesion is absence of keratin-74 rather than incorporation of a poison subunit - the mechanistic difference from the dominant KRT74 woolly-hair alleles, which act dominant-negatively.

intermediate filament organization GO:0045109 ↓ DECREASED

structural constituent of cytoskeleton GO:0005200 ⇓ LOSS OF FUNCTION

Downstream

Inner Root Sheath and Nail Epithelium Keratin Deficiency

Show evidence (2 references)

PMID:24714551 SUPPORT Human Clinical

"The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments."

States the proposed molecular defect: impaired keratin dimerization and intermediate filament instability.

PMID:24714551 SUPPORT Human Clinical

"hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution"

Establishes protein loss in patient tissue, distinguishing this recessive mechanism from the dominant-negative woolly-hair alleles.

Inner Root Sheath and Nail Epithelium Keratin Deficiency

Keratin-74 is normally expressed in the hair follicle inner root sheath and, in the nail unit, in the nail matrix, nail bed, and hyponychium. Its absence deprives exactly those compartments of mechanical support during the keratinization that shapes the emerging hair shaft and nail plate. This expression map is why the phenotype is restricted to hair and nails: the protein is simply not required in the ectodermal derivatives that PHNED spares.

Hair follicle cell CL:0002559 Nail matrix keratinocyte CL:4052064

keratinization GO:0031424 ↓ DECREASED

Downstream

Hypotrichosis with Brittle Hair

Nail Dystrophy

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles."

Establishes the anatomical expression domain of keratin-74, which determines which appendages fail when it is lost. The nail localization is from mouse distal digit tissue; the hair follicle localization is human.

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Pathograph

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Phenotypes

6

Head and Neck 2

Hypotrichosis with Brittle Hair Sparse scalp hair HP:0002209

No `frequency:` is asserted. The Edison review is explicit that the "4/4" counts describe one ascertainment family of siblings and must not be read as population frequencies, and per docs/frequency-evidence-guidelines.md an unjustifiable band is better omitted than fabricated.

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia."

Establishes brittle hair and hypotrichosis as cardinal features of the entity this KRT74 family was diagnosed with.

Hypodontia Absent EXCLUDED HP:0000668

∅ ABSENT

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"The affected individuals were otherwise healthy including normal skin, dentition and self-reported normal"

Disease-specific statement of normal dentition in the affected siblings of the only reported ECTD7 family, replacing the class-level PHNED sparing quote an earlier draft took from the HOXC13 literature.

Integument 2

Nail Dystrophy HP:0008404

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia."

Establishes onychodystrophy as a cardinal feature of PHNED. Nail involvement is also what distinguishes the recessive KRT74 phenotype from the dominant KRT74 woolly-hair phenotype, in which nails are generally normal.

Hypohidrosis Absent EXCLUDED HP:0000966

∅ ABSENT

Curated with `frequency: EXCLUDED` plus `modifier: ABSENT`, following the convention used in Osteogenesis_Imperfecta_Type_V and Epilepsy_with_Generalized_Tonic-Clonic_Seizures_Alone. Evidence is the family-specific statement in Raykova 2014 rather than the class-level PHNED sparing statement in the HOXC13 literature (PMID:28297138), which an earlier draft used. A negative asserted of one family should be evidenced from that family's own report.

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"The affected individuals were otherwise healthy including normal skin, dentition and self-reported normal"

Disease-specific observation from the only reported ECTD7 family. The quoted sentence continues "sweating", but that final word is hyphen-folded across a line break in the cached full text ("sweat-" / "ing"), so the quote stops one word short of it; the sentence's subject is the normality of skin, dentition and sweating in the affected siblings.

Other 2

Micronychia Small nail HP:0001792

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia."

Names micronychia as part of the PHNED phenotype. `preferred_term` keeps the clinical term "Micronychia" while the ontology binding uses HPO's canonical label "Small nail"; HPO has no separate micronychia term.

Distal Onycholysis HP:0001806

Distal onycholysis is described in the body of PMID:24714551 rather than in its abstract, so this phenotype is curated without an evidence block per the evidence SOP rather than with an unverifiable snippet. Note that the Edison report proposed `HP:0012203` for onycholysis; that CURIE is actually "Unusual fungal nail infection". The correct term, HP:0001806, was substituted after OAK validation.

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Genetic Associations

1

KRT74 Biallelic Loss-of-Function Variant

Gene: KRT74 hgnc:28929 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13."

Establishes KRT74 as a third PHNED gene, identified specifically by excluding the two previously known causes in a linked family.

Variants (1)

c.821T>C (p.Phe274Ser) coil 1B missense

MISSENSE

Homozygous missense variant (dbSNP rs147962513, transcript NM_175053) replacing a phenylalanine conserved across species and in 25 of 26 human type II keratins. Phe274 lies in the coil 1B rod domain required for long-range keratin dimerization, and patient hair follicles and epidermis showed no detectable keratin-74, indicating loss of function rather than a dominant-negative effect. This is the only ECTD7 allele reported to date.

Show evidence (2 references)

PMID:24714551 SUPPORT Human Clinical

"The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments."

Localizes the variant to the coil 1B dimerization domain and states the predicted structural consequence.

PMID:24714551 SUPPORT Human Clinical

"hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution"

Patient-tissue immunohistochemistry establishing absent keratin-74 protein, the functional evidence for loss of function.

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Medical Actions

2

Symptomatic and Supportive Management

Action: Symptomatic Therapy NCIT:C170740

No disease-modifying therapy exists. Management is supportive: gentle hair care avoiding traction, harsh chemicals, and excessive heat; conservative nail care with protection from trauma and prolonged moisture; and treatment of proven bacterial or fungal superinfection by standard dermatologic practice. Minoxidil is not a mechanism-directed option, since the lesion is a structural keratin defect rather than a follicular growth-cycle abnormality.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for autosomal recessive inheritance with a 25% sibling recurrence risk, cascade carrier testing once the familial variant is known, and prenatal or preimplantation genetic testing where desired. Counseling must distinguish the recessive ECTD7 phenotype from the dominant KRT74 woolly-hair phenotype, because the two carry entirely different recurrence risks for the same gene.

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Diagnosis

1

Molecular Genetic Testing

Diagnosis starts from congenital hypotrichosis plus nail dystrophy, with deliberate examination of the appendages that should be normal - skin, teeth, and sweating - and a three-generation pedigree. Confirmation is molecular: a hereditary hypotrichosis / ectodermal-dysplasia panel containing KRT74, KRT85, and HOXC13, or exome sequencing when the phenotype is nonspecific. Because ECTD7 is recessive, the diagnosis requires two pathogenic or likely pathogenic KRT74 alleles in trans, so parental segregation or phasing is part of the confirmation rather than an optional extra. Single-gene KRT74 sequencing is efficient when the phenotype and family structure are strongly suggestive; genome sequencing is reasonable after a negative panel or exome, though its incremental yield here is unknown.

