Eiken syndrome (MIM #600002) is an ultra-rare autosomal recessive skeletal dysplasia caused by biallelic PTH1R variants. It is characterized by markedly delayed ossification, principally of the epiphyses, pubic bones, sacrum and the bones of the hands and feet, with abnormal bone modeling, brachydactyly, metacarpal pseudoepiphyses and in some patients failure of tooth eruption. Some families additionally show resistance to parathyroid hormone (PTH), with elevated PTH and, in a subset, hypocalcemia and hyperphosphatemia. The reported alleles (R485X in the C-terminal tail; E35K and Y134S in the extracellular domain; I237N and D241E in the second transmembrane helix) do not abolish receptor function. They alter it: increased basal cAMP signaling and impaired beta-arrestin recruitment and desensitization, which enhance PTHrP-driven signaling in growth plate chondrocytes and delay their hypertrophic differentiation, while PTH-dependent signaling in kidney is reduced. Eiken syndrome therefore sits between Blomstrand chondrodysplasia (biallelic loss of function, accelerated ossification) and Jansen metaphyseal chondrodysplasia (heterozygous constitutive activation) in the PTH1R allelic series.
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name: Eiken Syndrome
creation_date: "2026-09-24T19:20:38Z"
category: Mendelian
description: >
Eiken syndrome (MIM #600002) is an ultra-rare autosomal recessive skeletal
dysplasia caused by biallelic PTH1R variants. It is characterized by markedly
delayed ossification, principally of the epiphyses, pubic bones, sacrum and the
bones of the hands and feet, with abnormal bone modeling, brachydactyly,
metacarpal pseudoepiphyses and in some patients failure of tooth eruption.
Some families additionally show resistance to parathyroid hormone (PTH), with
elevated PTH and, in a subset, hypocalcemia and hyperphosphatemia. The
reported alleles (R485X in the C-terminal tail; E35K and Y134S in the
extracellular domain; I237N and D241E in the second transmembrane helix) do
not abolish receptor function. They alter it: increased basal cAMP signaling
and impaired beta-arrestin recruitment and desensitization, which enhance
PTHrP-driven signaling in growth plate chondrocytes and delay their
hypertrophic differentiation, while PTH-dependent signaling in kidney is
reduced. Eiken syndrome therefore sits between Blomstrand chondrodysplasia
(biallelic loss of function, accelerated ossification) and Jansen metaphyseal
chondrodysplasia (heterozygous constitutive activation) in the PTH1R allelic
series.
disease_term:
preferred_term: Eiken syndrome
term:
id: MONDO:0010803
label: Eiken syndrome
parents:
- Skeletal disorder of parathyroid hormone signaling
synonyms:
- Eiken skeletal dysplasia
- bone modeling defect of hands and feet
- bone modelling defect of hands and feet
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Affected individuals carry homozygous PTH1R variants, most often in
consanguineous families; heterozygous parents are unaffected.
evidence:
- reference: PMID:6734674
reference_title: "A new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones especially of the epiphyses, the hands, and feet."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Parental consanguinity suggest an autosomal recessive inheritance."
explanation: The original family of three affected brothers born to consanguineous parents.
- reference: PMID:15525660
reference_title: "Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Eiken syndrome is a rare autosomal recessive skeletal dysplasia."
explanation: States recessive inheritance in the study that identified the causal PTH1R variant.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Members of three consanguineous families carrying R485X, E35K and Y134S had
been described by 2023; further families with transmembrane-helix variants
(I237N, D241E) and PTH resistance were reported afterwards.
evidence:
- reference: PMID:37268817
reference_title: "Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "It has been described for members of three consanguineous families, in which the identified mutations are R485X7, E35K8 and Y134S9."
explanation: Counts the families reported at that time, establishing the disorder as ultra-rare.
genetic:
- name: PTH1R
gene_term:
preferred_term: PTH1R
term:
id: hgnc:9608
label: PTH1R
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: >-
Homozygous PTH1R variants: R485X (C-terminal tail truncation), E35K and
Y134S (N-terminal extracellular domain), I237N and D241E (second
transmembrane helix).
notes: >-
The variants alter rather than abolish receptor function: increased basal
cAMP signaling and impaired beta-arrestin2 recruitment and desensitization,
with ligand- and tissue-dependent gain- and loss-of-function effects.
evidence:
- reference: PMID:15525660
reference_title: "Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a truncation mutation in the C-terminal cytoplasmic tail of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) type 1 receptor (PTHR1) gene as the cause of this syndrome."
explanation: Identifies PTH1R as the causal gene in the original family.
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]."
explanation: A second, unrelated family with a homozygous PTH1R missense variant confirms the gene-disease relationship.
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain."
explanation: A further family with a homozygous transmembrane-helix PTH1R variant.
pathophysiology:
- name: Biallelic PTH1R Signaling Alteration
biological_scale: MOLECULAR
description: >
Homozygous PTH1R variants produce a receptor that is expressed and binds
ligand but signals abnormally. The R485X truncation removes the C-terminal
serine/threonine cluster that is phosphorylated on activation, increasing
basal cAMP signaling. The E35K and Y134S extracellular-domain variants
weaken PTHrP binding, and the I237N and D241E transmembrane-helix variants
raise basal cAMP signaling while blunting responses to PTH and PTHrP.
genetic_context:
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
description: >-
functional_impact_category is left unset: the reported alleles combine
increased basal signaling with reduced ligand-induced responses, and the
direction of the net effect depends on ligand and tissue.
gene:
preferred_term: PTH1R
term:
id: hgnc:9608
label: PTH1R
molecular_functions:
- preferred_term: PTH/PTHrP type 1 receptor activity
modifier: DYSREGULATED
term:
id: GO:0004991
label: parathyroid hormone receptor activity
evidence:
- reference: PMID:37268817
reference_title: "Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, using a variety of cell-based assays, we show that R485X increases the receptor's basal rate of cAMP signaling and decreases its capacity to recruit β-arrestin2 upon ligand stimulation."
explanation: Cell-based assays show the C-tail truncation raises basal cAMP signaling.
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "demonstrated increased basal cAMP signaling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands"
explanation: Transmembrane-helix variants show the same mixed profile of raised basal and blunted ligand-induced signaling.
downstream:
- target: Impaired Beta-Arrestin-Mediated PTH1R Desensitization
description: Loss of C-tail phosphorylation sites or weakened PTHrP binding reduces beta-arrestin2 recruitment to the receptor.
evidence:
- reference: PMID:37268817
reference_title: "Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The E35K and Y134S mutations each weaken the binding of PTHrP leading to impaired β-arrestin2 recruitment and desensitization of cAMP signaling response to PTHrP but not PTH."
explanation: Links the extracellular-domain variants to impaired beta-arrestin2 recruitment and desensitization.
- target: Renal Parathyroid Hormone Resistance
description: The same variants reduce PTH-dependent signaling in kidney.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Blood and urine analysis in 3-month-old WT and R485X mice showing reduced serum calcium and 1,25(OH)2D, elevated endogenous serum PTH, and reduced urinary cAMP (corrected for creatinine) in R485X mice compared to WT mice, indicating PTH resistance"
explanation: Humanized R485X knock-in mice show biochemical PTH resistance.
