👪

Inheritance

1

Autosomal recessive HP:0000007

HJMD follows autosomal recessive inheritance. Most reported families are consanguineous, with affected individuals homozygous for CDH3 mutations. Compound heterozygosity has also been documented. Heterozygous carriers are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:11544476 SUPPORT Human Clinical

"Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."

The seminal paper identifying CDH3 as the HJMD gene confirms autosomal recessive inheritance through homozygosity mapping in consanguineous families.

PMID:33837674 SUPPORT Human Clinical

"Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin."

Confirms autosomal recessive inheritance with biallelic CDH3 variants in a Japanese family with compound heterozygous mutations.

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Subtypes

2

Hypotrichosis with Juvenile Macular Dystrophy (HJMD) MONDO:0011107

Classic presentation with congenital hypotrichosis and progressive juvenile-onset macular dystrophy without limb malformations. The most commonly reported CDH3-related phenotype.

Show evidence (1 reference)

PMID:11544476 SUPPORT Human Clinical

"Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."

The seminal paper defines the classic HJMD phenotype as hair loss with progressive macular degeneration.

Ectodermal Dysplasia, Ectrodactyly, and Macular Dystrophy (EEM) MONDO:0009155

CDH3-related phenotype additionally featuring limb malformations (ectrodactyly) alongside hypotrichosis and macular dystrophy. Now considered part of the same continuous phenotypic spectrum as HJMD rather than a separate genetic disorder.

Show evidence (1 reference)

PMID:35038959 SUPPORT Human Clinical

"Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS), both of which are rare autosomal recessive disorders characterized by..."

Confirms HJMD and EEM as two phenotypic presentations of CDH3-related disease.

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Pathophysiology

4

Loss of P-Cadherin-Mediated Cell-Cell Adhesion

CDH3 encodes P-cadherin, a classical cadherin that mediates calcium-dependent homophilic cell-cell adhesion at adherens junctions. Biallelic loss-of-function mutations (deletions, nonsense, missense, splice-site) abolish or severely impair P-cadherin function, disrupting intercellular adhesion in tissues where it is selectively expressed: the retinal pigment epithelium and hair follicles.

Retinal pigment epithelial cell link Hair follicle cell link

Calcium-dependent cell-cell adhesion link ↓ DECREASED Cell-cell adhesion mediated by cadherin link ↓ DECREASED

Downstream

Retinal Pigment Epithelium Degeneration

Hair Follicle Dysfunction

Show evidence (2 references)

PMID:11544476 SUPPORT Human Clinical

"This region contains CDH3, encoding P-cadherin, which is expressed in the retinal pigment epithelium and hair follicles. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3."

The discovery paper establishes that CDH3/P-cadherin is expressed in RPE and hair follicles and that homozygous CDH3 mutations cause HJMD.

PMID:35066146 SUPPORT Human Clinical

"Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells."

This review confirms P-cadherin's role in adherens junctions between RPE cells and that biallelic CDH3 variants cause HJMD.

Retinal Pigment Epithelium Degeneration

Loss of P-cadherin disrupts adherens and tight-junction integrity between RPE cells, including the outer blood-retinal barrier adhesion context. Secondary photoreceptor loss occurs as the RPE monolayer fails to support photoreceptor maintenance. This manifests as chorioretinal atrophy confined to the posterior pole, with preservation of the peripheral retina. The macular dysfunction is progressive, with deteriorating visual acuity over time.

Retinal pigment epithelial cell link

Retinal pigment epithelium development link ↕ DYSREGULATED Adherens junction organization link ↓ DECREASED

Downstream

Secondary Photoreceptor Degeneration

Show evidence (3 references)

PMID:27386845 SUPPORT Human Clinical

"These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole."

The largest HJMD case series characterizes the retinal phenotype as progressive chorioretinal atrophy limited to the posterior pole.

PMID:33837674 SUPPORT Human Clinical

"extensive atrophy of the retina, RPE, and choroid, relatively sparing the fovea"

OCT findings in Japanese HJMD patients show extensive atrophy of retina, RPE, and choroid with relative foveal sparing, consistent with progressive RPE degeneration.

PMID:35066146 SUPPORT Other

"Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival."

This review supports the RPE outer blood-retinal barrier adhesion context for retinal cadherin disease.

Secondary Photoreceptor Degeneration

Loss of RPE integrity and function leads to secondary degeneration of photoreceptors in the posterior pole. P-cadherin is expressed in the RPE but not in photoreceptors; therefore, photoreceptor loss is a downstream consequence of RPE dysfunction rather than a primary cell-autonomous defect. This manifests as progressive central visual loss with preserved peripheral retinal function.

Photoreceptor cell link

Photoreceptor cell maintenance link ↓ DECREASED

Show evidence (1 reference)

PMID:33837674 SUPPORT Human Clinical

"P‐cadherin is expressed in the RPE, and not the photoreceptors; therefore, the decreased central responses (Figure 1e) due to loss of photoreceptors may be secondary to P‐cadherin dysfunction caused by biallelic CDH3 variants."

Directly establishes that photoreceptor loss is secondary to RPE dysfunction from P-cadherin deficiency, not a primary photoreceptor defect.

Hair Follicle Dysfunction

P-cadherin is expressed in hair follicle placodes during development and in the hair matrix. Loss of P-cadherin disrupts normal hair follicle cycling and anchoring of the hair shaft, resulting in sparse, short, slow-growing scalp hair from birth. Body hair, eyebrows, and eyelashes are typically spared or less severely affected.

Hair follicle cell link Hair follicular keratinocyte link

Hair follicle development link ↕ DYSREGULATED

Show evidence (2 references)

PMID:11544476 SUPPORT Human Clinical

"Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."

The discovery paper confirms congenital hair loss as a cardinal feature preceding visual symptoms.

PMID:35038959 SUPPORT Human Clinical

"expressed in the retinal pigment epithelial cells and hair follicles."

Documents P-cadherin expression in hair follicles, explaining why loss-of-function CDH3 mutations cause hair follicle dysfunction.

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Pathograph

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●

Phenotypes

10

Eye 5

Progressive Macular Dystrophy VERY_FREQUENT Macular dystrophy (HP:0007754)

Show evidence (2 references)

PMID:27386845 SUPPORT Human Clinical

"These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole."

The largest case series (10 patients) establishes progressive chorioretinal atrophy confined to the posterior pole as the characteristic retinal phenotype.

PMID:33837674 SUPPORT Human Clinical

"Ophthalmologically, they exhibited progressive loss of visual acuity and chorioretinal macular atrophy"

Confirms progressive visual acuity loss and chorioretinal macular atrophy documented by multimodal imaging.

Central Visual Loss VERY_FREQUENT Visual loss (HP:0000572)

Show evidence (2 references)

PMID:27386845 SUPPORT Human Clinical

"of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration."

Demonstrates progressive visual acuity loss in the majority of HJMD patients over longitudinal follow-up.

PMID:29260097 SUPPORT Human Clinical

"It is characterized by sparse hair and progressive degeneration of the central retina, leading to legal blindness during the first 30 years of life."

Confirms that progressive central retinal degeneration typically leads to legal blindness by age 30.

Central Scotoma FREQUENT Central scotoma (HP:0000603)

Show evidence (1 reference)

PMID:33837674 SUPPORT Human Clinical

"Goldmann perimetry (GP) showed central scotomas"

Demonstrates central scotomas with preserved peripheral fields on formal visual field testing in HJMD patients.

Abnormal Retinal Pigmentation VERY_FREQUENT Abnormal retinal pigmentation (HP:0007703)

Show evidence (1 reference)

PMID:29260097 SUPPORT Human Clinical

"Fundus examination revealed bilateral ring-shaped atrophy of the retinal pigment epithelium with patchy intraretinal pigment clumping at the posterior pole."

Documents characteristic ring-shaped RPE atrophy with intraretinal pigment clumping in a Turkish HJMD patient.

Abnormal Electroretinogram FREQUENT Abnormal electroretinogram (HP:0000512)

Show evidence (2 references)

PMID:27386845 SUPPORT Human Clinical

"Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients."

Documents the electrophysiological pattern in HJMD with predominant macular dysfunction and occasional mild generalized retinal involvement.

PMID:30710256 SUPPORT Human Clinical

"This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails."

Documents that some CDH3 mutations can cause more widespread cone-rod dystrophy beyond isolated macular dysfunction.

Head and Neck 1

Congenital Sparse Scalp Hair VERY_FREQUENT Sparse scalp hair (HP:0002209)

Show evidence (2 references)

PMID:16120155 SUPPORT Human Clinical

"Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness."

Confirms congenital onset of sparse scalp hair as characteristic of HJMD.

PMID:27386845 SUPPORT Human Clinical

"The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair."

Confirms that sparse scalp hair is universal in HJMD and a key diagnostic distinguishing feature.

Integument 1

Nail Dystrophy OCCASIONAL Nail dystrophy (HP:0008404)

Show evidence (1 reference)

PMID:30710256 SUPPORT Human Clinical

"This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails."

Documents hypoplastic nails as an additional ectodermal feature in a CDH3 mutation carrier.

Limbs 1

Limb Abnormalities OCCASIONAL Ectrodactyly (HP:0100257)

Limb anomalies are the distinguishing feature between HJMD and EEM syndrome. The same CDH3 mutation can cause HJMD in one family and EEM in another, suggesting modifier gene involvement.

Show evidence (2 references)

PMID:27386845 SUPPORT Human Clinical

"Patients may have additional limb abnormalities."

Notes that limb abnormalities can be part of the CDH3-related disease spectrum.

PMID:35038959 SUPPORT Human Clinical

"Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS), both of which are rare autosomal recessive disorders characterized by..."

