RHYNS syndrome is a TMEM67 ciliopathy, and it is worth being explicit that this was not known when the syndrome was named. The acronym was coined in 1997 from a single 17-year-old boy with retinitis pigmentosa, hypopituitarism, nephronophthisis and mild skeletal dysplasia; two affected brothers were reported in 2001; the genetic basis stayed unknown for twenty-one years, until exome sequencing of the original family found compound heterozygous TMEM67 variants in 2018. Everything mechanistic in this entry is therefore inference from TMEM67 biology onto a four-patient clinical description, and the entry is built to make that visible rather than to smooth it over. TMEM67 encodes meckelin, a transmembrane protein of the ciliary transition zone. Its allelic series is one of the widest in the ciliopathies - the report identifying RHYNS describes it as extending to eight distinguishable clinical conditions, from early lethality in Meckel-Gruber syndrome to adults with isolated liver fibrosis - so RHYNS is the mild end of a spectrum rather than a separate lesion. That is the strongest argument for keeping it as its own entry: the four reported patients share a phenotype combination that is unique within the series, and it is the combination, not any single feature, that the diagnosis rests on. The molecular account comes from mouse work rather than from patients. Meckelin is a receptor for Wnt5a, required for phosphorylation of the non-canonical Wnt receptor ROR2, with which it colocalises at the transition zone, and it normally represses Shh signalling. Every element of that is Tmem67-knockout mouse or in vitro data. The mouse reproduces the developmental abnormalities of severe TMEM67 ciliopathies rather than the RHYNS phenotype, so a HUMAN_MODEL_MISMATCH discussion records the gap: no model carries RHYNS-type hypomorphic alleles, and none has retinitis pigmentosa or hypopituitarism. Two curation notes. Inheritance is autosomal recessive on the molecular evidence, but the 2001 report could not exclude X-linkage because all four known patients were male, and that history is preserved because it explains why the syndrome sat in an ambiguous nosological position for so long. And the skeletal phenotype is described as "mild" in the index case and "acromelic" in the brothers, which are not the same claim; both are curated as reported.
Ask a research question about RHYNS Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: RHYNS Syndrome
creation_date: "2026-09-03T16:10:00Z"
category: Mendelian
synonyms:
- retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia
- retinitis pigmentosa-hypopituitarism-nephronophthisis-skeletal dysplasia syndrome
description: >
RHYNS syndrome is a TMEM67 ciliopathy, and it is worth being explicit that this was not
known when the syndrome was named. The acronym was coined in 1997 from a single
17-year-old boy with retinitis pigmentosa, hypopituitarism, nephronophthisis and mild
skeletal dysplasia; two affected brothers were reported in 2001; the genetic basis stayed
unknown for twenty-one years, until exome sequencing of the original family found
compound heterozygous TMEM67 variants in 2018. Everything mechanistic in this entry is
therefore inference from TMEM67 biology onto a four-patient clinical description, and the
entry is built to make that visible rather than to smooth it over.
TMEM67 encodes meckelin, a transmembrane protein of the ciliary transition zone. Its
allelic series is one of the widest in the ciliopathies - the report identifying RHYNS
describes it as extending to eight distinguishable clinical conditions, from early
lethality in Meckel-Gruber syndrome to adults with isolated liver fibrosis - so RHYNS is
the mild end of a spectrum rather than a separate lesion. That is the strongest argument
for keeping it as its own entry: the four reported patients share a phenotype combination
that is unique within the series, and it is the combination, not any single feature, that
the diagnosis rests on.
The molecular account comes from mouse work rather than from patients. Meckelin is a
receptor for Wnt5a, required for phosphorylation of the non-canonical Wnt receptor ROR2,
with which it colocalises at the transition zone, and it normally represses Shh
signalling. Every element of that is Tmem67-knockout mouse or in vitro data. The mouse
reproduces the developmental abnormalities of severe TMEM67 ciliopathies rather than the
RHYNS phenotype, so a HUMAN_MODEL_MISMATCH discussion records the gap: no model carries
RHYNS-type hypomorphic alleles, and none has retinitis pigmentosa or hypopituitarism.
Two curation notes. Inheritance is autosomal recessive on the molecular evidence, but the
2001 report could not exclude X-linkage because all four known patients were male, and
that history is preserved because it explains why the syndrome sat in an ambiguous
nosological position for so long. And the skeletal phenotype is described as "mild" in
the index case and "acromelic" in the brothers, which are not the same claim; both are
curated as reported.
disease_term:
preferred_term: RHYNS syndrome
term:
id: MONDO:0011202
label: RHYNS syndrome
parents:
- Ciliopathy
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Autosomal recessive, established molecularly by compound heterozygosity in the original
family: a paternally inherited nonsense allele and a maternally inherited missense allele.
Before the gene was known, recessive inheritance was inferred from two affected brothers,
with the caveat that X-linkage could not be excluded because all four reported patients
were male. The molecular finding resolves that in favour of autosomal recessive.
evidence:
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13."
explanation: >-
Biparental inheritance of two different TMEM67 alleles establishes autosomal recessive
inheritance directly.
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The presence of RHYNS in two siblings supports an autosomal recessive mode of inheritance; however, since all four known cases were male, an X-linked mode of inheritance cannot be excluded."
explanation: >-
The pre-molecular segregation argument, with its own stated limitation. Graded INDIRECT
because it infers the mode from sibship structure rather than from genotypes, and is
curated to preserve why the mode was uncertain for seventeen years.
genetic:
- name: TMEM67
gene_term:
preferred_term: TMEM67
term:
id: hgnc:28396
label: TMEM67
association: CAUSATIVE
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >
Biallelic TMEM67 variants, identified by whole-exome sequencing of the originally
described family. TMEM67 encodes meckelin, a ciliary transition zone protein, and carries
one of the widest allelic series in the ciliopathies; RHYNS was the eighth distinguishable
clinical condition attributed to it. The RHYNS genotype in the index family pairs a
truncating allele with a missense allele that acts through mis-splicing rather than
through amino acid substitution alone, which is consistent with a hypomorphic combination
at the mild end of the series.
variants:
- name: c.622A>T (p.Arg208*)
description: >-
Paternally inherited nonsense allele.
clinical_significance: PATHOGENIC
- name: c.1289A>G (p.Asp430Gly)
description: >-
Maternally inherited missense allele that perturbs correct splicing of exon 13, so its
consequence is a splicing defect rather than the substitution itself.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67."
explanation: >-
Establishes TMEM67 as the causative gene, in the family the syndrome was defined from.
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome."
explanation: >-
Places RHYNS within the TMEM67 allelic series and states its breadth, which is the basis
for treating RHYNS as the mild end of a spectrum.
- reference: PMID:28719906
reference_title: "A Common Ancestral Asn242Ser Mutation in TMEM67 Identified in Multiple Iranian Families with Joubert Syndrome."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families"
explanation: >-
Demonstrates that a single TMEM67 allele can recur across many families as a founder
mutation. Graded INDIRECT because those families have Joubert syndrome rather than RHYNS,
and the relevance is to the allelic series rather than to this phenotype.