Chromosomal microarray, karyotyping, FISH, mitochondrial sequencing, repeat-expansion testing, and metabolomic or proteomic testing are not first-line absent a separate indication. Trichoscopy and light microscopy may document shaft fragility but no KRT74-specific pattern is validated. Keratin-74 immunohistochemistry on a hair or skin biopsy showed loss of staining in the reported family and is mechanistically informative, but it is research-supportive rather than a standardized clinical assay.

Show evidence (1 reference)

PMID:24714551 SUPPORT Human Clinical

"Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family."

The discovery family was resolved by exome sequencing plus segregation testing, the route this diagnostic strategy generalizes.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Four affected individuals in one consanguineous Pakistani family constitute the entire reported ECTD7 literature. The discovery paper's approximate "one per million" figure is a Hardy-Weinberg extrapolation from a historical Exome Variant Server allele frequency, not a measured prevalence, and assumes random mating, equilibrium, full penetrance, and that p.Phe274Ser alone accounts for disease burden. It is particularly unreliable in consanguineous populations and is therefore not recorded as a rate here.

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from KRT74-Related Pure Hair-Nail Ectodermal Dysplasia:

Autosomal dominant KRT74 woolly hair / hypotrichosis simplex

Overlapping Features The allelic trap. Heterozygous KRT74 variants cause a dominantly inherited, hair-predominant phenotype without the nail involvement that defines ECTD7, and it shows vertical transmission rather than the consanguineous recessive pattern. Curated separately as `Isolated_Woolly_Hair`. Distinguishing the two is a matter of zygosity and nail status, not of the gene.

Hypohidrotic and syndromic ectodermal dysplasias

Overlapping Features Normal teeth and sweating are what exclude the hypohidrotic forms (EDA/EDAR/EDARADD) and the syndromic ectodermal dysplasias. This is the positive diagnostic use of the two EXCLUDED phenotypes curated above.

{ }

Source YAML

click to show

name: KRT74-Related Pure Hair-Nail Ectodermal Dysplasia
creation_date: "2026-08-17T00:00:00Z"
description: >-
  Ectodermal dysplasia 7, hair/nail type (ECTD7) is an exceptionally rare
  autosomal recessive pure hair and nail ectodermal dysplasia caused by
  biallelic variants in KRT74, a type II keratin of the hair follicle inner root
  sheath that is also expressed in the nail matrix, nail bed, and hyponychium.
  Affected individuals have congenital hypotrichosis with sparse brittle hair
  together with dystrophic, spoon-shaped, small nails and distal onycholysis,
  while skin, dentition, and sweating are normal. ECTD7 is the recessive member
  of an allelic pair: heterozygous KRT74 variants cause autosomal dominant
  woolly hair / hypotrichosis simplex, a hair-predominant disease without the
  nail involvement that defines ECTD7. The entire disease-specific evidence base
  is a single 2014 report of one consanguineous Pakistani family with four
  affected siblings homozygous for p.Phe274Ser.
category: Genetic
parents:
- Ectodermal Dysplasia
disease_term:
  preferred_term: ectodermal dysplasia 7, hair/nail type
  term:
    id: MONDO:0013975
    label: ectodermal dysplasia 7, hair/nail type
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The single reported ECTD7 family segregates a homozygous KRT74 missense
    variant across four affected siblings; unaffected relatives are heterozygous
    or wild type. Heterozygosity for this allele produced no hair or nail
    phenotype in that family, which is the observation that separates ECTD7 from
    the dominant KRT74 woolly-hair phenotype caused by other alleles.
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing of affected individuals revealed homozygosity for a
      rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR
      PHNED in the family.
    explanation: >-
      Documents homozygous segregation of the causal allele with autosomal
      recessive PHNED in the reported family.
genetic:
- name: KRT74 Biallelic Loss-of-Function Variant
  gene_term:
    preferred_term: KRT74
    term:
      id: hgnc:28929
      label: KRT74
  relationship_type: CAUSATIVE
  variants:
  - name: c.821T>C (p.Phe274Ser) coil 1B missense
    description: >-
      Homozygous missense variant (dbSNP rs147962513, transcript NM_175053)
      replacing a phenylalanine conserved across species and in 25 of 26 human
      type II keratins. Phe274 lies in the coil 1B rod domain required for
      long-range keratin dimerization, and patient hair follicles and epidermis
      showed no detectable keratin-74, indicating loss of function rather than a
      dominant-negative effect. This is the only ECTD7 allele reported to date.
    type: MISSENSE
    evidence:
    - reference: PMID:24714551
      reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The transition alters the highly conserved Phe274 residue in the coil 1B
        domain required for long-range dimerization of keratins, suggesting that
        the mutation compromises the stability of intermediate filaments.
      explanation: >-
        Localizes the variant to the coil 1B dimerization domain and states the
        predicted structural consequence.
    - reference: PMID:24714551
      reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hair follicles and epidermis of an affected family member stained
        negative for Keratin-74 suggesting a loss of function mechanism mediated
        by the Phe274Ser substitution
      explanation: >-
        Patient-tissue immunohistochemistry establishing absent keratin-74
        protein, the functional evidence for loss of function.
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated a consanguineous Pakistani family with AR PHNED linked to
      the keratin gene cluster on 12p11.1 but without detectable mutations in
      KRT85 and HOXC13.
    explanation: >-
      Establishes KRT74 as a third PHNED gene, identified specifically by
      excluding the two previously known causes in a linked family.
  notes: >-
    No contemporary ClinVar assertion or formal ACMG/AMP classification for
    p.Phe274Ser was established by the Edison deep-research review; a diagnostic
    laboratory should classify the variant independently against current
    population and functional data. The reported allele frequency (~0.0002) came
    from the historical Exome Variant Server and should be rechecked against
    current gnomAD before clinical reporting.