Supports the concept that HJMD and EEM with ectrodactyly are part of a continuous CDH3-related phenotypic spectrum.

Other 2

Chorioretinal Atrophy VERY_FREQUENT Chorioretinal atrophy (HP:0000533)

Show evidence (1 reference)

PMID:27386845 SUPPORT Human Clinical

"Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging."

Chorioretinal atrophy of the posterior pole was present in 9 of 10 patients in the largest HJMD case series.

Progressive Hypotrichosis VERY_FREQUENT Progressive hypotrichosis (HP:0002296)

Show evidence (1 reference)

PMID:33837674 SUPPORT Human Clinical

"Dermatological examination revealed diffuse thinning of the scalp hair, which was sparse and fragile."

Documents diffuse thinning of sparse and fragile scalp hair in Japanese HJMD patients.

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Genetic Associations

1

CDH3 (Causative)

Show evidence (3 references)

PMID:11544476 SUPPORT Human Clinical

"We used homozygosity mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin"

The seminal paper identifying CDH3 as the HJMD gene through homozygosity mapping.

PMID:33837674 SUPPORT Human Clinical

"Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin."

Confirms biallelic CDH3 variants as the cause of HJMD.

PMID:29260097 SUPPORT Human Clinical

"In HJMD patients, no phenotype-genotype correlation has been established for hair and retinal changes between the type of mutation and its location along the CDH3 gene."

Documents the lack of genotype-phenotype correlation, noting that the same mutation can cause different clinical manifestations.

💊

Treatments

4

Genetic Counseling

Action: genetic counseling MAXO:0000079

Genetic counseling for affected families and carriers, particularly important given the high prevalence in consanguineous populations.

Show evidence (1 reference)

PMID:29260097 SUPPORT Human Clinical

"These findings have significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in our region."

Emphasizes the importance of genetic counseling and mutational analysis for HJMD families.

Ophthalmological Surveillance

Action: ophthalmologist evaluation MAXO:0000703

Regular ophthalmological monitoring for all patients with congenital hypotrichosis, as macular changes may precede visual symptoms. Serial retinal imaging (OCT, fundus autofluorescence) is important to track disease progression.

Show evidence (1 reference)

PMID:16120155 SUPPORT Human Clinical

"all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation."

Recommends fundus examination in all patients with congenital hypotrichosis as a diagnostic and surveillance measure.

Low Vision Aids

Action: supportive care MAXO:0000950

Supportive management of progressive central visual loss with low vision aids and rehabilitation. No curative or disease-modifying therapy currently exists for the retinal dystrophy.

Gene Therapy (Investigational)

Action: gene therapy MAXO:0001001

Retinal cadherinopathies including HJMD are considered potentially treatable with molecular therapeutic approaches, but this entry does not model any approved therapy, active clinical trial, or CDH3-specific preclinical efficacy study. Gene replacement or gene editing strategies targeting CDH3 in the RPE remain future directions inferred from the broader retinal cadherinopathy review literature.

Show evidence (1 reference)

PMID:35066146 PARTIAL Other

"This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy."

This review supports a future therapeutic rationale, not an approved CDH3-specific gene therapy or clinical trial.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hypotrichosis with Juvenile Macular Dystrophy:

EEM syndrome Not Yet Curated MONDO:0009155

Overlapping Features EEM is part of the CDH3 allelic spectrum and overlaps with hypotrichosis and macular dystrophy, but ectrodactyly and nail/limb malformations should be scoped to the EEM subtype rather than generic HJMD.

Distinguishing Features

Ectrodactyly or limb malformations favor EEM within the CDH3-related spectrum.
HJMD lacks limb malformations and is dominated by scalp hypotrichosis plus posterior-pole macular dystrophy.

Show evidence (1 reference)

PMID:35038959 SUPPORT Human Clinical

"Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS)"

This supports EEM as an allelic CDH3 diagnosis that should be separated by limb findings.

Stargardt disease MONDO:0019353

Overlapping Features Stargardt disease is a common juvenile macular dystrophy differential, but it lacks the universally thin and sparse scalp hair that distinguishes CDH3-related HJMD.

Distinguishing Features

Thin sparse scalp hair from birth supports HJMD over Stargardt disease.
ABCA4 molecular findings and a Stargardt retinal phenotype support Stargardt disease.

Show evidence (1 reference)

PMID:27386845 SUPPORT Human Clinical

"The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair."

The HJMD hair phenotype distinguishes it from Stargardt and other juvenile macular dystrophies.

Best vitelliform macular dystrophy Not Yet Curated MONDO:0007931

Overlapping Features Best disease can present with childhood macular disease but is usually caused by BEST1 variants and does not include congenital sparse scalp hair.

Distinguishing Features

Congenital hypotrichosis and biallelic CDH3 variants favor HJMD.
Vitelliform lesions and BEST1 variants favor Best vitelliform macular dystrophy.

Other autosomal recessive macular dystrophies

Overlapping Features Other inherited macular dystrophies may overlap through childhood central visual loss, central scotoma, and macular atrophy, but should lack the congenital hair phenotype and biallelic CDH3 variants.

Distinguishing Features

Lifelong sparse scalp hair and CDH3 variants favor HJMD.
Disease-specific retinal imaging, systemic findings, or non-CDH3 molecular results support another inherited macular dystrophy.

{ }

Source YAML

click to show

name: Hypotrichosis with Juvenile Macular Dystrophy
creation_date: "2026-04-24T00:00:00Z"
updated_date: "2026-04-24T12:00:00Z"
category: Mendelian
description: >
  Hypotrichosis with juvenile macular dystrophy (HJMD; OMIM 601553) is a rare autosomal
  recessive disorder caused by biallelic loss-of-function mutations in CDH3, encoding
  P-cadherin, a calcium-dependent cell-cell adhesion molecule. P-cadherin is expressed
  at adherens junctions between retinal pigment epithelium (RPE) cells and in hair follicle
  placodes during development. Loss of P-cadherin disrupts intercellular adhesion in these
  tissues, leading to two cardinal features: congenital sparse scalp hair (hypotrichosis)
  and progressive juvenile-onset macular dystrophy with chorioretinal atrophy of the
  posterior pole, eventually causing severe central visual loss. The peripheral retina
  is typically preserved. HJMD overlaps phenotypically with ectodermal dysplasia,
  ectrodactyly, and macular dystrophy syndrome (EEM; OMIM 225280), which additionally
  features limb malformations; both are now considered part of the CDH3-related syndrome
  spectrum.
disease_term:
  preferred_term: congenital hypotrichosis with juvenile macular dystrophy
  term:
    id: MONDO:0011107
    label: congenital hypotrichosis with juvenile macular dystrophy
synonyms:
- HJMD
- CDH3-related hypotrichosis with juvenile macular dystrophy
- P-cadherin deficiency
parents:
- Ectodermal Dysplasia
- Inherited Macular Dystrophy
- Hair Disorder
has_subtypes:
- name: HJMD
  display_name: Hypotrichosis with Juvenile Macular Dystrophy (HJMD)
  subtype_term:
    preferred_term: congenital hypotrichosis with juvenile macular dystrophy
    term:
      id: MONDO:0011107
      label: congenital hypotrichosis with juvenile macular dystrophy
  description: >
    Classic presentation with congenital hypotrichosis and progressive juvenile-onset
    macular dystrophy without limb malformations. The most commonly reported CDH3-related
    phenotype.
  evidence:
  - reference: PMID:11544476
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."
    explanation: The seminal paper defines the classic HJMD phenotype as hair loss with progressive macular degeneration.
- name: EEM
  display_name: Ectodermal Dysplasia, Ectrodactyly, and Macular Dystrophy (EEM)
  subtype_term:
    preferred_term: EEM syndrome
    term:
      id: MONDO:0009155
      label: EEM syndrome
  description: >
    CDH3-related phenotype additionally featuring limb malformations (ectrodactyly)
    alongside hypotrichosis and macular dystrophy. Now considered part of the same
    continuous phenotypic spectrum as HJMD rather than a separate genetic disorder.
  evidence:
  - reference: PMID:35038959
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS), both of which are rare autosomal recessive disorders characterized by hypotrichosis and progressive macular dystrophy."
    explanation: Confirms HJMD and EEM as two phenotypic presentations of CDH3-related disease.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    HJMD follows autosomal recessive inheritance. Most reported families are
    consanguineous, with affected individuals homozygous for CDH3 mutations.
    Compound heterozygosity has also been documented. Heterozygous carriers
    are unaffected.
  evidence:
  - reference: PMID:11544476
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."
    explanation: The seminal paper identifying CDH3 as the HJMD gene confirms autosomal recessive inheritance through homozygosity mapping in consanguineous families.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin."
    explanation: Confirms autosomal recessive inheritance with biallelic CDH3 variants in a Japanese family with compound heterozygous mutations.
prevalence:
- population: Global
  percentage: unknown
  notes: >-
    Extremely rare. Fewer than 50 patients have been reported worldwide since
    the first description in 1935. Most cases are from consanguineous families
    in Middle Eastern, Turkish, and Pakistani populations, though cases have
    been reported from Brazil, Japan, Colombia, Jordan, and European populations.
  evidence:
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its prevalence is unknown and has only been reported in approximately 30 patients since the first case was described in 1935 by Wagner."
    explanation: This 2017 review documents the extreme rarity of HJMD with approximately 30 reported patients at that time.
  - reference: PMID:40330852
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the first Colombian case of clinical and molecular diagnosis of hypotrichosis with juvenile macular dystrophy associated with CDH3."
    explanation: Documents the expanding geographic distribution of HJMD with the first Colombian case.
  - reference: PMID:31696509
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel CDH3 variants in Brazilian families with hypotrichosis and juvenile macular dystrophy revealed by exome sequencing."
    explanation: Documents novel CDH3 variants in Brazilian families, further broadening the known global distribution.
pathophysiology:
- name: Loss of P-Cadherin-Mediated Cell-Cell Adhesion
  description: >
    CDH3 encodes P-cadherin, a classical cadherin that mediates calcium-dependent
    homophilic cell-cell adhesion at adherens junctions. Biallelic loss-of-function
    mutations (deletions, nonsense, missense, splice-site) abolish or severely impair
    P-cadherin function, disrupting intercellular adhesion in tissues where it is
    selectively expressed: the retinal pigment epithelium and hair follicles.
  cell_types:
  - preferred_term: Retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  - preferred_term: Hair follicle cell
    term:
      id: CL:0002559
      label: hair follicle cell
  biological_processes:
  - preferred_term: Calcium-dependent cell-cell adhesion
    term:
      id: GO:0016339
      label: calcium-dependent cell-cell adhesion
    modifier: DECREASED
  - preferred_term: Cell-cell adhesion mediated by cadherin
    term:
      id: GO:0044331
      label: cell-cell adhesion mediated by cadherin
    modifier: DECREASED
  evidence:
  - reference: PMID:11544476
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This region contains CDH3, encoding P-cadherin, which is expressed in the retinal pigment epithelium and hair follicles. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3."
    explanation: The discovery paper establishes that CDH3/P-cadherin is expressed in RPE and hair follicles and that homozygous CDH3 mutations cause HJMD.
  - reference: PMID:35066146
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotrichosis with juvenile macular dystrophy results from biallelic variants in CDH3, which contributes to adherens tight junctions between RPE cells."
    explanation: This review confirms P-cadherin's role in adherens junctions between RPE cells and that biallelic CDH3 variants cause HJMD.
  downstream:
  - target: Retinal Pigment Epithelium Degeneration
  - target: Hair Follicle Dysfunction