- name: Oligogenic contribution from other ciliopathy genes
association: MODIFIER
relationship_type: MODIFIER
variant_origin: GERMLINE
features: >
An open possibility rather than a finding in RHYNS. Oligogenic inheritance is documented in
the transition zone ciliopathies, where a second variant in another ciliopathy gene has
been proposed to modify the phenotype. That is relevant here because the entry's central
inference is that the RHYNS genotype sits at the hypomorphic end of the TMEM67 series, and
a modifier is one of the ways a genotype ends up there. No second-locus variant has been
reported in a RHYNS patient; the original family was solved by exome sequencing, which
would have had the opportunity to find one.
evidence:
- reference: PMID:21493627
reference_title: "B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The fetus inherited an additional likely pathogenic novel missense change to a second MKS gene, CEP290; p.R2210C, suggesting oligogenic inheritance in this disorder."
explanation: >-
Documents oligogenic inheritance in a transition zone ciliopathy. Graded INDIRECT because
the case is Meckel syndrome with B9D1 and CEP290 rather than RHYNS with TMEM67; it
establishes the possibility, not its occurrence here.
pathophysiology:
- name: Biallelic Loss of Meckelin Function
biological_scale: MOLECULAR
description: >
Compound heterozygosity for a truncating and a mis-splicing TMEM67 allele reduces
functional meckelin. The residual function matters for this entry: the same gene null
gives early lethality, so the RHYNS phenotype implies a hypomorphic combination rather
than complete loss, which is an inference from the allelic series rather than a measured
property of these alleles.
genetic_context:
gene:
preferred_term: TMEM67
term:
id: hgnc:28396
label: TMEM67
allele_type: SNV
variant_origin: GERMLINE
zygosity: COMPOUND_HETEROZYGOUS
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
description: >-
One nonsense and one mis-splicing missense allele. Scored as partial loss of function on
the reasoning that complete loss produces a lethal phenotype in the same allelic series;
this has not been measured for these alleles.
cellular_components:
- preferred_term: ciliary transition zone
term:
id: GO:0035869
label: ciliary transition zone
downstream:
- target: Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
causal_link_type: DIRECT
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium."
explanation: >-
Establishes that loss of meckelin function directly abolishes ROR2 phosphorylation, which
is the causal step this edge asserts.
- target: Loss of Shh Repression
causal_link_type: DIRECT
evidence:
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67."
explanation: >-
Establishes the biallelic TMEM67 genotype that this node describes.
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone."
explanation: >-
Locates meckelin at the ciliary transition zone with its signalling partner, the cellular
component annotated on this node.
- name: Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
biological_scale: MOLECULAR
description: >
Meckelin is a receptor for Wnt5a, binding it through its extracellular N-terminal domain,
and is required for ROR2 phosphorylation on Wnt5a stimulation. Loss of meckelin therefore
breaks the Wnt5a-TMEM67-ROR2 axis. The evidence is entirely mouse and in vitro; there is
no patient-derived demonstration of this step in RHYNS or in any other TMEM67 phenotype.
biological_processes:
- preferred_term: non-canonical Wnt signaling pathway
term:
id: GO:0035567
label: non-canonical Wnt signaling pathway
modifier: DECREASED
- preferred_term: protein phosphorylation
term:
id: GO:0006468
label: protein phosphorylation
modifier: DECREASED
downstream:
- target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
causal_link_type: DIRECT
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a."
explanation: >-
Shows the signalling failure produces the morphogenetic defect in the same system, which
is the causal step this edge asserts.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay."
explanation: >-
Establishes direct Wnt5a binding by meckelin, the receptor role this node describes.
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling."
explanation: >-
The authors' summary of meckelin's role, stated as a proposal, which is the epistemic status
this node carries.
- name: Loss of Shh Repression
biological_scale: MOLECULAR
description: >
Meckelin normally represses Shh signalling, so its loss de-represses that pathway. In the
severe end of the TMEM67 series the neurological phenotype is instead associated with
diminished Shh signalling alongside de-regulated canonical Wnt, so the direction of the
Shh disturbance is not uniform across the allelic series. This node records the
de-repression claim and the discussion below records the inconsistency rather than
picking one.
biological_processes:
- preferred_term: smoothened signaling pathway
term:
id: GO:0007224
label: smoothened signaling pathway
modifier: INCREASED
downstream:
- target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Anterior Pituitary Hormone Deficiency
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung."
explanation: >-
Establishes that the intact Wnt5a-meckelin axis inhibits Shh, so its loss de-represses Shh.
- reference: PMID:23283079
reference_title: "Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects."
supports: REFUTE
evidence_source: MODEL_ORGANISM
snippet: "An MKS-like incipient congenic group (F6 to F10) manifested very variable neurological features (including exencephaly, and frontal/occipital encephalocele) that were associated with the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube"
explanation: >-
Graded REFUTE against the de-repression direction: in TMEM67-mutant mice on a different
background the neurological phenotype is associated with *diminished* Shh signalling. Both
are curated so the node does not assert a single direction the literature does not support.
- name: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
biological_scale: TISSUE
description: >
Tmem67-knockout mice show basal body and kinocilium positioning defects with the basal
body complex uncoupled from the hair bundle, together with failed epithelial branching
morphogenesis, pulmonary hypoplasia, axial shortening and limb abnormalities. Notably,
planar cell polarity and apical planar asymmetry in the organ of Corti were normal, so the
defect is basal body migration rather than polarity establishment. None of this
corresponds to the RHYNS phenotype, which is the point of the model mismatch recorded
below; it is the developmental mechanism the gene is known to serve.
biological_processes:
- preferred_term: branching morphogenesis of an epithelial tube
term:
id: GO:0048754
label: branching morphogenesis of an epithelial tube
modifier: DECREASED
downstream:
- target: Progressive Renal Tubulointerstitial Disease
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Skeletal dysplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Photoreceptor Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal."
explanation: >-
Reports the basal body positioning defect and, importantly, that planar cell polarity is
spared, which is what localises the lesion to basal body migration.
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects."
explanation: >-
Lists the developmental abnormalities recorded on this node.
- name: Photoreceptor Degeneration
biological_scale: TISSUE
description: >
Retinal photoreceptor degeneration giving retinitis pigmentosa, present in all four
reported patients and the first letter of the acronym. The mechanism is assumed rather
than shown: the photoreceptor connecting cilium is a specialised transition zone, which is
where meckelin sits, so a transition zone defect is the obvious candidate route. No source
curated here demonstrates it in TMEM67 disease.
What the sources do show cuts the other way and makes this node the most anomalous thing in
the entry. In a prospectively evaluated cohort of 100 patients with Joubert syndrome and
related disorders, retinal degeneration was *absent* in TMEM67 patients as a
genotype-phenotype correlation. So retinitis pigmentosa is not merely unexplained in RHYNS,
it runs against the established pattern for the gene, which is recorded as a knowledge gap
below and which strengthens rather than weakens the case for RHYNS as a distinct entity.
cell_types:
- preferred_term: photoreceptor cell
term:
id: CL:0000210
label: photoreceptor cell
downstream:
- target: Retinitis pigmentosa
causal_link_type: DIRECT
evidence:
- reference: PMID:28125082
reference_title: "Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants."
explanation: >-
Graded REFUTE against the expectation that a TMEM67 defect produces retinal degeneration:
across 100 prospectively evaluated patients, retinal degeneration was absent in the TMEM67
genotype group. This node exists because RHYNS patients have retinitis pigmentosa anyway,
and the contradiction is the point.
- reference: PMID:28125082
reference_title: "Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "TMEM67 was frequently associated with kidney disease."
explanation: >-
Corroborates the renal limb of the phenotype as typical for the gene, which is the contrast
that makes the retinal limb atypical. Graded INDIRECT because the cohort is Joubert syndrome
and related disorders rather than RHYNS.
- name: Progressive Renal Tubulointerstitial Disease
biological_scale: TISSUE
description: >
Nephronophthisis, the ciliopathy renal lesion: a tubulointerstitial disease presenting
insidiously with polyuria, polydipsia, anaemia and growth failure, and progressing to
end-stage renal disease during childhood. It is the feature that dominates prognosis in
the reported patients. The clinical course quoted here is from the nephronophthisis
literature in Joubert-related syndromes rather than from RHYNS patients, of whom there
are too few to describe a course.
locations:
- preferred_term: kidney
term:
id: UBERON:0002113
label: kidney
downstream:
- target: Nephronophthisis
causal_link_type: DIRECT
- target: Stage 5 chronic kidney disease
causal_link_type: DIRECT
evidence:
- reference: PMID:15384098
reference_title: "Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure"
explanation: >-
Gives the clinical course of nephronophthisis in Joubert-related cerebello-oculo-renal
syndromes. Graded INDIRECT because the cohort is not RHYNS; it is cited for the natural
history of the shared renal lesion.
