Zlotogora-Ogur syndrome (CLPED1) is a rare autosomal recessive disorder caused by biallelic loss-of-function variants 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, and 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 and was later reported at high frequency on Margarita Island in Venezuela, where homozygous W185X causes CLPED1. A proposed heterozygote advantage against alpha-herpesvirus infection remains a population-genetic hypothesis rather than an established disease mechanism.
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name: Zlotogora-Ogur Syndrome
creation_date: '2026-04-24T00:00:00Z'
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 biallelic loss-of-function variants 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, and 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 and was later
reported at high frequency on Margarita Island in Venezuela, where homozygous
W185X causes CLPED1.
A proposed heterozygote advantage against alpha-herpesvirus infection remains
a population-genetic hypothesis rather than an established disease mechanism.
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
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
CLPED1 is inherited in an autosomal recessive manner and is caused by
biallelic pathogenic NECTIN1 variants.
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: >-
The molecular discovery study explicitly identifies CLPED1 as an
autosomal recessive PVRL1-associated syndrome.
pathophysiology:
- name: Loss of Nectin-1 Cell Adhesion
biological_scale: MOLECULAR
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 adherens-junction and
tight-junction formation. The four PVRL1 variants reported through 2015
produced truncated proteins lacking the transmembrane and intracellular
domains required to initiate nectin-1-mediated adhesion. In the related
PVRL4-associated ectodermal dysplasia-syndactyly syndrome, mutant nectin-4
loses its ability to bind nectin-1 and alters junction-complex localization
in hair follicles. This is cross-nectinopathy evidence, not direct evidence
from NECTIN1-deficient appendages.
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: >-
Identifies PVRL1 as the causative adhesion-molecule gene for CLPED1.
- 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: >-
Supports nectin-1 junction function and its face-and-palate expression.
- 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: >-
Supports nectin-4/nectin-1 interaction in a related PVRL4 nectinopathy;
it does not establish a NECTIN1 hair, tooth, nail, or sweat-gland chain.
downstream:
- target: Impaired Palate Shelf Elevation and Fusion
description: >-
Experimental loss of Nectin1 impairs palate closure, and combined loss of
Nectin1 and Nectin4 produces severe cleft palate in mice.
causal_link_type: DIRECT
evidence:
- 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: >-
We implicate Nectin1 and Nectin4 as being crucially involved, as loss of
either induces a low penetrance of mild palate closure defects, while
loss of both causes severe CP with a frequency similar to Afdn loss
explanation: >-
Directly supports a palate-closure consequence of experimental Nectin1
loss; it does not establish a cleft-lip mechanism.
- target: Cleft Lip
description: >-
Human genetic studies establish cleft lip/palate as part of
PVRL1-associated CLPED1, but the specific cleft-lip developmental
mechanism is not resolved by the cited evidence.
causal_link_type: UNKNOWN
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: >-
Direct human evidence links PVRL1 to the CL/P syndrome; the UNKNOWN edge
avoids extending the palate-only mouse mechanism to cleft lip.
- target: NECTIN1-Associated Ectodermal Dysplasia
description: >-
Human CLPED1 cases with homozygous PVRL1 loss-of-function variants have
ectodermal dysplasia, but the intervening tissue mechanisms remain
unresolved.
causal_link_type: UNKNOWN
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: >-
Cleft lip/palate-ectodermal dysplasia syndrome is a rare, autosomal
recessive disorder caused by homozygous loss-of-function mutations of
the poliovirus receptor-like 1 (PVRL1) gene encoding nectin-1
explanation: >-
Establishes PVRL1 loss of function as the cause of the human syndrome;
the edge is UNKNOWN because it does not resolve the appendage mechanism.