- name: Retinal Pigment Epithelium Degeneration
  description: >
    Loss of P-cadherin disrupts adherens and tight-junction integrity between
    RPE cells, including the outer blood-retinal barrier adhesion context. Secondary
    photoreceptor loss occurs as the RPE monolayer fails to support photoreceptor
    maintenance. This manifests as chorioretinal atrophy confined to the posterior
    pole, with preservation of the peripheral retina. The macular dysfunction is
    progressive, with deteriorating visual acuity over time.
  cell_types:
  - preferred_term: Retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: Retinal pigment epithelium development
    term:
      id: GO:0003406
      label: retinal pigment epithelium development
    modifier: DYSREGULATED
  - preferred_term: Adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: DECREASED
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole."
    explanation: The largest HJMD case series characterizes the retinal phenotype as progressive chorioretinal atrophy limited to the posterior pole.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "extensive atrophy of the retina, RPE, and choroid, relatively sparing the fovea"
    explanation: OCT findings in Japanese HJMD patients show extensive atrophy of retina, RPE, and choroid with relative foveal sparing, consistent with progressive RPE degeneration.
  - reference: PMID:35066146
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Within the retina and retinal pigment epithelium (RPE), cadherins contribute to tissue morphogenesis, neural circuit formation, adherens junctions of the outer blood-retinal barrier, photoreceptor disc morphogenesis, maintenance and survival."
    explanation: This review supports the RPE outer blood-retinal barrier adhesion context for retinal cadherin disease.
  downstream:
  - target: Secondary Photoreceptor Degeneration

- name: Secondary Photoreceptor Degeneration
  description: >
    Loss of RPE integrity and function leads to secondary degeneration of
    photoreceptors in the posterior pole. P-cadherin is expressed in the RPE
    but not in photoreceptors; therefore, photoreceptor loss is a downstream
    consequence of RPE dysfunction rather than a primary cell-autonomous defect.
    This manifests as progressive central visual loss with preserved peripheral
    retinal function.
  cell_types:
  - preferred_term: Photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: Photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P‐cadherin is expressed in the RPE, and not the photoreceptors; therefore, the decreased central responses (Figure 1e) due to loss of photoreceptors may be secondary to P‐cadherin dysfunction caused by biallelic CDH3 variants."
    explanation: Directly establishes that photoreceptor loss is secondary to RPE dysfunction from P-cadherin deficiency, not a primary photoreceptor defect.

- name: Hair Follicle Dysfunction
  description: >
    P-cadherin is expressed in hair follicle placodes during development and in the
    hair matrix. Loss of P-cadherin disrupts normal hair follicle cycling and
    anchoring of the hair shaft, resulting in sparse, short, slow-growing scalp
    hair from birth. Body hair, eyebrows, and eyelashes are typically spared
    or less severely affected.
  cell_types:
  - preferred_term: Hair follicle cell
    term:
      id: CL:0002559
      label: hair follicle cell
  - preferred_term: Hair follicular keratinocyte
    term:
      id: CL:2000092
      label: hair follicular keratinocyte
  biological_processes:
  - preferred_term: Hair follicle development
    term:
      id: GO:0001942
      label: hair follicle development
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:11544476
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital hypotrichosis associated with juvenile macular dystrophy (HJMD; MIM601553) is an autosomal recessive disorder of unknown etiology, characterized by hair loss heralding progressive macular degeneration and early blindness."
    explanation: The discovery paper confirms congenital hair loss as a cardinal feature preceding visual symptoms.
  - reference: PMID:35038959
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "expressed in the retinal pigment epithelial cells and hair follicles."
    explanation: Documents P-cadherin expression in hair follicles, explaining why loss-of-function CDH3 mutations cause hair follicle dysfunction.

phenotypes:
- category: Dermatological
  name: Congenital Sparse Scalp Hair
  frequency: VERY_FREQUENT
  description: >
    Sparse, short, and slow-growing scalp hair present from birth. Hair is thin,
    fragile, and easily lost. This is typically the earliest and most conspicuous
    clinical feature, often the presenting sign that leads to diagnosis.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:16120155
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive disorder characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness."
    explanation: Confirms congenital onset of sparse scalp hair as characteristic of HJMD.
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair."
    explanation: Confirms that sparse scalp hair is universal in HJMD and a key diagnostic distinguishing feature.

- category: Ophthalmological
  name: Progressive Macular Dystrophy
  frequency: VERY_FREQUENT
  description: >
    Progressive bilateral macular degeneration beginning in childhood or adolescence.
    Fundus examination reveals chorioretinal atrophy of the posterior pole contiguous
    with the optic disc, with loss of autofluorescence on fundus autofluorescence
    imaging. OCT shows variable atrophy of the outer retina, RPE, and choroid.
    Peripheral retina is typically preserved.
  phenotype_term:
    preferred_term: Macular dystrophy
    term:
      id: HP:0007754
      label: Macular dystrophy
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole."
    explanation: The largest case series (10 patients) establishes progressive chorioretinal atrophy confined to the posterior pole as the characteristic retinal phenotype.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmologically, they exhibited progressive loss of visual acuity and chorioretinal macular atrophy"
    explanation: Confirms progressive visual acuity loss and chorioretinal macular atrophy documented by multimodal imaging.

- category: Ophthalmological
  name: Central Visual Loss
  frequency: VERY_FREQUENT
  description: >
    Progressive bilateral central visual loss beginning in the first or second decade
    of life. Visual acuity deteriorates over time, often leading to legal blindness
    by the third decade. Peripheral visual fields are typically preserved.
  phenotype_term:
    preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration."
    explanation: Demonstrates progressive visual acuity loss in the majority of HJMD patients over longitudinal follow-up.
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by sparse hair and progressive degeneration of the central retina, leading to legal blindness during the first 30 years of life."
    explanation: Confirms that progressive central retinal degeneration typically leads to legal blindness by age 30.

- category: Ophthalmological
  name: Chorioretinal Atrophy
  frequency: VERY_FREQUENT
  description: >
    Bilateral chorioretinal atrophy confined to the posterior pole, contiguous with
    the optic disc. On fundus autofluorescence, there is marked loss of autofluorescence
    in affected areas. OCT demonstrates atrophy of the outer retina, RPE, and choroid,
    with outer retinal tubulations frequently observed.
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging."
    explanation: Chorioretinal atrophy of the posterior pole was present in 9 of 10 patients in the largest HJMD case series.

- category: Ophthalmological
  name: Central Scotoma
  frequency: FREQUENT
  description: >
    Central visual field defect corresponding to the area of macular atrophy.
    Peripheral visual fields are preserved, consistent with the restricted
    distribution of chorioretinal atrophy to the posterior pole.
  phenotype_term:
    preferred_term: Central scotoma
    term:
      id: HP:0000603
      label: Central scotoma
  evidence:
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldmann perimetry (GP) showed central scotomas"
    explanation: Demonstrates central scotomas with preserved peripheral fields on formal visual field testing in HJMD patients.

- category: Ophthalmological
  name: Abnormal Retinal Pigmentation
  frequency: VERY_FREQUENT
  description: >
    Patchy intraretinal pigment clumping and retinal pigment epithelium atrophy
    at the posterior pole. Fundus examination reveals ring-shaped RPE atrophy
    with pigmentary changes.
  phenotype_term:
    preferred_term: Abnormal retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundus examination revealed bilateral ring-shaped atrophy of the retinal pigment epithelium with patchy intraretinal pigment clumping at the posterior pole."
    explanation: Documents characteristic ring-shaped RPE atrophy with intraretinal pigment clumping in a Turkish HJMD patient.