- name: Anterior Pituitary Hormone Deficiency
biological_scale: ORGANISM
description: >
Hypopituitarism, with growth hormone deficiency in all reported patients and additional
TSH deficiency in the index case. This is the feature that distinguishes RHYNS within the
TMEM67 series, and it is also the one with no mechanistic account at all: no TMEM67 model
has a pituitary phenotype, and the entry does not offer a mechanism it cannot source.
downstream:
- target: Hypopituitarism
causal_link_type: DIRECT
- target: Secondary growth hormone deficiency
causal_link_type: DIRECT
- target: Hypothyroidism
causal_link_type: DIRECT
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports combined growth hormone and TSH deficiency in the index patient, the pituitary
involvement this node records.
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia."
explanation: >-
Confirms growth hormone deficiency in the two familial cases.
phenotypes:
- category: Ophthalmologic
name: Retinitis pigmentosa
description: >
Retinitis pigmentosa, present in all four reported patients and the first letter of the
acronym.
phenotype_term:
preferred_term: Retinitis pigmentosa
term:
id: HP:0000510
label: Rod-cone dystrophy
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia."
explanation: >-
Reports retinitis pigmentosa in the two familial cases.
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports retinitis pigmentosa in the index patient.
- category: Renal
name: Nephronophthisis
description: >
Nephronophthisis in the index patient. Note it is not documented in the two brothers,
whose report lists retinitis pigmentosa, growth hormone deficiency and skeletal dysplasia
only, so the feature is not established as universal despite being in the acronym.
phenotype_term:
preferred_term: Nephronophthisis
term:
id: HP:0000090
label: Nephronophthisis
diagnostic: true
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports nephronophthisis in the index patient.
- category: Renal
name: Stage 5 chronic kidney disease
description: >
End-stage renal disease, the expected endpoint of nephronophthisis during childhood.
Cited from the Joubert-related nephronophthisis literature rather than from RHYNS
patients.
phenotype_term:
preferred_term: Stage 5 chronic kidney disease
term:
id: HP:0003774
label: Stage 5 chronic kidney disease
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15384098
reference_title: "Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure"
explanation: >-
Establishes childhood end-stage renal disease as the course of nephronophthisis in
Joubert-related syndromes. Graded INDIRECT because the cohort is not RHYNS.
- category: Endocrine
name: Hypopituitarism
description: >
Anterior pituitary hormone deficiency, growth hormone in all patients and TSH in the
index case.
phenotype_term:
preferred_term: Hypopituitarism
term:
id: HP:0040075
label: Hypopituitarism
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports combined growth hormone and TSH deficiency, which is hypopituitarism.
- category: Endocrine
name: Secondary growth hormone deficiency
description: >
Growth hormone deficiency of pituitary origin, reported in all four patients.
phenotype_term:
preferred_term: Growth hormone deficiency
term:
id: HP:0008240
label: Secondary growth hormone deficiency
frequency: VERY_FREQUENT
evidence:
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia."
explanation: >-
Reports growth hormone deficiency in the two familial cases.
- category: Endocrine
name: Hypothyroidism
description: >
TSH deficiency in the index patient, that is central rather than primary hypothyroidism.
Reported in one of four patients.
phenotype_term:
preferred_term: Hypothyroidism
term:
id: HP:0000821
label: Hypothyroidism
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports TSH deficiency in the index patient.
- category: Skeletal
name: Skeletal dysplasia
description: >
Skeletal dysplasia, described as mild in the index patient and acromelic in the two
brothers. Those are different descriptions and are curated as reported rather than
reconciled; with four patients there is no basis for deciding which characterises the
syndrome.
phenotype_term:
preferred_term: Skeletal dysplasia
term:
id: HP:0002652
label: Skeletal dysplasia
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports mild skeletal dysplasia in the index patient.
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia."
explanation: >-
Reports acromelic skeletal dysplasia in the familial cases, a different description from
the index patient's.
- category: Auditory
name: Conductive hearing impairment
description: >
Transmissive, that is conductive, deafness in the index patient. Reported in one of four.
phenotype_term:
preferred_term: Conductive hearing impairment
term:
id: HP:0000405
label: Conductive hearing impairment
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports transmissive deafness in the index patient.
- category: Ophthalmologic
name: Ptosis
phenotype_term:
preferred_term: Ptosis
term:
id: HP:0000508
label: Ptosis
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports left upper eyelid ptosis in the index patient.
- category: Ophthalmologic
name: Enophthalmos
phenotype_term:
preferred_term: Enophthalmos
term:
id: HP:0000490
label: Deeply set eye
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Reports enophthalmos in the index patient. HPO has no distinct Enophthalmos term; the
concept is a synonym of Deeply set eye.
animal_models:
- name: Tmem67 knockout mouse (Tmem67 tm1Dgen/H1)
species: Mouse
genotype: Tmem67(tm1Dgen/H1) knockout
publication: PMID:26035863
description: >
A Tmem67-null mouse whose multi-organ developmental abnormalities closely resemble those
of Wnt5a and Ror2 knockouts, which is the observation that identified meckelin as a
Wnt5a-ROR2 axis component. It is the source of essentially the whole molecular account in
this entry, and it models severe TMEM67 ciliopathy rather than RHYNS.
modeled_mechanisms:
- target: Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Establishes the Wnt5a-TMEM67-ROR2 axis: meckelin binds Wnt5a, is required for ROR2
phosphorylation, and colocalises with ROR2 at the transition zone.
limitations: >-
A null allele, whereas the RHYNS genotype is a truncating plus mis-splicing combination
inferred to be hypomorphic. The signalling claim is about the gene rather than about these
alleles.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice."
explanation: >-
The phenotypic convergence with Wnt5a and Ror2 nulls is what makes this model informative
for the signalling node.
- target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Reproduces basal body and kinocilium positioning defects and failed Wnt5a-stimulated
epithelial branching.
limitations: >-
The organs affected are lung, heart, axial skeleton, limb and cochlea. The mouse has no
retinitis pigmentosa, no hypopituitarism and no nephronophthisis, so it does not model the
RHYNS phenotype.
readouts:
- name: Basal body and kinocilium coupling to the hair bundle
target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
direction: ALTERED
interpretation: Structural correlate of the basal body migration defect on this node.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal."
explanation: >-
Reports the measurement and, by the polarity control, what it is not.
- name: Wnt5a-stimulated epithelial branching in cultured lung
target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
direction: ABOLISHED
interpretation: Functional readout of the morphogenetic failure downstream of the signalling defect.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a."
explanation: >-
Reports the abolished branching response that grounds this readout.
- target: Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
relationship: RESCUES
fidelity: MODERATE
description: >-
Activating RhoA, downstream of the Wnt5a-TMEM67-ROR2 axis, rescued the pulmonary
hypoplasia phenotypes including loss of epithelial branching and cell polarity. This is
the causal test of the signalling model and the only intervention reported to reverse any
TMEM67 phenotype.
limitations: >-
Rescue is of the pulmonary phenotype in a mouse null, not of any RHYNS feature, and there
is no evidence bearing on whether a RhoA-directed intervention would affect retina,
pituitary or kidney.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA."
explanation: >-
Documents the rescue, which is what makes this a RESCUES link rather than a descriptive one.
evidence:
- reference: PMID:26035863
reference_title: "The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes."
explanation: >-
Establishes that the modelled gene is the human disease gene, which is the basis for
treating this model as informative at all.
treatments:
- name: Growth Hormone Replacement
description: >
Hormone replacement for the growth hormone deficiency, which is present in all four
reported patients and is one of only two treatable features of the syndrome. Note the
evidence status honestly: no RHYNS patient's response to growth hormone is reported in the
sources curated here. This record exists because the deficiency is documented and its
replacement is standard endocrine care, not because a treatment effect has been shown in
this disorder.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: recombinant growth hormone (somatropin)
term:
id: CHEBI:749556
label: somatropin
therapeutic_modality: PROTEIN_REPLACEMENT
target_mechanisms:
- target: Anterior Pituitary Hormone Deficiency
description: >-
Replaces the deficient hormone. It does not act on the ciliary lesion causing the
pituitary failure.
evidence:
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia."
explanation: >-
Documents the deficiency that this replacement addresses. Graded INDIRECT because it
reports the deficiency and not the response to replacement, which is not reported anywhere
in the sources curated here.