- name: Impaired Palate Shelf Elevation and Fusion
biological_scale: TISSUE
description: >
Mouse experiments show that the nectin-afadin axis is required for palate
shelf elevation and fusion. Palatal epithelial loss of afadin induces
high-penetrance cleft palate; loss of either Nectin1 or Nectin4 produces
mild palate-closure defects at low penetrance, and combined loss produces
severe cleft palate. Expression of human NECTIN1 W185X in mice causes cleft
palate with greater penetrance than Nectin1 loss, suggesting a dominant
interfering mechanism in that model.
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: roof of mouth
term:
id: UBERON:0007375
label: roof of mouth
evidence:
- 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: >-
Here, we use in utero lentiviral-mediated genetic approaches in mice to
provide the first direct evidence that the nectin-afadin axis is essential
for proper palate shelf elevation and fusion
explanation: >-
Directly supports the tissue-level palate mechanism in mice.
downstream:
- target: Cleft Palate
description: Failed palate shelf elevation and fusion produces cleft palate.
causal_link_type: DIRECT
evidence:
- 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: >-
palatal epithelial conditional loss of afadin (Afdn) - an obligate
nectin- and actin-binding protein - induces a high penetrance of CP
explanation: >-
Directly supports cleft palate downstream of disruption of the
nectin-afadin palate-fusion mechanism in mice; it does not support a
cleft-lip edge.
- name: NECTIN1-Associated Ectodermal Dysplasia
biological_scale: TISSUE
description: >
Human CLPED1 reports document hypohidrotic ectodermal dysplasia with sparse,
structurally abnormal hair, hypodontia, and cutaneous syndactyly. The
precise NECTIN1-dependent tissue mechanism for each feature is not
established. PVRL4-associated evidence supplies only cross-nectinopathy
plausibility for hair follicles and separating digits; it does not establish
NECTIN1 tooth- or sweat-gland mechanisms.
cell_types:
- preferred_term: ectodermal cell
term:
id: CL:0000221
label: ectodermal cell
genes:
- preferred_term: NECTIN1
term:
id: hgnc:9706
label: NECTIN1
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: >-
Directly supports the human ectodermal-dysplasia and syndactyly phenotype
cluster without specifying an intervening molecular chain.
downstream:
- target: Sparse Hair
description: >-
Sparse hair is a documented component of the human ectodermal dysplasia;
the intervening mechanism is not established.
causal_link_type: UNKNOWN
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: Directly documents sparse hair in a human CLPED1 case.
- target: Pili Torti
description: >-
Pili torti is a documented hair-shaft abnormality; the intervening
mechanism is not established.
causal_link_type: UNKNOWN
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: Directly documents pili torti in a human CLPED1 case.
- target: Hypodontia
description: >-
Hypodontia is a documented component of the human ectodermal dysplasia;
no NECTIN1-specific tooth-development chain is asserted.
causal_link_type: UNKNOWN
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: Directly documents hypodontia without inferring its mechanism.
- target: Cutaneous Syndactyly
description: >-
Cutaneous syndactyly is a documented component of the human syndrome;
the intervening digit-separation mechanism is not established.
causal_link_type: UNKNOWN
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: Directly documents cutaneous syndactyly in human CLPED1.
- target: Toe Syndactyly
description: >-
Toe syndactyly is documented in human CLPED1; the intervening mechanism is
not established.
causal_link_type: UNKNOWN
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: Directly documents toe involvement in human CLPED1.
- target: Hypohidrosis
description: >-
Hypohidrotic ectodermal dysplasia is documented in human CLPED1; no
NECTIN1-specific sweat-gland mechanism is asserted.
causal_link_type: UNKNOWN
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: >-
Directly documents a hypohidrotic phenotype without inferring the
sweat-gland causal chain.
phenotypes:
- name: Cleft Lip
description: >
Cleft lip is a defining clinical feature of the syndrome. The available
cited case-series snippets do not quantify laterality.
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.
- reference: ORPHA:3253
reference_title: "Cleft lip/palate-ectodermal dysplasia syndrome"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome characterized
by hair, skin and teeth anomalies, facial dysmophism with cleft lip and
palate, cutaneous syndactyly and, in some cases, intellectual disability.
explanation: >-
The pinned Orphanet structured record independently includes cleft lip in
the syndrome definition without assigning an unsupported frequency.
