Zlotogora-Ogur syndrome (CLPED1) is a rare autosomal recessive disorder caused by homozygous loss-of-function mutations in the PVRL1 (NECTIN1) gene encoding nectin-1, an immunoglobulin-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system. The syndrome is characterized by cleft lip and/or palate, ectodermal dysplasia (sparse hair with pili torti, hypodontia, nail dystrophy, hypohidrosis), cutaneous syndactyly of fingers and/or toes, and in some cases intellectual disability. Nectin-1 is expressed in keratinocytes, neurons, and the developing face and palate, and is critical for the initial step in adherens junction and tight junction formation. The disorder was first described in families from Israel and Brazil, with a high frequency on Margarita Island in Venezuela due to the W185X founder mutation, possibly maintained by heterozygote advantage against alpha-herpesvirus infection.
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name: Zlotogora-Ogur Syndrome
creation_date: '2026-04-24T00:00:00Z'
updated_date: '2026-04-25T00:00:00Z'
category: Mendelian
synonyms:
- Cleft lip/palate-ectodermal dysplasia syndrome
- CLPED1
- Zlotogora-Zilberman-Tenenbaum syndrome
- Margarita type ectodermal dysplasia
- Ectodermal dysplasia type 4
- Syndactyly-ectodermal dysplasia-cleft lip/palate
description: >
Zlotogora-Ogur syndrome (CLPED1) is a rare autosomal recessive disorder caused
by homozygous loss-of-function mutations in the PVRL1 (NECTIN1) gene encoding
nectin-1, an immunoglobulin-related transmembrane cell-cell adhesion molecule
that is part of the NAP cell adhesion system. The syndrome is characterized by
cleft lip and/or palate, ectodermal dysplasia (sparse hair with pili torti,
hypodontia, nail dystrophy, hypohidrosis), cutaneous syndactyly of fingers
and/or toes, and in some cases intellectual disability. Nectin-1 is expressed
in keratinocytes, neurons, and the developing face and palate, and is critical
for the initial step in adherens junction and tight junction formation. The
disorder was first described in families from Israel and Brazil, with a high
frequency on Margarita Island in Venezuela due to the W185X founder mutation,
possibly maintained by heterozygote advantage against alpha-herpesvirus
infection.
disease_term:
preferred_term: cleft lip/palate-ectodermal dysplasia syndrome
term:
id: MONDO:0009151
label: cleft lip/palate-ectodermal dysplasia syndrome
parents:
- Ectodermal dysplasia
- Orofacial cleft
- Autosomal recessive disease
pathophysiology:
- name: Loss of Nectin-1 Cell Adhesion
description: >
PVRL1 (NECTIN1) encodes nectin-1, an immunoglobulin-related transmembrane
cell-cell adhesion molecule that is part of the NAP cell adhesion system.
Nectin-1 is important for the initial step in the formation of adherens
junctions and tight junctions. All known PVRL1 mutations in CLPED1 result
in truncated proteins that lack the transmembrane domain and intracellular
domain of nectin-1, abolishing cell-cell adhesion. Nectin-4 (PVRL4) binds
nectin-1 in trans at adherens junctions; loss of either partner disrupts
the nectin-afadin and cadherin-catenin complexes essential for junction
formation.
cell_types:
- preferred_term: ectodermal cell
term:
id: CL:0000221
label: ectodermal cell
- preferred_term: epithelial cell
term:
id: CL:0000066
label: epithelial cell
biological_processes:
- preferred_term: calcium-independent cell-cell adhesion
term:
id: GO:0016338
label: calcium-independent cell-cell adhesion
- preferred_term: adherens junction organization
term:
id: GO:0034332
label: adherens junction organization
genes:
- preferred_term: NECTIN1
term:
id: hgnc:9706
label: NECTIN1
evidence:
- reference: PMID:10932188
reference_title: "Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe positional cloning of the gene responsible for an autosomal
recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously ED4;
ref. 2), which we identify as PVRL1, encoding nectin-1, an immunoglobulin
(Ig)-related transmembrane cell-cell adhesion molecule that is part of the
NAP cell adhesion system
explanation: >-
Landmark paper identifying PVRL1 as the gene responsible for CLPED1 through
positional cloning, establishing nectin-1 as the causative adhesion molecule.
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Nectin-1 is a cell-cell adhesion molecule that is important for the initial
step in the formation of adherens junctions and tight junctions; it is
expressed in keratinocytes, neurons, and the developing face and palate
explanation: >-
Describes nectin-1 function in adherens junction and tight junction formation
and its expression pattern relevant to disease pathophysiology.
- reference: PMID:20691405
reference_title: "Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In patient keratinocytes, mutated nectin-4 lost its capability to bind
nectin-1. Additionally, in discrete structures of the hair follicle, we
found alterations of the membrane localization of nectin-afadin and
cadherin-catenin complexes, which are essential for adherens junction
formation
explanation: >-
Demonstrates that nectin-1/nectin-4 trans-interaction is required for
adherens junction formation, and loss of either nectin disrupts junction
complexes in ectodermal tissues.
- name: Defective Epithelial Fusion in Facial Development
description: >
During embryonic development, fusion of the medial nasal processes and
maxillary processes requires nectin-1-mediated cell adhesion. Loss of
functional nectin-1 prevents proper epithelial fusion at the midline,
resulting in cleft lip and palate. Mouse models demonstrate that palatal
epithelial loss of afadin (the obligate nectin-binding partner) induces
high-penetrance cleft palate, and combined loss of Nectin1 and Nectin4
causes severe cleft palate similar to afadin loss. Expression of the
human W185X mutant in mice causes cleft palate with greater penetrance
than Nectin1 knockout, suggesting a dominant interfering mechanism.
cell_types:
- preferred_term: ectodermal cell
term:
id: CL:0000221
label: ectodermal cell
biological_processes:
- preferred_term: roof of mouth development
term:
id: GO:0060021
label: roof of mouth development
locations:
- preferred_term: upper lip
term:
id: UBERON:0001834
label: upper lip
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four PVRL1 mutations identified in cleft lip/palate-ectodermal
dysplasia syndrome to date, including this study, resulted in truncated
proteins that lack the transmembrane domain and intracellular domain of
nectin-1, which is necessary to initiate the cell-cell adhesion process
explanation: >-
Demonstrates that all known CLPED1 mutations produce truncated nectin-1
proteins lacking domains essential for cell-cell adhesion, explaining
the failure of epithelial fusion in facial development.