    Locus discrepancy, deliberately preserved: the quoted Raykova 2014 sentence
    above says the family was "linked to the keratin gene cluster on 12p11.1",
    whereas KRT74 and the type II keratin cluster are on 12q, and the rest of
    this entry and the PHNED grouping use 12q12-q14.1. The snippet is a verbatim
    quote that validates against the cached abstract, so the discrepancy is
    almost certainly a paper-side error. Do not "correct" the snippet to match
    the surrounding prose - that would make it a misquote.
pathophysiology:
- name: Keratin-74 Intermediate Filament Instability
  biological_scale: MOLECULAR
  description: >-
    KRT74 encodes a type II keratin that heterodimerizes with a type I partner
    to build intermediate filaments in the hair follicle inner root sheath and
    in nail-forming epithelium. The p.Phe274Ser substitution alters a conserved
    residue in the coil 1B rod domain required for long-range keratin
    dimerization, destabilizing filament assembly. In patient tissue the protein
    is undetectable, so the operative lesion is absence of keratin-74 rather
    than incorporation of a poison subunit - the mechanistic difference from the
    dominant KRT74 woolly-hair alleles, which act dominant-negatively.
  molecular_functions:
  - preferred_term: structural constituent of cytoskeleton
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
    modifier: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: intermediate filament organization
    term:
      id: GO:0045109
      label: intermediate filament organization
    modifier: DECREASED
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The transition alters the highly conserved Phe274 residue in the coil 1B
      domain required for long-range dimerization of keratins, suggesting that
      the mutation compromises the stability of intermediate filaments.
    explanation: >-
      States the proposed molecular defect: impaired keratin dimerization and
      intermediate filament instability.
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hair follicles and epidermis of an affected family member stained
      negative for Keratin-74 suggesting a loss of function mechanism mediated
      by the Phe274Ser substitution
    explanation: >-
      Establishes protein loss in patient tissue, distinguishing this recessive
      mechanism from the dominant-negative woolly-hair alleles.
  notes: >-
    The structural claim rests on domain position and residue conservation plus
    loss of immunostaining. No direct biochemical filament-assembly assay was
    performed for p.Phe274Ser, so the precise step at which assembly fails
    remains inferred rather than measured.
  downstream:
  - target: Inner Root Sheath and Nail Epithelium Keratin Deficiency
    causal_link_type: DIRECT
- name: Inner Root Sheath and Nail Epithelium Keratin Deficiency
  biological_scale: CELLULAR
  description: >-
    Keratin-74 is normally expressed in the hair follicle inner root sheath and,
    in the nail unit, in the nail matrix, nail bed, and hyponychium. Its absence
    deprives exactly those compartments of mechanical support during the
    keratinization that shapes the emerging hair shaft and nail plate. This
    expression map is why the phenotype is restricted to hair and nails: the
    protein is simply not required in the ectodermal derivatives that PHNED
    spares.
  cell_types:
  - preferred_term: Hair follicle cell
    term:
      id: CL:0002559
      label: hair follicle cell
  - preferred_term: Nail matrix keratinocyte
    term:
      id: CL:4052064
      label: nail matrix keratinocyte
  biological_processes:
  - preferred_term: keratinization
    term:
      id: GO:0031424
      label: keratinization
    modifier: DECREASED
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical (IHC) analyses confirmed a strong keratin-74
      expression in the nail matrix, the nail bed and the hyponychium of mouse
      distal digits, as well as in normal human hair follicles.
    explanation: >-
      Establishes the anatomical expression domain of keratin-74, which
      determines which appendages fail when it is lost. The nail localization is
      from mouse distal digit tissue; the hair follicle localization is human.
  downstream:
  - target: Hypotrichosis with Brittle Hair
    causal_link_type: DIRECT
  - target: Nail Dystrophy
    causal_link_type: DIRECT
phenotypes:
- category: Dermatologic
  name: Hypotrichosis with Brittle Hair
  description: >-
    Congenital hypotrichosis with sparse, brittle scalp hair and involvement of
    eyebrows and eyelashes. Present in all four affected siblings of the single
    reported family.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous
      group of rare heritable disorders characterized by brittle hair,
      hypotrichosis, onychodystrophy and micronychia.
    explanation: >-
      Establishes brittle hair and hypotrichosis as cardinal features of the
      entity this KRT74 family was diagnosed with.
  notes: >-
    No `frequency:` is asserted. The Edison review is explicit that the "4/4"
    counts describe one ascertainment family of siblings and must not be read as
    population frequencies, and per docs/frequency-evidence-guidelines.md an
    unjustifiable band is better omitted than fabricated.
- category: Dermatologic
  name: Nail Dystrophy
  description: >-
    Dystrophic, spoon-shaped (koilonychia-like) nails with distal onycholysis,
    reported in all four affected siblings.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous
      group of rare heritable disorders characterized by brittle hair,
      hypotrichosis, onychodystrophy and micronychia.
    explanation: >-
      Establishes onychodystrophy as a cardinal feature of PHNED. Nail
      involvement is also what distinguishes the recessive KRT74 phenotype from
      the dominant KRT74 woolly-hair phenotype, in which nails are generally
      normal.
- category: Dermatologic
  name: Micronychia
  description: >-
    Mildly small nail plates, described in affected members of the reported
    family alongside the dystrophic spooning.
  phenotype_term:
    preferred_term: Micronychia
    term:
      id: HP:0001792
      label: Small nail
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous
      group of rare heritable disorders characterized by brittle hair,
      hypotrichosis, onychodystrophy and micronychia.
    explanation: >-
      Names micronychia as part of the PHNED phenotype. `preferred_term` keeps
      the clinical term "Micronychia" while the ontology binding uses HPO's
      canonical label "Small nail"; HPO has no separate micronychia term.
- category: Dermatologic
  name: Distal Onycholysis
  description: >-
    Separation of the distal nail plate from the nail bed, reported in the
    affected siblings.
  phenotype_term:
    preferred_term: Onycholysis
    term:
      id: HP:0001806
      label: Onycholysis
  notes: >-
    Distal onycholysis is described in the body of PMID:24714551 rather than in
    its abstract, so this phenotype is curated without an evidence block per the
    evidence SOP rather than with an unverifiable snippet. Note that the Edison
    report proposed `HP:0012203` for onycholysis; that CURIE is actually
    "Unusual fungal nail infection". The correct term, HP:0001806, was
    substituted after OAK validation.
- category: Dermatologic
  name: Hypohidrosis Absent
  frequency: EXCLUDED
  diagnostic: true
  description: >-
    A defining exclusion. Sweating was normal in all affected members of the
    reported family. Preserved eccrine function is what separates ECTD7 from the
    hypohidrotic ectodermal dysplasias, in which hypohidrosis and heat
    intolerance carry the principal morbidity.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
    modifier: ABSENT
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals were otherwise healthy including normal skin,
      dentition and self-reported normal
    explanation: >-
      Disease-specific observation from the only reported ECTD7 family. The
      quoted sentence continues "sweating", but that final word is hyphen-folded
      across a line break in the cached full text ("sweat-" / "ing"), so the
      quote stops one word short of it; the sentence's subject is the normality
      of skin, dentition and sweating in the affected siblings.
  notes: >-
    Curated with `frequency: EXCLUDED` plus `modifier: ABSENT`, following the
    convention used in Osteogenesis_Imperfecta_Type_V and
    Epilepsy_with_Generalized_Tonic-Clonic_Seizures_Alone.