- name: Cleft Palate
description: >
Cleft palate is reported as part of the cleft lip/palate phenotype in this
syndrome; the cited evidence does not establish a frequency.
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.
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.
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 is a characteristic feature;
finger 2-3 involvement was documented in the original Brazilian siblings.
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: >
Nail dystrophy has been reported as a variable ectodermal feature. The
available primary article is image-only in the local evidence pipeline, so
no exact-text evidence block is attached.
category: Clinical
phenotype_term:
preferred_term: Nail dystrophy
term:
id: HP:0008404
label: Nail dystrophy
- name: Palmoplantar Keratoderma
description: >
Progressive palmoplantar keratoderma has been reported with age and may help
distinguish CLPED1 from EEC syndrome in older patients. The available
primary article is image-only in the local evidence pipeline, so no
exact-text evidence block is attached.
category: Clinical
phenotype_term:
preferred_term: Palmoplantar keratoderma
term:
id: HP:0000982
label: Palmoplantar keratoderma
clinical_course: PROGRESSIVE
- name: Toe Syndactyly
description: >
Cutaneous toe syndactyly is reported in addition to finger syndactyly. The
cited evidence does not establish how often the 2-3 pattern occurs.
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 occurs in some but not all affected individuals;
mild intellectual disability was documented in the cited Japanese patient.
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. The four variants reported
through 2015 produced truncated proteins lacking the transmembrane and
intracellular domains. Homozygous W185X causes CLPED1 on Margarita Island;
heterozygosity was associated with sporadic non-syndromic cleft lip/palate
in northern Venezuela. The cited evidence does not establish W185X as a
founder variant. The proposal that viral resistance maintains this allele
is an untested heterozygote-advantage hypothesis.
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.
Homozygosity causes CLPED1 on Margarita Island; heterozygosity is
associated with non-syndromic cleft lip/palate in northern Venezuela.
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: >-
Directly supports the homozygous W185X-CLPED1 relationship on Margarita
Island without asserting founder status.
- name: Frameshift at Trp185
description: >-
Single-base deletion at codon 185 (Trp185) causing a frameshift,
identified in an Israeli family and predicted to truncate nectin-1.
- name: Frameshift at Gly323
description: >-
Single-base duplication at codon 323 (Gly323) causing a frameshift,
identified in a Brazilian family and predicted to truncate nectin-1.
- 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
relationship_type: SUSCEPTIBILITY
features: >
Heterozygosity for the W185X variant in PVRL1 is significantly associated
with sporadic, non-syndromic cleft lip with or without cleft palate in
northern Venezuela. This susceptibility association is distinct from the
biallelic causal relationship for CLPED1.
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: >-
Directly supports W185X heterozygosity as a susceptibility relationship
for non-syndromic cleft lip/palate in this population.
prevalence:
- population: Margarita Island, Venezuela
measure_type: UNKNOWN
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
CLPED1 was reported to have a high frequency on Margarita Island in the
Caribbean Sea. Homozygous W185X causes CLPED1 in this population, but the
cited evidence does not establish a founder event. No syndrome-specific
prevalence estimate or carrier frequency is established. The cited study
proposed, but did not demonstrate, heterozygote advantage against
alpha-herpesvirus infection.
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 reported high frequency on Margarita Island and explicitly
frames viral-resistance heterozygote advantage as a possibility.
treatments:
- name: Cleft Lip/Palate Surgical Repair
description: >
Surgical cleft treatment and repair outcomes have been reported in a mixed
ectodermal-dysplasia cohort. This evidence does not define a CLPED1-specific
care protocol or establish syndrome-specific outcomes.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
evidence:
- reference: PMID:32864997
reference_title: "Cleft Lip and Palate in Ectodermal Dysplasia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected
the predominance of bilateral complete forms
explanation: >-
This mixed ectodermal-dysplasia cohort reports outcomes after cleft repair,
but it does not isolate CLPED1 patients.