- category: Ophthalmological
  name: Abnormal Electroretinogram
  frequency: FREQUENT
  description: >
    Macular dysfunction on electrophysiology with relatively preserved generalized
    retinal function. Full-field ERG may be normal or show mild generalized
    dysfunction, while multifocal ERG demonstrates markedly reduced central
    responses. Some patients may develop more widespread cone-rod dysfunction.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients."
    explanation: Documents the electrophysiological pattern in HJMD with predominant macular dysfunction and occasional mild generalized retinal involvement.
  - reference: PMID:30710256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails."
    explanation: Documents that some CDH3 mutations can cause more widespread cone-rod dystrophy beyond isolated macular dysfunction.

- category: Dermatological
  name: Progressive Hypotrichosis
  frequency: VERY_FREQUENT
  description: >
    Diffuse thinning and progressive loss of scalp hair. While hypotrichosis is
    present from birth, it may worsen over time with continued difficulty in
    hair growth.
  phenotype_term:
    preferred_term: Progressive hypotrichosis
    term:
      id: HP:0002296
      label: Progressive hypotrichosis
  evidence:
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dermatological examination revealed diffuse thinning of the scalp hair, which was sparse and fragile."
    explanation: Documents diffuse thinning of sparse and fragile scalp hair in Japanese HJMD patients.

- category: Musculoskeletal
  name: Limb Abnormalities
  subtype: EEM
  frequency: OCCASIONAL
  description: >
    Some patients with CDH3 mutations exhibit mild digit abnormalities or more severe
    ectrodactyly (split hand/foot malformation). The presence of limb anomalies,
    along with hypotrichosis and macular dystrophy, defines EEM syndrome, which
    is now considered part of the same CDH3-related phenotypic spectrum as HJMD.
  phenotype_term:
    preferred_term: Ectrodactyly
    term:
      id: HP:0100257
      label: Ectrodactyly
  notes: >
    Limb anomalies are the distinguishing feature between HJMD and EEM syndrome.
    The same CDH3 mutation can cause HJMD in one family and EEM in another,
    suggesting modifier gene involvement.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients may have additional limb abnormalities."
    explanation: Notes that limb abnormalities can be part of the CDH3-related disease spectrum.
  - reference: PMID:35038959
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS), both of which are rare autosomal recessive disorders characterized by hypotrichosis and progressive macular dystrophy."
    explanation: Supports the concept that HJMD and EEM with ectrodactyly are part of a continuous CDH3-related phenotypic spectrum.

- category: Dermatological
  name: Nail Dystrophy
  subtype: EEM
  frequency: OCCASIONAL
  description: >
    Some patients in the broader CDH3-related EEM spectrum exhibit nail
    abnormalities including hypoplastic nails, slow nail growth, or nail dystrophy.
    These findings should not be treated as core generic HJMD features.
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:30710256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case shows that a CDH3 mutation besides macula dystrophy can cause widespread cone-rod dystrophy with hypotrichosis without any other pathology besides hypoplastic nails."
    explanation: Documents hypoplastic nails as an additional ectodermal feature in a CDH3 mutation carrier.

genetic:
- name: CDH3
  gene_term:
    preferred_term: CDH3
    term:
      id: hgnc:1762
      label: CDH3
  association: Causative
  notes: >
    HJMD is caused by biallelic loss-of-function mutations in CDH3 (16q22.1),
    which encodes P-cadherin. Over 35 pathogenic variants have been reported,
    including frameshift deletions, nonsense mutations, splice-site mutations,
    missense mutations, and gross deletions. Most reported families are
    consanguineous with homozygous mutations, but compound heterozygosity
    has been documented. No clear genotype-phenotype correlation has been
    established; the same mutation can produce different clinical phenotypes
    (HJMD vs EEM) across families, suggesting modifier gene involvement.
  evidence:
  - reference: PMID:11544476
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used homozygosity mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin"
    explanation: The seminal paper identifying CDH3 as the HJMD gene through homozygosity mapping.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotrichosis with juvenile macular dystrophy (HJMD) is a rare autosomal recessive inherited disorder caused by biallelic variants in the CDH3 gene encoding P-cadherin."
    explanation: Confirms biallelic CDH3 variants as the cause of HJMD.
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In HJMD patients, no phenotype-genotype correlation has been established for hair and retinal changes between the type of mutation and its location along the CDH3 gene."
    explanation: Documents the lack of genotype-phenotype correlation, noting that the same mutation can cause different clinical manifestations.

diagnosis:
- name: CDH3 Molecular Genetic Testing
  description: >
    Molecular diagnosis is established by identifying biallelic pathogenic or
    likely pathogenic CDH3 variants in a patient with congenital hypotrichosis
    and juvenile-onset macular dystrophy. Testing may include inherited retinal
    dystrophy panels, Sanger sequencing, exome sequencing, or genome sequencing,
    with segregation testing when family samples are available.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: CDH3
        term:
          id: hgnc:1762
          label: CDH3
  results: Biallelic CDH3 variants confirm CDH3-related HJMD/EEM-spectrum disease.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular genetic investigation included bidirectional Sanger sequencing of all exons and intron-exon boundaries of CDH3 and whole-exome sequencing in 2 patients."
    explanation: This case series supports CDH3 sequencing and exome sequencing as molecular diagnostic approaches.
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations were identified in all patients, including 6 novel mutations."
    explanation: Biallelic CDH3 variant detection established the diagnosis across the HJMD cohort.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The WES analysis revealed novel compound heterozygous CDH3 variants"
    explanation: Whole-exome sequencing identified compound heterozygous CDH3 variants in affected siblings.
- name: Multimodal Ophthalmologic Examination
  description: >
    Ophthalmologic diagnosis combines visual acuity, dilated fundus examination,
    fundus autofluorescence, OCT, ERG, and visual-field testing to document
    posterior-pole chorioretinal atrophy, RPE/outer-retinal loss, macular
    dysfunction, and central scotomas with relative peripheral sparing.
  diagnosis_term:
    preferred_term: ophthalmologist evaluation
    term:
      id: MAXO:0000703
      label: ophthalmologist evaluation
  results: Posterior-pole chorioretinal atrophy with OCT/FAF and ERG/perimetry evidence supports CDH3-related HJMD.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten patients from 10 families underwent detailed clinical assessment, including serial retinal imaging and electrophysiologic evaluation"
    explanation: The largest case series used detailed clinical assessment, serial retinal imaging, and electrophysiology.
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging."
    explanation: Fundus examination and autofluorescence define the characteristic posterior-pole atrophy pattern.
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optical coherence tomography (OCT) demonstrated variable degrees of atrophy of the outer retina, retinal pigment epithelium, and choroid"
    explanation: OCT documents the RPE, outer retinal, and choroidal atrophy central to diagnosis.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Full-field electroretinography, assessing generalized retinal function, revealed nearly normal amplitudes of both rod- and cone-mediated responses."
    explanation: Full-field ERG helps distinguish predominant macular disease from generalized retinal degeneration.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multifocal electroretinography, reflecting macular function, showed extremely decreased responses in the central area"
    explanation: Multifocal ERG documents severe central macular dysfunction.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldmann perimetry (GP) showed central scotomas"
    explanation: Visual-field testing documents central scotoma and helps plan low-vision support.
- name: Hair Phenotype and Dermatologic Assessment
  description: >
    Clinical hair assessment documents congenital sparse, short, fragile scalp
    hair, evaluates whether facial/body hair is spared, and checks for nail or
    limb findings that would place the patient in the EEM end of the CDH3 spectrum.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  results: Lifelong thin and sparse scalp hair strongly supports HJMD when paired with juvenile macular dystrophy.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair."
    explanation: Lifelong sparse scalp hair with normal facial hair is a consistent diagnostic clue in the cohort.
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair."
    explanation: The hair phenotype is a key discriminator from other juvenile macular dystrophies.
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dermatological examination revealed diffuse thinning of the scalp hair, which was sparse and fragile."
    explanation: Dermatologic examination documents scalp hair thinning and fragility in molecularly confirmed HJMD.
- name: Fundus Screening in Congenital Hypotrichosis
  description: >
    Patients presenting first with congenital hypotrichosis should undergo fundus
    examination because pigmentary macular changes may be detectable before visual
    symptoms and can prompt CDH3 testing.
  diagnosis_term:
    preferred_term: ophthalmologist evaluation
    term:
      id: MAXO:0000703
      label: ophthalmologist evaluation
  results: Pigmentary macular changes in congenital hypotrichosis support CDH3-related HJMD.
  evidence:
  - reference: PMID:16120155
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation."
    explanation: This directly supports fundus screening and CDH3 suspicion in congenital hypotrichosis.
differential_diagnoses:
- name: EEM syndrome
  description: >
    EEM is part of the CDH3 allelic spectrum and overlaps with hypotrichosis and
    macular dystrophy, but ectrodactyly and nail/limb malformations should be
    scoped to the EEM subtype rather than generic HJMD.
  distinguishing_features:
  - Ectrodactyly or limb malformations favor EEM within the CDH3-related spectrum.
  - HJMD lacks limb malformations and is dominated by scalp hypotrichosis plus posterior-pole macular dystrophy.
  disease_term:
    preferred_term: EEM syndrome
    term:
      id: MONDO:0009155
      label: EEM syndrome
  evidence:
  - reference: PMID:35038959
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in the Cadherin 3 (CDH3) gene are responsible for the occurrence of Hypotrichosis with Juvenile Macular Dystrophy (HJMD) and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy Syndrome (EEMS)"
    explanation: This supports EEM as an allelic CDH3 diagnosis that should be separated by limb findings.
- name: Stargardt disease
  description: >
    Stargardt disease is a common juvenile macular dystrophy differential, but it
    lacks the universally thin and sparse scalp hair that distinguishes CDH3-related
    HJMD.
  distinguishing_features:
  - Thin sparse scalp hair from birth supports HJMD over Stargardt disease.
  - ABCA4 molecular findings and a Stargardt retinal phenotype support Stargardt disease.
  disease_term:
    preferred_term: Stargardt disease
    term:
      id: MONDO:0019353
      label: Stargardt disease
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair."
    explanation: The HJMD hair phenotype distinguishes it from Stargardt and other juvenile macular dystrophies.
- name: Best vitelliform macular dystrophy
  description: >
    Best disease can present with childhood macular disease but is usually caused
    by BEST1 variants and does not include congenital sparse scalp hair.
  distinguishing_features:
  - Congenital hypotrichosis and biallelic CDH3 variants favor HJMD.
  - Vitelliform lesions and BEST1 variants favor Best vitelliform macular dystrophy.
  disease_term:
    preferred_term: Best vitelliform macular dystrophy
    term:
      id: MONDO:0007931
      label: vitelliform macular dystrophy 2
- name: Other autosomal recessive macular dystrophies
  description: >
    Other inherited macular dystrophies may overlap through childhood central
    visual loss, central scotoma, and macular atrophy, but should lack the
    congenital hair phenotype and biallelic CDH3 variants.
  distinguishing_features:
  - Lifelong sparse scalp hair and CDH3 variants favor HJMD.
  - Disease-specific retinal imaging, systemic findings, or non-CDH3 molecular results support another inherited macular dystrophy.
treatments:
- name: Genetic Counseling
  description: >
    Genetic counseling for affected families and carriers, particularly important
    given the high prevalence in consanguineous populations.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings have significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in our region."
    explanation: Emphasizes the importance of genetic counseling and mutational analysis for HJMD families.