    Evidence is the family-specific statement in Raykova 2014 rather than the
    class-level PHNED sparing statement in the HOXC13 literature
    (PMID:28297138), which an earlier draft used. A negative asserted of one
    family should be evidenced from that family's own report.
- category: Dental
  name: Hypodontia Absent
  frequency: EXCLUDED
  diagnostic: true
  description: >-
    The second defining exclusion. Dentition was normal in all affected members
    of the reported family, consistent with the "pure" hair-and-nail
    restriction that names the entity.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
    modifier: ABSENT
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals were otherwise healthy including normal skin,
      dentition and self-reported normal
    explanation: >-
      Disease-specific statement of normal dentition in the affected siblings of
      the only reported ECTD7 family, replacing the class-level PHNED sparing
      quote an earlier draft took from the HOXC13 literature.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis starts from congenital hypotrichosis plus nail dystrophy, with
    deliberate examination of the appendages that should be normal - skin,
    teeth, and sweating - and a three-generation pedigree. Confirmation is
    molecular: a hereditary hypotrichosis / ectodermal-dysplasia panel
    containing KRT74, KRT85, and HOXC13, or exome sequencing when the phenotype
    is nonspecific. Because ECTD7 is recessive, the diagnosis requires two
    pathogenic or likely pathogenic KRT74 alleles in trans, so parental
    segregation or phasing is part of the confirmation rather than an optional
    extra. Single-gene KRT74 sequencing is efficient when the phenotype and
    family structure are strongly suggestive; genome sequencing is reasonable
    after a negative panel or exome, though its incremental yield here is
    unknown.
  evidence:
  - reference: PMID:24714551
    reference_title: "Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing of affected individuals revealed homozygosity for a
      rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR
      PHNED in the family.
    explanation: >-
      The discovery family was resolved by exome sequencing plus segregation
      testing, the route this diagnostic strategy generalizes.
  notes: >-
    Chromosomal microarray, karyotyping, FISH, mitochondrial sequencing,
    repeat-expansion testing, and metabolomic or proteomic testing are not
    first-line absent a separate indication. Trichoscopy and light microscopy
    may document shaft fragility but no KRT74-specific pattern is validated.
    Keratin-74 immunohistochemistry on a hair or skin biopsy showed loss of
    staining in the reported family and is mechanistically informative, but it
    is research-supportive rather than a standardized clinical assay.
differential_diagnoses:
- name: KRT85- and HOXC13-related PHNED
  description: >-
    The two sibling PHNED forms are clinically indistinguishable from ECTD7 and
    are separated only by the causal gene, which is why a panel covering all
    three is the recommended first test rather than single-gene KRT74
    sequencing.
- name: Autosomal dominant KRT74 woolly hair / hypotrichosis simplex
  description: >-
    The allelic trap. Heterozygous KRT74 variants cause a dominantly inherited,
    hair-predominant phenotype without the nail involvement that defines ECTD7,
    and it shows vertical transmission rather than the consanguineous recessive
    pattern. Curated separately as `Isolated_Woolly_Hair`. Distinguishing the
    two is a matter of zygosity and nail status, not of the gene.
- name: Hypohidrotic and syndromic ectodermal dysplasias
  description: >-
    Normal teeth and sweating are what exclude the hypohidrotic forms
    (EDA/EDAR/EDARADD) and the syndromic ectodermal dysplasias. This is the
    positive diagnostic use of the two EXCLUDED phenotypes curated above.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Four affected individuals in one consanguineous Pakistani family constitute
    the entire reported ECTD7 literature. The discovery paper's approximate "one
    per million" figure is a Hardy-Weinberg extrapolation from a historical
    Exome Variant Server allele frequency, not a measured prevalence, and
    assumes random mating, equilibrium, full penetrance, and that p.Phe274Ser
    alone accounts for disease burden. It is particularly unreliable in
    consanguineous populations and is therefore not recorded as a rate here.
treatments:
- name: Symptomatic and Supportive Management
  description: >-
    No disease-modifying therapy exists. Management is supportive: gentle hair
    care avoiding traction, harsh chemicals, and excessive heat; conservative
    nail care with protection from trauma and prolonged moisture; and treatment
    of proven bacterial or fungal superinfection by standard dermatologic
    practice. Minoxidil is not a mechanism-directed option, since the lesion is
    a structural keratin defect rather than a follicular growth-cycle
    abnormality.
  treatment_term:
    preferred_term: Symptomatic Therapy
    term:
      id: NCIT:C170740
      label: Symptomatic Therapy
  therapeutic_modality: OTHER
- name: Genetic Counseling
  description: >-
    Counseling for autosomal recessive inheritance with a 25% sibling recurrence
    risk, cascade carrier testing once the familial variant is known, and
    prenatal or preimplantation genetic testing where desired. Counseling must
    distinguish the recessive ECTD7 phenotype from the dominant KRT74
    woolly-hair phenotype, because the two carry entirely different recurrence
    risks for the same gene.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
notes: >-
  Allelism, and the trap it sets: heterozygous KRT74 variants cause autosomal
  dominant woolly hair / hypotrichosis simplex, curated separately in dismech as
  the "ADWH" subtype of `Isolated_Woolly_Hair` (MONDO:0020717), where the
  causative allele is the heterozygous helix-initiation-motif variant
  p.Asn148Lys acting in a dominant-negative manner (PMID:20346438). ECTD7 is a
  different disease with a different zygosity, a different molecular mechanism
  (absent protein rather than a poison subunit), and nail involvement that the
  dominant phenotype lacks. Do not merge the two entries or transfer evidence
  between them.

  Entry scope: this file covers only the KRT74 (ECTD7, MONDO:0013975) form of
  pure hair and nail ectodermal dysplasia. The KRT85 (ECTD4, MONDO:0011177) and
  HOXC13 (ECTD9, MONDO:0013976) forms are separate Disease entries. The
  MONDO:0019071 umbrella is modeled as the
  `Pure_Hair_and_Nail_Ectodermal_Dysplasias` Grouping.