- name: Syndactyly Surgical Repair
description: >
Functional or reconstructive surgery may be considered for cutaneous
syndactyly of the fingers or toes according to anatomy and functional need.
Syndrome-specific outcome evidence is not available.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: surgical procedure
term:
id: NCIT:C15329
label: Surgical Procedure
- name: Dental Rehabilitation
description: >
Hypodontia requires individualized dental and prosthodontic rehabilitation;
the appropriate approach depends on age, dentition, cleft anatomy, and
craniofacial growth. CLPED1-specific outcome evidence is not available.
treatment_term:
preferred_term: dental procedure
term:
id: NCIT:C38052
label: Dental Procedure
- name: Genetic Counseling
description: >
Genetic counseling should address autosomal recessive recurrence risk,
familial variant testing, and reproductive options. The W185X
heterozygote association with non-syndromic clefting in northern Venezuela
should be presented separately from biallelic CLPED1 causation.
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
discussions:
- discussion_id: clped1_w185x_mouse_human_allele_mechanism
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does the dominant-interfering effect of NECTIN1 W185X in mouse palatal
epithelium explain human CLPED1, which is inherited as a recessive disorder?
rationale: >-
W185X expression produces cleft palate with greater penetrance than Nectin1
loss in mice,
suggesting dominant interference, whereas human syndromic disease requires
biallelic pathogenic variants. The mouse result supports a role for the
nectin-afadin axis but does not establish the allelic mechanism in human
palate or ectodermal appendages.
attaches_to:
- pathophysiology#Impaired Palate Shelf Elevation and Fusion
evidence:
- 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: >-
The mouse study explicitly identifies the allele-mechanism mismatch that
remains unresolved in the recessively inherited human syndrome.
- discussion_id: clped1_natural_history_and_management_evidence
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
What are the syndrome-specific phenotype frequencies, natural history, and
outcomes of cleft, limb, dental, dermatologic, and developmental management?
rationale: >-
Published CLPED1 evidence is dominated by small pedigrees and case reports.
The entry therefore avoids unsupported frequency labels and does not infer
treatment efficacy from citations that only establish the corresponding
phenotype. Cached exact-text sources directly support hypodontia and dry
hair, but not separate dry-skin, sparse-eyebrow, nail-dysplasia,
palmoplantar-keratoderma, or broader dental-morphology assertions, nor a
congenital-to-progressive natural-history sequence. Mixed
ectodermal-dysplasia cohorts provide only indirect cleft-management evidence.
attaches_to:
- disease#Zlotogora-Ogur Syndrome
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.
(yoshida2015novelhomozygousmutation pages 1-3): Kazue Yoshida, Ryota Hayashi, Hideki Fujita, Masaya Kubota, Mai Kondo, Yutaka Shimomura, and Hironori Niizeki. Novel homozygous mutation, c.400c>t (p.arg134*), in the pvrl1 gene underlies cleft lip/palate‐ectodermal dysplasia syndrome in an asian patient. The Journal of Dermatology, 42:715-719, Jul 2015. URL: https://doi.org/10.1111/1346-8138.12882, doi:10.1111/1346-8138.12882. This article has 18 citations.
(zlotogora1994syndactylyectodermaldysplasia pages 1-2): 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.
(visinoni2009ectodermaldysplasiasclinical pages 2-3): Átila F. Visinoni, Toni Lisboa‐Costa, Nina A.B. Pagnan, and Eleidi A. Chautard‐Freire‐Maia. Ectodermal dysplasias: clinical and molecular review. American Journal of Medical Genetics Part A, 149A:1980-2002, Sep 2009. URL: https://doi.org/10.1002/ajmg.a.32864, doi:10.1002/ajmg.a.32864. This article has 244 citations.