- reference: PMID:32554531
reference_title: "Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
expression of the human disease mutant NECTIN1W185X causes CP with greater
penetrance than Nectin1 loss, suggesting this alteration may drive CP via
a dominant interfering mechanism
explanation: >-
Mouse model demonstrates that expressing the human W185X mutant causes
cleft palate with greater penetrance than simple Nectin1 loss, providing
direct experimental evidence for the pathogenic mechanism.
- name: Ectodermal Appendage Defects
description: >
Nectin-1 is expressed in hair follicle structures and the developing
ectodermal appendages. Loss of nectin-1 function disrupts adherens junction
formation in ectodermal tissues, leading to abnormal development of hair
follicles, teeth, nails, and sweat glands. The related nectinopathy caused
by PVRL4 mutations (ectodermal dysplasia-syndactyly syndrome) demonstrates
that nectin-4 expression in hair follicle structures and separating digits
is essential for ectodermal appendage morphogenesis through nectin-1/nectin-4
trans-binding.
cell_types:
- preferred_term: ectodermal cell
term:
id: CL:0000221
label: ectodermal cell
biological_processes:
- preferred_term: hair follicle development
term:
id: GO:0001942
label: hair follicle development
evidence:
- reference: PMID:20691405
reference_title: "Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We demonstrated high nectin-4 expression in hair follicle structures, as
well as in the separating digits of murine embryos, the tissues mainly
affected by the EDSS phenotype
explanation: >-
Demonstrates nectin expression in hair follicles and separating digits,
directly relevant to ectodermal dysplasia and syndactyly phenotypes in
nectinopathies including CLPED1.
phenotypes:
- name: Cleft Lip
description: >
Cleft lip, often bilateral, is a cardinal feature of the syndrome resulting
from failed fusion of facial processes during embryogenesis.
frequency: VERY_FREQUENT
category: Clinical
phenotype_term:
preferred_term: Cleft lip
term:
id: HP:0410030
label: Cleft lip
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations comprise a unique facial appearance with cleft
lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers
and/or toes, and in some cases, mental retardation
explanation: >-
Cleft lip/palate is listed as a cardinal clinical manifestation of CLPED1.
- reference: PMID:2167611
reference_title: "Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
3 Brazilian brothers born to normal consanguineous parents (F = 1/16) and
presenting ectodermal dysplasia, cleft lip/palate, mental retardation,
syndactyly of fingers 2-3
explanation: >-
Original clinical delineation of the syndrome confirms cleft lip/palate
as a defining feature in affected siblings.
- name: Cleft Palate
description: >
Cleft palate frequently accompanies cleft lip in this syndrome.
frequency: VERY_FREQUENT
category: Clinical
phenotype_term:
preferred_term: Cleft palate
term:
id: HP:0000175
label: Cleft palate
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations comprise a unique facial appearance with cleft
lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers
and/or toes, and in some cases, mental retardation
explanation: Cleft palate is a cardinal manifestation of CLPED1.
- name: Sparse Hair
description: >
Sparse, brittle, fine, dry scalp hair reflecting ectodermal dysplasia. Hair
shaft abnormalities include pili torti and pili trianguli et canaliculi.
frequency: VERY_FREQUENT
category: Clinical
phenotype_term:
preferred_term: Sparse scalp hair
term:
id: HP:0002209
label: Sparse scalp hair
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair
and hypodontia
explanation: >-
Sparse, brittle hair is documented as a core ectodermal dysplasia feature
in an affected patient.
- name: Pili Torti
description: >
Twisted hair shafts (pili torti) demonstrated on scanning electron
microscopy, a structural hair defect characteristic of ectodermal dysplasia.
category: Clinical
phenotype_term:
preferred_term: Pili torti
term:
id: HP:0003777
label: Pili torti
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Scanning electron microscopic examination of the hair demonstrated pili
torti and pili trianguli et canaliculi
explanation: >-
Pili torti confirmed on electron microscopy in an affected Japanese patient.
- name: Hypodontia
description: >
Congenital absence of teeth (hypodontia) reflecting ectodermal involvement
in tooth development.
frequency: VERY_FREQUENT
category: Clinical
phenotype_term:
preferred_term: Hypodontia
term:
id: HP:0000668
label: Hypodontia
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair
and hypodontia
explanation: Hypodontia documented as part of the ectodermal dysplasia phenotype.
- name: Cutaneous Syndactyly
description: >
Cutaneous syndactyly of fingers and/or toes, typically involving fingers 2-3,
is a characteristic feature.
frequency: VERY_FREQUENT
category: Clinical
phenotype_term:
preferred_term: Cutaneous syndactyly
term:
id: HP:0012725
label: Cutaneous syndactyly
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations comprise a unique facial appearance with cleft
lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers
and/or toes, and in some cases, mental retardation
explanation: >-
Cutaneous syndactyly is listed as a cardinal clinical feature of CLPED1.
- reference: PMID:2167611
reference_title: "Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
syndactyly of fingers 2-3
explanation: >-
Syndactyly specifically involving fingers 2-3 documented in original
clinical delineation.