- name: Thyroid Hormone Replacement
description: >
Levothyroxine for the central hypothyroidism arising from TSH deficiency, reported in the
index patient. As with growth hormone, this is standard care for a documented deficiency
rather than a reported treatment effect in this syndrome. The distinction matters
clinically: because the hypothyroidism is central, thyroid function must be monitored on
free T4 rather than TSH.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: levothyroxine
term:
id: NCIT:C62080
label: Levothyroxine
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Anterior Pituitary Hormone Deficiency
description: >-
Replaces thyroid hormone downstream of the pituitary TSH deficiency.
evidence:
- reference: PMID:9375913
reference_title: "Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome?"
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia."
explanation: >-
Documents the TSH deficiency this replacement addresses. Graded INDIRECT for the same
reason as growth hormone: the deficiency is reported, the treatment response is not.
- name: Renal Replacement Therapy
description: >
Dialysis and transplantation for the end-stage renal disease that nephronophthisis
progresses to during childhood. This is the feature that dominates prognosis. The natural
history is taken from nephronophthisis in Joubert-related syndromes rather than from RHYNS
patients, of whom there are too few to describe a course.
treatment_term:
preferred_term: Kidney Transplantation
term:
id: NCIT:C15265
label: Kidney Transplantation
therapeutic_modality: SURGERY
target_mechanisms:
- target: Progressive Renal Tubulointerstitial Disease
description: >-
Replaces the failed organ. It does not alter the ciliary defect in the retina, pituitary
or skeleton.
evidence:
- reference: PMID:15384098
reference_title: "Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure"
explanation: >-
Establishes childhood end-stage renal disease as the course requiring renal replacement.
Graded INDIRECT because the cohort is Joubert-related cerebello-oculo-renal syndromes
rather than RHYNS.
diagnosis:
- name: Molecular diagnosis by exome sequencing or a ciliopathy gene panel
description: >
RHYNS is diagnosed clinically on the phenotype combination and confirmed molecularly by
finding biallelic TMEM67 variants. The genetic basis was unknown for twenty-one years and
was solved by whole-exome sequencing of the originally described family, which is the
practical point: a targeted single-gene approach would not have found it, because nobody
knew which gene to target. With four reported patients and a gene whose allelic series
spans eight clinical conditions, a broad ciliopathy panel or exome is the appropriate test
rather than a RHYNS-specific one.
evidence:
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67."
explanation: >-
Records the method by which the molecular diagnosis was established.
- reference: PMID:28125082
reference_title: "Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES)."
explanation: >-
Establishes panel-then-exome as the working diagnostic approach in TMEM67-related
ciliopathies. Graded INDIRECT because the cohort is Joubert syndrome and related disorders.
discussions:
- discussion_id: no_rhyns_model_exists
kind: HUMAN_MODEL_MISMATCH
prompt: >-
Does the Tmem67-null mouse bear on RHYNS syndrome, given that it has none of the four
defining features and carries a null rather than a hypomorphic genotype?
attaches_to:
- pathophysiology#Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
- pathophysiology#Disrupted Basal Body Positioning and Epithelial Branching Morphogenesis
- animal_models#Mouse
rationale: >
Every mechanistic node in this entry above the genotype is sourced from the Tmem67-null
mouse or from in vitro work with it. That mouse has pulmonary hypoplasia, ventricular
septal defects, axial shortening, limb abnormalities and cochlear defects. RHYNS is
retinitis pigmentosa, hypopituitarism, nephronophthisis and skeletal dysplasia. The only
shared element is a skeletal phenotype, and the mouse's is axial and limb while the
patients' is mild or acromelic. So the model supplies the gene's molecular function and
supplies nothing about how that function produces this phenotype. Compounding it, the
mouse is a null and the RHYNS genotype is inferred hypomorphic, which in an allelic series
where the null equivalent is lethal is precisely the difference that matters. Recorded as
HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the model evidence is strong on its
own terms; what is open is its translation.
proposed_experiments:
- experiment_id: rhyns_allele_knockin_mouse
name: Knock-in mouse carrying the RHYNS compound heterozygous genotype
description: >
Generate mice carrying the index family's alleles in trans - a Tmem67 nonsense allele
equivalent to p.Arg208* over a knock-in of the exon 13 mis-splicing allele - and
phenotype the retina, anterior pituitary and kidney specifically, against Tmem67-null and
wild-type littermates.
would_support:
- pathophysiology#Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
supporting_outcome:
- >-
Compound heterozygous mice are viable and develop retinal degeneration, reduced growth
hormone secretion and tubulointerstitial renal disease, while nulls die early, showing the
RHYNS phenotype is the hypomorphic expression of the same signalling lesion.
would_refute:
- pathophysiology#Failure of Wnt5a-ROR2 Non-canonical Wnt Signaling
refuting_outcome:
- >-
Compound heterozygous mice show the mouse null organ phenotypes at reduced severity with
no retinal, pituitary or renal involvement, which would mean the RHYNS organ selectivity is
not explained by dose along this axis and requires a species or modifier account.
- discussion_id: shh_direction_inconsistent
kind: KNOWLEDGE_GAP
prompt: >-
Is Shh signalling increased or decreased when meckelin is lost?
attaches_to:
- pathophysiology#Loss of Shh Repression
rationale: >
The two mouse datasets point opposite ways. Wnt5a inhibits Shh in wild-type embryonic lung,
so loss of the meckelin-dependent axis should de-repress Shh, and the authors state
meckelin normally represses Shh. But in TMEM67-mutant mice on an MKS-like congenic
background the neurological phenotype is associated with diminished Shh signalling
alongside de-regulated canonical Wnt. Both are the same gene in the same species, differing
in genetic background and in the organ examined, and neither study addresses the other. The
node carries the de-repression direction with a REFUTE item for the contrary result rather
than choosing, because for RHYNS specifically - where there is no tissue and no model -
there is no basis to choose.
- discussion_id: rp_anomalous_for_tmem67
kind: KNOWLEDGE_GAP
prompt: >-
Why do RHYNS patients have retinitis pigmentosa when retinal degeneration is characteristically
absent in TMEM67 disease?
attaches_to:
- pathophysiology#Photoreceptor Degeneration
- phenotypes#Retinitis pigmentosa
rationale: >
Retinitis pigmentosa is the first letter of the acronym and is present in all four reported
patients, so it is as defining as any feature of this syndrome. But a prospective
genotype-phenotype study of 100 patients with Joubert syndrome and related disorders found
retinal degeneration *absent* in the TMEM67 group specifically, while kidney disease was
frequent. So the renal limb of RHYNS is typical for the gene and the retinal limb runs
against it.
Three readings are open and nothing here separates them. The RHYNS alleles could act
differently on the photoreceptor connecting cilium, which is a specialised transition zone
and the obvious candidate site, than the alleles in the Joubert cohort. A modifier or a
second locus could contribute, which is why the oligogenic record exists in the genetic
section. Or the four RHYNS patients could be an ascertainment artefact, since a syndrome
named for its retinal feature will only ever be diagnosed in patients who have it.
This gap matters beyond mechanism: it is also the strongest argument that RHYNS is a
distinct entity within the TMEM67 series rather than a chance combination, because it is
the feature the series does not otherwise produce.