  Named Entity Confusion risk: the Edison report backing this entry passed
  `just preflight-dr` against MONDO:0013975 (KRT74 mentioned 41 times against
  KRT85 3 and HOXC13 3), and its single extracted reference resolved.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 7 citations 2026-08-17T13:54:00.916543

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: KRT74-Related Pure Hair-Nail Ectodermal Dysplasia
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on KRT74-Related Pure Hair-Nail Ectodermal Dysplasia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

KRT74-Related Pure Hair–Nail Ectodermal Dysplasia

Executive summary and evidence boundary

KRT74-related pure hair–nail ectodermal dysplasia is an exceptionally rare, congenital, autosomal-recessive keratin disorder in which abnormalities are restricted principally to hair and nails. The disease-specific evidence located is a single 2014 report of one consanguineous Pakistani family containing four affected siblings. All were homozygous for KRT74 NM_175053:c.821T>C (p.Phe274Ser); unaffected relatives were heterozygous or wild type. The phenotype comprised congenital hypotrichosis with sparse, brittle, shaggy hair and spoon-shaped dystrophic nails with mild micronychia and distal onycholysis. Skin, teeth, sweating, and general health were reported as normal. Consequently, frequencies such as “4/4” below describe this ascertainment family and must not be interpreted as population estimates. (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

No additional disease-specific primary study from 2023–2024, natural-history cohort, validated therapy, or relevant registered clinical trial was identified. The absence of recent publications is itself an important result: current understanding still rests primarily on the 2014 discovery paper.

1. Disease information

Definition. Pure hair–nail ectodermal dysplasia (PHNED) denotes hereditary disorders affecting hair and nails without the dental, sweat-gland, or broader systemic abnormalities typical of many ectodermal dysplasias. The KRT74-related subtype is the recessive phenotype caused by biallelic KRT74 dysfunction. It is allelic but clinically distinct from heterozygous KRT74-associated autosomal-dominant woolly hair/hypotrichosis, in which nail disease is generally absent. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 1-2)

Identifiers and terminology. The discovery paper assigns OMIM 614929 to the KRT74-associated recessive PHNED entity. Useful names include “KRT74-related pure hair and nail ectodermal dysplasia,” “autosomal recessive pure hair–nail ectodermal dysplasia,” and “hair and nail ectodermal dysplasia caused by KRT74.” A disease-specific MONDO, Orphanet, MeSH, ICD-10, or ICD-11 identifier could not be verified from the retrieved primary literature; these should not be inferred from broader ectodermal-dysplasia records. Generic ICD coding would be less specific than the molecular diagnosis. (raykova2014autosomalrecessivetransmission pages 1-2)

This report synthesizes aggregated publication-level evidence, not individual EHR records. However, the aggregate itself derives from four individually described relatives in one pedigree.

Key primary source: Raykova et al., PLoS ONE, April 2014, DOI/URL: https://doi.org/10.1371/journal.pone.0093607. A directly supporting abstract statement is: “Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family.” (raykova2014autosomalrecessivetransmission pages 1-2)

2. Etiology, risk, protective factors, and environment

The primary cause is germline biallelic KRT74 variation. In the reported family, consanguinity increased the probability that both parents transmitted the same rare allele; it is a reproductive/genetic risk context, not a biological cause independent of the variant. Each child of two heterozygous carriers has the standard autosomal-recessive theoretical probabilities of 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy.

The only established disease allele is p.Phe274Ser in the disease-specific evidence retrieved. Family history and parental relatedness are therefore the principal recognizable risk indicators. Sex, age, diet, smoking, occupation, toxins, infection, and other exposures have not been shown to alter occurrence. There are no established susceptibility loci, modifier genes, protective variants, protective environmental factors, or gene–environment interactions. Hair grooming and mechanical/chemical trauma may plausibly worsen breakage or onycholysis but do not cause the congenital disorder; this is supportive-care inference rather than KRT74-specific trial evidence.

The allele was reported at approximately 0.0002 in the historical Exome Variant Server, absent from 350 in-house, 200 Swedish, and 200 Pakistani control exomes, and not observed homozygously. These are older databases and must be rechecked against current gnomAD before clinical reporting. The paper’s approximate “one per million” calculation was Hardy–Weinberg extrapolation from that allele frequency, not measured prevalence. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4)

3. Phenotypes

All reported manifestations were congenital. No standardized severity scale, longitudinal progression measurement, patient-reported outcome, EQ-5D, SF-36, or disease-specific quality-of-life study was found.

Hypotrichosis/sparse hair: 4/4 reported siblings; scalp hair was sparse, brittle, and shaggy, with eyebrow and eyelash involvement. Suggested HPO: HP:0001006 Hypotrichosis, plus current HPO terms for sparse scalp hair, brittle hair, sparse eyebrows, and sparse eyelashes after ontology validation. The principal impact is likely cosmetic, grooming-related, and psychosocial, but this has not been quantified in KRT74-PHNED. (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Nail dystrophy/koilonychia-like spooning: 4/4; nails were dystrophic and spoon-shaped. Suggested HPO: onychodystrophy and koilonychia terms, with current IDs validated before ingestion. (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 2-4)
Distal onycholysis: 4/4 in the family description. Suggested HPO: HP:0012203 Onycholysis. It can interfere with fine manipulation and predispose to traumatic separation, although disease-specific disability data are unavailable. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Micronychia: mild in affected relatives. Suggested HPO: HP:0001813 Micronychia. (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2)
Important negative findings: normal skin, dentition, and sweating; affected individuals were otherwise healthy. These negatives help distinguish “pure” hair–nail disease from hypohidrotic or multisystem ectodermal dysplasias. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

Frequency estimates are not generalizable because n=4 and all affected persons were siblings. Behavioral, neurodevelopmental, metabolic, hematologic, and immune abnormalities have not been reported.

4. Genetic and molecular information

Gene. KRT74 encodes keratin 74, a type II basic keratin in the chromosome 12 keratin cluster. The disease paper used transcript NM_175053. Gene-level HGNC and current NCBI Gene identifiers should be imported directly from HGNC/NCBI rather than inferred from the paper.

Variant. The reported allele is NM_175053:c.821T>C; p.(Phe274Ser), rs147962513, a germline missense substitution in exon 4 and the conserved coil 1B rod domain. Four affected siblings were homozygous; parents and unaffected siblings were carriers or wild type. Phe274 was completely conserved among species with available KRT74 sequences and in 25 of 26 human type II keratins. Historical computational prediction called it probably damaging. (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 2-4)

The segregation, rarity, conservation, phenotype specificity, and loss of keratin-74 immunostaining constitute strong case-level pathogenic evidence. Nevertheless, a current ClinVar assertion and a formal contemporary ACMG/AMP classification were not established in the retrieved evidence; a diagnostic laboratory should independently classify the variant using current population and functional data.