- name: Nail Dystrophy
description: >
Dystrophic nails as part of the ectodermal dysplasia spectrum.
category: Clinical
phenotype_term:
preferred_term: Nail dystrophy
term:
id: HP:0008404
label: Nail dystrophy
- name: Palmoplantar Keratoderma
description: >
Progressive palmoplantar keratoderma is a characteristic feature that may
become more evident with age. This progressive dermatologic manifestation
can help distinguish Zlotogora-Ogur syndrome from EEC syndrome in older
patients.
category: Clinical
phenotype_term:
preferred_term: Palmoplantar keratoderma
term:
id: HP:0000982
label: Palmoplantar keratoderma
clinical_course: PROGRESSIVE
- name: Toe Syndactyly
description: >
Cutaneous syndactyly of toes, especially 2-3, is a frequently reported
feature in addition to finger syndactyly.
category: Clinical
phenotype_term:
preferred_term: 2-3 toe syndactyly
term:
id: HP:0004691
label: 2-3 toe syndactyly
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
cutaneous syndactyly of the fingers and/or toes
explanation: >-
Toe syndactyly is explicitly included in the clinical phenotype description
of CLPED1.
- name: Ear Anomalies
description: >
Malformed ears and ear anomalies reported as variable features in affected
individuals.
category: Clinical
phenotype_term:
preferred_term: Abnormal ear morphology
term:
id: HP:0031703
label: Abnormal ear morphology
evidence:
- reference: PMID:2167611
reference_title: "Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
accessory nipples, and ear anomalies
explanation: >-
Ear anomalies documented in the original Zlotogora-Ogur syndrome
delineation by Rodini & Richieri-Costa.
- name: Accessory Nipples
description: >
Supernumerary nipples reported as a variable associated finding in some
affected individuals.
category: Clinical
phenotype_term:
preferred_term: Supernumerary nipple
term:
id: HP:0002558
label: Supernumerary nipple
evidence:
- reference: PMID:2167611
reference_title: "Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
accessory nipples, and ear anomalies
explanation: >-
Accessory nipples documented in the three affected Brazilian brothers in
the original Zlotogora-Ogur syndrome clinical delineation.
- name: Hypohidrosis
description: >
Reduced sweating capacity reflecting hypohidrotic ectodermal dysplasia.
category: Clinical
phenotype_term:
preferred_term: Hypohidrosis
term:
id: HP:0000966
label: Hypohidrosis
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair
and hypodontia
explanation: >-
The ectodermal dysplasia in CLPED1 is specifically described as
hypohidrotic in this patient report.
- name: Intellectual Disability
description: >
Intellectual disability, typically mild, occurs in some but not all affected
individuals.
frequency: FREQUENT
category: Clinical
phenotype_term:
preferred_term: Mild intellectual disability
term:
id: HP:0001256
label: Mild intellectual disability
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
cutaneous syndactyly of the fingers and mild mental retardation
explanation: >-
Mild intellectual disability documented in an affected patient, consistent
with variable occurrence in the syndrome.
- reference: PMID:2167611
reference_title: "Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the Zlotogora-Ogur syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ectodermal dysplasia, cleft lip/palate, mental retardation, syndactyly
of fingers 2-3
explanation: >-
Mental retardation listed as a feature in the original Zlotogora-Ogur
syndrome delineation.
genetic:
- name: PVRL1 (NECTIN1) mutations
features: >
Autosomal recessive loss-of-function mutations in PVRL1 (now NECTIN1),
encoding nectin-1, cause Zlotogora-Ogur syndrome. All known mutations result
in truncated proteins lacking the transmembrane and intracellular domains.
The most common mutation is the W185X nonsense mutation, which is a founder
mutation on Margarita Island, Venezuela. Heterozygosity for W185X is
significantly associated with sporadic non-syndromic cleft lip/palate in
northern Venezuela. The high frequency of this mutation may result from
heterozygote advantage, as nectin-1 is also the principal cell surface
receptor for alpha-herpesviruses.
inheritance:
- name: Autosomal recessive
evidence:
- reference: PMID:10932188
reference_title: "Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe positional cloning of the gene responsible for an autosomal
recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously
ED4; ref. 2), which we identify as PVRL1
explanation: Autosomal recessive inheritance established in the gene identification paper.
gene_term:
preferred_term: NECTIN1
term:
id: hgnc:9706
label: NECTIN1
variants:
- name: W185X (c.554G>A)
description: >-
Nonsense mutation creating a premature stop codon at position 185. Founder
mutation on Margarita Island, Venezuela. Homozygosity causes CLPED1;
heterozygosity is associated with non-syndromic cleft lip/palate.
evidence:
- reference: PMID:11559849
reference_title: "Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homozygosity for a nonsense mutation of PVRL1, W185X, results in an
autosomal recessive CL/P syndrome on Margarita Island, CLPED1
explanation: Confirms W185X as the Margarita Island founder mutation.
- name: Frameshift at Trp185
description: >-
Single-base deletion at codon 185 (Trp185) causing a frameshift,
identified in an Israeli family. Results in truncated nectin-1.
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four PVRL1 mutations identified in cleft lip/palate-ectodermal
dysplasia syndrome to date, including this study, resulted in truncated
proteins that lack the transmembrane domain and intracellular domain of
nectin-1
explanation: >-
One of the four known PVRL1 mutations, all producing truncated proteins.
- name: Frameshift at Gly323
description: >-
Single-base duplication at codon 323 (Gly323) causing a frameshift,
identified in a Brazilian family. Results in truncated nectin-1.
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four PVRL1 mutations identified in cleft lip/palate-ectodermal
dysplasia syndrome to date, including this study, resulted in truncated
proteins that lack the transmembrane domain and intracellular domain of
nectin-1
explanation: >-
One of the four known PVRL1 mutations, all producing truncated proteins.
- name: p.Arg134* (c.400C>T)
description: >-
Novel homozygous nonsense mutation identified in a Japanese patient.
Results in truncated nectin-1 lacking transmembrane and intracellular
domains.