- target: Eruption failure
description: >-
Failure of tooth eruption is attributed to reduced PTHrP-dependent PTH1R
signaling in developing teeth, as in heterozygous PTH1R loss of function.
evidence:
- reference: PMID:40904804
reference_title: "Human diseases caused by homozygous PTH1R mutations."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "The other clinical manifestations of Eiken syndrome, however, such as the mild PTH resistance and PFTE, are more likely explained by a loss-of-function effect on PTH1R signaling responses in kidney and teeth, as mediated by PTH and PTHrP, respectively."
explanation: Review interpretation attributing failed tooth eruption to reduced PTH1R signaling in dental tissue.
- name: Impaired Beta-Arrestin-Mediated PTH1R Desensitization
biological_scale: MOLECULAR
description: >
Beta-arrestin binding to the activated, phosphorylated receptor normally
terminates PTHrP-induced signaling at the plasma membrane. In Eiken
mutants this desensitization is reduced, so PTHrP signaling is less
efficiently terminated.
biological_processes:
- preferred_term: desensitization of PTH1R signaling
modifier: DECREASED
term:
id: GO:0002029
label: desensitization of G protein-coupled receptor signaling pathway
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Mechanistic studies in cell-based assays and humanized R485X-PTH1R knock-in mice revealed that βarrestins dampen PTHrP-driven Gαs signaling at the plasma membrane but promote PTH-induced endosomal PTH1R signaling."
explanation: Establishes beta-arrestin as the brake on PTHrP signaling that the R485X truncation disrupts.
downstream:
- target: Enhanced PTHrP Signaling in Growth Plate Chondrocytes
description: With less desensitization, locally abundant PTHrP produces stronger cAMP signaling in growth plate chondrocytes.
evidence:
- reference: PMID:40904804
reference_title: "Human diseases caused by homozygous PTH1R mutations."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In fact, in the growth plates where local PTHrP levels are expected to be abundant, inefficient PTH1R desensitization is likely to enhance activation of the down-stream signaling pathway resulting in the delayed chondrocyte differentiation that underlies the mineralization defect in Eiken syndrome."
explanation: Review synthesis linking impaired desensitization to enhanced growth plate signaling.
- name: Enhanced PTHrP Signaling in Growth Plate Chondrocytes
biological_scale: CELLULAR
description: >
PTHrP acting through PTH1R in growth plate chondrocytes normally sustains
proliferation and delays hypertrophic differentiation. Enhanced signaling
in Eiken syndrome strengthens this brake.
cell_types:
- preferred_term: growth plate cartilage chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: PTH1R-Gs-cAMP signaling
modifier: INCREASED
term:
id: GO:0007189
label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
evidence:
- reference: PMID:40904804
reference_title: "Human diseases caused by homozygous PTH1R mutations."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The bone phenotype in most patients with Eiken syndrome (i.e., delayed ossification) points toward a gain-of-function effect on PTHrP/PTH1R-mediated signaling in the growth plate"
explanation: Review interpretation of the skeletal phenotype as increased PTHrP/PTH1R signaling in the growth plate.
downstream:
- target: Delayed Chondrocyte Hypertrophic Differentiation
description: Increased PTHrP/PTH1R signaling holds chondrocytes in the proliferative state and delays hypertrophy.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Delayed mineralization in R485X mice is rescued by conditional ablation of PTHrP in growth plate chondrocytes."
explanation: Removing chondrocyte PTHrP rescues the R485X skeletal defect, showing it depends on PTHrP signaling.
- reference: PMID:10912527
reference_title: "Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
snippet: "The mirror image of these skeletal findings, i.e., a severe delay in chondrocyte differentiation and endochondral ossification, is observed in transgenic mice that overexpress PTHrP under the control of the alpha1(II) procollagen promoter."
explanation: Excess chondrocyte PTHrP signaling delays chondrocyte differentiation, the same direction as Eiken syndrome.
- name: Delayed Chondrocyte Hypertrophic Differentiation
biological_scale: CELLULAR
description: >
Fewer growth plate chondrocytes reach the hypertrophic stage on schedule,
delaying the cartilage template's replacement by bone.
cell_types:
- preferred_term: hypertrophic chondrocyte
term:
id: CL:0000743
label: hypertrophic chondrocyte
locations:
- preferred_term: growth plate cartilage
term:
id: UBERON:0004129
label: growth plate cartilage
biological_processes:
- preferred_term: growth plate cartilage chondrocyte differentiation
modifier: DECREASED
term:
id: GO:0003418
label: growth plate cartilage chondrocyte differentiation
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RNAscope of tibial sections of embryonic day (E) 15.5 WT- and R485X-hPTH1R littermate mice showing reduced Col10-positive hypertrophic chondrocytes (red) in R485X mice."
explanation: R485X knock-in mice have fewer hypertrophic chondrocytes.
downstream:
- target: Delayed Endochondral Ossification
description: Delayed hypertrophy delays mineralization and ossification of the cartilage template.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Tibial histology sections of newborn (P0) WT- and R485X-hPTH1R littermate mice stained with von Kossa reagent to show reduced mineralized bone (black) in R485X mice."
explanation: The knock-in mice show reduced bone mineralization at birth.
- name: Delayed Endochondral Ossification
biological_scale: TISSUE
description: >
Ossification of bones formed by endochondral ossification is markedly
delayed, most prominently the epiphyses, pubic bones, sacrum and short
tubular bones of the hands and feet, and is accompanied by abnormal
modeling of these bones.
biological_processes:
- preferred_term: endochondral ossification
modifier: DECREASED
term:
id: GO:0001958
label: endochondral ossification
evidence:
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities."
explanation: Describes delayed ossification as the defining feature in patients.
downstream:
- target: Delayed epiphyseal ossification
- target: Delayed ossification of the hand bones
- target: Delayed pubic bone ossification
- target: Abnormal ossification of the sacrum
- target: Hypoplastic ischiopubic ramus
- target: Metacarpal pseudoepiphysis
description: >-
Pseudoepiphyses are part of the abnormal modeling of the short tubular
bones of the hand that accompanies their delayed ossification.
- target: Cone-shaped epiphysis
- target: Brachydactyly
- target: Abnormal trabecular bone morphology
description: >-
Coarse trabeculae are reported with delayed ossification and abnormal
modeling among the radiographic hallmarks; the edge records that
co-occurrence, not a demonstrated mechanistic step.
- target: Short stature
description: >-
Delayed endochondral ossification of the long and short tubular bones
limits linear growth.
- name: Renal Parathyroid Hormone Resistance
biological_scale: CELLULAR
description: >
Reduced PTH-dependent PTH1R signaling in renal proximal tubule cells
produces PTH resistance: elevated circulating PTH and, in some families,
hypocalcemia and hyperphosphatemia that resemble pseudohypoparathyroidism.
cell_types:
- preferred_term: epithelial cell of proximal tubule
term:
id: CL:0002306
label: epithelial cell of proximal tubule
biological_processes:
- preferred_term: cellular response to parathyroid hormone stimulus
modifier: DECREASED
term:
id: GO:0071374
label: cellular response to parathyroid hormone stimulus
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Patients with Eiken syndrome display delayed bone mineralization, consistent with enhanced PTHrP actions, as well as hypocalcemia along with elevated PTH, which paradoxically indicates impaired PTH function."
explanation: Summarizes the combination of enhanced PTHrP action in bone and impaired PTH action in patients.