Functional consequence. Replacement of hydrophobic phenylalanine by polar serine is predicted to impair long-range keratin dimerization and intermediate-filament stability. Patient hair follicles and epidermis lacked detectable keratin-74 staining, supporting protein loss or degradation. This is consistent with loss of function, but no direct filament-assembly assay established the exact biochemical step. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4, raykova2014autosomalrecessivetransmission pages 4-5)

No validated modifier genes, epigenetic disease signature, pathogenic structural rearrangement, somatic event, methylation abnormality, or chromosomal anomaly has been reported.

5. Environmental information

No toxin, radiation, pollutant, occupation, lifestyle behavior, diet, medication, or infectious agent is known to cause or trigger KRT74-PHNED. It is not infectious and has no zoonotic transmission. Environmental factors may affect the condition of already fragile hair or nails but do not alter the underlying genotype. There are no disease-specific CTD-style chemical associations supported by human evidence.

6. Mechanism and pathophysiology

The best-supported causal chain is:

biallelic p.Phe274Ser → disruption of conserved coil 1B keratin interactions → impaired dimer/intermediate-filament stability and loss of detectable keratin-74 → defective mechanical differentiation/support in the hair-follicle inner root sheath and nail-forming epithelia → malformed, fragile hair shafts and dystrophic small nails with onycholysis. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4, raykova2014autosomalrecessivetransmission pages 4-5)

The upstream event is the germline missense variant. The proximal molecular defect is impaired keratin assembly/protein stability. Downstream effects are appendage-specific structural failure and the clinical hair/nail phenotype. Unlike EDA–NF-κB ectodermal dysplasias, no evidence implicates Wnt, MAPK, mTOR, PI3K–AKT, inflammation, autoimmunity, or metabolic deficiency as the primary pathway here.

Suggested GO annotations include keratin filament, intermediate filament organization, keratinization, epithelial cell differentiation, and structural constituent of cytoskeleton; exact current IDs should be validated through GO. Suggested cell types are hair-follicle inner-root-sheath keratinocytes and nail-matrix/nail-bed keratinocytes; corresponding CL terms require validation because specialized appendage keratinocytes may not have granular standalone CL entries.

No disease-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, multi-omic, CRISPR-screen, RNAi-screen, or patient-derived organoid/iPSC study was found. The immunohistochemistry is tissue-level protein-localization evidence, not comprehensive proteomics.

7. Anatomical structures affected

At organ/system level, involvement is confined to the integumentary system, principally hair follicles and nail units. Sites described include scalp hair, eyebrows, eyelashes, fingernails, and toenails. No lateralization or consistent asymmetry was reported. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

At tissue level, keratin-74 is expressed in the hair-follicle inner root sheath, nail matrix, nail bed, and hyponychium. Mouse distal-digit immunohistochemistry supported the nail localization, while normal human follicles supported hair localization. Suggested UBERON concepts are hair follicle, inner root sheath, nail, nail matrix, nail bed, and hyponychium, with exact IDs validated before entry. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 4-5)

At subcellular level, the relevant structure is the cytoplasmic keratin intermediate-filament network. “Keratin filament” and “intermediate filament cytoskeleton” are appropriate GO cellular-component concepts. No primary nuclear, mitochondrial, lysosomal, ER, vascular, neural, or immune compartment abnormality has been demonstrated.

8. Temporal development

Onset was congenital/present from birth. The disorder should be considered chronic and lifelong because it reflects formation of repeatedly regenerated appendages from genetically altered epithelia. However, the publication did not provide serial measurements, defined stages, progression rates, remission, age-dependent penetrance, or critical treatment windows. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

There is no evidence for episodic attacks, spontaneous remission, relapsing–remitting behavior, or genetic anticipation. The developmental period of hair-shaft and nail-plate formation is mechanistically relevant, but no intervention window has been tested.

9. Inheritance and population

Inheritance is autosomal recessive. Within the reported pedigree, segregation was consistent and heterozygous relatives had normal hair and nails, suggesting complete penetrance for homozygotes in that family and no phenotype from this allele in heterozygotes. Population-wide penetrance and expressivity remain unknown. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 4-5)

The only disease family reported in the retrieved evidence was consanguineous and Pakistani. This does not establish ethnic susceptibility, geographic endemicity, or a founder effect. Both sexes can theoretically be affected equally; no valid sex ratio can be calculated from four siblings. Incidence, measured prevalence, carrier frequency, mosaicism rate, and age distribution are unknown. Germline mosaicism has not been reported but cannot be excluded generically.

The historical allele-frequency extrapolation of approximately one affected person per million is not epidemiologic observation and assumes random mating, equilibrium, full penetrance, and that p.Phe274Ser alone represents disease burden. It is particularly unreliable in consanguineous populations. (raykova2014autosomalrecessivetransmission pages 5-6)

10. Diagnostics

Diagnosis begins with congenital hypotrichosis plus nail dystrophy, careful examination of scalp hair, eyebrows, eyelashes, all nails, skin, teeth, and sweating, and a three-generation pedigree. Trichoscopy and light microscopy may document shaft fragility or shape but no KRT74-specific pattern has been validated. Routine blood chemistry, imaging, electrophysiology, and organ-function testing are not diagnostic.

Genetic testing strategy:

Use a hereditary hypotrichosis/ectodermal-dysplasia panel containing KRT74, KRT85, HOXC13, and phenotype-overlap genes, or exome sequencing when the phenotype is nonspecific.
Confirm candidate variants and phase/segregation in parents and relatives; diagnosis requires two pathogenic/likely pathogenic KRT74 alleles in trans for this recessive entity.
WGS is reasonable after negative panel/WES testing to assess poorly covered, intronic, or structural variants, but its incremental yield is unknown.
Single-gene KRT74 sequencing is efficient when phenotype and family structure are strongly suggestive.
CMA, karyotyping, FISH, mitochondrial sequencing, repeat-expansion testing, RNA sequencing, proteomics, metabolomics, epigenomics, and liquid biopsy are not first-line tests absent additional indications.

The discovery family was resolved by whole-exome sequencing followed by segregation testing. Skin/hair biopsy and keratin-74 immunohistochemistry demonstrated loss of staining, but IHC is research-supportive rather than a standardized clinical biomarker. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

Differential diagnosis: KRT85- and HOXC13-related PHNED; dominant KRT74 woolly hair/hypotrichosis; other isolated woolly-hair/hypotrichosis genes; nonsyndromic nail dysplasias; and syndromic ectodermal dysplasias. Normal teeth and sweating favor pure PHNED. Dominant KRT74 disease is distinguished by vertical transmission/heterozygosity and predominantly hair-only disease, whereas the p.Phe274Ser recessive phenotype includes nails. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 1-2)

No consensus clinical criteria or population/newborn screening program exists. Cascade testing of relatives is appropriate once a familial variant is established.