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mutation analysis of exon 2 of PVRL1 revealed a novel homozygous nonsense
mutation, c.400C>T (p.Arg134*)
explanation: Novel truncating mutation demonstrating allelic heterogeneity.
evidence:
- reference: PMID:10932188
reference_title: "Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we describe positional cloning of the gene responsible for an autosomal
recessive CL/P-ectodermal dysplasia (ED) syndrome (CLPED1; previously
ED4; ref. 2), which we identify as PVRL1, encoding nectin-1, an
immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule
that is part of the NAP cell adhesion system
explanation: >-
Landmark paper identifying PVRL1 as the causative gene through positional
cloning.
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All four PVRL1 mutations identified in cleft lip/palate-ectodermal
dysplasia syndrome to date, including this study, resulted in truncated
proteins that lack the transmembrane domain and intracellular domain of
nectin-1, which is necessary to initiate the cell-cell adhesion process
explanation: >-
Confirms that all known mutations result in loss of the nectin-1
transmembrane and intracellular domains.
- reference: CGGV:assertion_c1264fce-e800-4f7d-8395-543d2e266d02-2024-06-20T160000.000Z
reference_title: "NECTIN1 / cleft lip/palate-ectodermal dysplasia syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "NECTIN1 | HGNC:9706 | cleft lip/palate-ectodermal dysplasia syndrome | MONDO:0009151 | AR | Definitive"
explanation: ClinGen classifies the NECTIN1-cleft lip/palate-ectodermal dysplasia syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
- name: PVRL1 heterozygote risk for non-syndromic CL/P
features: >
Heterozygosity for the W185X mutation in PVRL1 is significantly associated
with sporadic, non-syndromic cleft lip with or without cleft palate in
northern Venezuela, indicating that PVRL1 also contributes to common
non-syndromic orofacial clefting as a susceptibility allele.
gene_term:
preferred_term: NECTIN1
term:
id: hgnc:9706
label: NECTIN1
evidence:
- reference: PMID:11559849
reference_title: "Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we demonstrate highly significant association between heterozygosity
for this mutation and sporadic, non-syndromic CL/P in northern Venezuela
explanation: >-
Demonstrates that PVRL1 W185X heterozygosity is a risk factor for
common non-syndromic CL/P beyond its role in the recessive syndrome.
prevalence:
- population: Margarita Island, Venezuela
notes: >-
CLPED1 has a notably high frequency on Margarita Island in the Caribbean Sea
due to the W185X founder mutation. The high carrier frequency may be
maintained by heterozygote advantage against alpha-herpesvirus infection,
as nectin-1 is the principal cell surface receptor for these viruses.
evidence:
- reference: PMID:10932188
reference_title: "Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the high frequency of CLPED1 on Margarita Island in the Caribbean Sea
might result from resistance of heterozygotes to infection by these viruses
explanation: >-
Documents the high frequency of CLPED1 on Margarita Island and proposes
heterozygote advantage as an explanation.
treatments:
- name: Cleft Lip/Palate Surgical Repair
description: >
Surgical correction of cleft lip and palate is the primary treatment
intervention, typically performed in infancy with staged procedures.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations comprise a unique facial appearance with cleft
lip/palate, ectodermal dysplasia, cutaneous syndactyly of the fingers
and/or toes, and in some cases, mental retardation
explanation: >-
Cleft lip/palate is a cardinal feature of molecularly confirmed CLPED1,
requiring surgical correction.
- name: Syndactyly Surgical Repair
description: >
Surgical correction of cutaneous syndactyly of fingers and/or toes.
Syndactyly repair was documented in a molecularly confirmed CLPED1 patient.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
cutaneous syndactyly of the fingers and mild mental retardation
explanation: >-
Cutaneous syndactyly is a cardinal feature in molecularly confirmed
CLPED1 patients, requiring surgical correction as documented in case
reports.
- name: Dental Implantation
description: >
Dental implantation and prosthetic replacement for missing teeth
due to hypodontia from ectodermal dysplasia.
treatment_term:
preferred_term: dental implantation
term:
id: MAXO:0001534
label: dental implantation
evidence:
- reference: PMID:25913853
reference_title: "Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene underlies cleft lip/palate-ectodermal dysplasia syndrome in an Asian patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypohidrotic ectodermal dysplasia with sparse, brittle, fine, dry hair
and hypodontia
explanation: >-
Hypodontia is a documented feature of the syndrome, requiring dental
implantation and prosthetic management.
- name: Genetic Counseling
description: >
Genetic counseling for families with affected children, given the
autosomal recessive inheritance pattern, carrier detection options,
and the known association of heterozygosity with non-syndromic CL/P risk.
treatment_term:
preferred_term: genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
evidence:
- reference: PMID:11559849
reference_title: "Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homozygosity for a nonsense mutation of PVRL1, W185X, results in an
autosomal recessive CL/P syndrome on Margarita Island, CLPED1
explanation: >-
Autosomal recessive inheritance and known carrier risk for non-syndromic
CL/P underscores the importance of genetic counseling for affected families.