- discussion_id: pituitary_mechanism_absent
kind: KNOWLEDGE_GAP
prompt: >-
How does loss of meckelin produce anterior pituitary hormone deficiency?
attaches_to:
- pathophysiology#Anterior Pituitary Hormone Deficiency
rationale: >
Hypopituitarism is the feature that distinguishes RHYNS within the TMEM67 allelic series,
and it is the feature with no mechanistic account. No TMEM67 model reports a pituitary
phenotype, and the Wnt5a-ROR2 and Shh work does not extend to pituitary development. Growth
hormone deficiency does recur in ciliopathies with Joubert-related genes, which suggests a
shared ciliary requirement in the anterior pituitary, but nothing in the sources curated
here demonstrates one. The node deliberately asserts no mechanism.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Four patients in the literature: the 1997 index case, an earlier Italian patient the index
report treated as the same entity, and the two brothers reported in 2001. The 2018 report
that identified TMEM67 studied the original family and describes RHYNS as a rare syndrome
with a single reported familial case, so no larger series exists.
evidence:
- reference: PMID:29891882
reference_title: "Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance."
explanation: >-
Establishes the reported case count and that only one familial case exists.
- reference: PMID:11391657
reference_title: "Retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia in two brothers: possible familial RHYNS syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The presence of RHYNS in two siblings supports an autosomal recessive mode of inheritance; however, since all four known cases were male, an X-linked mode of inheritance cannot be excluded."
explanation: >-
States that four cases were known as of 2001, the basis for this count.
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: RHYNS Syndrome (TMEM67 ciliopathy) · 2026-09-03T16:04:58Z · View source
De novo curation of RHYNS syndrome (MONDO:0011202) as a Disease entry. entry_type DISEASE rather than a has_subtypes line on a TMEM67 or Joubert entry: RHYNS is the eighth distinguishable clinical condition in the TMEM67 allelic series and its four reported patients share a phenotype combination that is unique within that series, but the entry is explicit that it is the mild end of a spectrum rather than a separate lesion. Correction to my own claim issue: I wrote in issue #10715 that RHYNS is attributed to TBC1D32. That is wrong. PMID:29891882 identified biallelic TMEM67 (meckelin) variants by exome sequencing of the originally described family, and TMEM67 is what this entry curates. The error was mine, from memory, and was caught by fetching the primary report before writing anything. Deep research: one openscientist run (research/RHYNS_Syndrome-deep-research-openscientist.md). It shipped with no reference_validation and no term_validation block, like three of the five runs in this batch; term validation aborted on a 5-second EBI OLS read timeout on CL:0000210. This is dismech#10396, where I commented with the batch-wide reproduction and then corrected my own count. The reference section was retro-fitted with just validate-research-reference and is worth reading: 27/27 references resolved, 20 of 27 on topic, 1 off topic (PMID:32156598, a prostate cancer TACC3 paper sharing only the term 'meckelin'; not used), and 16 of 19 quoted claims found in source with all three failures being ellipsis or paraphrase near-misses rather than confabulations. Used from the report: PMID:26035863 (Tmem67 knockout mouse establishing meckelin as a Wnt5a receptor required for ROR2 phosphorylation at the ciliary transition zone, and the RhoA rescue), PMID:23283079 (TMEM67-mutant mice on an MKS-like congenic background showing diminished Shh signalling), PMID:15384098 (natural history of nephronophthisis in Joubert-related cerebello-oculo-renal syndromes) and PMID:28719906 (TMEM67 p.Asn242Ser founder allele in 22 affected members of 12 Iranian families). Three things this entry is deliberately careful about. First, every mechanistic node above the genotype is mouse or in vitro data, and a HUMAN_MODEL_MISMATCH discussion records that the Tmem67-null mouse shares no defining RHYNS feature and carries a null where the RHYNS genotype is inferred hypomorphic; a proposed knock-in experiment specifies the test with both outcomes. Second, the Shh direction is contradictory across two mouse datasets, so the node carries the de-repression direction with a REFUTE evidence item for the contrary result rather than choosing; a KNOWLEDGE_GAP discussion explains why there is no basis to choose for RHYNS specifically. Third, hypopituitarism is the feature that distinguishes RHYNS within the series and has no mechanistic account at all, so its node asserts none and a third discussion records that. Phenotype-level honesty notes carried in the entry: nephronophthisis is in the acronym but is documented only in the index patient, not in the two brothers; and the skeletal phenotype is 'mild' in the index case and 'acromelic' in the brothers, which are curated as reported rather than reconciled. Ontology notes: HPO has no distinct Retinitis pigmentosa or Enophthalmos term, so those bind HP:0000510 (Rod-cone dystrophy) and HP:0000490 (Deeply set eye) with the clinical name in preferred_term, both being exact synonyms. Growth hormone deficiency binds HP:0008240 (Secondary growth hormone deficiency) because the deficiency is pituitary in origin. Validation: just validate passes; 37/37 snippets verified. check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-snippet-grading and check-title-snippets all pass.
RHYNS syndrome is a Mendelian, autosomal recessive ciliopathy characterized by the tetrad of Retinitis pigmentosa, HYpopituitarism, Nephronophthisis, and Skeletal dysplasia. The disease was proposed as "a new syndrome" by Di Rocco and colleagues in 1997 based on a single 17-year-old boy presenting with nephronophthisis, retinitis pigmentosa, left upper-eyelid ptosis, enophthalmos, transmissive (conductive) deafness, growth-hormone (GH) and thyroid-stimulating-hormone (TSH) deficiency, and mild skeletal dysplasia (PMID: 9375913).
"We report on a 17 6/12-year-old boy with nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia." — PMID: 9375913
Key identifiers:
| Resource | Identifier |
|---|---|
| OMIM | 602152 (RHYNS SYNDROME) |
| MONDO | MONDO:0011202 |
| Orphanet | Ultra-rare; grouped with syndromic retinitis pigmentosa / ciliopathies |
| Causal gene | TMEM67 (OMIM 609884), 8q22.1 |
| MeSH | No dedicated descriptor; indexed under ciliopathies / retinitis pigmentosa |
Synonyms / alternative names: Retinitis pigmentosa–hypopituitarism–nephronophthisis–skeletal dysplasia syndrome; RHYNS. Given its molecular basis, RHYNS is best understood as a TMEM67-opathy at the mild end of the ciliopathy continuum.
Information source: This report is derived from aggregated disease-level resources (OMIM, primary case reports, and the broader TMEM67/Joubert/Meckel literature), not individual EHR data. The RHYNS phenotype itself is defined by only a small number of published patients.
Disease causal factors — genetic. RHYNS is caused by biallelic (recessive) variants in the ciliary gene TMEM67. Whole-exome sequencing of the originally described RHYNS family identified compound heterozygous TMEM67 variants: a paternally inherited nonsense variant c.622A>T, p.(Arg208*) and a maternally inherited missense variant c.1289A>G, p.(Asp430Gly), the latter perturbing correct splicing of exon 13 (PMID: 29891882). This confirmed the 1997 clinical hypothesis of autosomal recessive inheritance (PMID: 9375913).
"Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13." — PMID: 29891882
Genetic risk factors. The sole established causal factor is biallelic TMEM67 dysfunction. There are no reported common susceptibility loci or GWAS signals — RHYNS is fully Mendelian. Consanguinity and founder effects increase the risk of homozygous TMEM67 genotypes in TMEM67-related disease generally; a recurrent founder missense variant p.Asn242Ser segregated across 22 affected members of 12 Iranian families with Joubert syndrome (PMID: 28719906).
Environmental risk factors, protective factors, and gene–environment interactions. None are established for RHYNS. As a monogenic developmental disorder, disease occurrence is determined by genotype rather than environmental exposure. No protective alleles or modifier-driven risk reduction have been reported. This category is not applicable in the conventional epidemiologic sense.
