NOG-related symphalangism spectrum disorder (NOG-SSD) is the autosomal dominant disorder of joint formation caused by heterozygous loss-of-function variants in NOG, which encodes noggin, a secreted antagonist of bone morphogenetic proteins (BMPs). Its hallmark is proximal symphalangism, bony fusion of the proximal interphalangeal joints. Conductive hearing loss from stapes ankylosis, hyperopia, carpal and tarsal coalitions, broad thumbs and great toes, and a hemicylindrical nose are frequent but inconsistent. Five syndromes once described separately, all later traced to NOG, form one spectrum: proximal symphalangism (SYM1A), multiple synostoses syndrome 1 (SYNS1), stapes ankylosis with broad thumbs and toes (SABTT), tarsal-carpal coalition syndrome (TCC) and brachydactyly type B2 (BDB2). Expression varies within families that carry the same variant. Without enough noggin, BMP signalling at the sites of future joints goes unopposed, so the joint interzone fails to form and adjacent skeletal elements, including the stapes footplate and the otic capsule, stay fused.
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name: NOG-Related Symphalangism Spectrum Disorder
synonyms:
- NOG-SSD
- NOG-related symphalangism spectrum disorder
- noggin-related symphalangism spectrum disorder
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
description: >-
NOG-related symphalangism spectrum disorder (NOG-SSD) is the autosomal dominant
disorder of joint formation caused by heterozygous loss-of-function variants in
NOG, which encodes noggin, a secreted antagonist of bone morphogenetic proteins
(BMPs). Its hallmark is proximal symphalangism, bony fusion of the proximal
interphalangeal joints. Conductive hearing loss from stapes ankylosis,
hyperopia, carpal and tarsal coalitions, broad thumbs and great toes, and a
hemicylindrical nose are frequent but inconsistent. Five syndromes once
described separately, all later traced to NOG, form one spectrum: proximal
symphalangism (SYM1A), multiple synostoses syndrome 1 (SYNS1), stapes ankylosis
with broad thumbs and toes (SABTT), tarsal-carpal coalition syndrome (TCC) and
brachydactyly type B2 (BDB2). Expression varies within families that carry the
same variant. Without enough noggin, BMP signalling at the sites of future
joints goes unopposed, so the joint interzone fails to form and adjacent
skeletal elements, including the stapes footplate and the otic capsule, stay
fused.
disease_term:
preferred_term: NOG-related symphalangism spectrum disorder
term:
id: MONDO:0100521
label: NOG-related symphalangism spectrum disorder
parents:
- Joint Disorders
- Limb Development Disorders
notes: >-
No GeneReviews chapter exists for this disorder: a PubMed search for
"symphalangism[TI] AND genereviews[book]" returns nothing, and no title in
cache/bookshelf/genereviews.csv names symphalangism, synostoses, stapes
ankylosis or NOG. The single-spectrum term comes from the Potti et al. 2011
review (PMID:21538686), and ClinGen adopted it when it merged the five MIM
phenotypes into MONDO:0100521. A small 17q22 deletion that removes NOG
produces a phenotype comparable to a NOG point variant and is in scope here.
The larger 17q22 microdeletion syndromes, which add intellectual disability
and other anomalies from neighbouring genes, are a differential diagnosis.
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
expressivity: VARIABLE
penetrance: COMPLETE
description: >-
Heterozygous NOG variants segregate dominantly. Expression varies widely
within and between families, including among relatives who carry the same
variant, which is why the five historical syndromes are treated as one
spectrum. Penetrance is reported as complete in at least one family. De
novo variants occur, and recurrence in two brothers of unaffected parents
points to parental gonadal or low-level somatic mosaicism.
evidence:
- reference: PMID:10080184
reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents."
explanation: Establishes dominant segregation of heterozygous NOG variants and the occurrence of de novo variants.
- reference: PMID:21538686
reference_title: "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD)"
explanation: Documents variable expressivity within families and among families carrying the same variant.
- reference: PMID:26474326
reference_title: "Temporal Bone Histopathology in NOG-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "inherited in an autosomal dominant pattern with complete penetrance"
explanation: Complete penetrance in one NOG-SSD family.
- reference: PMID:15736221
reference_title: Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This indicates the presence of gonadal mosaicism or a low level of somatic mosaicism in one of the parents."
explanation: Recurrence in siblings of unaffected parents implies parental mosaicism.
has_subtypes:
- name: SYM1A
display_name: Proximal symphalangism 1A
subtype_term:
preferred_term: proximal symphalangism 1A
term:
id: MONDO:0020733
label: proximal symphalangism 1A
description: >-
Fusion of the proximal interphalangeal joints, often with conductive hearing
loss, as the predominant presentation. This is the form in which NOG variants
were first identified.
evidence:
- reference: PMID:10080184
reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800)"
explanation: Identifies NOG as the cause of proximal symphalangism.
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The most common clinical features are the immobility of the proximal interphalangia (PIP) joints of the hands and toes, and congenital conductive hearing loss due to stapes ankylosis"
explanation: States that conductive hearing loss commonly accompanies the symphalangism in SYM1.
- name: SYNS1
display_name: Multiple synostoses syndrome 1
curated_in: Multiple_Synostoses_Syndrome
description: >-
The more extensive form of the spectrum: proximal symphalangism with
carpal, tarsal, humeroradial and vertebral fusions and conductive hearing
loss. Curated in full in Multiple_Synostoses_Syndrome, which covers all
four multiple synostoses genes (NOG, GDF5, FGF9 and GDF6). That entry's
disease term is the broader multiple synostoses syndrome (MONDO:0017923),
and it maps SYNS1 (MONDO:0008519) as a narrower match.
evidence:
- reference: PMID:10080184
reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature."
explanation: Places NOG-caused SYNS1 in the same multiple-joint-fusion spectrum as SYM1.
- name: SABTT
display_name: Stapes ankylosis with broad thumbs and toes
subtype_term:
preferred_term: stapes ankylosis with broad thumbs and toes
term:
id: MONDO:0008484
label: stapes ankylosis with broad thumbs and toes
description: >-
Congenital or early-onset stapes ankylosis with hyperopia, a hemicylindrical
nose, and broad thumbs and great toes, and sometimes without symphalangism.