datasets:
Zlotogora–Ogur syndrome is now generally considered part of cleft lip/palate–ectodermal dysplasia syndrome 1 (CLPED1) (also historically called Margarita Island ectodermal dysplasia / Margarita Island type), a rare autosomal recessive disorder characterized by orofacial clefting, ectodermal dysplasia (hair/skin/teeth/nails/sweat gland abnormalities), and limb anomalies (syndactyly), with variable neurodevelopmental involvement. The condition is caused by biallelic loss-of-function variants in PVRL1 (NECTIN1), encoding the cell–cell adhesion molecule nectin-1. (suzuki2000mutationsofpvrl1 pages 1-1, zlotogora1994syndactylyectodermaldysplasia pages 2-3, suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3)
Clinically, the syndrome was delineated as a pleiotropic association of cleft lip/palate, syndactyly, ectodermal dysplasia, and (in some reports) psychomotor retardation/intellectual disability. A widely cited clinical synthesis reports: “The summary of the clinical manifestations is based on 31 patients affected with the syndrome observed from the age of 4 months to 65 years”. (zlotogora1994syndactylyectodermaldysplasia pages 1-2)
Molecularly, the disorder corresponds to autosomal recessive cleft lip/palate–ectodermal dysplasia (CLPED1) due to PVRL1/NECTIN1 mutations. (suzuki2000mutationsofpvrl1 pages 1-1, suzuki2000mutationsofpvrl1 pages 1-3)
Commonly used names in the literature include: * Zlotogora–Ogur syndrome * Syndactyly, ectodermal dysplasia, and cleft lip/palate * Cleft lip/palate–ectodermal dysplasia syndrome * CLPED1 * Margarita Island ectodermal dysplasia / Margarita Island type These synonym relationships are made explicit in molecular-era CLPED1 work and ED reviews. (suzuki2000mutationsofpvrl1 pages 1-1, visinoni2009ectodermaldysplasiasclinical pages 2-3, ganske2021cleftlipand pages 1-2)
Evidence is derived from: * Patient-level case reports/series (human clinical) describing multiple affected families and syndromic features (rodini1990autosomalrecessiveectodermal pages 3-4, rodini1990autosomalrecessiveectodermal pages 1-3) * Aggregated clinical synthesis (human clinical summary of multiple reports; 31 cases across wide age range) (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * Molecular genetics (human genetic studies defining PVRL1/NECTIN1 as causal) (suzuki2000mutationsofpvrl1 pages 1-1, suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3) * Experimental model systems (mouse/in vitro) supporting a nectin–afadin developmental mechanism relevant to palate/periderm biology (lough2020disruptionofthe pages 1-3, lough2020disruptionofthe pages 3-5)
Primary cause: biallelic pathogenic variants in PVRL1 (NECTIN1), encoding nectin-1, a cell–cell adhesion molecule. * Molecular definition: CLPED1 is described as an “autosomal recessive CL/P-ectodermal dysplasia (CLPED1; previously ED4)” and the locus is identified as PVRL1, “encoding nectin-1”. (suzuki2000mutationsofpvrl1 pages 1-1)
No established environmental risk factors for CLPED1/Zlotogora–Ogur syndrome were identified in the retrieved evidence.
No genetic or environmental protective factors were identified in the retrieved evidence.
No gene–environment interaction evidence was identified in the retrieved corpus.
Across the clinical synthesis and primary reports, major features include: * Orofacial clefting: “Cleft lip/palate is present in most patients.” (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * Syndactyly: “Cutaneous syndactyly is frequently present in fingers 2-3-4” and “In the feet syndactyly of toes 2-3 is usually present.” (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * Ectodermal dysplasia: sparse/short hair with structural defects (“pili torti” / “kinky hair”), dental anomalies, nail anomalies, hypohidrosis, and progressive palmoplantar hyperkeratosis. (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3) * Neurodevelopment: variable impairment; “Mental status may be impaired” and family-to-family differences were noted. (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3)
The syndrome demonstrates marked variable expressivity: “The variability of the syndrome is evident…”. (zlotogora1994syndactylyectodermaldysplasia pages 1-2)
Formal QoL instruments (EQ-5D/SF-36/PROMIS) were not identified in the retrieved evidence for CLPED1 specifically. However, the phenotype implies significant functional burden (feeding/speech/hearing/dental/dermatologic and surgical needs).
A curated phenotype-to-HPO mapping table is provided in Artifact-01.
| Phenotype / clinical description | Suggested HPO term(s) | Typical onset | Frequency / variability notes | Key supporting citations |
|---|---|---|---|---|
| Cleft lip and/or cleft palate; often bilateral, but some affected individuals may lack overt clefting and instead have philtrum/uvula anomalies | Cleft upper lip HP:0000204; Cleft palate HP:0000175 | Congenital | Present in most patients; not fully penetrant across all reported families; neonatal deaths in some sibs with clefting were reported | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Cutaneous syndactyly of fingers, especially 2-3-4; classic reports also note 2-3 finger involvement | 2-3 finger syndactyly HP:0006101; Cutaneous syndactyly of fingers HP:0010709 | Congenital | Frequently present; variable severity and exact digits involved between families | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Toe syndactyly, especially 2-3 toes | 2-3 toe syndactyly HP:0001780 | Congenital | Usually present in reported cases, though variable and sometimes less emphasized than hand findings | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Sparse, short, kinky hair; hair-shaft defects including pili torti; brittle/fine hair in later molecularly confirmed case | Sparse hair HP:0008070; Pili torti HP:0003792; Abnormal hair texture HP:0011359 | Congenital / early childhood | Common ectodermal feature; one review noted progressive scalp involvement with complete alopecia by the fifth decade in some patients | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, yoshida2015novelhomozygousmutation pages 1-3) |
| Hypohidrosis / reduced sweating with generally preserved heat tolerance | Hypohidrosis HP:0000975 | Childhood or lifelong | Reported in most but not all patients; variable severity | (zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Progressive palmar and plantar hyperkeratosis / palmoplantar keratoderma | Palmoplantar keratoderma HP:0000982; Hyperkeratosis HP:0000962 | Childhood; may become more evident with age | Progressive feature; one report noted appearance around age 4 years; useful in differential diagnosis versus EEC in older patients | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3) |