RHYNS is defined by four cardinal features plus additional craniofacial, sensory, and endocrine anomalies. Because the reported patient count is small, frequencies are qualitative and drawn from the index case (PMID: 9375913) and the first familial cases (two brothers; PMID: 11391657).
| Phenotype | Type | HPO term (suggested) | Onset / progression | Frequency |
|---|---|---|---|---|
| Retinitis pigmentosa | Clinical sign / lab (ERG) | HP:0000510 | Childhood-onset, progressive | Cardinal (all cases) |
| Hypopituitarism (GH + TSH deficiency) | Lab abnormality | HP:0000871 (hypopituitarism); HP:0000824 (hypothyroidism) | Childhood; progressive growth failure | Cardinal |
| Nephronophthisis / ESRD | Clinical sign / lab | HP:0000090 | Insidious, childhood → ESRD | Cardinal |
| Skeletal dysplasia (acromelic) | Physical manifestation | HP:0002652; HP:0009826 (acromelia) | Congenital/childhood | Cardinal |
| Ptosis (left upper eyelid) | Physical sign | HP:0000508 | Congenital | Index case |
| Enophthalmos | Physical sign | HP:0000490 | — | Index case |
| Conductive (transmissive) hearing loss | Clinical sign | HP:0000405 | Childhood | Index case |
| Short stature / growth failure | Physical manifestation | HP:0004322 | Childhood | Common (GH deficiency) |
The index patient was a 17-year-old boy with "nephronophthisis, retinitis pigmentosa, left upper eyelid ptosis, enopthalmos, transmissive deafness, GH and TSH deficiency, and mild skeletal dysplasia" (PMID: 9375913). The two familial cases had "retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia" (PMID: 11391657):
"Here we report two brothers with retinitis pigmentosa, growth hormone deficiency, and acromelic skeletal dysplasia. We propose that their clinical picture is consistent with RHYNS syndrome." — PMID: 11391657
RHYNS is cited in recent reviews as a bona fide ciliopathy cause of syndromic retinitis pigmentosa, distinct from the more common Usher and Bardet-Biedl syndromes:
"Less common ciliopathies include Cohen syndrome, Joubert syndrome, cranioectodermal dysplasia, asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, and RHYNS syndrome." — PMID: 39733931
Quality-of-life impact. Progressive visual loss (RP), end-stage renal disease requiring dialysis/transplant, short stature and endocrine dysfunction, and hearing impairment each impose a substantial daily-functioning burden. Disease-specific QoL instruments have not been applied to this ultra-rare condition; impact is inferred from the component disorders.
Causal gene: TMEM67 (transmembrane protein 67; encodes meckelin), OMIM 609884, located at 8q22.1. Biallelic variants cause RHYNS (PMID: 29891882).
Pathogenic variants in the index RHYNS family:
| Variant (cDNA) | Protein | Type | Inheritance | Functional consequence |
|---|---|---|---|---|
| c.622A>T | p.(Arg208*) | Nonsense | Paternal | Loss of function (truncation) |
| c.1289A>G | p.(Asp430Gly) | Missense | Maternal | Disrupts splicing of exon 13 |
Both variants act via loss of function. In the broader TMEM67 spectrum, variant classification per ACMG/AMP ranges from pathogenic nonsense/frameshift (e.g., c.296delA p.Lys99SerfsTer6, PMID: 38311563) to likely-pathogenic missense (e.g., c.1243G>A p.Val415Met, same report; c.1645C>T p.R549C in MKS3, PMID: 26191240). Variant types documented across TMEM67 disease include missense, nonsense, frameshift, and splice-altering changes; allele frequencies of pathogenic variants are rare/absent in gnomAD and population controls (e.g., c.1645C>T absent in 200 control chromosomes, PMID: 26191240). All are germline.
Allelic spectrum and genotype–phenotype associations. TMEM67 biallelic variants produce ≥8 distinguishable clinical conditions ranging from early-lethal Meckel-Gruber syndrome to adults with only liver fibrosis — one of the widest continua in ciliopathies (PMID: 29891882). Key correlations from large Joubert cohorts:
"Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease." — PMID: 28125082
Notably, RHYNS is distinguished within the TMEM67 spectrum by the presence of retinitis pigmentosa, which is comparatively uncommon in typical TMEM67-Joubert patients — highlighting variable expressivity.
Modifier genes. Ciliary transition-zone modules interact synergistically; e.g., TMEM218 physically interacts with TMEM67/meckelin, and reduced TMEM218 dosage interacts with the NPHP module (Nphp4) to modulate ciliopathy severity (PMID: 35137054). Oligogenic contributions (second-locus variants in other ciliopathy genes) can modify expressivity (PMID: 21493627).
Chromosomal abnormalities / epigenetics. No recurrent epigenetic mechanism is established. A notable structural mechanism producing homozygosity for a TMEM67 mutation is maternal uniparental disomy of chromosome 8 (upd(8)mat), reported as an unexpected cause of Meckel-Gruber syndrome (PMID: 28620746) — relevant to genetic counseling and recurrence-risk assessment.
RHYNS is a purely genetic monogenic disorder. There are no established environmental factors, lifestyle factors, or infectious agents contributing to its causation or triggering. This section is not applicable beyond noting that environmental modifiers of the component organ diseases (e.g., nephrotoxin avoidance in chronic kidney disease) are general clinical considerations rather than RHYNS-specific etiologic factors.
Biallelic TMEM67 LoF
│
Dysfunctional meckelin (ciliary transition zone)
│
Defective TZ gating / abnormal ciliogenesis
│
Failed Wnt5a–ROR2 non-canonical Wnt signalling
+ deregulated Shh & canonical Wnt/β-catenin
│
┌───────┼────────────────────────┐
▼ ▼ ▼
[4A] [4B] [4C, inferred]
Dev. Renal/hepatic Photoreceptor
patterning epithelial Wnt↑ connecting cilium
│ │ │
Skeletal Cystic tubulointerstitial Retinitis
dysplasia, fibrosis → NPHP → ESRD pigmentosa
craniofacial,
inner ear,
pituitary → hypopituitarism
Molecular pathways. The core lesion is in non-canonical Wnt (planar cell polarity) signalling via Wnt5a–ROR2, with meckelin essential for ROR2 phosphorylation:
"TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone." — PMID: 26035863
Downstream, Tmem67 loss produces "the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube… high de-regulated canonical Wnt/β-catenin signalling" (PMID: 23283079). Suggested pathway terms: Wnt signalling, Shh signalling, planar cell polarity.
Cellular processes. Ciliogenesis, ciliary transition-zone gating, basal-body positioning, epithelial branching morphogenesis, and cilium-dependent signal transduction. Meckelin is required for cilia-dependent Shh signalling and retinoic-acid-dependent neural differentiation in mouse embryonic stem cells:
"differentiating along the neuronal lineage activate the cilia-dependent sonic hedgehog signaling machinery, which is impaired in Meckelin knock-out cells." — PMID: 24613594
Protein dysfunction. Meckelin (TMEM67) is a transmembrane transition-zone protein; nonsense and splice-disrupting variants cause loss of function. Meckelin also interacts with filamin A, and disruption of the filamin A–meckelin interaction impairs primary cilium formation (PMID: 32156598).
Tissue-damage mechanisms. Chronic sclerosing tubulointerstitial nephropathy with cortico-medullary cysts (fibrosis) drives renal failure; photoreceptor degeneration drives retinal disease.
Suggested ontology terms. GO:0060271 (cilium assembly), GO:0035869 (ciliary transition zone), GO:0035567 (non-canonical Wnt signaling pathway), GO:0007224 (smoothened/Shh signaling); CL:0000210 (photoreceptor cell), CL:1000507 (kidney tubule cell); UBERON:0002113 (kidney), UBERON:0000970 (eye), UBERON:0000007 (pituitary gland).
Organ level (primary): - Kidney (UBERON:0002113) — nephronophthisis, cortico-medullary cysts, tubulointerstitial fibrosis, ESRD. - Eye / retina (UBERON:0000970 / UBERON:0000966) — retinitis pigmentosa; photoreceptor layer. - Pituitary gland / hypothalamic-pituitary axis (UBERON:0000007) — GH and TSH deficiency (hypopituitarism). - Skeleton (UBERON:0004288) — acromelic/mild skeletal dysplasia.