Includes Teunissen-Cremers syndrome. The variants reported in the defining
families truncate or disrupt the cysteine-rich C-terminal domain.
evidence:
- reference: PMID:12089654
reference_title: "Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain."
explanation: Defines the SABTT presentation and the variant class reported in its founding families.
- name: TCC
display_name: Tarsal-carpal coalition syndrome
subtype_term:
preferred_term: tarsal-carpal coalition syndrome
term:
id: MONDO:0008521
label: tarsal-carpal coalition syndrome
description: >-
Carpal and tarsal coalitions as the dominant feature, with variable
symphalangism and toe anomalies.
evidence:
- reference: PMID:29159868
reference_title: "Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family."
explanation: A NOG variant segregates with tarsal-carpal coalition syndrome in a dominant family.
- reference: PMID:15736221
reference_title: Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two siblings with carpal and tarsal synostoses associated with transverse deficiencies of the toes."
explanation: Carpal and tarsal synostoses with toe anomalies as the presenting features in NOG variant carriers.
- name: BDB2
display_name: Brachydactyly type B2
curated_in: Brachydactyly_Type_B2
subtype_term:
preferred_term: brachydactyly type B2
term:
id: MONDO:0012658
label: brachydactyly type B2
description: >-
Terminal deficiency of fingers and toes II-V together with proximal
symphalangism and carpal synostosis. Curated in full in
Brachydactyly_Type_B2. The BDB2 missense variants do not appear to cause a
major loss of noggin function, so this stratum departs most from the
haploinsufficiency mechanism described below.
evidence:
- reference: PMID:17668388
reference_title: "A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
explanation: Defines BDB2 and its NOG point mutations.
pathophysiology:
- name: NOG Loss of Function
description: >-
Heterozygous NOG variants reduce the amount of functional noggin. Truncating
variants act as null alleles, and the missense variants tested reduce or
abolish secretion of functional dimeric noggin without interfering with the
wild-type protein. NOG is a single-exon gene, and heterozygous null mice
develop carpal and tarsal fusions and stapes fixation, depending on strain,
so haploinsufficiency is the core mechanism. Variants in the heparin-binding
site, and the BDB2 missense variants, alter how noggin binds rather than how
much is secreted.
biological_scale: MOLECULAR
genes:
- preferred_term: NOG
term:
id: hgnc:7866
label: NOG
molecular_functions:
- preferred_term: BMP binding
term:
id: GO:0036122
label: BMP binding
modifier: DECREASED
evidence:
- reference: PMID:16598734
reference_title: The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: BACKGROUND
snippet: "Noggin is a secreted peptide that binds and inactivates Bone Morphogenetic Proteins, members of the transforming growth factor beta superfamily of secreted signaling molecules."
explanation: States noggin's molecular function, BMP binding, which variants that reduce the amount of secreted noggin diminish.
- reference: PMID:11562478
reference_title: "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin."
explanation: Shows that disease-causing missense variants are hypomorphic and reduce secretion of functional noggin.
- reference: PMID:11562478
reference_title: "Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion."
explanation: Argues against a dominant-negative mechanism for these variants.
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associated with NOG mutations are due to haploinsufficiency of NOGGIN."
explanation: Heterozygous null mice reproduce the conductive hearing loss, supporting haploinsufficiency.
downstream:
- target: Unopposed BMP Signaling at Prospective Joint Sites
causal_link_type: DIRECT
description: Less noggin leaves BMP ligands free to signal where noggin would normally antagonize them.
evidence:
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5)."
explanation: In heterozygous null mice, halving noggin dose is enough to leave BMP activity unopposed.
- reference: PMID:24735539
reference_title: "A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss."
supports: SUPPORT
evidence_source: COMPUTATIONAL
directness: INDIRECT
snippet: "We propose that the decreased binding affinity of NOG with the p.R136C mutation to HSPG leads to an excess of BMP signaling and underlies the SYM1 and conductive hearing loss phenotype of carriers."
explanation: Links a NOG variant to excess BMP signalling through in silico docking; a proposed rather than demonstrated step.
- name: Unopposed BMP Signaling at Prospective Joint Sites
description: >-
Noggin binds BMP and GDF ligands, including BMP4 and GDF5, and keeps them
from their receptors. With less noggin, BMP activity in condensing cartilage
is higher than normal. More cells are recruited into cartilage, and
chondrocytes stop responding to the positional cues that would make a joint.
biological_scale: CELLULAR
biological_processes:
- preferred_term: BMP signaling pathway
term:
id: GO:0030509
label: BMP signaling pathway
modifier: INCREASED
- preferred_term: negative regulation of BMP signaling pathway
term:
id: GO:0030514
label: negative regulation of BMP signaling pathway
modifier: DECREASED
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
evidence:
- reference: PMID:9603738
reference_title: "Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Excess BMP activity in the absence of Noggin antagonism may enhance the recruitment of cells into cartilage, resulting in oversized growth plates; chondrocytes are also refractory to joint-inducing positional cues."
explanation: In Nog-null mice, unopposed BMP activity expands cartilage and makes chondrocytes unresponsive to joint-inducing cues.
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5)."
explanation: The heterozygous state, which matches the human genotype, also shows unopposed BMP activity.
downstream:
- target: Failure of Joint Interzone Formation
causal_link_type: DIRECT
evidence:
- reference: PMID:9603738
reference_title: "Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In mice lacking Noggin, cartilage condensations initiated normally but developed hyperplasia, and initiation of joint development failed as measured by the expression of growth and differentiation factor-5."
explanation: Without noggin, cartilage condensations form but joint initiation fails.