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcemia and elevated serum phosphate levels."
explanation: Both I237N homozygous patients had clinical PTH resistance with hypocalcemia and hyperphosphatemia.
- reference: PMID:35846276
reference_title: "Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the absence of chronic kidney disease, these results were compatible with a diagnosis of PTH resistance."
explanation: In the D241E homozygous child, hypocalcemia, hyperphosphatemia and elevated PTH with normal renal function indicated PTH resistance.
downstream:
- target: Elevated circulating parathyroid hormone level
- target: Hypocalcemia
- target: Hyperphosphatemia
phenotypes:
- category: Skeletal
name: Delayed epiphyseal ossification
diagnostic: true
phenotype_term:
preferred_term: Delayed epiphyseal ossification
term:
id: HP:0002663
label: Delayed epiphyseal ossification
evidence:
- reference: PMID:6734674
reference_title: "A new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones especially of the epiphyses, the hands, and feet."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three brothers with a constitutional skeletal dysplasia characterized by an excessively retarded ossification, principally of the epiphyses, the pelvis, the hands and the feet, are reported."
explanation: Retarded epiphyseal ossification in the original three brothers.
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities."
explanation: Delayed epiphyseal ossification is listed among the hallmarks.
- category: Skeletal
name: Delayed ossification of the hand bones
diagnostic: true
phenotype_term:
preferred_term: Delayed ossification of the hand bones
term:
id: HP:0004052
label: Delayed ossification of the hand bones
evidence:
- reference: PMID:6734674
reference_title: "A new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones especially of the epiphyses, the hands, and feet."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the hands and feet the retarded ossification is combined with an abnormal modeling of the bones."
explanation: Retarded ossification of the hand and foot bones with abnormal modeling.
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities."
explanation: Delayed ossification of the primary centers of the short tubular bones.
- category: Skeletal
name: Delayed pubic bone ossification
diagnostic: true
phenotype_term:
preferred_term: Delayed pubic bone ossification
term:
id: HP:0008788
label: Delayed pubic bone ossification
evidence:
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities."
explanation: Delayed ossification of the pubic symphysis is a hallmark.
- category: Skeletal
name: Abnormal ossification of the sacrum
phenotype_term:
preferred_term: Deficient sacral ossification
term:
id: HP:0025370
label: Abnormal ossification of the sacrum
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: Deficient sacral ossification in both I237N patients.
- category: Skeletal
name: Hypoplastic ischiopubic ramus
phenotype_term:
preferred_term: Ischiopubic hypoplasia
term:
id: HP:0008822
label: Hypoplastic ischiopubic ramus
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: Ischiopubic hypoplasia in both I237N patients.
- category: Skeletal
name: Metacarpal pseudoepiphysis
phenotype_term:
preferred_term: Metacarpal pseudoepiphysis
term:
id: HP:0009193
label: Metacarpal pseudoepiphysis
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: Extensive metacarpal pseudoepiphyses in both I237N patients.
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband."
explanation: Supernumerary epiphyses of the hand tubular bones in the E35K patient.
- category: Skeletal
name: Cone-shaped epiphysis
phenotype_term:
preferred_term: Elongated cone-shaped epiphyses
term:
id: HP:0010579
label: Cone-shaped epiphysis
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: Elongated cone-shaped epiphyses in both I237N patients.
- category: Skeletal
name: Brachydactyly
phenotype_term:
preferred_term: Brachydactyly
term:
id: HP:0001156
label: Brachydactyly
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: Brachydactyly in both I237N patients.
- category: Skeletal
name: Abnormal trabecular bone morphology
phenotype_term:
preferred_term: Coarse bone trabeculae
term:
id: HP:0100671
label: Abnormal trabecular bone morphology
evidence:
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities."
explanation: Coarse bone trabeculae are listed among the hallmarks.
- category: Growth
name: Short stature
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:6734674
reference_title: "A new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones especially of the epiphyses, the hands, and feet."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the time of examination a moderate degree of dwarfism could be predicted."
explanation: The original report predicts, rather than measures, moderate short stature in the three brothers.
- reference: PMID:40904804
reference_title: "Human diseases caused by homozygous PTH1R mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "A sibling presented at age 9 years with short stature (3.4 standard deviations below WHO standard)"
explanation: Observed height of one of the original R485X brothers, 3.4 SD below the WHO standard at age 9.
- category: Dental
name: Eruption failure
phenotype_term:
preferred_term: Primary failure of tooth eruption
term:
id: HP:0000706
label: Eruption failure
evidence:
- reference: PMID:29987841
reference_title: "Report of second case and clinical and molecular characterization of Eiken syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband."
explanation: Primary failure of tooth eruption in the E35K patient.
- category: Endocrine
name: Elevated circulating parathyroid hormone level
phenotype_term:
preferred_term: Elevated circulating parathyroid hormone level
term:
id: HP:0003165
label: Elevated circulating parathyroid hormone level
evidence:
- reference: PMID:37268817
reference_title: "Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "individuals with the E35K8 or R485X mutation7 exhibited moderately elevated serum levels of PTH, indicating some degree of PTH resistance"
explanation: Elevated PTH in patients with E35K or R485X, indicating PTH resistance.
- reference: PMID:35846276
reference_title: "Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A diagnosis of PTH resistance was made on the basis of severe hypocalcemia, hyperphosphatemia, elevated PTH and normal vitamin D levels on blood sample."
explanation: Elevated PTH in the D241E homozygous child.
- category: Endocrine
name: Hypocalcemia
phenotype_term:
preferred_term: Hypocalcemia
term:
id: HP:0002901
label: Hypocalcemia
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcemia and elevated serum phosphate levels."
explanation: Hypocalcemia from PTH resistance in both I237N patients.
- category: Endocrine
name: Hyperphosphatemia
phenotype_term:
preferred_term: Hyperphosphatemia
term:
id: HP:0002905
label: Hyperphosphatemia
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Strikingly, both patients exhibited clinically manifest parathyroid hormone (PTH) resistance with hypocalcemia and elevated serum phosphate levels."
explanation: Elevated serum phosphate from PTH resistance in both I237N patients.
diagnosis:
- name: Skeletal radiographic evaluation
description: >-
Radiographs of the hands, pelvis and spine show the delayed ossification
and modeling abnormalities that suggest Eiken syndrome, including in
patients who first present with PTH-resistant hypocalcemia.
diagnosis_term:
preferred_term: skeletal radiography
term:
id: NCIT:C38101
label: X-Ray Imaging
results: >-
Delayed ossification, brachydactyly with short metacarpals, metacarpal
pseudoepiphyses, cone-shaped epiphyses, ischiopubic hypoplasia and
deficient sacral ossification.
evidence:
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome."
explanation: The radiographic skeletal pattern suggested Eiken syndrome in both I237N patients.
- reference: PMID:35846276
reference_title: "Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hand x-rays showed diffuse delayed bone age, osteopenia, short metacarpal bones and cone-shaped distal phalanges."
explanation: Hand radiographs showed delayed ossification in the D241E child.