| Dental anomalies: delayed eruption, microdontia, hypodontia, anodontia | Hypodontia HP:0000670; Anodontia HP:0000674; Microdontia HP:0000691; Delayed eruption of teeth HP:0000684 | Childhood | Very common ectodermal finding; severity ranges from delayed eruption to absent teeth in adults | (zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Nail anomalies / brittle nails / onychodysplasia | Nail dysplasia HP:0002164; Brittle nails HP:0001808 | Childhood | Variable; nails can be normal in some affected individuals | (zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Intellectual disability / mental retardation and delayed psychomotor development | Intellectual disability HP:0001249; Global developmental delay HP:0001263 | Infancy / childhood | Variable across families; initially thought obligatory, but later reports documented normal intelligence in some families; may reflect variable expressivity | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Ear anomalies / malformed ears / preauricular pit | Abnormality of the ear HP:0000598; Preauricular pit HP:0004467 | Congenital | Recurrent but variably reported; malformed ears emphasized in early descriptions | (rodini1990autosomalrecessiveectodermal pages 3-4, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Hearing loss / deafness | Hearing impairment HP:0000365 | Childhood | Variable between families; present in some pedigrees but absent in others | (rodini1990autosomalrecessiveectodermal pages 3-4, zlotogora1994syndactylyectodermaldysplasia pages 2-3) |
| Genitourinary / renal anomalies | Genitourinary abnormality HP:0000078; Renal abnormality HP:0000077 | Congenital | Inconsistent finding; reported in some families/case summaries, absent in others | (rodini1990autosomalrecessiveectodermal pages 3-4, zlotogora1994syndactylyectodermaldysplasia pages 2-3) |
| Accessory nipples / nipple anomalies | Supernumerary nipple HP:0100807 | Congenital | Reported in several patients/families, but may represent a variable associated finding rather than a core feature | (rodini1990autosomalrecessiveectodermal pages 3-4, rodini1990autosomalrecessiveectodermal pages 1-3) |
| Dry skin / eczematous or dermatitis-like skin changes | Xerosis HP:0000963; Eczema HP:0000964 | Infancy / childhood | Reported as part of ectodermal dysplasia spectrum; later molecularly confirmed case had treatment for eczematous skin/atopic dermatitis from infancy | (rodini1990autosomalrecessiveectodermal pages 3-4, yoshida2015novelhomozygousmutation pages 1-3) |
| Early death (neonatal death or death in early childhood) in some affected sibships | Neonatal death HP:0003811; Sudden death in infancy / early death HP:0001522 | Neonatal / infancy | Not universal; several reports describe neonatal or early-childhood deaths among presumed affected sibs, with cause often unknown | (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3, rodini1990autosomalrecessiveectodermal pages 1-3) |
Table: This table summarizes the core and variably reported phenotypes of Zlotogora-Ogur syndrome / CLPED1, with suggested HPO mappings, typical timing, and brief notes on expressivity. It is useful for knowledge-base curation and phenotype-to-ontology annotation.
PVRL1 (NECTIN1) encodes nectin-1, an immunoglobulin superfamily adhesion protein. * Molecular identification: “which we identify as PVRL1, encoding nectin-1, an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule.” (suzuki2000mutationsofpvrl1 pages 1-1)
From the gene-discovery study and subsequent case report: * Trp185Ter (W185X): “At codon Trp185 (TGG), a homozygous nonsense mutation (TAG) was found…” (suzuki2000mutationsofpvrl1 pages 1-3) * Frameshift at codon 185 (single-base deletion at Trp185): “a homozygous frameshift (TG–)…” (suzuki2000mutationsofpvrl1 pages 1-3) * Frameshift at Gly323 (single-base duplication): “At codon Gly323 (GGT), a homozygous frameshift (GGTT)…” (suzuki2000mutationsofpvrl1 pages 1-3) * c.400C>T (p.Arg134*): “Novel homozygous mutation, c.400C>T (p.Arg134*), in the PVRL1 gene…” (yoshida2015novelhomozygousmutation pages 1-3)
The truncating variants are predicted to abrogate nectin-1’s intracellular interactions and adhesion signaling. * Mechanism statement: the truncating mutations “would truncate…nectin-1…thereby abolishing interaction with 1-afadin and thus abrogating…cell-cell adhesion.” (suzuki2000mutationsofpvrl1 pages 1-3)
No validated modifier genes or epigenetic signatures were identified in the retrieved CLPED1-specific evidence. Karyotype was reported normal in a classic clinical family. (rodini1990autosomalrecessiveectodermal pages 3-4)
No specific environmental/lifestyle/infectious contributors were identified in the retrieved evidence; CLPED1 is primarily a monogenic Mendelian disorder in the reviewed sources.
A convergent theme is disruption of adherens junction formation and epithelial adhesion in craniofacial and ectodermal tissues.
Recent work does not primarily expand CLPED1 patient series, but refines mechanistic understanding of the same junctional module:
(a) 2023 mechanobiology (preprint; protein–protein interaction under force): Afadin PDZ–nectin-1 binding exhibits force-stabilized behavior. The preprint reports short solution lifetimes (“bond lifetimes of 1.2…s for the nectin-1…ICDs”) and concludes “PDZ domains can serve as force-responsive mechanical anchors at cell-cell adhesion complexes.” (vachharajani2023pdzdomainsfrom pages 1-3)
(b) 2024 human genetics and network biology (peer-reviewed): AFDN (afadin) damaging variants were proposed to contribute to nonsyndromic cleft risk, with analyses highlighting AFADIN’s direct interactions with nectins and a reported association of afadin–nectin interaction networks with CLPED biology (FDR reported in the paper). (awotoye2024damagingmutationsin pages 13-16, awotoye2024damagingmutationsin pages 9-13)
Evidence-type labeling: * (a) computational + single-molecule biophysics; preprint (bioRxiv) (vachharajani2023pdzdomainsfrom pages 1-3) * (b) human genetics cohorts + computational structural/network analyses; peer-reviewed primary research (awotoye2024damagingmutationsin pages 13-16, awotoye2024damagingmutationsin pages 9-13)
Based on the phenotype profile: * Craniofacial: lip and palate (UBERON: lip/palate structures), dental primordia/teeth. (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3) * Integumentary system: skin, hair follicles, sweat glands, nails. (zlotogora1994syndactylyectodermaldysplasia pages 1-2, zlotogora1994syndactylyectodermaldysplasia pages 2-3) * Limbs: fingers/toes (cutaneous syndactyly). (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * Potential additional systems: auditory system (hearing loss), renal/genitourinary anomalies variably. (rodini1990autosomalrecessiveectodermal pages 3-4)
Cell types (CL suggestions) most directly implicated by the mechanism include epithelial cells of palatal shelves and epidermis/periderm (supported mechanistically by mouse epithelial perturbation studies). (lough2020disruptionofthe pages 3-5)
Subcellular components (GO Cellular Component) implicated: adherens junction complexes and associated cytoskeleton (supported conceptually; afadin/nectin are junctional/cytoskeletal linkers). (suzuki2000mutationsofpvrl1 pages 1-3, vachharajani2023pdzdomainsfrom pages 1-3)
Autosomal recessive inheritance is consistently supported: * “The syndrome is inherited as an autosomal recessive trait.” (zlotogora1994syndactylyectodermaldysplasia pages 2-3) * Multiple reports cite parental consanguinity: “In all the families reported up to now the parents of the affected children were related.” (zlotogora1994syndactylyectodermaldysplasia pages 2-3)
Syndrome-specific prevalence/incidence was not identified in the retrieved evidence.