- name: Failure of Joint Interzone Formation
description: >-
The joint interzone, which normally separates adjacent cartilage elements and
later cavitates, does not form. The elements remain continuous and ossify as
one, causing symphalangism and carpal and tarsal coalition. In the middle
ear, the same failure of separation fuses the stapes to surrounding bone.
biological_scale: TISSUE
biological_processes:
- preferred_term: embryonic skeletal joint development
term:
id: GO:0072498
label: embryonic skeletal joint development
modifier: DECREASED
locations:
- preferred_term: interphalangeal joint
term:
id: UBERON:0006658
label: interphalangeal joint
evidence:
- reference: PMID:10080184
reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The findings reported here confirm that NOG is essential for joint formation"
explanation: Human genetic evidence that noggin is required for joint formation.
downstream:
- target: Proximal Symphalangism
causal_link_type: DIRECT
- target: Carpal Synostosis
causal_link_type: DIRECT
evidence:
- reference: PMID:16598734
reference_title: The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we have discovered Noggin haploinsufficiency leading to carpal and tarsal fusions reminiscent of some phenotypes reported for NOGGIN haploinsufficiency in humans."
explanation: Halving Noggin dose in mice is enough to fuse carpal and tarsal bones.
- target: Tarsal Synostosis
causal_link_type: DIRECT
evidence:
- reference: PMID:16598734
reference_title: The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we have discovered Noggin haploinsufficiency leading to carpal and tarsal fusions reminiscent of some phenotypes reported for NOGGIN haploinsufficiency in humans."
explanation: Halving Noggin dose in mice is enough to fuse carpal and tarsal bones.
- target: Stapes Fixation to the Otic Capsule
causal_link_type: DIRECT
evidence:
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development."
explanation: The middle-ear fusion arises from the same failure of skeletal elements to separate.
- name: Stapes Fixation to the Otic Capsule
description: >-
The stapes footplate is fixed to the surrounding bone. In the one human
temporal bone examined, the stapedovestibular joint space was bridged by a
ring of calcified cartilage. In heterozygous Nog mice, an ectopic bone bridge
joins the stapes to the wall of the tympanum. Fixation may be incomplete at
birth and progress in early childhood.
biological_scale: TISSUE
locations:
- preferred_term: stapes
term:
id: UBERON:0001687
label: stapes bone
evidence:
- reference: PMID:26474326
reference_title: "Temporal Bone Histopathology in NOG-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The temporal bone pathologic correlate for conductive hearing loss in this patient with a NOG mutation was circumferentially calcified cartilage bridging the stapedovestibular joint space."
explanation: Human histopathology of the stapes fixation.
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The conductive hearing loss in Nog(+/-) mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle."
explanation: The mouse counterpart of the human stapes fixation.
downstream:
- target: Stapes Ankylosis
causal_link_type: DIRECT
- target: Conductive Hearing Loss
causal_link_type: DIRECT
evidence:
- reference: PMID:26474326
reference_title: "Temporal Bone Histopathology in NOG-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The temporal bone pathologic correlate for conductive hearing loss in this patient with a NOG mutation was circumferentially calcified cartilage bridging the stapedovestibular joint space."
explanation: Ties the conductive hearing loss to the stapes fixation.
phenotypes:
- category: Musculoskeletal
name: Proximal Symphalangism
description: >-
Bony fusion of the proximal interphalangeal joints of the hands and feet;
the defining feature of the spectrum.
phenotype_term:
preferred_term: Proximal symphalangism
term:
id: HP:0100264
label: Proximal symphalangism
sequelae:
- target: Limitation of Joint Mobility
description: Fusion of the proximal interphalangeal joints limits finger mobility.
evidence:
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There was symphalangism in both hands, resulting in limited mobility of the fingers."
explanation: States that the symphalangism resulted in limited finger mobility.
evidence:
- reference: PMID:21538686
reference_title: "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet."
explanation: Names proximal symphalangism as the hallmark of the spectrum.
- category: Auditory
name: Conductive Hearing Loss
description: >-
Conductive hearing loss from stapes fixation, usually bilateral. It is
often described as congenital, but in one SABTT child hearing was normal on
early testing and then declined.
phenotype_term:
preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: PMID:21538686
reference_title: "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia."
explanation: Conductive hearing loss from stapes fixation is a common feature of the spectrum.
- reference: PMID:29605356
reference_title: "Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss."
explanation: Frequency of bilateral conductive hearing loss in one affected family.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The most common sign in NOG-SSD is conductive hearing loss related to congenital stapes fixation"
explanation: States conductive hearing loss is the most common sign across the spectrum.
- reference: PMID:33588412
reference_title: "Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "According to hearing test results, the stapes ankylosis in our SABTT patient seemed to be incomplete at birth and progressive in early childhood."
explanation: Shows the hearing loss can be progressive rather than present at birth.
- category: Auditory
name: Stapes Ankylosis
description: Fixation of the stapes, confirmed at surgery in affected family members.
phenotype_term:
preferred_term: Stapes ankylosis
term:
id: HP:0000381
label: Stapes ankylosis
evidence:
- reference: PMID:25815513
reference_title: "A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stapedotomy were performed in subjects F13-2, F13-3, F13-5 and F13-7 and operation identified stapes ankylosis in all."
explanation: Stapes ankylosis confirmed at surgery in four affected members of a family carrying a 1.6-Mb deletion that includes NOG.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For individuals II-2, II-4, II-5 and III-6, stapes ankylosis was confirmed and repaired surgically"
explanation: Surgically confirmed stapes ankylosis in a NOG-SSD family.
- category: Ophthalmological
name: Hyperopia
phenotype_term:
preferred_term: Hyperopia
term:
id: HP:0000540
label: Hypermetropia
evidence:
- reference: PMID:21538686
reference_title: "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia."
explanation: Hyperopia is a common feature of the spectrum.
- category: Ophthalmological
name: Strabismus
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: PMID:25815513
reference_title: "A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Other symptoms of NOG-SSD may include conductive hearing impairment due to stapes ankylosis, fusion of the carpals and tarsals, brachydactyly, abnormal faces, hyperopia and strabismus."
explanation: Lists strabismus among NOG-SSD features.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Strabismus is present and corrected by eyeglasses"
explanation: Strabismus in a family with a NOG point variant.