(ganske2021cleftlipand pages 1-2): Ingrid M. Ganske, Tim Irwin, Olivia Langa, Joseph Upton, Wen-Hann Tan, and John B. Mulliken. Cleft lip and palate in ectodermal dysplasia. The Cleft Palate-Craniofacial Journal, 58:237-243, Aug 2021. URL: https://doi.org/10.1177/1055665620949124, doi:10.1177/1055665620949124. This article has 11 citations.
(zlotogora1994syndactylyectodermaldysplasia pages 3-4): 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.
(rodini1990autosomalrecessiveectodermal pages 3-4): Elaine S. O. Rodini and A. Richieri‐Costa. Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the zlotogora-ogur syndrome. American journal of medical genetics, 36 4:473-6, Aug 1990. URL: https://doi.org/10.1002/ajmg.1320360420, doi:10.1002/ajmg.1320360420. This article has 26 citations.
(rodini1990autosomalrecessiveectodermal pages 1-3): Elaine S. O. Rodini and A. Richieri‐Costa. Autosomal recessive ectodermal dysplasia, cleft lip/palate, mental retardation, and syndactyly: the zlotogora-ogur syndrome. American journal of medical genetics, 36 4:473-6, Aug 1990. URL: https://doi.org/10.1002/ajmg.1320360420, doi:10.1002/ajmg.1320360420. This article has 26 citations.
(lough2020disruptionofthe pages 1-3): Kendall J. Lough, Danielle C. Spitzer, Abby J. Bergman, Jessica J. Wu, Kevin M. Byrd, and Scott E. Williams. Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome clped1. Development, Jan 2020. URL: https://doi.org/10.1242/dev.189241, doi:10.1242/dev.189241. This article has 26 citations and is from a domain leading peer-reviewed journal.
(lough2020disruptionofthe pages 3-5): Kendall J. Lough, Danielle C. Spitzer, Abby J. Bergman, Jessica J. Wu, Kevin M. Byrd, and Scott E. Williams. Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome clped1. Development, Jan 2020. URL: https://doi.org/10.1242/dev.189241, doi:10.1242/dev.189241. This article has 26 citations and is from a domain leading peer-reviewed journal.
(awotoye2024damagingmutationsin pages 9-13): Waheed Awotoye, Peter A Mossey, Jacqueline B Hetmanski, Lord J J Gowans, Mekonen A Eshete, Wasiu L Adeyemo, Azeez Alade, Erliang Zeng, Olawale Adamson, Olutayo James, Azeez Fashina, Modupe O Ogunlewe, Thirona Naicker, Chinyere Adeleke, Tamara Busch, Mary Li, Aline Petrin, Abimbola Oladayo, Sami Kayali, Joy Olotu, Veronica Sule, Mohaned Hassan, John Pape, Emmanuel T Aladenika, Peter Donkor, Fareed K N Arthur, Solomon Obiri-Yeboah, Daniel K Sabbah, Pius Agbenorku, Debashree Ray, Gyikua Plange-Rhule, Alexander Acheampong Oti, Daniah Albokhari, Nara Sobreira, Martine Dunnwald, Terri H Beaty, Margaret Taub, Mary L Marazita, Adebowale A Adeyemo, Jeffrey C Murray, and Azeez Butali. Damaging mutations in afdn contribute to risk of nonsyndromic cleft lip with or without cleft palate. The Cleft Palate Craniofacial Journal, 61:697-705, Nov 2024. URL: https://doi.org/10.1177/10556656221135926, doi:10.1177/10556656221135926. This article has 6 citations.
(vachharajani2023pdzdomainsfrom pages 1-3): Vipul T. Vachharajani, Matthew P. DeJong, Soumya Dutta, Jonathan Chapman, Eashani Ghosh, Abhishek Singharoy, and Alexander R. Dunn. Pdz domains from the junctional proteins afadin and zo-1 act as mechanosensors. bioRxiv, Oct 2023. URL: https://doi.org/10.1101/2023.09.24.559210, doi:10.1101/2023.09.24.559210. This article has 9 citations.