Available quantitative proxies: * A clinical synthesis aggregated 31 patients across reports. (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * In a large ED clinic cohort (not CLPED1-specific), 24/170 (14%) ED patients had CL/P. (ganske2021cleftlipand pages 2-4)
Repeated consanguinity suggests founder effects in reported families. (zlotogora1994syndactylyectodermaldysplasia pages 2-3) Carrier frequency and population allele frequencies for specific PVRL1 pathogenic alleles were not available in the retrieved evidence.
A practical clinical definition is based on co-occurrence of: 1) CL/P, 2) ectodermal abnormalities (hair/teeth/nails/sweating/skin), 3) syndactyly.
In the ED-spectrum framing, “A diagnosis of ED requires defects in two or more ectodermal derivatives…”. (ganske2021cleftlipand pages 1-2)
Zlotogora (1994) highlights distinction from EEC syndrome, noting differences in inheritance and features; it suggests palmoplantar hyperkeratosis in older patients can help distinguish the disorders. (zlotogora1994syndactylyectodermaldysplasia pages 2-3)
Evidence-supported approach: * Sequence PVRL1 (NECTIN1) to confirm CLPED1 in suspected cases, especially in consanguineous families. (yoshida2015novelhomozygousmutation pages 1-3) * Yoshida et al. performed direct sequencing of PVRL1 and family testing; parents were heterozygous carriers. (yoshida2015novelhomozygousmutation pages 1-3)
In the molecularly confirmed Japanese case, the work-up included: * physiologic testing for hypohidrosis (sympathetic skin response) * microscopy/SEM for hair-shaft abnormalities * dermatologic evaluation and management for dermatitis. (yoshida2015novelhomozygousmutation pages 1-3)
Long-term prognosis is variable and not captured in prospective natural history studies in the retrieved corpus.
Observed outcomes include: * Survival into adulthood (clinical synthesis includes patients up to 65 years). (zlotogora1994syndactylyectodermaldysplasia pages 1-2) * Developmental disability can persist when present (classic family with affected brothers). (rodini1990autosomalrecessiveectodermal pages 1-3) * Neonatal/early childhood deaths reported in some pedigrees, with unclear attribution. (zlotogora1994syndactylyectodermaldysplasia pages 2-3)
No disease-modifying molecular therapy exists in the retrieved evidence; management is supportive and surgical.
While not CLPED1-specific, ED-CL/P cohort outcomes provide real-world expectations for syndromic cleft care: * In an ED cohort, 3/9 (33%) older bilateral cases had velopharyngeal insufficiency; palatal fistula occurred (count reported). (ganske2021cleftlipand pages 2-4) * Patients may have perioperative respiratory complications requiring ICU monitoring. (ganske2021cleftlipand pages 5-6)
No CLPED1/Zlotogora–Ogur–specific therapeutic trials were identified; trials returned by broad searches primarily involved NECTIN4 oncology targets and are not relevant to treating CLPED1. (clinical-trials tool results; no relevant CLPED1 trials)
Primary prevention is not applicable in the usual public-health sense for a monogenic Mendelian disorder. Prevention strategies are genetic: * Carrier testing and reproductive counseling in affected families (supported by AR inheritance and consanguinity patterns). (zlotogora1994syndactylyectodermaldysplasia pages 2-3) * Prenatal / preimplantation genetic testing is logically enabled when familial PVRL1 pathogenic variants are known (inference from established causality; family-based heterozygosity demonstrated). (suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3)
No naturally occurring veterinary analogs were identified in the retrieved evidence.
Experimental systems show that disruption of the nectin–afadin axis can produce palatal fusion defects in mouse.