Secondary / additional involvement: Eyelid (ptosis), orbit (enophthalmos), inner/middle ear (conductive hearing loss). Within the broader TMEM67 spectrum, liver (fibrosis, ductal plate malformation) is frequently affected (PMID: 26092869).
Body systems: urinary/renal, visual/nervous, endocrine, skeletal, auditory.
Tissue and cell level: Ciliated epithelia are the common target — renal tubular epithelial cells, retinal photoreceptors (whose connecting cilium is a modified transition zone), and (inferred) pituitary/hypothalamic ciliated cells. Suggested CL terms: CL:0000210 (photoreceptor cell), CL:1000507 (kidney tubule cell).
Subcellular level: The primary cilium and specifically the ciliary transition zone (GO:0035869), plus the basal body (GO:0036064). Meckelin is a transmembrane protein of the ciliary membrane/transition zone.
Localization / lateralization: Kidney and retinal involvement are bilateral; ptosis in the index case was unilateral (left upper eyelid).
Onset. Childhood-onset and insidious. The nephronophthisis component "presents insidiously with polyuria, polydipsia, anemia and growth failure, progressing to end-stage renal disease during childhood" (PMID: 15384098). Skeletal dysplasia is congenital/early-childhood; RP and hypopituitarism manifest in childhood and progress.
"All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure. Decreased urinary concentrating ability and excessive sodium loss were the characteristic laboratory findings." — PMID: 15384098
Progression. Chronic, progressive, lifelong. Nephronophthisis advances to ESRD, typically in the first two decades. Retinitis pigmentosa is progressive. Within severe TMEM67 compound-heterozygous genotypes, kidney disease can present as early as neonatal ESRD (PMID: 28726664); RHYNS itself represents a milder, viable end of the spectrum with survival into adulthood (index case aged 17).
Critical periods. Childhood is the window for growth-hormone/thyroid replacement (to permit catch-up growth) and for renal-protective monitoring before ESRD. Prenatally, severe TMEM67 genotypes are detectable by ultrasound and molecular testing.
Epidemiology. RHYNS is ultra-rare — only a handful of patients have been reported (the 1997 index case and the two familial brothers). No formal prevalence/incidence figures exist. For context, nephronophthisis (the "N") is a leading monogenic cause of childhood ESRD, accounting for 7–20% of terminal renal failure in the first two decades of life (PMID: 3524015):
"Its frequency is reported to vary between 7 and 20% of all cases of terminal renal failure in childhood. Usually the onset is insidious, with polyuria, polydipsia and anaemia being the main clinical features." — PMID: 3524015
Inheritance. Autosomal recessive, confirmed by biallelic TMEM67 variants (PMID: 29891882). The first familial cases (two affected brothers) supported recessive inheritance, though the authors noted that because all four known cases were male at the time, an X-linked mode could not be formally excluded (PMID: 11391657); the subsequent TMEM67 discovery settled this as autosomal recessive.
Penetrance / expressivity. Biallelic TMEM67 loss is highly penetrant for ciliopathy, but expressivity is markedly variable — the same gene produces phenotypes from lethal Meckel-Gruber to adult liver-only disease. RHYNS occupies the mild/viable pole.
Founder effects / consanguinity. Consanguinity increases homozygous-genotype risk. A founder p.Asn242Ser variant was identified across 22 affected members of 12 Iranian Joubert families:
"confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. We propose that Asn242Ser is a founder mutation." — PMID: 28719906
Uniparental disomy (upd(8)mat) is a rare non-Mendelian route to homozygosity (PMID: 28620746).
Demographics. No established ethnic predilection specific to RHYNS. Reported cases have been male, but the small number precludes conclusions about sex ratio; autosomal recessive inheritance predicts an equal sex distribution.
Clinical/laboratory tests. - Renal: decreased urinary concentrating ability, excessive sodium (salt) loss, anemia, rising creatinine; renal ultrasound showing normal-to-small kidneys with increased echogenicity and cortico-medullary cysts; renal biopsy showing chronic sclerosing tubulointerstitial nephropathy (PMID: 15384098; PMID: 3524015). - Endocrine: provocative GH testing, IGF-1, TSH/free T4 confirming GH and TSH deficiency; pituitary MRI (may show hypoplasia / stalk abnormalities, by analogy to pituitary stalk interruption syndrome — a ciliary-signalling-related developmental defect, PMID: 34238482). - Ophthalmologic: electroretinography (ERG) showing rod-cone dysfunction, fundoscopy with pigmentary retinopathy, OCT. - Auditory: audiometry (conductive hearing loss). - Skeletal: radiographic skeletal survey (acromelic dysplasia).
Genetic testing (definitive). Molecular confirmation via whole-exome sequencing or ciliopathy/nephronophthisis gene panels including TMEM67; single-gene TMEM67 testing where phenotype is highly suggestive. WES identified the causal variants in the index RHYNS family (PMID: 29891882). Chromosomal microarray may be added; note UPD(8) can be detected by SNP array (PMID: 28620746). Genetic diagnosis is "essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations" (PMID: 28125082).
Differential diagnosis. Other syndromic RP/ciliopathies: Senior-Løken syndrome (nephronophthisis + retinal dystrophy, e.g., IQCB1/NPHP5, PMID: 41316455), Joubert syndrome (molar-tooth sign), Bardet-Biedl syndrome, Alström syndrome, and other nephronophthisis-related ciliopathies. The distinguishing feature of RHYNS is the combination of hypopituitarism + skeletal dysplasia with RP and NPHP.
Screening. Cascade testing of at-risk relatives once the familial TMEM67 variants are known; prenatal and preimplantation genetic diagnosis are available.
Survival/mortality. RHYNS is compatible with survival into adulthood (index case aged 17). The principal life-limiting complication is end-stage renal disease from nephronophthisis, which without renal replacement is fatal. There are no cohort-derived survival statistics for RHYNS specifically.
Morbidity/function. Substantial: progressive blindness (RP), dialysis dependence or transplant, short stature and endocrine dysfunction, hearing impairment. Quality of life is affected across visual, renal, growth, and auditory domains.
Disease course and complications. Chronic and progressive. Renal transplantation is definitive for the renal component (see Treatment). Within fibrocystic liver-kidney disease broadly, catch-up growth has been observed after transplantation (PMID: 22360404).
Prognostic factors. Severity of the TMEM67 genotype (truncating vs. hypomorphic missense) correlates with overall disease severity across the allelic spectrum; earlier ESRD onset (even neonatal in severe compound-heterozygotes, PMID: 28726664) portends worse renal prognosis. Timeliness of hormone replacement affects growth outcome.
No disease-modifying or gene-targeted therapy exists. Management is multidisciplinary, supportive, and organ-directed (PMID: 28125082).
| Organ system | Intervention | NCIT (suggested) |
|---|---|---|
| Kidney (ESRD) | Dialysis; kidney transplantation (definitive) | NCIT:C15366 (Kidney Transplantation); NCIT:C15248 (Dialysis) |
| Endocrine | Growth hormone replacement; thyroid hormone (levothyroxine) replacement | NCIT:C1301 (Recombinant Human GH); NCIT:C29171 (Levothyroxine) |
| Eye (RP) | Low-vision aids, ophthalmologic surveillance; nutritional support explored in ciliopathy RP | NCIT:C15277 (Supportive Care) |
| Hearing | Hearing aids / audiologic support | — |
Kidney transplantation is a turning point in nephronophthisis-related ciliopathy:
"kidney transplant is a turning point" — PMID: 42538694
Critically, nephronophthisis does not recur in the renal allograft because it is an intrinsic tubular disease, making transplantation effectively curative for the renal component. Pediatric outcomes for fibrocystic liver-kidney disease show a median age at first transplant of 9.7 years with generally favorable graft survival (PMID: 25074681).
Hormone replacement for hypopituitarism (GH, thyroid hormone) treats the endocrine component and, with timely initiation, supports catch-up growth (catch-up growth after transplantation has been documented in fibrocystic disease, PMID: 22360404). Retinitis pigmentosa currently has no curative therapy; management is low-vision support and surveillance, with nutritional/adjunctive strategies under exploration in ciliopathy RP (PMID: 40642756).