- category: Ophthalmological
name: Amblyopia
phenotype_term:
preferred_term: Amblyopia
term:
id: HP:0000646
label: Amblyopia
evidence:
- reference: PMID:25815513
reference_title: "A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this study we reported a dominant Chinese Han family segregating with typical NOG-SSD symptoms including proximal symphalangism, conductive hearing loss, amblyopia and strabismus, but not intellectual disability."
explanation: Amblyopia segregated with NOG-SSD in this family. The family carries a 17q22 deletion, so the observation comes from a NOG deletion rather than a point variant.
- category: Craniofacial
name: Hemicylindrical Nose
description: >-
A broad, tubular nose with a bulbous tip. HPO has no term for the
hemicylindrical shape, so the binding captures only the bulbous tip.
phenotype_term:
preferred_term: Hemicylindrical nose with bulbous tip
term:
id: HP:0000414
label: Bulbous nose
evidence:
- reference: PMID:26994744
reference_title: "Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Proximal symphalangism is commonly observed in patients bearing mutations in this gene, however secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip"
explanation: Describes the characteristic nasal shape.
- category: Musculoskeletal
name: Carpal Synostosis
phenotype_term:
preferred_term: Carpal synostosis
term:
id: HP:0009702
label: Carpal synostosis
evidence:
- reference: PMID:15736221
reference_title: Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two siblings with carpal and tarsal synostoses associated with transverse deficiencies of the toes."
explanation: Carpal synostosis in NOG variant carriers.
- reference: PMID:17668388
reference_title: "A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis"
explanation: Carpal synostosis is part of the BDB2 definition.
- category: Musculoskeletal
name: Tarsal Synostosis
phenotype_term:
preferred_term: Tarsal synostosis
term:
id: HP:0008368
label: Tarsal synostosis
evidence:
- reference: PMID:15736221
reference_title: Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe two siblings with carpal and tarsal synostoses associated with transverse deficiencies of the toes."
explanation: Tarsal synostosis in NOG variant carriers.
- category: Musculoskeletal
name: Broad Thumb
subtype: SABTT
phenotype_term:
preferred_term: Broad thumb
term:
id: HP:0011304
label: Broad thumb
evidence:
- reference: PMID:12089654
reference_title: "Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism"
explanation: Broad thumbs are part of the SABTT presentation.
- category: Musculoskeletal
name: Broad Hallux
subtype: SABTT
phenotype_term:
preferred_term: Broad hallux
term:
id: HP:0010055
label: Broad hallux
evidence:
- reference: PMID:12089654
reference_title: "Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism"
explanation: Broad great toes are part of the SABTT presentation.
- category: Musculoskeletal
name: Brachydactyly
subtype: BDB2
description: Terminal deficiency of fingers and toes in the BDB2 stratum.
phenotype_term:
preferred_term: Type B brachydactyly
term:
id: HP:0005831
label: Type B brachydactyly
evidence:
- reference: PMID:17668388
reference_title: "A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes"
explanation: Defines the type B digital pattern.
- reference: PMID:17668388
reference_title: "A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG)."
explanation: Type B brachydactyly in patients with NOG point mutations.
- category: Musculoskeletal
name: Syndactyly
phenotype_term:
preferred_term: Syndactyly
term:
id: HP:0001159
label: Syndactyly
evidence:
- reference: PMID:29605356
reference_title: "Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All the affected members had syndactyly and symphalangism."
explanation: Syndactyly in every affected member of one NOG family.
- category: Musculoskeletal
name: Limitation of Joint Mobility
phenotype_term:
preferred_term: Reduced mobility of multiple joints
term:
id: HP:0001376
label: Limitation of joint mobility
evidence:
- reference: PMID:26994744
reference_title: "Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints"
explanation: Reduced joint mobility is a recurrent secondary feature.
- category: Musculoskeletal
name: Arthralgia
phenotype_term:
preferred_term: Recurrent pain from affected joints
term:
id: HP:0002829
label: Arthralgia
evidence:
- reference: PMID:26994744
reference_title: "Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints"
explanation: Pain in affected joints is a recurrent secondary feature.
- category: Musculoskeletal
name: Fused Cervical Vertebrae
description: Fusion of cervical vertebrae limiting neck movement, mainly in the more extensive SYNS1 presentation.
phenotype_term:
preferred_term: Fused cervical vertebrae
term:
id: HP:0002949
label: Fused cervical vertebrae
evidence:
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He also has limitation of his neck motion due to C2-C3 vertebral fusion"
explanation: C2-C3 fusion in a NOG-SSD patient.
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hyperopia, broad thumbs and first toes, symphalangism, syndactyly, and fused cervical vertebrae"
explanation: Lists fused cervical vertebrae among findings in NOG families.
- category: Craniofacial
name: Thin Upper Lip Vermilion
phenotype_term:
preferred_term: Thin upper lip vermilion
term:
id: HP:0000219
label: Thin upper lip vermilion
evidence:
- reference: CGGV:assertion_ab71a633-1fd2-45b8-93f3-40648526631d-2023-07-05T160000.000Z
supports: SUPPORT
evidence_source: OTHER
snippet: "characteristic facial features including a broad, tubular-shaped nose and a thin upper vermilion"
explanation: ClinGen lists a thin upper vermilion among the characteristic facial features.
- category: Growth
name: Tall Stature in Childhood
description: >-
Children in two families with NOG variants were tall, but the adults in
those families were not consistently tall. Evidence is limited to these two
families.
phenotype_term:
preferred_term: Tall stature in childhood
term:
id: HP:0000098
label: Tall stature
onset:
onset_category: CHILDHOOD
evidence:
- reference: PMID:18204269
reference_title: Growth and skeletal development in families with NOGGIN gene mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults."
explanation: Reports childhood tall stature in two NOG families.