11. Outcome and prognosis

No deaths, systemic complications, or shortened survival were reported; affected relatives were otherwise healthy. The available phenotype therefore suggests normal life expectancy, but this is an inference from four individuals rather than survival analysis. (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

Expected morbidity is primarily cosmetic/psychosocial and functional inconvenience from hair fragility and dystrophic nails. Possible secondary issues include traumatic nail separation and local infection, but no complication rate has been measured. There are no 5- or 10-year survival statistics, mortality rates, disability scores, quality-of-life instruments, prognostic models, or prognostic biomarkers. Genotype may predict phenotype broadly—biallelic p.Phe274Ser produced hair+nail disease, while other heterozygous KRT74 alleles cause dominant hair disease—but robust variant-specific prognostication is impossible. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 4-5)

12. Treatment and applications

There is no disease-modifying or approved KRT74-specific therapy. Current implementation is supportive:

gentle hair care; avoidance of traction, harsh chemicals, excessive heat, and traumatic grooming;
cosmetic hair replacement or camouflage where desired;
regular conservative nail care, protection from trauma and prolonged moisture, and treatment of proven bacterial/fungal superinfection according to standard dermatologic practice;
dermatology follow-up and psychosocial support;
genetic counseling and genotype-informed family testing.

Potential NCIt intervention concepts include Genetic Counseling, Genetic Testing, Supportive Care, and prosthetic/cosmetic hair replacement terms, subject to current NCIt validation. No disease-specific drug, pharmacogenomic guidance, surgery, rehabilitation protocol, gene therapy, cell therapy, ASO/siRNA/mRNA treatment, CRISPR intervention, immunotherapy, or combination regimen has been evaluated. Minoxidil cannot be recommended as a mechanism-correcting therapy because this is a structural keratin defect, and no KRT74-PHNED response data were found.

The ClinicalTrials.gov search produced no relevant KRT74/PHNED study; therefore, there are no applicable NCT identifiers, response rates, or adverse-event datasets.

13. Prevention

The phenotype cannot presently be prevented in an individual who inherits two causal alleles. There is no vaccine, medication prophylaxis, lifestyle program, or environmental intervention.

Primary reproductive prevention options after molecular confirmation include carrier testing, partner testing, genetic counseling, preimplantation genetic testing for monogenic disease, and targeted prenatal diagnosis, subject to local law and family preferences. Secondary prevention consists of early molecular diagnosis and cascade testing, avoiding repeated diagnostic procedures. Tertiary prevention consists of reducing hair/nail trauma and promptly managing complications. Population-wide or newborn screening is not justified by current evidence and no public-health program exists.

14. Other species and natural disease

The 2014 study used mouse (Mus musculus; NCBI Taxonomy 10090) nail tissues for normal keratin-74 localization in nail matrix, bed, and hyponychium. This was comparative expression evidence, not a naturally affected animal or a disease model. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 4-5)

KRT74 orthologues and hair keratin biology are evolutionarily conserved across mammals, consistent with the cross-species conservation of Phe274. Nevertheless, no naturally occurring veterinary disorder that exactly reproduces biallelic human KRT74 hair–nail dysplasia was established in the retrieved evidence. There is no zoonotic or cross-species transmission because this is a germline structural-protein disorder.

15. Model organisms

No Krt74 p.Phe274Ser knock-in, Krt74-null animal, patient-derived organoid, iPSC model, or validated cellular filament-assembly model specific to this disease was identified. The available experimental systems are limited to human patient tissue IHC and normal mouse distal-digit IHC. Their strength is anatomically concordant localization; their limitation is that they do not directly quantify filament assembly, nail biomechanics, longitudinal progression, or therapeutic rescue. (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4)

A disease-specific knock-in mouse or differentiated hair-follicle/nail keratinocyte model would be valuable for testing protein stability, keratin-pair interactions, filament architecture, appendage biomechanics, and allele-specific rescue.

Ontology-ready summary

The following table separates direct evidence from candidate ontology mappings that require validation against current releases.