Experimental / future therapeutics. No RHYNS-specific clinical trials. Gene-therapy and read-through approaches are conceptually relevant given the recessive loss-of-function mechanism but remain preclinical.
RHYNS cannot be prevented in the primary (public-health) sense — it is a monogenic congenital disorder. Prevention is reproductive and genetic:
Immunization and behavioral/environmental interventions are not applicable to disease causation.
TMEM67 is evolutionarily conserved; disease-relevant orthologs exist in mouse (Tmem67), zebrafish (tmem67), and sheep (TMEM67). The R549 meckelin residue is conserved "across human, rat, mouse, zebrafish, chicken, wolf and platypus genomes" (PMID: 26191240). A naturally occurring ovine (sheep) model carrying homozygous TMEM67 p.(Ile681Asn; Ile687Ser) missense mutations displays hepatorenal fibrocystic disease with dysmorphic primary cilia — the first large-animal natural model of a Meckel-like TMEM67 ciliopathy:
"Here we describe an ovine model of MKS, with kidney and liver abnormalities, without polydactyly or occipital encephalocoele. Homozygous missense p.(Ile681Asn; Ile687Ser) mutations identified in ovine TMEM67 were pathogenic in zebrafish phenotype rescue assays." — PMID: 28487520
This natural model has veterinary and comparative-pathology relevance, demonstrating evolutionary conservation of the transition-zone ciliary mechanism. There is no zoonotic potential (non-infectious genetic disease).
| Model | Type | Phenotype recapitulation | Reference |
|---|---|---|---|
| Tmem67-null mouse (bpck) | Mammalian knockout | Renal cystic disease, plus eye, skeletal, and inner-ear abnormalities; upregulated canonical Wnt in cyst linings/fibroblasts | PMID: 23393159 |
| Tmem67(tm1Dgen/H1) knockout mouse | Mammalian knockout | Pulmonary hypoplasia, ventricular septal defects, shortened body axis, limb abnormalities, basal-body/kinocilium mispositioning — phenocopies Wnt5a and Ror2 knockouts | PMID: 26035863 |
| Zebrafish tmem67 morphants | Vertebrate | MKS/ciliopathy phenotypes; used to validate variant pathogenicity in rescue assays | PMID: 23393159; PMID: 28487520 |
| Ovine (sheep) | Mammalian, natural | Hepatorenal fibrocystic disease, dysmorphic primary cilia | PMID: 28487520 |
| Mouse embryonic stem cells | In vitro / cellular | Impaired cilia-dependent Shh signalling; defective retinoic-acid-dependent neural differentiation | PMID: 24613594 |
"we analyzed phenotypes in the Tmem67 null mouse (bpck) and in zebrafish tmem67 morphants. Phenotypes similar to those in human MKS and other ciliopathy models were observed, with additional eye, skeletal and inner ear abnormalities characterized in the bpck mouse." — PMID: 23393159
Model limitations. These models capture the renal, skeletal, ocular, and inner-ear ciliopathy phenotypes and the Wnt/Shh mechanism, but no model has been reported that specifically recapitulates the hypopituitarism of RHYNS, and the RHYNS phenotype itself (mild/viable) differs from the more severe MKS end modeled by nulls. Resources: MGI (mouse), ZFIN (zebrafish).
RHYNS is best understood as one point on a continuum of TMEM67 transition-zone ciliopathy. A single molecular lesion — biallelic loss of meckelin at the ciliary transition zone — produces pleiotropic, multi-organ disease because the primary cilium is a signalling hub required in nearly every tissue. The unifying pathogenic node is failure of Wnt5a–ROR2 non-canonical Wnt signalling, with secondary deregulation of Shh and canonical Wnt/β-catenin. This branches into a developmental patterning program (skeletal dysplasia, craniofacial/inner-ear anomalies, and inferred pituitary maldevelopment) and an epithelial-maintenance program (fibrocystic nephronophthisis; photoreceptor degeneration).
What distinguishes RHYNS clinically from typical TMEM67-Joubert is its particular combination: retinitis pigmentosa is present (uncommon in most TMEM67 patients, where retinal degeneration is often absent, PMID: 28125082) alongside hypopituitarism and skeletal dysplasia, without the pathognomonic molar-tooth sign emphasized in Joubert. This underscores the variable expressivity that is the hallmark of TMEM67 disease. The specific compound-heterozygous genotype in the index family (a truncating p.Arg208* combined with a splice-perturbing hypomorphic p.Asp430Gly) likely produces a partial, tissue-modulated loss of function that lands the phenotype at the mild/viable end rather than at lethal Meckel-Gruber.
| PMID | Title (abbreviated) | Role |
|---|---|---|
| 29891882 | Biallelic TMEM67 variants cause RHYNS | Defines causal gene & variants; landmark |
| 9375913 | RHYNS: a new syndrome? | Original clinical description (tetrad) |
| 11391657 | Familial RHYNS in two brothers | Familial/AR evidence, expressivity |
| 26035863 | TMEM67 controls basal body positioning via non-canonical Wnt | Core mechanism (Wnt5a-ROR2) |
| 23283079 | Deregulated ciliogenesis, Shh & Wnt in ciliopathy spectrum | Downstream Shh/Wnt deregulation |
| 23393159 | Meckelin regulator of cilia function (bpck mouse, zebrafish) | Animal models; renal/eye/skeletal |
| 28487520 | Ovine hepatorenal fibrocystic TMEM67 model | Natural large-animal model |
| 24613594 | Meckelin required for Shh-dependent neural differentiation | Developmental patterning link |
| 28125082 | Joubert 100-patient genotype-phenotype | TMEM67 kidney/retina correlations; management |
| 26092869 | Joubert genetic heterogeneity review | TMEM67–liver fibrosis/coloboma |
| 28719906 | Founder Asn242Ser in Iranian families | Founder effect |
| 15384098 | Nephronophthisis in Joubert-related disorders | NPHP clinical/lab course |
| 3524015 | Familial juvenile nephronophthisis | NPHP epidemiology |
| 28726664 | Expanded TMEM67 phenotype (neonatal ESRD) | Severity spectrum |
| 42538694 | Kidney transplant in Joubert | Definitive renal management |
| 25074681 | Transplant in fibrocystic liver-kidney disease | Transplant outcomes |
| 39733931 | Syndromic retinitis pigmentosa | RHYNS recognized as ciliopathy |
| 28620746 | UPD(8) causing MKS | Non-Mendelian mechanism/counseling |
| 26191240 | TMEM67 missense causing MKS3 | Variant conservation/pathogenicity |
| 35137054 | TMEM218–NPHP module interaction | Modifier/oligogenic biology |
Report compiled from 8 confirmed findings and 35 reviewed papers across 5 investigation iterations. Evidence types: human clinical case reports and cohorts, model organism (mouse, zebrafish, sheep), and in vitro/cellular studies.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 27 |
| Resolved | 27 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 19 |
| Quoted claims found in source | 16 |
| Quoted claims not found in source | 3 |
| References weighed for topical relevance | 27 |
| On topic | 20 |
| Off topic | 1 |
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:
Every one 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:23283079 (abstract only): "the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube… high de-regulated canonical Wnt/β-catenin signalling"PMID:15384098 (abstract only): "presents insidiously with polyuria, polydipsia, anemia and growth failure, progressing to end-stage renal disease during childhood"PMID:28719906 (abstract only): "confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. We propose that Asn242Ser is a founder mutation."These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:32156598 (2 mentions) - TACC3 promotes prostate cancer cell proliferation and restrains primary cilium formation.Weighed against this report's own most characteristic terms: tmem67, rhyn, disease, renal, ciliopathy, nephronophthisis, pigmentosa, hypopituitarism, retinitis, skeletal, phenotype, variant, meckelin, kidney, loss, joubert, syndrome, dysplasia, ciliary, clinical.