- category: Gastrointestinal
name: Esophageal Atresia
description: >-
Type C esophageal atresia with tracheoesophageal fistula, reported in a
single newborn with a de novo NOG nonsense variant. It is also reported in
17q22 deletions that include NOG. Whether it belongs to the spectrum
remains a suggestion.
phenotype_term:
preferred_term: Esophageal atresia
term:
id: HP:0002032
label: Esophageal atresia
evidence:
- reference: PMID:34472207
reference_title: Esophageal atresia/tracheoesophageal fistula and proximal symphalangism in a patient with a NOG nonsense mutation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation."
explanation: A single case links a NOG truncating variant to esophageal atresia.
genetic:
- name: NOG
gene_term:
preferred_term: NOG
term:
id: hgnc:7866
label: NOG
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
Missense, nonsense and frameshift variants and whole-gene deletions are all
reported. Heterozygous loss of function is the established mechanism. The
BDB2 missense variants are the exception: they appear to change noggin's
binding to BMPs and GDFs rather than abolish its activity.
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_ab71a633-1fd2-45b8-93f3-40648526631d-2023-07-05T160000.000Z
evidence:
- reference: CGGV:assertion_ab71a633-1fd2-45b8-93f3-40648526631d-2023-07-05T160000.000Z
supports: SUPPORT
evidence_source: OTHER
snippet: "NOG | HGNC:7866 | NOG-related symphalangism spectrum disorder | MONDO:0100521 | AD | Definitive"
explanation: ClinGen classifies NOG as definitively associated with this disease.
evidence:
- reference: CGGV:assertion_ab71a633-1fd2-45b8-93f3-40648526631d-2023-07-05T160000.000Z
supports: SUPPORT
evidence_source: OTHER
snippet: "Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, phenotypic variability, and inheritance pattern of the five disease assertions."
explanation: ClinGen's reason for merging the five NOG syndromes into this one disease.
- reference: CGGV:assertion_ab71a633-1fd2-45b8-93f3-40648526631d-2023-07-05T160000.000Z
supports: SUPPORT
evidence_source: OTHER
snippet: "The mechanism of pathogenicity is known to be loss of function"
explanation: ClinGen records loss of function as the mechanism.
- reference: PMID:10080184
reference_title: "Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All seven NOG mutations alter evolutionarily conserved amino acid residues."
explanation: The original NOG variant series.
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These results together with the literature review indicated that there are no clear genotype-phenotype correlations for NOG mutations."
explanation: Variant type and position do not reliably predict which presentation of the spectrum a family shows.
- reference: PMID:33308208
reference_title: "Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by an NOG mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This suggests that disease expression can be independent of the location and type of NOG mutation."
explanation: A second family study reaching the same conclusion on genotype-phenotype correlation.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions"
explanation: A small deletion removing NOG behaves like a point variant, so such deletions belong to NOG-SSD.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Family 2 harbors a missense mutation in NOG leading to absence of noggin protein"
explanation: In transfected cells the L14P missense variant produced no detectable noggin, a loss-of-function allele.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
description: >-
Suspect NOG-SSD in a person with conductive hearing loss and proximal
symphalangism, carpal or tarsal coalition, broad thumbs or hyperopia,
especially with a dominant family history. Hand and foot radiographs show
the fusions. Confirmation is by NOG sequencing or by detecting a 17q22
deletion. Genetic testing separates syndromic stapes ankylosis from
otosclerosis, which it can closely resemble, and even mild skeletal
findings should prompt testing.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities."
explanation: NOG variants were absent from 33 otosclerosis patients without symphalangism.
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease."
explanation: Recommends genetic testing to separate NOG-SSD from otosclerosis.
- reference: PMID:25815513
reference_title: "A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "genomic deletions in chromosome 17q22 should be screened in the NOG-SSD patients in which no pathogenic mutation is identified by conventional sequencing methods"
explanation: Supports deletion testing when sequencing is negative.
treatments:
- name: Stapes Surgery
description: >-
Stapedotomy or stapedectomy for conductive hearing loss. Hearing improves,
and in one family the improvement lasted for decades without re-fixation,
although other reports describe hearing declining again from bone regrowth
two to five years after surgery. In the one NOG-SSD temporal bone measured,
the distance from the incus to the footplate was longer than in
otosclerosis, so surgeons are advised to have longer prostheses available.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: stapes surgery
term:
id: NCIT:C15329
label: Surgical Procedure
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
target_mechanisms:
- target: Stapes Fixation to the Otic Capsule
evidence:
- reference: PMID:29605356
reference_title: "Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years."
explanation: Long-term durability of stapedectomy in a NOG family.
- reference: PMID:33588412
reference_title: "Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stapes surgery was performed, and his post-operative hearing threshold improved to normal in both ears."
explanation: Hearing returned to normal after stapes surgery in an SABTT patient.
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "most of the patients in these three families with NOG mutations showed remarkable air-bone gap recovery after stapes surgery"
explanation: Surgical benefit across three NOG families.
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis."
explanation: A surgical consideration specific to NOG-SSD.
- reference: PMID:33308208
reference_title: "Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by an NOG mutation."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Some reports describe progressive hearing loss due to bone regrowth 2-5 years after surgery."
explanation: Other reports describe hearing declining again from bone regrowth a few years after surgery, which qualifies the claim that the benefit lasts.
- name: Hearing Aids
description: >-
Amplification for conductive hearing loss, used in young children before
stapes surgery or as an alternative to it.
therapeutic_modality: DEVICE
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: PMID:34049328
reference_title: "Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "was fitted with bilateral hearing aids at age 3y"
explanation: Hearing aids used in a child with NOG-SSD.
- name: Audiological Surveillance
description: >-
Periodic hearing tests for children with a family history or a congenital
joint anomaly. Stapes fixation can be incomplete at birth, so newborn
hearing screening may be normal.
target_phenotypes:
- preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: PMID:33588412
reference_title: "Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hence, children with a family history and/or known congenital joint abnormality should undergo periodic hearing tests due to possible progressive hearing loss."
explanation: Recommends hearing surveillance in at-risk children.
animal_models:
- name: Nog heterozygous mouse
species: Mouse
genotype: Nog+/-
publication: PMID:18096605
description: >-
Depending on genetic background, heterozygous null mice show mild conductive
hearing loss from an ectopic bone bridge fixing the stapes, and carpal and
tarsal fusions.
modeled_mechanisms:
- target: Stapes Fixation to the Otic Capsule
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
limitations: >-
The penetrance of the hearing loss depends on genetic background, and the
mouse bone bridge joins the stapes to the posterior wall of the tympanum,
whereas the one human temporal bone showed calcified cartilage across the
stapedovestibular joint.
evidence:
- reference: PMID:18096605
reference_title: "Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "More importantly, these results establish Nog(+/-) mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders."
explanation: Positions the heterozygous mouse as a model of NOG-related conductive hearing loss.