- name: PTH1R molecular testing
description: >-
Sequencing identifies biallelic PTH1R variants. In patients presenting with
PTH resistance, GNAS analysis is typically normal, which separates Eiken
syndrome from pseudohypoparathyroidism.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: NCIT:C19770
label: Molecular Analysis
results: Homozygous PTH1R variant; no GNAS defect.
evidence:
- reference: PMID:35846276
reference_title: "Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GNAS gene analysis showed no pathogenic variation, but a likely pathogenic homozygous substitution c.723C>G p.(Asp241Glu) in PTH1R gene was found by trio-based whole exome sequencing."
explanation: Normal GNAS analysis followed by detection of homozygous PTH1R D241E by trio exome sequencing.
- reference: PMID:39276366
reference_title: "Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In both patients, however, a homozygous novel PTH1R variant was identified (c.710 T > A; p.IIe237Asn, p.I237N) that is located in the second transmembrane helical domain."
explanation: Homozygous PTH1R I237N identified in both patients initially suspected of pseudohypoparathyroidism.
treatments:
- name: Calcium and Active Vitamin D Supplementation
description: >-
Oral calcium and an active vitamin D analogue to correct symptomatic
hypocalcemia in patients with PTH resistance. Management of the skeletal
and dental features is otherwise supportive; no disease-specific therapy
exists.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: calcium carbonate
term:
id: CHEBI:3311
label: calcium carbonate
- preferred_term: alfacalcidol
term:
id: CHEBI:31186
label: alfacalcidol
target_mechanisms:
- target: Hypocalcemia
description: Supplementation raises serum calcium.
evidence:
- reference: PMID:40904804
reference_title: "Human diseases caused by homozygous PTH1R mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "However, by age 1 year, he developed symptomatic hypocalcemia (ionized calcium: 0.68 mM; nl 1.2-1.4), requiring treatment with calcium carbonate and alfa calcidiol."
explanation: A patient with delayed ossification and PTH resistance (D241E) was treated with calcium carbonate and alfacalcidol.
- reference: PMID:35846276
reference_title: "Case Report: Inactivating PTH/PTHrP Signaling Disorder Type 1 Presenting With PTH Resistance."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient was treated with calcium carbonate and alfacalcidol leading to rapid bio-clinical improvement."
explanation: Primary case report of the D241E child; calcium carbonate and alfacalcidol corrected the biochemical and clinical abnormalities.
animal_models:
- name: Humanized R485X-PTH1R knock-in mouse
species: Mouse
genotype: humanized PTH1R R485X knock-in
publication: PMID:42722652
description: >-
Mice expressing humanized PTH1R carrying the Eiken R485X truncation show
short tails, absent mineralization of carpal, metacarpal, tarsal and
metatarsal bones at postnatal day 3, fewer hypertrophic chondrocytes, and
biochemical PTH resistance. Delayed mineralization is rescued by
chondrocyte-specific PTHrP ablation or prenatal PTHrP(7-36) antagonist.
modeled_mechanisms:
- target: Delayed Chondrocyte Hypertrophic Differentiation
relationship: RECAPITULATES
fidelity: HIGH
model_scale: TISSUE
description: Reduced Col10-positive hypertrophic chondrocytes in the tibial growth plate.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RNAscope of tibial sections of embryonic day (E) 15.5 WT- and R485X-hPTH1R littermate mice showing reduced Col10-positive hypertrophic chondrocytes (red) in R485X mice."
explanation: The knock-in reproduces the delayed hypertrophic differentiation.
- target: Renal Parathyroid Hormone Resistance
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: Reduced serum calcium and 1,25(OH)2D, elevated PTH and reduced urinary cAMP.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Blood and urine analysis in 3-month-old WT and R485X mice showing reduced serum calcium and 1,25(OH)2D, elevated endogenous serum PTH, and reduced urinary cAMP (corrected for creatinine) in R485X mice compared to WT mice, indicating PTH resistance"
explanation: The knock-in reproduces biochemical PTH resistance.
evidence:
- reference: PMID:42722652
reference_title: "Spatial control of parathyroid hormone receptor-1 signaling dictates ligand-specific biological outcomes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Newborn R485X mice treated prenatally with the antagonist exhibited increased bone mineralization compared to R485X mice treated prenatally with the vehicle."
explanation: Pharmacological PTHrP antagonism improves mineralization in the model.
notes: >-
Diagnostic pitfall: patients homozygous for PTH1R I237N presented with
hypocalcemia and hyperphosphatemia that initially suggested
pseudohypoparathyroidism, usually a GNAS disorder; the skeletal radiographic
features pointed to Eiken syndrome. No GeneReviews chapter exists for Eiken
syndrome. The ISDS 2023 nosology (PMID:36779427) places PTH1R disorders in a
parathyroid hormone signaling group, but the cached text of that reference
does not name Eiken syndrome, so no classification is recorded here.
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: Eiken_Syndrome · 2026-09-24T19:27:27Z · View source
New entry for Eiken syndrome (MONDO:0010803), biallelic PTH1R. Six pathophysiology nodes model altered rather than absent receptor signaling (raised basal cAMP, impaired beta-arrestin2 desensitization) leading to enhanced PTHrP signaling in growth plate chondrocytes, delayed hypertrophic differentiation and delayed endochondral ossification, with a branch to renal PTH resistance and to failure of tooth eruption. Fourteen HP-bound phenotypes, all wired into the pathograph. Evidence drawn from the original family report, the PTH1R identification, two further family reports, the 2023 cell-signaling study, the 2025 review of homozygous PTH1R disorders and the 2026 humanized R485X knock-in mouse (recorded as an animal model). Deep research: an OpenScientist report from an earlier attempt was reused, not rerun; preflight-dr WARN only because PTH (the receptor ligand) is frequently mentioned, which is expected. Its unresolved HP CURIEs were not used. ISDS classification not added because the cached nosology text does not name Eiken syndrome. No GeneReviews chapter exists (check-genereviews NO_CHAPTER). Validated with validate, validate-terms, count-verified-snippets (41/41), entity-ref, causal-target and the other offline gates, and validate-disorders.
Disease: Eiken Syndrome (Eiken familial skeletal dysplasia) MONDO ID: MONDO:0010803 · OMIM: #600002 · Orphanet: ORPHA:79106 · UMLS: C1854486 Category: Mendelian (autosomal recessive skeletal dysplasia) Causal gene: PTH1R (HGNC:9608; OMIM *168468; NCBI Gene 5745; locus 3p21.31)
Eiken syndrome is an ultra-rare autosomal-recessive skeletal dysplasia caused by biallelic (homozygous) hypomorphic/altered-function variants in PTH1R, the gene encoding the parathyroid hormone / parathyroid hormone-related peptide receptor type 1 (the PTH/PTHrP receptor). First described by Eiken and colleagues in 1984 in three brothers from a consanguineous Danish family, the disorder is defined radiographically by severely delayed (retarded) endochondral ossification — especially of the epiphyses, pelvis, hands and feet — together with abnormal bone modeling, brachydactyly, coarse trabeculae, supernumerary/pseudo-epiphyses, and primary failure of tooth eruption. Only about four to five unrelated families have been reported worldwide since 1984, spanning European, Indian, and East-African ancestries. Affected individuals have normal intelligence, normal lifespan, and are normal at birth, with skeletal abnormalities becoming apparent during childhood growth.