- name: Ophthalmological Surveillance
  description: >
    Regular ophthalmological monitoring for all patients with congenital
    hypotrichosis, as macular changes may precede visual symptoms. Serial
    retinal imaging (OCT, fundus autofluorescence) is important to track
    disease progression.
  treatment_term:
    preferred_term: ophthalmologist evaluation
    term:
      id: MAXO:0000703
      label: ophthalmologist evaluation
  evidence:
  - reference: PMID:16120155
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients with congenital hypotrichosis should undergo thorough fundus examination, which, when revealing pigmentary macular changes, can be considered as indicative of an underlying CDH3 causative mutation."
    explanation: Recommends fundus examination in all patients with congenital hypotrichosis as a diagnostic and surveillance measure.

- name: Low Vision Aids
  description: >
    Supportive management of progressive central visual loss with low vision
    aids and rehabilitation. No curative or disease-modifying therapy currently
    exists for the retinal dystrophy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care

- name: Gene Therapy (Investigational)
  description: >
    Retinal cadherinopathies including HJMD are considered potentially treatable
    with molecular therapeutic approaches, but this entry does not model any
    approved therapy, active clinical trial, or CDH3-specific preclinical efficacy
    study. Gene replacement or gene editing strategies targeting CDH3 in the RPE
    remain future directions inferred from the broader retinal cadherinopathy
    review literature.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  evidence:
  - reference: PMID:35066146
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "This group of disorders is potentially treatable; we summarise the likely molecular therapeutic approaches and future directions for each retinal cadherinopathy."
    explanation: This review supports a future therapeutic rationale, not an approved CDH3-specific gene therapy or clinical trial.

progression:
- phase: Congenital Hypotrichosis
  notes: >
    Sparse, short scalp hair is present from birth and is typically the first
    recognized clinical feature.
- phase: Childhood Visual Symptoms
  notes: >
    Central visual disturbance begins in the first or second decade of life.
    Fundus changes may be detectable before symptomatic visual loss.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair."
    explanation: Documents childhood onset of visual symptoms in all patients in the largest HJMD case series.
- phase: Progressive Macular Atrophy
  notes: >
    Chorioretinal atrophy progresses with decreasing retinal thickness and
    deteriorating macular function. The area of atrophy may remain relatively
    stable, but visual acuity continues to decline. Legal blindness may occur
    by the third decade.
  evidence:
  - reference: PMID:27386845
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The area of atrophy did not progress with time, but retinal thickness decreased on OCT. Electrophysiologic evaluation in 1 patient found deterioration of macular function after 13 years of follow-up, but the mild, generalized photoreceptor dysfunction remained stable."
    explanation: Documents the progressive nature of macular dysfunction with stable area of atrophy but decreasing retinal thickness over time.
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by sparse hair and progressive degeneration of the central retina, leading to legal blindness during the first 30 years of life."
    explanation: Confirms progressive central retinal degeneration leading to legal blindness typically by age 30.
- phase: Low-Vision Rehabilitation and Educational Planning
  notes: >
    Progressive central visual loss and central scotomas should trigger low-vision
    rehabilitation, assistive technology, educational accommodations, and
    orientation or mobility planning while peripheral retinal function is often
    relatively preserved.
  evidence:
  - reference: PMID:33837674
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Goldmann perimetry (GP) showed central scotomas"
    explanation: Central scotoma supports low-vision planning focused on central vision impairment.
  - reference: PMID:29260097
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by sparse hair and progressive degeneration of the central retina, leading to legal blindness during the first 30 years of life."
    explanation: Legal blindness risk supports proactive low-vision rehabilitation and accommodations.

notes: >
  HJMD was first described in 1935 by Wagner. The molecular basis was identified
  in 2001 when Sprecher et al. mapped the disease to CDH3. The disorder exists on
  a phenotypic spectrum with EEM syndrome (ectodermal dysplasia, ectrodactyly,
  and macular dystrophy), which additionally features limb malformations. Both
  disorders are caused by biallelic CDH3 mutations, and the same mutation can
  produce either phenotype in different families, suggesting the involvement of
  modifier genes. P-cadherin structure includes five extracellular domains (EC1-EC5),
  a transmembrane domain, and an intracytoplasmic domain. The EC1 domain is
  critical for homophilic adhesion and contains conserved tryptophan residues
  responsible for trans-cadherin binding. Most cases have been reported from
  Middle Eastern and South Asian populations, but the disorder has now been
  identified in Japanese, Brazilian, Colombian, Jordanian, and European populations.

datasets:

📚

References & Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hypotrichosis with Juvenile Macular Dystrophy. Core disease mechanisms, mo...

Asta Scientific Corpus Retrieval 17 citations 2026-04-24T20:05:23.964621

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hypotrichosis with Juvenile Macular Dystrophy. Core disease mechanisms, mo...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 17
Snippets retrieved: 20

Relevant Papers

[1] Do you know this syndrome?*

Authors: Renata Hubner Frainer, Luciana Boff de Abreu, G. Pinto, A. V. E. de Carvalho, Luana Pizarro Meneghello
Year: 2013
Venue: Anais brasileiros de dermatologia
URL: https://www.semanticscholar.org/paper/1e70afca5e9acff065a2b79aa6aa6d2c6bc66518
DOI: 10.1590/S0365-05962013000100023
PMID: 23539021
PMCID: 3699942
Citations: 39
Influential citations: 2
Summary: Congenital hypotrichosis and Stargardt macular dystrophy are rare autosomal recessive disorder of unknown etiology respectively characterized by hair loss, macular degeneration and severe progressive vision reduction. There are few reports in the literature with this association. Studies show that the defective gene is on the chromosome I6q22.1 and involve cadherin molecule in the pathogenesis. Early recognition of these disorders often starts with hair changes and should alert the dermatolog...
Evidence snippets:
Snippet 1 (score: 0.593) > Congenital hypotrichosis and Stargardt's macular dystrophy are rare autosomal recessive disorders of unknown etiologies, characterized respectively by hair loss, macular degeneration, and precocious and progressive severe vision reduction. 1,2,3he defective gene in hypotrichosis with juvenile macular dystrophy is located on the chromosome 16q22.1.This chromosome has CDH3 gene encoding the protein P-cadherin, expressed in the retinal pigment epithelium and hair follicles.The analysis of this mutation shows that all the families involved had homozygous deletion in the DNA region of the DNA 8 of the gene CDH3.These results established the molecular etiology of hypotrichosis associated with juvenile macular dystrophy and led for the first time to a cadherin molecule in the pathogenesis of such diseases. 1targardt's macular dystrophy affects one in 10.000 people and is usually inherited as an autosomal recessive disorder.It is characterized by progressive and severe reduction of central vision, typically in the first and second decades of life. 4,5The retinal pigment epithelium and the photoreceptor layer from the macular region are the most affected sites. 3,6The decrease in visual acuity often precedes the fundus changes and depends on the age of onset of the symptoms: the later the onset, the lower the probability of visual loss. 7,8e congenital hypotrichosis can be classified as focal or diffuse.The diffuse pattern may be associated with ichthyosis, basal cell carcinoma, epidermolysis bullosa, mental retardation, epilepsy, chromosomal abnormalities, bone abnormalities, ocular and ectodermal dysplasia, and in the latter, heredity as an important causal role. 6reire-Maia has proposed a classification of ectodermal dysplasias which divides them into two groups.One of this are associated to ectodermal structural change, such as the retina. 7