- target: Failure of Joint Interzone Formation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
limitations: >-
Heterozygous mice show carpal and tarsal fusions but are otherwise
described as largely normal; the proximal symphalangism that defines the
human disease is not reported in them.
evidence:
- reference: PMID:16598734
reference_title: The Noggin null mouse phenotype is strain dependent and haploinsufficiency leads to skeletal defects.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "we have discovered Noggin haploinsufficiency leading to carpal and tarsal fusions reminiscent of some phenotypes reported for NOGGIN haploinsufficiency in humans."
explanation: Halving Nog dose in mice reproduces the carpal and tarsal fusions.
progression:
- phase: Congenital skeletal fusions
age_range: Congenital
subtype: SYM1A
notes: >-
Joint immobility and stapes ankylosis are described as congenital features
of proximal symphalangism.
evidence:
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "The most common clinical features are the immobility of the proximal interphalangia (PIP) joints of the hands and toes, and congenital conductive hearing loss due to stapes ankylosis"
explanation: Describes the joint immobility and congenital hearing loss of proximal symphalangism.
- phase: Progressive bony fusion in multiple synostoses
subtype: SYNS1
notes: >-
Applies to the multiple synostoses form only, not to isolated proximal
symphalangism.
evidence:
- reference: PMID:22288654
reference_title: "Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Multiple synostosis syndrome (SYNS1: MIM#186500) (1) is characterized by a more severe phenotype of the proximal symphalangism, such as progressive and expanded bony fusion of joints and unique facial manifestations"
explanation: States that SYNS1 involves progressive, expanded bony fusion beyond proximal symphalangism.
- phase: Stapes fixation incomplete at birth, progressive in early childhood
subtype: SABTT
age_range: Early childhood
notes: >-
Inferred by the authors from hearing tests in a single SABTT patient;
not shown to generalize across the spectrum.
evidence:
- reference: PMID:33588412
reference_title: "Is the Conductive Hearing Loss in NOG-Related Symphalangism Spectrum Disorder Congenital?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "According to hearing test results, the stapes ankylosis in our SABTT patient seemed to be incomplete at birth and progressive in early childhood."
explanation: Single-patient report that stapes ankylosis was incomplete at birth and progressed in early childhood.
references:
- reference: PMID:21538686
title: "A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)."
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: NOG-Related_Symphalangism_Spectrum_Disorder · 2026-10-14T17:22:42Z · View source
Created a Disease entry for MONDO:0100521 with five has_subtypes rows (SYM1A, SYNS1, SABTT, TCC, BDB2). The lump follows the ClinGen Lumping and Splitting Working Group, which merged the five MIM phenotypes into this MONDO term (CGGV assertion, Definitive, recorded on the NOG gene row). SYNS1 and BDB2 are pointer subtypes (curated_in) to Multiple_Synostoses_Syndrome and Brachydactyly_Type_B2. SYNS1 deliberately has no subtype_term, because that entry already maps MONDO:0008519 as narrowMatch. Pathograph: NOG loss of function -> unopposed BMP signalling at prospective joints -> failure of joint interzone formation -> symphalangism, carpal/tarsal synostosis and stapes fixation -> conductive hearing loss. Deep research: falcon was requested but failed Edison authentication (503); dr_fallback='--fallback' and '--fallback-provider claude_code' both failed to switch providers on that error, so claude_code was run directly (research/NOG-Related_Symphalangism_Spectrum_Disorder-deep-research-claude_code.md: 26/26 references resolved, 2 report quotes unsupported (PMID:17668388, PMID:33308208); no report quote was reused, and both papers are quoted here from their cached text; preflight-dr PASS). No GeneReviews chapter exists (check-genereviews NO_CHAPTER). Validated: just validate, count-verified-snippets 55/55, check-entity-refs, check-causal-targets, check-granularity (2 pointers, no mismatch), and the KB-wide snippet gates. A fresh-context review pass before the PR led to these changes. 17q22 deletions that remove only NOG are now in scope (PMID:34049328), with the larger microdeletion syndromes left as the differential. Heterozygous-mouse evidence (PMID:18096605) now supports the haploinsufficiency edge and the BMP node. The loss-of-function node description was narrowed to what the sources show. BDB2 brachydactyly is bound to HP:0005831 Type B brachydactyly. Primary-source evidence was added for strabismus, stapes ankylosis and conductive hearing loss. Fused cervical vertebrae and thin upper lip vermilion were added, along with penetrance, parental mosaicism and a stapes location. Hearing aids and audiological surveillance are now separate treatment rows. The final run gave 73/73 snippets verified and validate-disorders passed.
Overview. NOG-SSD is an umbrella term proposed in 2011. It covers five autosomal dominant joint-development syndromes, all caused by heterozygous variants in NOG, the gene for the BMP antagonist noggin.
"The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia." — PMID:21538686 (Potti et al., Hum Mutat 2011, review)
"Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD)" — PMID:21538686
The five syndromes it covers, with OMIM numbers (as listed in PMID:34049328):
| Syndrome | Abbrev. | OMIM |
|---|---|---|
| Proximal symphalangism 1 | SYM1 | 185800 |
| Multiple synostoses syndrome 1 | SYNS1 | 186500 |
| Stapes ankylosis with broad thumbs and toes (includes Teunissen-Cremers syndrome) | SABTT | 184460 |
| Tarsal-carpal coalition syndrome | TCC | 186570 |
| Brachydactyly type B2 | BDB2 | 611377 |
The gene is NOG, OMIM 602991 (PMID:33308208), HGNC hgnc:7866 ✓ (NOG). Facio-audio-symphalangism syndrome is a historical synonym (PMID:26994744, PMID:29605356).