Mechanistically, Eiken syndrome occupies the mild, non-lethal middle of the PTH1R allelic spectrum. PTH1R is a class B G-protein-coupled receptor that, through the PTHrP–Indian hedgehog (Ihh) feedback loop, paces the proliferation and hypertrophic differentiation of growth-plate chondrocytes and therefore the timing of endochondral ossification. Eiken-associated mutations — distributed across the extracellular domain (E35K, Y134S), the transmembrane helices (I237N, D241E), and the intracellular C-terminal tail (R485X) — bias receptor signaling: cell-based assays show increased basal cAMP tone combined with impaired β-arrestin2 recruitment and defective desensitization of the PTHrP response. Because sustained PTHrP-type signaling delays chondrocyte hypertrophy (the mirror image of the accelerated ossification seen in complete loss-of-function Blomstrand lethal chondrodysplasia), the net effect is delayed ossification — the phenotypic hallmark of Eiken syndrome. A transmembrane-helix-2 subset of variants additionally produces overt PTH resistance (hypocalcemia, hyperphosphatemia), placing those patients at the interface with pseudohypoparathyroidism-like disorders.
The evidence base is exclusively case-report and in-vitro functional-assay level; there are no registries, natural-history cohorts, quality-of-life instruments, or omics datasets specific to Eiken syndrome. Management is entirely supportive — calcium and active vitamin D for the PTH-resistant subset, orthopedic and dental care, and genetic counseling for consanguineous families. No targeted or curative therapy exists. Humanized PTH1R knock-in mice and conditional/global mouse models of the PTHrP–PTH1R axis reproduce key skeletal phenotypes and provide the primary in-vivo platform for the disease family.
The original 1984 description of three affected brothers from a consanguineous family established autosomal recessive inheritance on clinical/pedigree grounds, with the authors noting that "Parental consanguinity suggest an autosomal recessive inheritance" (PMID: 6734674). Molecular confirmation came later: "Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R" (PMID: 29987841). The reported causal alleles are homozygous and span multiple receptor domains — R485X (C-terminal tail truncation), E35K and Y134S (extracellular domain), and the newer transmembrane-helix-2 variants I237N and D241E. The second reported case carried homozygous c.103G>A p.(Glu35Lys) (PMID: 29987841). A recent review summarizing homozygous PTH1R disorders states that "homozygous mutations located in the transmembrane helices, extracellular domains and C-tail of the PTH1R were identified in patients with milder conditions characterized by variable degrees of skeletal and mineral abnormalities. These include delayed ossification in Eiken syndrome" (PMID: 40904804). The disorder is ultra-rare, with only ~4–5 families known.
The defining molecular signature of Eiken syndrome is not simple loss or gain of function but a rebalancing of the receptor's signaling outputs. In HEK293 cell assays, "R485X increases the receptor's basal rate of cAMP signaling and decreases its capacity to recruit β-arrestin2 upon ligand stimulation. The E35K and Y134S mutations each weaken the binding of PTHrP leading to impaired β-arrestin2 recruitment and desensitization of cAMP signaling response to PTHrP but not PTH" (PMID: 37268817). The authors conclude that "Our findings support a critical role for interaction with β-arrestin in the mechanism by which the PTH1R regulates bone formation" (PMID: 37268817). The transmembrane-helix-2 variants behave similarly at the cAMP level: functional analysis "demonstrated increased basal cAMP signaling for both variants, with relative blunting of responses to both PTH and PTH-related peptide (PTHrP) ligands" (PMID: 39276366). The common thread is elevated ligand-independent (basal) cAMP tone combined with defective desensitization/β-arrestin signaling, particularly toward PTHrP.
The skeletal phenotype is explained by the physiological role of PTH1R signaling in the growth plate. PTHrP acts through PTH1R as an autocrine/paracrine brake on chondrocyte hypertrophic differentiation, and is itself induced by Ihh in a negative-feedback loop. Loss of the signal accelerates differentiation: "Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus premature ossification of those bones that are formed through an endochondral process" (PMID: 10912527). Excess signal does the opposite: "a severe delay in chondrocyte differentiation and endochondral ossification, is observed in transgenic mice that overexpress PTHrP" (PMID: 10912527) — the same phenotypic direction as Eiken syndrome. This bracketing is reinforced by the contrast with the lethal end of the spectrum, which is "incompatible with life as in Blomstrand's lethal chondrodysplasia, characterized by accelerated growth plate ossification" (PMID: 40904804). Because Eiken variants sustain PTHrP-type (basal cAMP) signaling tone, they delay hypertrophic differentiation and therefore delay ossification.
The core radiographic phenotype comprises "delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities" (PMID: 29987841). The original report described "an excessively retarded ossification, principally of the epiphyses, the pelvis, the hands and the feet, are reported. In the hands and feet the retarded ossification is combined with an abnormal modeling of the bones" (PMID: 6734674); patients were normal at birth, with predicted moderate dwarfism, no mental retardation, and normal chromosomes and urine mucopolysaccharides. Additional features include supernumerary epiphyses of the tubular bones of the hands and primary failure of tooth eruption. The PTH-resistant subset (TM2 variants) show a shared skeletal signature: "Both patients shared skeletal features, including brachydactyly, extensive metacarpal pseudo-epiphyses, elongated cone-shaped epiphyses, ischiopubic hypoplasia, and deficient sacral ossification, suggestive of Eiken syndrome" together with hypocalcemia and elevated serum phosphate (PMID: 39276366).
PTH1R is a paradigmatic allelic-series gene, and understanding Eiken requires positioning it within that series. Homozygous mutations produce a graded set of phenotypes: "These include delayed ossification in Eiken syndrome, hypocalcemia in a pseudohypoparathyroidism-like disorder, and non-syndromic primary failure of tooth eruption; which is usually caused by heterozygous PTH1R mutations" (PMID: 40904804). The dominant, heterozygous end of the spectrum — non-syndromic primary failure of tooth eruption (PFE) — operates by haploinsufficiency: "Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency" (PMID: 23771181); in that study 12/30 variants were pathogenic across 70 PFE index cases. Some PFE mutants act by a dominant-negative mechanism: "the PTH1R mutants are functionally inactive and mutant PTH1R/Gly452Glu has a dominant negative effect on the signaling of PTH1R wild type. Confocal imaging revealed that wild type PTH1R is expressed on the cell surface, whereas PTH1R/Gly452Glu mutant is mostly retained inside the cell" (PMID: 27898723).
| Disorder | Zygosity | Functional effect | Ossification/skeletal effect | Inheritance |
|---|---|---|---|---|
| Jansen metaphyseal chondrodysplasia | Heterozygous | Constitutively activating | Delayed differentiation, metaphyseal dysplasia, hypercalcemia | AD |
| Eiken syndrome | Homozygous | Hypomorphic / biased (↑basal cAMP, ↓β-arrestin) | Severely delayed ossification, modeling defects | AR |
| Pseudohypoparathyroidism-like disorder | Homozygous | Reduced PTH responsiveness | Hypocalcemia, hyperphosphatemia (PTH resistance) | AR |
| Blomstrand lethal chondrodysplasia | Homozygous | Complete loss of function | Accelerated growth-plate ossification; perinatally lethal | AR |
| Primary failure of tooth eruption (PFE) | Heterozygous | Haploinsufficiency / dominant-negative | Failed tooth eruption, posterior open bite | AD (incomplete penetrance) |
Mouse genetics provide the in-vivo backbone for the disease family. A humanized PTH1R knock-in strain reproduces a skeletal phenotype: "Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones" (PMID: 41031626). Conditional deletion demonstrates PTH1R's role in digit segmentation: "PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation" (PMID: 26620087). Together with the global PTHrP-null/PTH1R-null (accelerated ossification) and PTHrP-overexpressing (delayed ossification) models (PMID: 10912527), these systems bracket the Eiken phenotypic direction and are the natural platform for testing disease mechanism and future therapeutics.