(awotoye2024damagingmutationsin pages 13-16): Waheed Awotoye, Peter A Mossey, Jacqueline B Hetmanski, Lord J J Gowans, Mekonen A Eshete, Wasiu L Adeyemo, Azeez Alade, Erliang Zeng, Olawale Adamson, Olutayo James, Azeez Fashina, Modupe O Ogunlewe, Thirona Naicker, Chinyere Adeleke, Tamara Busch, Mary Li, Aline Petrin, Abimbola Oladayo, Sami Kayali, Joy Olotu, Veronica Sule, Mohaned Hassan, John Pape, Emmanuel T Aladenika, Peter Donkor, Fareed K N Arthur, Solomon Obiri-Yeboah, Daniel K Sabbah, Pius Agbenorku, Debashree Ray, Gyikua Plange-Rhule, Alexander Acheampong Oti, Daniah Albokhari, Nara Sobreira, Martine Dunnwald, Terri H Beaty, Margaret Taub, Mary L Marazita, Adebowale A Adeyemo, Jeffrey C Murray, and Azeez Butali. Damaging mutations in afdn contribute to risk of nonsyndromic cleft lip with or without cleft palate. The Cleft Palate Craniofacial Journal, 61:697-705, Nov 2024. URL: https://doi.org/10.1177/10556656221135926, doi:10.1177/10556656221135926. This article has 6 citations.
(ganske2021cleftlipand pages 2-4): Ingrid M. Ganske, Tim Irwin, Olivia Langa, Joseph Upton, Wen-Hann Tan, and John B. Mulliken. Cleft lip and palate in ectodermal dysplasia. The Cleft Palate-Craniofacial Journal, 58:237-243, Aug 2021. URL: https://doi.org/10.1177/1055665620949124, doi:10.1177/1055665620949124. This article has 11 citations.
(ganske2021cleftlipand pages 4-5): Ingrid M. Ganske, Tim Irwin, Olivia Langa, Joseph Upton, Wen-Hann Tan, and John B. Mulliken. Cleft lip and palate in ectodermal dysplasia. The Cleft Palate-Craniofacial Journal, 58:237-243, Aug 2021. URL: https://doi.org/10.1177/1055665620949124, doi:10.1177/1055665620949124. This article has 11 citations.
(ganske2021cleftlipand pages 5-6): Ingrid M. Ganske, Tim Irwin, Olivia Langa, Joseph Upton, Wen-Hann Tan, and John B. Mulliken. Cleft lip and palate in ectodermal dysplasia. The Cleft Palate-Craniofacial Journal, 58:237-243, Aug 2021. URL: https://doi.org/10.1177/1055665620949124, doi:10.1177/1055665620949124. This article has 11 citations.
(shu2015mutationanalysisof pages 3-7): S.Y. Shu, M.J. Zhang, H.Q. Cheng, S.J. Tang, W.L. Chen, S.R. Wu, Y. Lin, and Q.S. Chen. Mutation analysis of pvrl1 in patients with non-syndromic cleft of the lip and/or palate in guangdong. Genetics and molecular research : GMR, 14 2:3400-8, Apr 2015. URL: https://doi.org/10.4238/2015.april.15.3, doi:10.4238/2015.april.15.3. This article has 5 citations.
(freihofer1997ectodermaldysplasiacleft pages 5-5): Hans Peter M. Freihofer, Sajjad Walji, and Han G. Brunner. Ectodermal dysplasia, cleft lip/palate, and severe cutaneous and osseous syndactyly in a mentally retarded girl: a new multiple malformation syndrome. American journal of medical genetics, 70 3:211-5, Jun 1997. URL: https://doi.org/10.1002/(sici)1096-8628(19970613)70:3<211::aid-ajmg1>3.0.co;2-z, doi:10.1002/(sici)1096-8628(19970613)70:3<211::aid-ajmg1>3.0.co;2-z. This article has 6 citations.