Identifiers. MONDO:0100521 is the entry's disease term. I could not confirm an Orphanet code for the NOG-SSD umbrella. Orphanet lists the component syndromes separately, and the web search did not find an umbrella ORPHA entry. I did not verify ICD-10/ICD-11 or MeSH codes. The relevant MeSH headings are Synostosis, Stapes/abnormalities and Hand Deformities, Congenital (taken from the MeSH indexing of PMID:21538686).
Data provenance. All of the evidence is aggregated from case reports, family studies and reviews. There are no EHR-derived or registry data. A locus-specific variant database exists (https://NOG.lovd.nl, PMID:21538686).
Suggested subtype modelling: five has_subtypes rows (SYM1, SYNS1, SABTT, TCC, BDB2). BDB2 has a different molecular mechanism (section 6), so it is the only one that is more than a clinical label.
hgnc:4220 ✓) and FGF9 (hgnc:3687 ✓): "Currently, three genes, NOG, GDF5, and FGF9, have been identified as causative of SYNS" (PMID:25241334). Those cases are outside NOG-SSD by definition, but they matter for the differential diagnosis.The HPO terms below were checked against cache/hp/terms.csv ✓. Frequencies are qualitative because no cohort-level frequency study exists. Onset is congenital unless noted.
| Phenotype | HPO ✓ | Notes / evidence |
|---|---|---|
| Proximal symphalangism | HP:0100264 Proximal symphalangism; HP:0006152 Proximal finger symphalangism; HP:0010179 Toe symphalangism | The hallmark (PMID:21538686). It can be absent in SABTT, which was described as "lacked symphalangism" (PMID:12089654). |
| Conductive hearing loss from stapes ankylosis | HP:0000405 Conductive hearing impairment | "The most common sign in NOG-SSD is conductive hearing loss related to congenital stapes fixation" (PMID:34049328). It may be progressive in early childhood: normal ABR at 9 months and 1–2 years, then progressive CHL (PMID:33588412). It is absent in some families, for example C230Y (PMID:26994744). Severity is mild to moderate-severe. |
| Hyperopia | HP:0000540 Hypermetropia; HP:0008499 High hypermetropia | Present in all 8 affected members across the two families of PMID:34049328, including +8 D in one proband. |
| Strabismus / amblyopia | HP:0000486 Strabismus; HP:0000646 Amblyopia | Reported in PMID:34049328 and PMID:25815513. |
| Hemicylindrical or bulbous nose | HP:0000414 Bulbous nose (no "hemicylindrical nose" term was found in the cache) | PMID:21538686, PMID:26994744. Coarse binding; record the descriptor in preferred_term. |
| Other facial features | HP:0000233 Thin vermilion border; HP:0000322 Short philtrum | From Table 1 of PMID:34049328 (thin upper lip, short philtrum, maxillary hypoplasia, micrognathia). |
| Broad thumbs / halluces | HP:0011304 Broad thumb; HP:0010055 Broad hallux | Characteristic of SABTT (PMID:12089654). |
| Carpal and tarsal synostosis | HP:0009702 Carpal synostosis; HP:0008368 Tarsal synostosis; HP:0100266 Synostosis of carpals/tarsals | Defines TCC (PMID:29159868) and occurs in BDB2 (PMID:17668388). |
| Elbow / humeroradial synostosis | HP:0003041 Humeroradial synostosis; HP:0003070 Elbow ankylosis | Seen in SYNS1. The review literature supports it, but none of the cached abstracts quotes it. Needs a source. |
| Cervical vertebral fusion | HP:0002948 Vertebral fusion | C2–C3 fusion in the L14P proband (PMID:34049328). |
| Brachydactyly (terminal digit deficiency) | HP:0001156 Brachydactyly | BDB2 (PMID:17668388). |
| Syndactyly | HP:0012725 Cutaneous syndactyly; HP:0001770 Toe syndactyly | "All the affected members had syndactyly and symphalangism" (PMID:29605356). |
| Transverse toe reduction defects | — | PMID:15736221 (one sibship). |
| Tall stature in childhood | HP:0000098 Tall stature | "Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults" (PMID:18204269). Two families only. |
| Esophageal atresia / TEF (rare, single case) | HP:0002032; HP:0002575 | "suggests that the clinical spectrum of NOG-related symphalangism spectrum disorders may include EA/TEF" (PMID:34472207). Model it as a candidate feature, not a core one. |
| Malleus/incus fixation (rare) | — | "has not previously been reported in individuals with NOG-SSD" before PMID:34049328. Also reported with a start-codon variant [uncached; PMC6679842]. |
| Joint pain, reduced range of motion | — | "recurrent pain from affected joints" (PMID:26994744). |
Inheritance and expressivity terms: HP:0000006 Autosomal dominant inheritance ✓ and HP:0003828 Variable expressivity ✓.
Quality of life. No validated QoL instrument data exist. The main functional burdens are hearing loss during school age and reduced hand dexterity. The authors of PMID:33588412 give that as the reason for early surgery. This is expert opinion, not measured data.