Eiken syndrome carries stable identifiers: OMIM #600002; MONDO:0010803; Orphanet ORPHA:79106; UMLS C1854486; ICD-10 Q78.8 (no dedicated code). Its causal gene PTH1R maps to 3p21.31 (HGNC:9608, OMIM *168468, NCBI Gene 5745). Orphanet lists prevalence as <1/1,000,000 ("unknown"). Only ~4–5 unrelated families have been reported since 1984: the original Danish consanguineous family of three affected brothers (PMID: 6734674 — "Three brothers with a constitutional skeletal dysplasia characterized by an excessively retarded ossification, principally of the epiphyses, the pelvis, the hands and the feet, are reported"), a second case from India (PMID: 29987841 — "Only one affected family has been known to-date"), a third family (PMID: 31297790), and an East-African family with PTH resistance (PMID: 39276366). Both sexes are affected; consanguinity is the principal risk context. All evidence is case-report level.
Eiken syndrome is a constitutional (developmental) skeletal dysplasia characterized by markedly delayed and abnormal endochondral ossification with abnormal bone modeling, brachydactyly, and dental abnormalities, caused by biallelic variants in PTH1R. Key identifiers: OMIM #600002; MONDO:0010803; Orphanet ORPHA:79106; UMLS C1854486; ICD-10 Q78.8 (no unique code); MeSH — no dedicated descriptor (indexed under skeletal dysplasias / PTH1R-related disorders). Synonyms/alternative names: "Eiken familial skeletal dysplasia"; "Eiken skeletal dysplasia"; historically "a new familial skeletal dysplasia with severely retarded ossification and abnormal modeling of bones" (PMID: 6734674). Source of information: disease-level aggregated resources (OMIM, Orphanet) plus a small number of individual patient case reports; no EHR-derived cohorts exist.
Causal factor: purely genetic — biallelic hypomorphic/biased-function PTH1R variants (PMID: 29987841, PMID: 40904804). Genetic risk factors: homozygosity for a pathogenic PTH1R allele; consanguinity is the dominant risk context (original family was consanguineous, PMID: 6734674). No susceptibility loci, modifier genes, protective alleles, environmental risk/protective factors, or gene–environment interactions have been identified — consistent with a fully penetrant single-gene Mendelian disorder. Not applicable: environmental toxins, infectious agents, lifestyle factors.
Phenotypes are physical manifestations, clinical signs, and laboratory abnormalities; there are no behavioral phenotypes (intelligence is normal, PMID: 6734674). Onset is not congenital in appearance (normal at birth) but becomes apparent in childhood as ossification fails to progress; the course is chronic and non-progressive after skeletal maturity.
| Phenotype | Type | HPO suggestion | Onset / frequency |
|---|---|---|---|
| Delayed/retarded ossification of epiphyses | Radiographic sign | HP:0002662 (Delayed epiphyseal ossification) | Childhood; hallmark (all cases) |
| Delayed ossification of pubic symphysis / pelvis | Radiographic sign | HP:0008788 (Delayed pelvic bone ossification) | Childhood; frequent |
| Brachydactyly | Physical | HP:0001156 | Frequent |
| Abnormal bone modeling (hands/feet) | Radiographic sign | HP:0011314 (Abnormal diaphysis morphology) | Hallmark |
| Coarse bone trabeculae | Radiographic sign | HP:0100671 (related) | Frequent |
| Supernumerary/pseudo-epiphyses | Radiographic sign | HP:0010580 (related) | Reported |
| Cone-shaped epiphyses | Radiographic sign | HP:0010579 | PTH-resistant subset |
| Ischiopubic hypoplasia / deficient sacral ossification | Radiographic sign | HP:0008821 (related) | PTH-resistant subset |
| Primary failure of tooth eruption | Dental sign | HP:0006348 (related) | Reported |
| Short stature / moderate dwarfism | Physical | HP:0004322 | Predicted/variable |
| Hypocalcemia | Lab abnormality | HP:0002901 | PTH-resistant subset |
| Hyperphosphatemia | Lab abnormality | HP:0002905 | PTH-resistant subset |
Quality-of-life impact is not formally measured; functional impact is primarily skeletal/orthopedic and dental, with normal cognition and lifespan.
Causal gene: PTH1R (HGNC:9608; OMIM *168468; NCBI Gene 5745; 3p21.31), a class B GPCR. Reported pathogenic variants: R485X (nonsense, C-tail truncation), E35K / c.103G>A p.(Glu35Lys) (missense, extracellular), Y134S (missense, extracellular), I237N and D241E (missense, transmembrane helix 2). Variant classification: pathogenic/likely pathogenic per ACMG in the context of biallelic segregation and functional data. Variant types: predominantly missense plus one nonsense; germline, homozygous. Allele frequencies: extremely rare/absent in gnomAD (private to individual consanguineous families). Functional consequence: biased/altered function — increased basal cAMP with impaired β-arrestin2 recruitment and defective desensitization (PMID: 37268817, PMID: 39276366) — rather than clean LOF or GOF. Modifier genes / epigenetics / chromosomal abnormalities: none reported (chromosomes normal, PMID: 6734674).
Not applicable. Eiken syndrome is a monogenic Mendelian disorder. No environmental toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents are implicated. The only relevant non-genetic contributor is consanguinity (a demographic/social factor increasing homozygosity risk).
Ordered causal chain (initiating lesion → clinical manifestation):
(Step 3's precise coupling between "increased basal cAMP" and "delayed differentiation" is inferred from the PTHrP-overexpression mouse phenotype and the LOF/Blomstrand contrast rather than demonstrated directly in Eiken tissue.)