[2] Current Genetics in Hair Diseases

Authors: Y. Shimomura
Year: 2013
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/98f0f630201e132295da988b63ef8eb2a4811174
DOI: 10.5772/54004
Citations: 3
Summary: HF development is operated through reciprocal interactions between skin epithelial cells and underlying dermal cells, and it has been shown that many signaling molecules, such as Wnt, ectodysplasin (Eda), are involved.
Evidence snippets:
Snippet 1 (score: 0.532) > these classical cadherins in the HF has been further supported by two hereditary diseases resulting from mutations in the P-cadherin gene (CDH3). First, mutations in the CDH3 gene are known to underlie hypotrichosis with juvenile macular dystrophy (HJMD; MIM 601553), which is an autosomal recessive disease characterized by sparse hair and weak eyesight due to macular dystrophy of the retina [52]. In addition, it has been reported that another disease, ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM syndrome; MIM 225280), is also caused by recessively-inherited mutations in the CDH3 gene [53]. Affected individuals with EEM syndrome show common hair and eye phenotype with HJMD. > However, EEM patients also shows split hand/foot malformation (ectrodactyly), suggesting crucial roles of P-cadherin in the development of not only hair and retina, but also the limbs in humans. There are no clear genotype-phenotype correlations in CDH3 mutations, as it has been reported that a same mutation in the CDH3 gene caused HJMD in one family [54], while EEM syndrome in another family [53]. Identification of modifier gene(s) may reveal this paradox in the future. > Gap junction (GJ) is a specialized intercellular structure that provides a pathway for both metabolic and ionic coupling between adjacent cells and maintains tissue homeostasis [55]. Connexins (Cxs) are 4-pass transmembrane proteins and the major component of the GJs. Clouston syndrome (MIM 129500), also known as hidrotic ectodermal dysplasia, is an autosomal dominant condition characterized by hypotrichosis, nail dystrophy, and palmoplantar keratoderma. The disease is caused by mutations in GJB6 gene which encodes Cx30 [56]. In addition, mutations in GJB2 gene encoding Cx26 are known to underlie keratitis-ichthyosis-

[3] 58th Annual Symposium of the International Society for Clinical Electrophysiology of Vision (ISCEV 2020)

Authors: R. Hamilton, L. Butler, D. McCulloch, A. Mcneil, Kaleena Michael et al.
Year: 2020
Venue: Documenta Ophthalmologica. Advances in Ophthalmology
URL: https://www.semanticscholar.org/paper/c85a40d6317fc5066636ef6932344976b9c2dfce
DOI: 10.1007/s10633-020-09789-6
PMID: 32915376
PMCID: 7484607
Citations: 3
Summary: Visual electrodiagnostic tests have an important role in clinical evaluation of children with neurofibromatosis type 1 (NF1) with or without optic pathway glioma, and normal VEP responses might imply intact visual pathway function.
Evidence snippets:
Snippet 1 (score: 0.506) > For achromatopsia, clinical phase 3 treatment trials are running. Purpose Hypotrichosis with juvenile macular dystrophy (HJMD, OMIM: 601553) has been described as a rare autosomal recessive disease associated with sparse scalp hair and progressive retinal degeneration caused by CHD3 (cadherin 3) gene mutation located on 16q22.1. We report the fullfield electroretinography findings of a child with hypotrichosis and retinal dystrophy. Methods A 9 year old boy with decreased visual acuity, nyctalopia and hypotrichosis underwent complete ophthalmological examination including fundus photography, optical coherence tomography (OCT) and flash ERG. The patient was referred for genetic evaluation. Results The best corrected visual acuity was 20/200 in both eyes. Fundus evaluation showed severe atrophy of the central macular region with pigment clumping and retinal atrophy at the posterior pole in particular. Flash ERG revealed severe reduction of light-adapted and dark-adapted amplitude, the latter more prominent, indicating that the disease affected the entire retina. OCT indicated disruption and loss of inner and outer retinal layers with atrophic changes extending along the posterior pole. A homozygous c.830del mutation was demonstrated on CDH3 gene. Conclusion HJMD should be kept in mind in children with early onset retinal dystrophy and congenital hypotrichosis. ERG is indispensable for the diagnosis and may reveal generalized retinal dysfunction despite marked macular involvement. Conflict of interest: None. Purpose Understanding normal maturation of retinal function and the acquisition of normal age-related data is fundamental to detect, monitor, and understand pathologic processes that affect the paediatric retina. In the present study, we report darkadapted (DA) and light-adapted (LA) ERGs to full-field white flash stimuli including the ISCEV Standard stimuli in children and compared these to adult ERGs. Methods Thirty-two participants of European descent with normal ocular and general health were recruited to this crosssectional study.

[4] Macular dystrophies associated with Stargardt-like phenotypes

Authors: R. A. S. Amaral, Olivia Araújo Zin, M. V. Salles, F. Motta, J. Sallum
Year: 2023
Venue: Arquivos Brasileiros de Oftalmologia
URL: https://www.semanticscholar.org/paper/87b1b56d8b2886a9853c330997c5e59ddf505221
DOI: 10.5935/0004-2749.2021-0415
PMID: 36995812
PMCID: 11619082
Citations: 1
Summary: Macular dystrophies may have phenotypic similarities to Stargardt-like phenotype associated with other genes besides the classic ones, and these genes may be associated with pathogenic variants related to the phenotypes.
Evidence snippets:
Snippet 1 (score: 0.500) > The pharmacological modulation of the visual cycle serves as a novel approach to the potential treatment of degenerative retinal diseases. Finding the involved genes in the phenotypes leads to new possibilities of discovering treatments by increasing or decreasing the function on the metabolic pathways of those genes. As the pathophysiology of STGD1 is complex, a multitargeted approach could help in the identification of alternative pathways or modification factors involving the disease mechanism. > In this report of four patients with macular dystrophy and history suggesting Stargardt-like disease, two patient's phenotypes were related to AD genes (RIMS1 and CRX) and those of the other two patients were related to AR genes (CRB1 and RDH12). STGD1 is the most common inherited macular dystrophy but has a wide clinical spectrum, and several inherited macular dystrophies have phenotypic similarities that can make clinical diagnosis challenging. As the disease progress, clinical appearance may change over time, and its end-stage appearance of diffuse atrophy and peripheral involvement are almost indistinguishable from each other. Functional tests are still important for the characterization of the phenotype and help in the diagnostic definition, especially in cone dystrophies, which are often the main differential diagnosis for STGD1. > Molecular genetic studies and detailed clinical descriptions have demonstrated that a central atrophic lesion with surrounding subretinal yellow flecks can arise secondary to mutations in different genes. With the improvement of potential treatments for inherited retinal dystrophies, correct molecular diagnosis is essential.

[5] Genetic Hair Disorders: A Review

Authors: Azhar A. Ahmed, Hind M. Almohanna, Jacob Griggs, A. Tosti
Year: 2019
Venue: Dermatology and Therapy
URL: https://www.semanticscholar.org/paper/ecf7b5e9e6265ba893e147b651dcfa3a9623a948
DOI: 10.1007/s13555-019-0313-2
PMID: 31332722
PMCID: 6704196
Citations: 44
Influential citations: 2
Summary: Detailed history including family history and physical examination of hair and other ectodermal structures with the use of dermoscopic devices and biopsy all provide important clues to establish the correct diagnosis.
Evidence snippets:
Snippet 1 (score: 0.489) > Congenital hypotrichosis associated with juvenile macular dystrophy (MIM 601553) is a rare autosomal recessive disorder characterized by early hair loss, heralding progressive Fig. 1 Autosomal recessive woolly hair/hypotrichosis. Note sparse blond curled hair degeneration of the retinal macula leading to early blindness during the second to third decade of life [23,24]. HJMD prevalence is unknown and has only been reported in approximately 30 patients [25][26][27][28][29][30]. Sprecher et al. [23] used mapping in four consanguineous families to localize the gene defective in HJMD to 16q22.1. This region contains CDH3, encoding P-cadherin, which is expressed in the hair follicles and retinal pigment epithelium. Mutation analysis shows in all families a common homozygous deletion in exon 8 of CDH3. These findings establish for the first time the molecular etiology of HJMD and link a cadherin molecule in the pathogenesis of this hair and retinal disorder [23]. Furthermore, Indelman et al. reported another four members of a consanguineous family with HJMD. Light and scanning electron microscopy of the hair shaft revealed pili torti. Fundus examination of the eyes showed marked degeneration of the macular pigment epithelium. DNA analysis of the entire coding sequence of CDH3 revealed, in all affected individuals, a homozygous missense mutation resulting in a single amino acid substitution at position 503 of P-cadherin sequence (R503H). This is considered the first missense mutation reported in CDH3 and second mutation found to underlie HJMD [31]. > Additionally, Indelman and his colleagues assessed nine patients belonging to five families to further characterize the CDH3 mutation spectrum and delineate possible phenotype-genotype correlations. Significant inter-and intrafamilial differences in hair morphology were found, as well as differences in associated skin findings, severity, and age of onset of visual disability [32].

[6] Hypotrichosis and juvenile macular dystrophy caused by CDH3 mutation: A candidate disease for retinal gene therapy

Authors: Mandeep S. Singh, S. Broadgate, R. Mathur, R. Holt, S. Halford et al.
Year: 2016
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/2f577720d956ea379369d53412be89b2c6c9ce40
DOI: 10.1038/srep23674
PMID: 27157923
PMCID: 4860587
Citations: 16
Influential citations: 1
Summary: The number of reported cases of HJMD is expanded and the phenotypic characteristics to consider when selecting candidates for retinal gene therapy are highlighted, which suggests the presence of a therapeutic window for gene augmentation therapy to preserve visual acuity.
Evidence snippets:
Snippet 1 (score: 0.468) > Hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder that causes childhood visual impairment. HJMD is caused by mutations in CDH3 which encodes cadherin-3, a protein expressed in retinal pigment epithelium (RPE) cells that may have a key role in intercellular adhesion. We present a case of HJMD and analyse its phenotypic and molecular characteristics to assess the potential for retinal gene therapy as a means of preventing severe visual loss in this condition. Longitudinal in vivo imaging of the retina showed the relative anatomical preservation of the macula, which suggested the presence of a therapeutic window for gene augmentation therapy to preserve visual acuity. The coding sequence of CDH3 fits within the packaging limit of recombinant adeno-associated virus vectors that have been shown to be safe in clinical trials and can efficiently target RPE cells. This report expands the number of reported cases of HJMD and highlights the phenotypic characteristics to consider when selecting candidates for retinal gene therapy.