domain	finding	suggested ontology term(s)/identifier(s)	evidence strength/limitations
Disease entity	KRT74-related pure hair-nail ectodermal dysplasia; autosomal recessive hair/nail ectodermal dysplasia caused by biallelic KRT74 variation; reported as PHNED/ectodermal dysplasia hair and nail type	OMIM: 614929; MONDO: candidate requiring ontology validation; synonym candidates: pure hair and nail ectodermal dysplasia, ectodermal dysplasia hair/nail type, KRT74-related PHNED	Strong for existence of a distinct KRT74-associated entity, but evidence is limited to n=4 affected siblings from one consanguineous Pakistani family (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Causal gene/protein	KRT74 encodes keratin-74, a type II keratin involved in hair/nail epithelial appendages	KRT74; candidate HGNC/NCBI identifiers require ontology validation; protein: Keratin-74	Strong gene-disease association within the single family; broader literature supports KRT74 as a hair keratin, but disease-specific evidence remains sparse (raykova2014autosomalrecessivetransmission pages 2-4, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 6-7)
Inheritance	Autosomal recessive segregation with unaffected heterozygous parents/siblings and homozygous affected siblings	HP:0000007 Autosomal recessive inheritance	Strong segregation evidence in one pedigree only; penetrance beyond this family is unknown (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 2-4)
Pathogenic variant	Homozygous NM_175053:c.821T>C, p.Phe274Ser in KRT74; missense in coil 1B domain; rs147962513 reported	HGVS: NM_175053:c.821T>C; p.Phe274Ser; dbSNP: rs147962513; ACMG class: candidate pathogenic/likely pathogenic requiring current database re-validation	Strong family-level causal evidence plus conservation and IHC support; formal contemporary ACMG/ClinVar status was not established here and should be rechecked (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4)
Onset	Hair and nail abnormalities present since birth; congenital onset	HP:0003577 Congenital onset; candidate HPO term requiring validation if more specific onset term desired	Strong within reported family; no longitudinal natural history cohorts (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Hair phenotype	Congenital hypotrichosis with sparse, brittle, shaggy scalp hair; involvement of eyebrows and eyelashes	HP:0001006 Hypotrichosis; candidate HPO terms requiring validation: sparse scalp hair, brittle hair, abnormal eyebrow hair, sparse eyelashes	Strong descriptive evidence in n=4; exact standardized HPO mapping for “shaggy” hair and eyebrow/eyelash involvement should be ontology-validated (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Nail phenotype	Spoon-shaped dystrophic nails with onychodystrophy, distal onycholysis, and mild micronychia	HP:0012203 Onycholysis; HP:0001813 Micronychia; candidate HPO terms requiring validation: spoon-shaped nails, nail dystrophy/onychodystrophy	Strong descriptive evidence in n=4; some nail morphology terms need validation against current HPO nomenclature (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Negative ectodermal/systemic findings	Otherwise healthy; no skin abnormalities; dentition and sweating reported as normal	Candidate HPO negatives requiring validation: normal skin morphology, normal dentition, normal sweating	Useful for differential diagnosis, but negative findings are only from the single family report and were not deeply phenotyped by standardized instruments (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Primary anatomy	Hair follicle and nail unit are the principal affected structures	UBERON candidate terms requiring validation: hair follicle, nail unit, scalp hair, eyebrow, eyelash	Strong clinicopathologic concordance; disease appears appendage-restricted in available evidence (raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)
Tissue/cell localization	Keratin-74 expression demonstrated in hair follicle inner root sheath and in nail matrix, nail bed, and hyponychium	UBERON/CL candidates requiring validation: hair follicle inner root sheath, nail matrix, nail bed, hyponychium; CL candidate: hair follicle keratinocyte	Strong localization evidence by immunohistochemistry, including mouse distal digit/nail tissues and normal human hair follicles; cell ontology mapping needs validation (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 2-4)
Molecular function/pathway	Conserved Phe274 in coil 1B domain is predicted to be required for keratin long-range dimerization and intermediate filament stability; disease mechanism consistent with keratinization/intermediate filament defect	GO candidate terms requiring validation: intermediate filament organization, keratin filament, keratinization, structural constituent of cytoskeleton	Moderate mechanistic strength: supported by domain/conservation analysis and loss of staining, but no direct biochemical filament-assembly assay in patient cells was reported (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4, raykova2014autosomalrecessivetransmission pages 4-5)
Functional consequence	Affected hair follicles/epidermis stained negative for keratin-74, supporting loss of function/protein degradation	GO candidate: loss of protein expression requiring validation	Moderate evidence from IHC; absence of signal supports loss of function but does not fully resolve whether degradation, failed translation, or epitope loss predominates (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4)
Population data	Variant reported as extremely rare; present heterozygously at very low frequency in older population resources and not observed homozygously	Population resource annotation candidates requiring re-validation in current gnomAD/dbSNP	Weak-to-moderate because frequency estimates cited are from older EVS/dbSNP-era resources; modern population frequency should be rechecked (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 2-4)
Differential diagnosis	Distinguish from KRT85-related PHNED, HOXC13-related PHNED, and dominant KRT74-associated woolly hair/hypotrichosis without nail disease	OMIM candidates requiring validation for differential entities; HPO pattern: hair+nail ectodermal dysplasia versus isolated woolly hair/hypotrichosis	Strong conceptual differential, but comparative phenotypic granularity is limited by few cases and literature availability (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 4-5)
Evidence scope	Human evidence base consists of one published family with four affected full siblings; no dedicated clinical trial, biomarker study, or natural history cohort identified	Evidence annotation candidate: single-family case series	Critical limitation for all downstream assertions; ontology entry should flag very low case count and need for replication (raykova2014autosomalrecessivetransmission pages 4-5, raykova2014autosomalrecessivetransmission pages 1-2, raykova2014autosomalrecessivetransmission pages 2-4)

Table: This table summarizes ontology-ready disease, phenotype, anatomy, and mechanism annotations for KRT74-related pure hair-nail ectodermal dysplasia. It emphasizes the narrow evidence base: four affected individuals from a single family, with several ontology IDs marked as candidates requiring validation.

Evidence assessment and current research priorities

The strongest evidence is human genetic segregation plus tissue-level IHC: four homozygous affected siblings, unaffected heterozygotes, an evolutionarily conserved rod-domain substitution, extreme rarity, and loss of detectable protein in relevant tissue. The authors summarized the central mechanistic conclusion as: “The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments.” (raykova2014autosomalrecessivetransmission pages 5-6, raykova2014autosomalrecessivetransmission pages 1-2)

Major unresolved questions are whether additional biallelic KRT74 alleles produce the same phenotype, the true penetrance and prevalence, the natural history of nail and hair changes, current population frequency of p.Phe274Ser, the exact keratin-binding/filament defect, quality-of-life burden, and whether appendage-targeted gene or RNA correction is technically feasible. For a knowledge base, the disease should therefore be represented as a valid but very-low-case-count gene–disease entity, with all frequency and prognostic assertions tagged as limited or unknown.

References

(raykova2014autosomalrecessivetransmission pages 4-5): Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, and Niklas Dahl. Autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis. PLoS ONE, 9:e93607, Apr 2014. URL: https://doi.org/10.1371/journal.pone.0093607, doi:10.1371/journal.pone.0093607. This article has 20 citations and is from a peer-reviewed journal.
(raykova2014autosomalrecessivetransmission pages 1-2): Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, and Niklas Dahl. Autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis. PLoS ONE, 9:e93607, Apr 2014. URL: https://doi.org/10.1371/journal.pone.0093607, doi:10.1371/journal.pone.0093607. This article has 20 citations and is from a peer-reviewed journal.
(raykova2014autosomalrecessivetransmission pages 2-4): Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, and Niklas Dahl. Autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis. PLoS ONE, 9:e93607, Apr 2014. URL: https://doi.org/10.1371/journal.pone.0093607, doi:10.1371/journal.pone.0093607. This article has 20 citations and is from a peer-reviewed journal.
(raykova2014autosomalrecessivetransmission pages 5-6): Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, and Niklas Dahl. Autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis. PLoS ONE, 9:e93607, Apr 2014. URL: https://doi.org/10.1371/journal.pone.0093607, doi:10.1371/journal.pone.0093607. This article has 20 citations and is from a peer-reviewed journal.
(raykova2014autosomalrecessivetransmission pages 6-7): Doroteya Raykova, Joakim Klar, Aysha Azhar, Tahir Naeem Khan, Naveed Altaf Malik, Muhammad Iqbal, Muhammad Tariq, Shahid Mahmood Baig, and Niklas Dahl. Autosomal recessive transmission of a rare krt74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis. PLoS ONE, 9:e93607, Apr 2014. URL: https://doi.org/10.1371/journal.pone.0093607, doi:10.1371/journal.pone.0093607. This article has 20 citations and is from a peer-reviewed journal.

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KRT74-Related Pure Hair–Nail Ectodermal Dysplasia

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1. Disease information

2. Etiology, risk, protective factors, and environment

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

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