Representative variants:
| Variant | Phenotype | Functional data | Source |
|---|---|---|---|
| c.41T>C p.L14P (signal peptide) | SYNS1 | Protein completely absent; partly rescued by proteasome inhibition but still not secreted | PMID:34049328 |
| p.P170L | Congenital CHL / stapes ankylosis | Impaired secretion | PMID:31628072, PMID:34049328 |
| c.328C>T p.Q110*; c.252_253insC | SABTT | Disrupts the cysteine-rich C-terminal domain | PMID:12089654 |
| c.645C>A p.C215* | SABTT, progressive CHL | — | PMID:33588412 |
| c.406C>T p.R136C (heparin-binding site) | SYM1 + CHL | In silico loss of a heparin salt bridge | PMID:24735539 |
| p.P35A/S, A36P, E48K, R167G, P187S | BDB2 | Not a major loss of function; altered BMP/GDF binding | PMID:17668388 |
| p.C178R | SABTT-like, mild | ACMG likely pathogenic | PMID:33308208 |
| p.C230Y | SYNS1 without hearing loss | — | PMID:26994744 |
| c.688_699del p.Cys230_Cys232delins11 | Stapes fixation, syndactyly | ACMG likely pathogenic | PMID:29605356 |
| c.611G>A | TCC | — | PMID:29159868 |
| p.P42A + p.P50R (in cis, de novo) | Carpal/tarsal synostosis, toe reduction | Parental gonadal mosaicism | PMID:15736221 |
| p.M190V; p.P42R | Symphalangism, tall stature | — | PMID:18204269 |
| c.222C>A p.Y74* | Stapes ankylosis, hyperopia | — | Sonoyama 2023 [uncached; PMC10097708] |
| c.2T>C (start loss) | Incus and stapes malformation | — | 2019 [uncached; PMC6679842] |
somatic-mosaicism skill it must not be bound to HP:0001442. A de novo variant in an affected mother has also been inferred (PMID:34049328).just check-gene-validity and the ClinGen cache before recording any validity tier; do not assign one.No environmental, lifestyle or infectious contributors are known. Treat this as not applicable.
Dosage and species caveat. Nog−/− mice die at birth. Heterozygous mice were first reported as normal (PMID:11562478), but later work found carpal/tarsal fusions in some strains (PMID:16598734) and conductive hearing loss (PMID:18096605). In other words, the human dominant phenotype only partly reproduces in mice. That fits a HUMAN_MODEL_MISMATCH discussion.
All checked against the cache ✓.
hgnc:7866; BMP4 hgnc:1071 ✓; GDF5 hgnc:4220 ✓.Omics, single-cell, spatial and CRISPR data: none found for this disease.
progression: phases: prenatal joint-formation failure; congenital or early-childhood stapes fixation; childhood progression of CHL and joint fusion; stable adult phenotype.prevalence_class: NOT_YET_DOCUMENTED with measure_type: UNKNOWN.just check-genereviews before writing a "no chapter exists" note.There is no disease-modifying therapy. NCIT IDs below are not verified in this session; check them with runoak or cache/ncit/terms.csv before binding.
| Treatment | Modality | Evidence | NCIT suggestion |
|---|---|---|---|
| Stapedectomy / laser stapedotomy | SURGERY | PMID:29605356, PMID:34049328, PMID:33588412, PMID:26474326 | Surgical Procedure (NCIT:C15329 per CLAUDE.md) |
| Surgical note: long or custom prosthesis (4.5–5.5 mm; a modified malleus-attachment piston) | — | "we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis" (PMID:34049328) | Record in the description; NCIT device terms do not belong in TreatmentTerm |
| Assess malleus/incus mobility during surgery; consider atticotomy | SURGERY | PMID:34049328 | — |
| Hearing aids | DEVICE | Used before surgery (PMID:34049328) | No NCIT action term; use the device qualifier pattern |
| Spectacles for hyperopia and strabismus | DEVICE | PMID:34049328 | — |
| Physical / occupational therapy | BEHAVIORAL | Expert practice; no specific citation found | NCIT:C15302 / NCIT:C121351 |
| Genetic counseling | OTHER | — | NCIT:C15240 |
Pharmacotherapy, gene therapy, RNA therapies and clinical trials: none. I found no NCT or ICTRP registrations; this was a web search, and ClinicalTrials.gov itself was not queried.
No naturally occurring animal disease was found; OMIA was not searched in this session. Noggin is highly conserved across vertebrates. The causal variants "alter evolutionarily conserved amino acid residues" (PMID:10080184), and L14 is conserved in more than 100 species (PMID:34049328). Joint requirements differ between species: "NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species" (PMID:10080184).
| Model | Phenotype | Fidelity / limitation | Source |
|---|---|---|---|
| Nog−/− mouse (129X1/SvJ and other strains) | Lethal at birth or about E18.5; cartilage hyperplasia; joint fusions; failed GDF5 joint induction | Recessive lethal, so a supraphysiological dose reduction compared with human heterozygotes. Use PARTIALLY_RECAPITULATES for joint failure. | PMID:9603738, PMID:16598734 |
| Nog+/− mouse | Strain-dependent carpal/tarsal fusions; mild conductive hearing loss from an ectopic stapes–tympanum bone bridge | The best model for CHL ("the first animal model for the study of conductive rather than neurosensory hearing loss"). Background-dependent. The human pathology is a stapedovestibular cartilage bridge, not a stapes–tympanum bridge. | PMID:18096605, PMID:16598734 |
| COS-7 / HEK293T secretion assays | Variant-specific loss of secretion and dimerization | IN_VITRO; no skeletal context | PMID:11562478, PMID:34049328 |
| Xenopus oocytes | SYNS1 mutant can still dimerize | Species-specific processing | PMID:11562478 |
| Chick limb micromass culture | BDB2 variants retain function | IN_VITRO | PMID:17668388 |
| In silico docking (noggin–heparin; NOG–GDF5) | R136C loses a salt bridge; free-energy calculations for BDB2 | COMPUTATIONAL | PMID:24735539, PMID:17668388 |
just fetch-reference Before Usereferences_cache/: PMID:21538686, 10080184, 11562478, 12089654, 15736221, 16598734, 17668388, 18096605, 18204269, 24735539, 25241334, 25815513, 26474326, 26994744, 29159868, 29605356, 31628072, 33308208, 33588412, 34049328, 34472207, 9603738 (36004948 and 9634411 are cached with no abstract content)Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 26 |
| Resolved | 26 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 31 |
| Quoted claims found in source | 29 |
| Quoted claims not found in source | 2 |
| References weighed for topical relevance | 26 |
| On topic | 20 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
1 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:17668388 (abstract only): "do not indicate a major loss of function … Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way"PMID:33308208: "No obvious abnormalities were found … on ear computed tomography"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 55 |
| Resolved | 54 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 0 |
These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:000557654 of 55 terms resolved to a current term; the rest could not be looked up either way.