[7] Hypotrichosis with juvenile macular dystrophy: a case report with molecular study.

Authors: Lucas Perez Vicente, S. Finzi, R. Susanna, T. Young
Year: 2017
Venue: Arquivos brasileiros de oftalmologia
URL: https://www.semanticscholar.org/paper/e5dbf2554d58e8a9f2190e3da17949a1f31ede41
DOI: 10.5935/0004-2749.20170013
PMID: 28380103
Citations: 7
Summary: An 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes is described, who has a novel in-frame mutation that converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.
Evidence snippets:
Snippet 1 (score: 0.466) > Hypotrichosis with juvenile macular dystrophy: a case report with molecular study.

[8] Hypotrichosis with juvenile macular dystrophy: Combination of whole‐genome sequencing and genome‐wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole‐exome sequencing—A lesson from next‐generation sequencing

Authors: A. Saeidian, H. Vahidnezhad, L. Youssefian, Soheila Sotudeh, M. Sargazi et al.
Year: 2019
Venue: Molecular Genetics & Genomic Medicine
URL: https://www.semanticscholar.org/paper/890fd0b20b1a5bb93e353dc828631628beeb42de
DOI: 10.1002/mgg3.975
PMID: 31560841
PMCID: 6825862
Citations: 8
Summary: The genetic basis of HJMD in a large consanguineous family with 12 affected patients, 1–76 years of age, with characteristic phenotypes is explored.
Evidence snippets:
Snippet 1 (score: 0.456) > Alu-mediated deletion mutation, hypotrichosis with juvenile macular dystrophy, next-generation sequencing | 3 of 8 SAEIDIAN Et Al. mutation(s) in this family. All 298 genes within the shared 7.2 Mb ROH were interrogated manually and CDH3 was the only relevant candidate gene. However, subsequent analysis of DNA from three affected individuals by WES failed to identify a causative mutation in CDH3. Bioinformatics analysis of the WES data revealed, however, a missense variant in a closely linked gene (1.4 Mb distance), FHOD1: c.1306A>G, p.Arg436Gly. This variant was homozygous in all affected individuals and was found to be heterozygous in 18 out of the 19 obligate carriers. Bioinformatics predictions by ANNOVAR (Wang, Li, & Hakonarson, 2010) suggested this missense mutation to be pathogenic with a CADD score (Rentzsch, Witten, Cooper, Shendure, & Kircher, 2019) of 23.7 (for details of the methods, see Youssefian et al., 2019). This variant was also predicted by MutationTaster as a disease-causing variant. In attempts to confirm the pathogenicity of this FHOD1 mutation, a knock-in mouse for this variant was made by the CRISPR/ Cas9 technique at The Jackson Laboratory (Bar Harbor, Maine). However, careful examination of the mice up to several months of age, followed by complete necropsies, including histopathologic analysis of the skin, hair, and eyes, did not reveal any evidence of a disease phenotype (J. P. Sundberg, personal communication). > In further attempts to pursue the pathogenicity of the CDH3 gene whole-genome sequencing of DNA from the proband was performed, which identified a large deletion in CDH3: c.del161-811_246 + 1,044 (Figure 2b). This mutation deletes exon 3, which consists of 86 bp, predicting out of frame deletion of amino acids in the extracellular domain of P-cadherin
Snippet 2 (score: 0.453) > Hypotrichosis with juvenile macular dystrophy: Combination of whole‐genome sequencing and genome‐wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole‐exome sequencing—A lesson from next‐generation sequencing

[9] Hypotrichosis with Juvenile Macular Dystrophy

Authors: F. Almeida, Rui Carneiro-Freitas, R. Caldas, A. P. Vieira
Year: 2018
Venue: International Journal of Trichology
URL: https://www.semanticscholar.org/paper/e136c67de1daf2897a4ccb25c0e4134d2a34c933
DOI: 10.4103/ijt.ijt_60_18
PMID: 30607044
PMCID: 6290288
Citations: 6
Summary: A case of a 4-year-old female patient diagnosed with hypotrichosis with juvenile macular dystrophy, associated with mutations in the cadherin 3 gene, resulting in the abnormal expression of P-cadherin is reported.
Evidence snippets:
Snippet 1 (score: 0.453) > How to cite this article: Almeida FT, Carneiro-Freitas R, Caldas R, Vieira AP. Hypotrichosis with juvenile macular dystrophy. Int J Trichol 2018;10:234-6.
Snippet 2 (score: 0.453) > Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disease, characterized by hypotrichosis and progressive macular degeneration, leading to blindness in the first three decades of life. It is associated with mutations in the cadherin 3 gene, resulting in the abnormal expression of P-cadherin. We report a case of a 4-year-old female patient diagnosed with this genodermatosis.

[10] Hypotrichosis with Juvenile Macular Dystrophy in a Patient with Cadherin 3 (CDH3) Mutation.

Authors: Ekta Rishi, Sugandha Goel, S. Bassi, P. Rishi
Year: 2022
Venue: Nepalese journal of ophthalmology : a biannual peer-reviewed academic journal of the Nepal Ophthalmic Society : NEPJOPH
URL: https://www.semanticscholar.org/paper/f7cea56be48b4874051ef2b8c509eb37f142c46d
DOI: 10.3126/nepjoph.v14i1.37258
PMID: 35996915
Summary: Children with reduced vision not falling into a typical macular degeneration should be examined systemically and may just have sparse scalp hair and still have a genetic disease.
Evidence snippets:
Snippet 1 (score: 0.453) > Hypotrichosis with Juvenile Macular Dystrophy in a Patient with Cadherin 3 (CDH3) Mutation.

[11] Targeted next-generation sequencing identifies ABCA4 mutations in Chinese families with childhood-onset and adult-onset Stargardt disease

Authors: Ling-hui Qu, Xin Jin, Chao Zeng, N. Zhou, Yan-hong Liu et al.
Year: 2021
Venue: Bioscience Reports
URL: https://www.semanticscholar.org/paper/e73afe36c1c96f699f6bd94e5e7121f0291d30b8
DOI: 10.1042/BSR20203497
PMID: 33988224
PMCID: 8173525
Citations: 2
Summary: Childhood-onset Stargardt disease was associated with severe visual loss, generalized retinal dysfunction and was due to more severe variants in ABCA4 than those found in adult-ONSet disease, expanding the existing spectrum of STGD and revealing the genotype–phenotype relationships of theABCA4 mutations in Chinese patients.
Evidence snippets:
Snippet 1 (score: 0.450) > Stargardt disease (STGD; MIM 248200) is the most common inherited juvenile onset macular dystrophy, with a prevalence of approximately 1:8000 to 1:10000, depending on the population studied [1,2].It is characterized by a decrease in central vision and the presence of bilateral atrophic-appearing foveal lesions.These lesions may have a beaten metal appearance with or without yellowish-white fundus flecks at the posterior pole or mid-peripheral retina. > STGD is mostly inherited in autosomal recessive mode, although an autosomal dominant form has been also reported [3].Mutations in ABCA4 (MIM 601691; transcript number ENSP 00000359245.3),also known as ABCR, are responsible for most cases with autosomal recessive STGD, and are also implicated in other retinal degenerative diseases such as retinitis pigmentosa type 19, cone-rod dystrophy, and age-related macular degeneration [3,4].To date, more than 1200 disease-causing mutations have been reported in ABCA4 [5].Rare cases of STGD or 'STGD-like' disease phenotypes have been reported with mutations in PRPH2, VMD2, ELOVL4, and PROM1 genes with important roles in maintaining physiological macular function [3,[6][7][8].Moreover, it should be noted that STGD or 'STGD-like' disease presents with highly variable phenotypes and progression [3,[6][7][8].Clinical features as well as onset and progression of disease can be highly variable. > STGD is particularly devastating because affected individuals lose childhood central vision, which is necessary for common tasks including reading, schooling, driving, and recognizing faces.Ongoing stem cell-based therapy [9,10] or gene therapy [11] has paved the way to clinical trials for the treatment of STGD.Therefore, accurate and comprehensive molecular diagnosis is critical as an aid to clinical diagnosis, determining the visual prognosis, offering a basis for novel therapeutic approaches, and is also crucial for prenatal diagnosis.

[12] Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations

Authors: Chu-Hsuan Huang, Chung-May Yang, Chang-Hao Yang, Yu-Chih Hou, Ta-Ching Chen
Year: 2021
Venue: Genes
URL: https://www.semanticscholar.org/paper/f87a83288f48c94a76177e2a04e9c52ff5c48816
DOI: 10.3390/genes12081261
PMID: 34440435
PMCID: 8392113
Citations: 74
Influential citations: 4
Summary: By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA which would benefit the timing of the diagnosis and thus promote early intervention.
Evidence snippets:
Snippet 1 (score: 0.444) > Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

[13] Hypotrichosis with juvenile macular dystrophy: Portuguese case

Authors: F. Elfatoiki, F. Cordoliani, P. Regane, A. Affortit-Demoge, M. Rybojad
Year: 2020
Venue: Our Dermatology Online
URL: https://www.semanticscholar.org/paper/fd7033637f715f61dc9b5042be12fd4d4c1b8a75
DOI: 10.7241/ourd.2020e.20
Citations: 7
Summary: This dissertation aims to provide a history of ophtalmologie in France from 1910 to 1950, a period chosen in order to explore its roots as well as specific cases up to and including the year in which Adolphe de Rothschild died.
Evidence snippets:
Snippet 1 (score: 0.435) > Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder, mainly described in Israeli families of Arab Muslim origin.We report a case of this disease in portuguese family.
Snippet 2 (score: 0.431) > Hypotrichosis with juvenile macular dystrophy: Portuguese case