Molecular pathways: PTH1R → Gαs → adenylyl cyclase → cAMP → PKA; and β-arrestin-mediated desensitization/signaling; upstream integration with Indian hedgehog (Ihh) signaling in the PTHrP–Ihh loop. Related transcriptional control: Atf4 activates Ihh transcription and its loss causes delayed ossification — "Ablation of Atf4 (Atf4(-/-)) in mice leads to severe skeletal defects, including delayed ossification... The expression of Indian hedgehog (Ihh) is markedly decreased" (PMID: 19906842). Cellular processes: growth-plate chondrocyte proliferation and hypertrophic differentiation, endochondral ossification. Protein dysfunction: biased GPCR signaling; the R485X truncation removes C-tail regulatory elements; the dominant-negative PFE mutant (Gly452Glu) is intracellularly retained (PMID: 27898723). Biochemical abnormalities: dysregulated cAMP; in the TM2 subset, hypocalcemia/hyperphosphatemia. Suggested GO terms: GO:0001501 (skeletal system development), GO:0002062 (chondrocyte differentiation), GO:0001958 (endochondral ossification), GO:0007188 (adenylate cyclase-modulating GPCR signaling), GO:0007194 (negative regulation of adenylate cyclase activity). Suggested CL terms: CL:0000138 (chondrocyte), CL:0000743 (hypertrophic chondrocyte), CL:0000062 (osteoblast).
Organ/system level: skeletal system (primary); dentition; kidney/mineral homeostasis (secondary, PTH-resistant subset). Specific sites: epiphyses of long bones, pubic symphysis and pelvis, short tubular bones of hands and feet, sacrum, ischium/pubis, growth plates. Tissue level: cartilage (growth-plate/epiphyseal), bone. Cell level: growth-plate chondrocytes (proliferative and hypertrophic), osteoblasts. Subcellular: plasma membrane (receptor localization; note intracellular retention of the dominant-negative PFE mutant). Lateralization: bilateral and generally symmetric. Suggested UBERON terms: UBERON:0002204 (musculoskeletal system), UBERON:0001474 (bone element), UBERON:0006255 (growth plate cartilage), UBERON:0002472 (epiphysis, related), UBERON:0009853 (pubic symphysis), UBERON:0002398 (manus), UBERON:0002387 (pes).
Onset: patients are normal at birth (PMID: 6734674); the disorder manifests during childhood as ossification centers fail to appear/progress on schedule. Pattern: chronic, insidious, developmental. Progression: non-progressive in the degenerative sense — the abnormality is delayed maturation during the growth period; there is no evidence of ongoing organ deterioration. Duration: lifelong (constitutional). Critical period: the growth-plate-active window of childhood/adolescence is the period of vulnerability and the theoretical window for any future intervention. No remission occurs (structural/developmental disorder).
Inheritance: autosomal recessive (biallelic/homozygous PTH1R), PMID: 6734674, PMID: 29987841. Penetrance: effectively complete for homozygotes (heterozygous carriers are unaffected for Eiken, though heterozygous LOF causes the distinct dominant PFE with incomplete penetrance). Expressivity: variable — the TM2 subset adds PTH resistance. Epidemiology: Orphanet prevalence <1/1,000,000 ("unknown"); only ~4–5 families reported worldwide. Consanguinity: central (original family consanguineous). Founder effects/carrier frequency: none established; alleles are private. Populations: reported in European (Danish), Indian, and East-African ancestries; both sexes affected (original family: three brothers). No genetic anticipation (not a repeat-expansion disorder).
Imaging (primary diagnostic modality): skeletal survey/radiographs showing delayed epiphyseal, pelvic, and short-tubular-bone ossification; coarse trabeculae; abnormal modeling; cone-shaped/pseudo-epiphyses (PMID: 29987841, PMID: 6734674). Laboratory: serum calcium and phosphate (hypocalcemia/hyperphosphatemia in the PTH-resistant subset), PTH; normal urine mucopolysaccharides and normal karyotype help exclude storage disorders/aneuploidy (PMID: 6734674). Genetic testing (confirmatory): PTH1R single-gene sequencing, skeletal-dysplasia gene panels, or whole-exome/whole-genome sequencing to identify biallelic PTH1R variants; segregation analysis in consanguineous families. Differential diagnosis: other PTH1R disorders (Blomstrand — lethal/accelerated ossification; Jansen — activating; pseudohypoparathyroidism-like disorder; PFE), acrodysostosis and other brachydactyly-with-delayed-ossification dysplasias, pseudohypoparathyroidism. Screening: cascade carrier testing within affected families; prenatal/preimplantation testing feasible once the familial variant is known.
Prognosis is favorable. Lifespan is normal and intelligence is normal (PMID: 6734674). Morbidity is skeletal (short stature/moderate dwarfism, brachydactyly, orthopedic issues) and dental (failed eruption); the PTH-resistant subset requires mineral management. There is no disease-specific mortality, no malignant potential, and no progressive organ failure. Formal survival, disability, and quality-of-life metrics have not been published (case-report-only literature). Prognostic factors: presence of PTH resistance (TM2 variants) predicts the mineral-metabolism component.
No targeted or curative therapy exists. Management is supportive and symptomatic: - Pharmacotherapy (PTH-resistant subset): oral/active vitamin D (calcitriol/alfacalcidol) and calcium supplementation to correct hypocalcemia/hyperphosphatemia (analogous to pseudohypoparathyroidism management). Suggested NCIT: Calcium (NCIT:C376), Calcitriol/Vitamin D (NCIT:C1042/related). - Orthopedic care: monitoring and management of skeletal deformity, short stature, and modeling abnormalities; physical/occupational therapy. Suggested NCIT: Orthopedic Procedure (NCIT:C51826), Physical Therapy (NCIT:C15325). - Dental care: management of primary failure of tooth eruption (orthodontic/surgical, often refractory). - Genetic counseling: for recurrence risk in consanguineous families.
No pharmacogenomics, gene therapy, cell therapy, RNA therapy, immunotherapy, or disease-specific clinical trials (NCT identifiers) exist for Eiken syndrome. Signaling-biased pharmacology of PTH1R is a theoretical future avenue but untested.
Primary prevention is limited to genetic counseling and reproductive options in at-risk (consanguineous) families: carrier testing once the familial variant is known, prenatal diagnosis, and preimplantation genetic testing. Secondary/tertiary prevention consists of early orthopedic and dental surveillance and correction of mineral abnormalities in the PTH-resistant subset. No immunization, behavioral, public-health, or environmental interventions are applicable (monogenic disorder).
Taxonomy of models: Mus musculus (NCBI Taxon 10090). Ortholog: mouse Pth1r (NCBI Gene 19228); the gene and the PTHrP–Ihh axis are highly evolutionarily conserved across vertebrates. Natural disease: no well-documented naturally occurring Eiken-equivalent disorder in companion animals or wildlife is recorded in OMIA; the human phenotypes are recapitulated experimentally in mice (below). Zoonotic potential: none (non-transmissible genetic disorder).
Mouse is the primary model system. Relevant models: - Humanized PTH1R knock-in carrying p.E469K: "Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones" (PMID: 41031626) — a knock-in model reproducing a PTH1R skeletal phenotype. - Conditional Prx1-Cre;Pth1r deletion: "PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation" (PMID: 26620087). - Global PTHrP-null / Pth1r-null: accelerated chondrocyte differentiation and premature ossification; PTHrP-overexpressing transgenics: delayed differentiation and delayed endochondral ossification — the Eiken direction (PMID: 10912527). - Atf4-null: delayed ossification via reduced Ihh transcription (PMID: 19906842), illuminating the transcriptional layer of the loop.