These models support a mechanistic bridge from PVRL1/NECTIN1 loss to impaired epithelial adhesion during palatogenesis.
| Category | Details | Key reference(s) |
|---|---|---|
| Disease names / synonyms | Zlotogora-Ogur syndrome; syndactyly, ectodermal dysplasia, and cleft lip/palate; cleft lip/palate-ectodermal dysplasia syndrome; CLPED1; Margarita Island ectodermal dysplasia / Margarita Island type. Later reviews state Zlotogora-Ogur syndrome and Margarita Island type are considered the same condition within CLPED1. (suzuki2000mutationsofpvrl1 pages 1-1, zlotogora1994syndactylyectodermaldysplasia pages 1-2, visinoni2009ectodermaldysplasiasclinical pages 2-3) | Zlotogora 1994, J Med Genet 31:957-959, DOI: https://doi.org/10.1136/jmg.31.12.957; Suzuki et al. 2000, Nat Genet 25:427-430, DOI: https://doi.org/10.1038/78119 |
| Key identifiers (OMIM) | Historical OMIM usage in the literature is inconsistent. Primary molecular-era identifier for CLPED1 / Margarita Island type is OMIM 225060; reviews note the former Zlotogora-Ogur entry OMIM 225000 was reassigned to Rosselli-Gulienetti syndrome, while older papers variably cited 225000/22500 for the cleft-ED-syndactyly phenotype. (zlotogora1994syndactylyectodermaldysplasia pages 3-4, visinoni2009ectodermaldysplasiasclinical pages 2-3, ganske2021cleftlipand pages 1-2) | Visinoni et al. 2009, Am J Med Genet A 149A:1980-2002, DOI: https://doi.org/10.1002/ajmg.a.32864; Ganske et al. 2021, Cleft Palate Craniofac J 58:237-243, DOI: https://doi.org/10.1177/1055665620949124 |
| Inheritance | Autosomal recessive; early case reports emphasized consanguinity in affected families and later molecular studies confirmed affected individuals were homozygous for pathogenic variants while parents were heterozygous carriers. (rodini1990autosomalrecessiveectodermal pages 3-4, zlotogora1994syndactylyectodermaldysplasia pages 2-3, suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3, visinoni2009ectodermaldysplasiasclinical pages 2-3) | Rodini & Richieri-Costa 1990, Am J Med Genet 36:473-476, DOI: https://doi.org/10.1002/ajmg.1320360420 |
| Causal gene | PVRL1 (also known as NECTIN1), encoding nectin-1, a cell-cell adhesion molecule/herpesvirus receptor. Loss-of-function variants truncate nectin-1 and are reported to abolish afadin-associated adhesion functions relevant to craniofacial and ectodermal development. (suzuki2000mutationsofpvrl1 pages 1-1, suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3, ganske2021cleftlipand pages 1-2) | Suzuki et al. 2000, Nat Genet 25:427-430, DOI: https://doi.org/10.1038/78119 |
| Representative pathogenic variants | Reported homozygous loss-of-function variants include Trp185Ter / W185X (TGG→TAG), frameshift at codon 185 (single-base deletion), frameshift at Gly323 (GGT→GGTT), and c.400C>T (p.Arg134*) in a Japanese patient. (suzuki2000mutationsofpvrl1 pages 1-3, yoshida2015novelhomozygousmutation pages 1-3, shu2015mutationanalysisof pages 3-7) | Suzuki et al. 2000, DOI: https://doi.org/10.1038/78119; Yoshida et al. 2015, J Dermatol 42:715-719, DOI: https://doi.org/10.1111/1346-8138.12882 |
| First clinical description / delineation | Early delineation came from families reported by Zlotogora and Ogur and by Rodini & Richieri-Costa, with core findings of cleft lip/palate, ectodermal dysplasia, syndactyly, and variable intellectual disability/psychomotor delay. (zlotogora1994syndactylyectodermaldysplasia pages 1-2, rodini1990autosomalrecessiveectodermal pages 3-4, freihofer1997ectodermaldysplasiacleft pages 5-5) | Rodini & Richieri-Costa 1990, Am J Med Genet 36:473-476, DOI: https://doi.org/10.1002/ajmg.1320360420; Zlotogora 1994 review, DOI: https://doi.org/10.1136/jmg.31.12.957 |
| Gene discovery milestone | Positional/molecular work showed that CLPED1, including Zlotogora-Ogur syndrome, is caused by PVRL1/NECTIN1 mutations. (suzuki2000mutationsofpvrl1 pages 1-1, suzuki2000mutationsofpvrl1 pages 1-3) | Suzuki et al. 2000, Nat Genet 25:427-430, DOI: https://doi.org/10.1038/78119 |
| Later case report / phenotype expansion | A later Asian case confirmed homozygous c.400C>T (p.Arg134*) in PVRL1 and documented cleft lip/palate, hypohidrotic ectodermal dysplasia, cutaneous syndactyly, hypodontia, and hair-shaft abnormalities. (yoshida2015novelhomozygousmutation pages 1-3) | Yoshida et al. 2015, J Dermatol 42:715-719, DOI: https://doi.org/10.1111/1346-8138.12882 |
Table: This table summarizes the main disease names, OMIM identifier history, inheritance, causal gene, and landmark references for Zlotogora-Ogur syndrome/CLPED1. It is useful for reconciling older clinical nomenclature with the later molecular definition based on PVRL1/NECTIN1.
References
(suzuki2000mutationsofpvrl1 pages 1-1): Koji Suzuki, Diane Hu, Tania Bustos, Joel Zlotogora, Antonio Richieri-Costa, Jill A. Helms, and Richard A. Spritz. Mutations of pvrl1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nature Genetics, 25:427-430, Aug 2000. URL: https://doi.org/10.1038/78119, doi:10.1038/78119. This article has 437 citations and is from a highest quality peer-reviewed journal.
(zlotogora1994syndactylyectodermaldysplasia pages 2-3): J. Zlotogora. Syndactyly, ectodermal dysplasia, and cleft lip/palate. Journal of Medical Genetics, 31:957-959, Dec 1994. URL: https://doi.org/10.1136/jmg.31.12.957, doi:10.1136/jmg.31.12.957. This article has 30 citations and is from a domain leading peer-reviewed journal.
(suzuki2000mutationsofpvrl1 pages 1-3): Koji Suzuki, Diane Hu, Tania Bustos, Joel Zlotogora, Antonio Richieri-Costa, Jill A. Helms, and Richard A. Spritz. Mutations of pvrl1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nature Genetics, 25:427-430, Aug 2000. URL: https://doi.org/10.1038/78119, doi:10.1038/78119. This article has 437 citations and is from a highest quality peer-reviewed journal.
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