[14] How to Set Up Genetic Counselling for Inherited Macular Dystrophies: Focus on Genetic Characterization

Authors: R. Raimondi, F. D’Esposito, Tania Sorrentino, Panos Tsoutsanis, Francesco Paolo De Rosa et al.
Year: 2023
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/03e4f156766c221f495fac2ba601f6021b1cf7e5
DOI: 10.3390/ijms24119722
PMID: 37298674
PMCID: 10253412
Citations: 5
Summary: This review aims to provide comprehensive guidelines to enhance the genetic characterization of patients and improve counselling efficacy by combining updated literature with the authors' own experiences to contribute to the establishment of state-of-the-art genetic counselling services for inherited macular dystrophies.
Evidence snippets:
Snippet 1 (score: 0.435) > Choroidal neovascularization is a possible compliance of this condition, resembling an early onset of age-related macular dystrophy (AMD) [20]. > Sorsby Fundus Dystrophy is an autosomal dominant retinal degeneration related to the presence of pathogenic variants in the TIMP3 gene (OMIM #188826, consisting of five exons, with 39 variants reported). Visual acuity decay and metamorphopsias usually occur around the fourth to sixth decade, and choroidal neovascularizations are not uncommon [21]. > Occult Macular Dystrophy (OMD) is characterized by normal fundus appearance and progressive loss of visual acuity. The known underlying gene is dominantly inherited RP1L1 (OMIM #608581, four exons, 545 reported variants); this is also potentially a cause of RP when recessively inherited [22,23]. > The CDH3 gene (OMIM # 114021) causes a recessive form of macular dystrophy associated with hypotrichosis [24,25]. > In the complex scenario of IRDs, some genes display a marked phenotypic heterogeneity, potentially causing either distinct macular dystrophies or diffused diseases. In particular, this is the case for genes PROM1, IMPG1, FSCN2, OTX2, CRX, RAB28, and GUCA1A [26,27]. > When encountering phenotypes of macular dystrophies, differential diagnosis must be considered. This is especially the case with infectious diseases, such as toxoplasmosis (significantly resembling North Carolina MD), CMV, or toxocariasis. In addition, some systemic drugs with retinal toxicity may mimic the phenotype of an IRD, such as hydroxychloroquine, tamoxifen, and Pentosan Polysulfate Sodium [28]. These causes of similar phenotypes could be very misleading when seeking correct diagnosis and management, hence the importance of careful interviewing of the patient with ad hoc questions.

[15] Uncovering the genetic architecture of inherited retinal disease in a consanguineous Iranian cohort

Authors: Lieselot Vincke, K. Van Schil, H. Ahmadieh, Afrooz Moghaddasi, Hamideh Sabbaghi et al.
Year: 2025
Venue: NPJ Genomic Medicine
URL: https://www.semanticscholar.org/paper/a8ba76fa031c9324db053d33cd9f3ff7008423fb
DOI: 10.1038/s41525-025-00473-9
PMID: 40055385
PMCID: 11889135
Summary: This integrated study using WES and in-depth variant assessment significantly expanded the molecular spectrum of IRD in Iran, an understudied population.
Evidence snippets:
Snippet 1 (score: 0.433) > The macular aspect of this phenotype could be in line with the DRAM2-associated AR retinal dystrophy with early macular involvement 23 . However, the phenotype of F97, end-stage RP without mention of macular problems, is atypical for DRAM2-associated IRD (see Supplementary Figs. 3 and 6 for available clinical data). > A homozygous CDH3 deletion of exons 1-2 was identified in F111, a patient with early RCD with macular dystrophy. CDH3 variants, however, are associated with congenital hypotrichosis with juvenile macular dystrophy (HJMD) (OMIM #601553) 24 . Symptoms of this disease are childhood-onset and progressive macular dystrophy combined with sparse scalp hair (hypotrichosis). Interestingly, CDH3 variants have also been shown to cause CRD, with the hypotrichosis confined to hypoplastic nails only 25 . In a family of Druze origin, three siblings with a CDH3 variant were additionally identified, their phenotype was described as RP, without skin or hair abnormalities 26 . Our findings could confirm this rare association of biallelic CDH3 variants with non-syndromic RP. Clinical reexamination to exclude extra-ocular symptoms was, however, not possible. Available clinical data is included in Supplementary Fig. 7. > Biallelic variants in CEP78 are typically associated with AR CRD and hearing loss (CRDHL) (OMIM #617236). Two causal variants (c.356 C > T, p.(Ser119Leu) and c.515 T > G, p.(Ile172Arg)) in this gene were found in homozygous state in two families in this Iranian cohort. In F141, with a clinical diagnosis of CRDHL (see Supplementary Fig. 8), c.515 T > G, p.(Ile172Arg) was identified, which has already been found in patients with CRDHL 27 .

[16] The Notch signaling pathway in skeletal muscle health and disease

Authors: D. Vargas-Franco, R. Kalra, Isabelle Draper, C. A. Pacak, A. Asakura et al.
Year: 2022
Venue: Muscle & Nerve
URL: https://www.semanticscholar.org/paper/2bc32ef6a1acc95f1c31b7e3ef5a268aadda4024
DOI: 10.1002/mus.27684
PMID: 35968817
PMCID: 9804383
Citations: 37
Summary: The clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases are reviewed.
Evidence snippets:
Snippet 1 (score: 0.431) > Since the landmark discovery in 1986 of DMD (dystrophin), 1 the causative gene for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), dozens of additional genes have been associated with various phenotypic subtypes of muscular dystrophy. > Common disease mechanisms across multiple subtypes have, however, been more difficult to identify, with only a few major clusters such as the dystroglycanopathies identified to date. Given the common phenotypic features within muscular dystrophy categories, such as limb-girdle muscular dystrophy (LGMD), there is a high likelihood that convergent disease mechanisms exist across more muscular dystrophy subtypes than is currently recognized. > There are therapeutic implications of identifying deeper biological ties between muscular dystrophy subtypes. In recent years, the US Food and Drug Administration (FDA) has approved several molecular and genetic therapies for neuromuscular disorders that target specific genes and even specific mutation types within those genes. These approaches are being applied to ever rarer forms of muscular dystrophies. However, proceeding through the preclinical and clinical research studies needed to attain FDA approval for a new therapy is lengthy and costly, and on the current trajectory it will be decades before molecular and genetic therapies are available for all known subtypes of muscular dystrophy. > The identification and characterization of disease mechanisms that are shared by multiple muscular dystrophy subtypes could pave the way for new pathway-based treatments that have therapeutic effects for multiple disease subtypes. 2 This has the potential to accelerate the timeline for broader therapeutic coverage of patients with muscular dystrophy, with a greater impact on the entire muscular dystrophy population. > One disease mechanism that bears further analysis is the Notch signaling pathway, which is known to maintain muscle stem cell (MuSC, also known as satellite cell) quiescence. Recently, three different muscle disease genes that are known to interact with the Notch signaling pathway have been identified: MEGF10, POGLUT1, and most recently JAG2.

[17] CDH3 gene related hypotrichosis and juvenile macular dystrophy – A case with a novel mutation

Authors: O. Karti, S. Abalı, Ziya Ayhan, E. Gokmeydan, Serhad Nalçaçı et al.
Year: 2017
Venue: American Journal of Ophthalmology Case Reports
URL: https://www.semanticscholar.org/paper/589e811bb61e9396cccb01fd06e02a803dbb5e90
DOI: 10.1016/j.ajoc.2017.06.007
PMID: 29260097
PMCID: 5722150
Citations: 14
Influential citations: 2
Summary: A 13-year-old Turkish girl who experienced gradual bilateral visual deterioration with marked hair loss was related to a novel homozygous mutation, termed c.447_467del (p.149_156del), which has significance for the future mutational analysis and genetic counseling of families with HJMD, particularly in this region.
Evidence snippets:
Snippet 1 (score: 0.431) > CDH3 gene related hypotrichosis and juvenile macular dystrophy – A case with a novel mutation

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Hypotrichosis with Juvenile Macular Dystrophy

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hypotrichosis with Juvenile Macular Dystrophy. Core disease mechanisms, mo...

Relevant Papers

[1] Do you know this syndrome?*

[2] Current Genetics in Hair Diseases

[3] 58th Annual Symposium of the International Society for Clinical Electrophysiology of Vision (ISCEV 2020)

[4] Macular dystrophies associated with Stargardt-like phenotypes

[5] Genetic Hair Disorders: A Review

[6] Hypotrichosis and juvenile macular dystrophy caused by CDH3 mutation: A candidate disease for retinal gene therapy

[7] Hypotrichosis with juvenile macular dystrophy: a case report with molecular study.

[8] Hypotrichosis with juvenile macular dystrophy: Combination of whole‐genome sequencing and genome‐wide homozygosity mapping identifies a large deletion in CDH3 initially undetected by whole‐exome sequencing—A lesson from next‐generation sequencing

[9] Hypotrichosis with Juvenile Macular Dystrophy

[10] Hypotrichosis with Juvenile Macular Dystrophy in a Patient with Cadherin 3 (CDH3) Mutation.

[11] Targeted next-generation sequencing identifies ABCA4 mutations in Chinese families with childhood-onset and adult-onset Stargardt disease

[12] Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations

[13] Hypotrichosis with juvenile macular dystrophy: Portuguese case

[14] How to Set Up Genetic Counselling for Inherited Macular Dystrophies: Focus on Genetic Characterization

[15] Uncovering the genetic architecture of inherited retinal disease in a consanguineous Iranian cohort

[16] The Notch signaling pathway in skeletal muscle health and disease

[17] CDH3 gene related hypotrichosis and juvenile macular dystrophy – A case with a novel mutation

Notes