Phenotype recapitulation: the PTHrP-overexpression and humanized knock-in models capture the delayed-ossification/skeletal-modeling direction. Limitations: no mouse yet carries an exact homozygous Eiken allele (E35K/Y134S/R485X/I237N/D241E) with characterization of the β-arrestin/basal-cAMP signaling bias in vivo, and mouse–human differences in growth-plate dynamics constrain direct translation. Resources: MGI (mouse), IMPC/KOMP for Pth1r alleles; HEK293 cell-based signaling assays for variant functional analysis. In-vitro systems (HEK293 cAMP/β-arrestin assays, PMID: 37268817, PMID: 39276366) are the standard for classifying new variants.
Biallelic hypomorphic PTH1R variant
(E35K / Y134S ─ extracellular; I237N / D241E ─ TM2; R485X ─ C-tail)
│
▼
Biased receptor signaling
↑ basal (ligand-independent) cAMP tone
↓ β-arrestin2 recruitment + defective desensitization (esp. PTHrP)
│
┌───────────┴───────────────────────────┐
▼ ▼
GROWTH-PLATE branch MINERAL branch (TM2 subset)
Sustained PTHrP-type tone Impaired PTH-dependent
→ chondrocytes stay proliferative renal/mineral signaling
→ delayed hypertrophic differentiation → PTH resistance
(within PTHrP–Ihh feedback loop) → hypocalcemia + hyperphosphatemia
│
▼
DELAYED ENDOCHONDRAL OSSIFICATION ┌── DENTAL branch ──┐
+ abnormal bone modeling │ impaired follicle │
→ epiphyses, pelvis, hands/feet, │ PTH1R signaling │
coarse trabeculae, pseudo-epiphyses, │ → primary failure │
brachydactyly, short stature │ of tooth eruption│
└───────────────────┘
SPECTRUM CONTEXT (dose/direction of PTH1R signaling):
activating (Jansen, AD) ─ biased/hypomorphic (EIKEN, AR) ─ complete LOF (Blomstrand, AR, lethal)
delayed diff. DELAYED OSSIFICATION ACCELERATED ossification
The unifying insight is that Eiken syndrome is a "signaling-bias" disorder, not a simple loss- or gain-of-function disorder. The delayed-ossification phenotype aligns with excess PTHrP-type tone (paralleling PTHrP-overexpressing mice) and is the opposite pole from Blomstrand's complete loss of function (accelerated ossification), even though both are recessive. The β-arrestin/desensitization defect is mechanistically central: because the receptor cannot properly terminate PTHrP-driven cAMP signaling, chondrocyte hypertrophy is inappropriately restrained, delaying the cartilage-to-bone transition.
| PMID | Title (abbrev.) | Role in this report | Evidence type |
|---|---|---|---|
| 6734674 | Original 3-brother familial dysplasia | Defines the entity, phenotype, AR inheritance, normal cognition | Human clinical (case series) |
| 29987841 | Second case + molecular characterization | Establishes biallelic PTH1R etiology; enumerates hallmarks; documents rarity | Human clinical + molecular |
| 31297790 | Third family with Eiken syndrome | Confirms recurrence of the entity in a new family | Human clinical |
| 39276366 | Eiken with PTH resistance (TM2 I237N/D241E) | Adds the PTH-resistant subset; increased basal cAMP with blunted ligand response | Human clinical + in vitro |
| 37268817 | Altered signaling/desensitization in Eiken mutants | Core mechanism: ↑basal cAMP, ↓β-arrestin2 for R485X/E35K/Y134S | In vitro (HEK293) |
| 40904804 | Human diseases from homozygous PTH1R mutations | Places Eiken in the homozygous allelic spectrum vs Blomstrand | Review |
| 10912527 | PTHrP and Ihh in skeletal development | Growth-plate physiology; overexpression → delayed ossification (Eiken direction) | Model organism/review |
| 26620087 | Ihh/PTH1R in limb mesenchyme / digit formation | Conditional deletion → symphalangism; digit-bone role | Model organism (mouse) |
| 41031626 | Helix-8 PTH1R brachydactyly + humanized mouse | Humanized knock-in recapitulates skeletal phenotype | Model organism (mouse) |
| 27898723 | PFE PTH1R mutants disrupt G-protein signaling | Dominant-negative/intracellular-retention mechanism (spectrum context) | In vitro |
| 23771181 | Spectrum of PTH1R mutations in PFE | Haploinsufficiency mechanism for dominant PFE end of spectrum | Human clinical + molecular |
| 19906842 | Atf4 regulates chondrocyte differentiation via Ihh | Transcriptional control of the Ihh loop; Atf4-null → delayed ossification | Model organism (mouse) |
| 37840415 | Heterozygous PTH1R variant, incomplete penetrance | Illustrates AD/AR complexity of PTH1R | Human clinical |
| 24825834, 28257744, 31730001, 41898811 | PFE clinical/genetic series & review | Characterize the dominant PFE pole of the PTH1R spectrum | Human clinical/review |
Report compiled from a 5-iteration autonomous investigation. 7 findings confirmed; 17 papers reviewed. All quoted abstract snippets were verified against source records. Evidence is predominantly human case-report and in-vitro functional-assay level, supplemented by model-organism genetics of the PTHrP–PTH1R–Ihh axis.
Checked with linkml-reference-validator 0.3.0rc1.
| Outcome | Count |
|---|---|
| References checked | 17 |
| Resolved | 17 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 17 |
| On topic | 10 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 34 |
| Resolved | 30 |
| Unresolved (possible confabulation) | 2 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 25 |
| Terms named correctly | 11 |
| Terms named as a different term | 10 |
| Terms whose name is worth a second look | 4 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0001156 (1 mention) - the report calls it "Physical"; HP calls it BrachydactylyHP:0100671 (1 mention) - the report calls it "related"; HP calls it Abnormal trabecular bone morphologyHP:0010580 (1 mention) - the report calls it "related"; HP calls it Enlarged epiphysesHP:0010579 (1 mention) - the report calls it "Radiographic sign"; HP calls it Cone-shaped epiphysisHP:0008821 (1 mention) - the report calls it "related"; HP calls it Hypoplastic inferior iliaHP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short statureHP:0002901 (1 mention) - the report calls it "Lab abnormality"; HP calls it HypocalcemiaHP:0002905 (1 mention) - the report calls it "Lab abnormality"; HP calls it HyperphosphatemiaUBERON:0002472 (1 mention) - the report calls it "epiphysis, related"; UBERON calls it stylopodUBERON:0009853 (1 mention) - the report calls it "pubic symphysis"; UBERON calls it body of uterusThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0002662 (1 mention), reported as "Delayed epiphyseal ossification" - HP does not contain this termHP:0006348 (1 mention), reported as "related" - HP does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0008788 (1 mention) - the report calls it "Delayed pelvic bone ossification"; HP calls it Delayed pubic bone ossificationHP:0011314 (1 mention) - the report calls it "Abnormal diaphysis morphology"; HP calls it Abnormal long bone morphologyGO:0007188 (1 mention) - the report calls it "adenylate cyclase-modulating GPCR signaling"; GO calls it adenylate cyclase-modulating G protein-coupled receptor signaling pathway, and lists "adenylate cyclase-modulating GPCR signaling pathway" among its other namesUBERON:0006255 (1 mention) - the report calls it "growth plate cartilage"; UBERON calls it ischial pre-cartilage condensationTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.