Anauxetic Dysplasia: Disease-Characteristics Research Report

Executive summary

Anauxetic dysplasia (ANXD) is an ultra-rare, congenital, autosomal-recessive skeletal dysplasia at the severe end of the cartilage-hair hypoplasia–anauxetic dysplasia (CHH–AD) spectrum. Three molecular forms are recognized: ANXD1—RMRP, ANXD2—POP1, and ANXD3—NEPRO/C3orf17. The shared phenotype comprises extreme disproportionate short stature, brachydactyly, ligamentous laxity, joint hypermobility/dislocation, and severe spondylo-epi-metaphyseal abnormalities. Unlike classic cartilage-hair hypoplasia, “pure” ANXD usually lacks hypotrichosis, anemia, clinically important immunodeficiency, intestinal dysmotility, and established cancer predisposition, although the boundary is a spectrum and isolated extraskeletal findings require continued surveillance. (remmelzwaal2023expandingthephenotype pages 1-2, thiel2007typeandlevel pages 1-2)

The best-supported causal chain is biallelic disruption of an RNase-MRP component or interactor → defective pre-rRNA processing/ribosome biogenesis → impaired growth-plate chondrocyte differentiation and hypertrophy → disorganized endochondral ossification → severe short-limb dwarfism and skeletal deformity. This mechanism is strongest for RMRP and POP1; the precise function of NEPRO remains less resolved. No disease-modifying therapy, approved targeted drug, or ANXD-specific interventional trial was identified. Current care is supportive, orthopedic, rehabilitative, dental, and surveillance-based.

Table: This table summarizes the three recognized anauxetic dysplasia subtypes by gene, OMIM identifier, inheritance, phenotype, representative variants, and evidence strength. It is useful as a compact knowledge-base overview while highlighting that all forms are autosomal recessive and exceptionally rare.

1. Disease information

Definition and classification

ANXD is a Mendelian skeletal disorder characterized by prenatal-onset growth failure and severe spondyloepimetaphyseal dysplasia. A 2023 primary report describes it as “a rare autosomal recessive skeletal disorder at the severe end” of the CHH–AD spectrum and recognizes three types. (remmelzwaal2023expandingthephenotype pages 1-2)

Recognized molecular types and identifiers

• ANXD1: OMIM #607095, caused by biallelic RMRP variants.
• ANXD2: OMIM #617396, caused by biallelic POP1 variants.
• ANXD3: OMIM #618853, caused by biallelic NEPRO, formerly C3orf17, variants. (remmelzwaal2023expandingthephenotype pages 1-2)

A definitive MONDO identifier was not established in the retrieved primary literature and should be verified directly against the current MONDO release before database ingestion. Likewise, no dedicated MeSH, ICD-10, or ICD-11 code was demonstrated. In routine coding, ANXD will generally fall under broader congenital osteochondrodysplasia/skeletal-dysplasia categories; such parent codes should not be represented as disease-specific identifiers.

Synonyms: anauxetic dysplasia; anauxetic dysplasia type 1/2/3; ANXD/AD; RMRP-related anauxetic dysplasia; POP1-related skeletal dysplasia/anauxetic dysplasia; NEPRO-related anauxetic dysplasia; severe end of the cartilage-hair hypoplasia–anauxetic dysplasia spectrum. “AD” is ambiguous with autosomal dominant inheritance and should be avoided in knowledge-base displays.

Source granularity: OMIM/nosology-style statements are aggregated disease-level assertions, whereas much of the phenotype and natural-history evidence comes from individual patients or very small families. The 2023 ANXD3 publication was a single-patient case report; only five ANXD3 patients had been reported previously. (remmelzwaal2023expandingthephenotype pages 1-2, remmelzwaal2023expandingthephenotype pages 4-4)

2. Etiology

Causal factors

ANXD is genetic. All recognized forms result from germline biallelic variants in genes connected to RNase MRP/ribosome biology:

1. RMRP: encodes the untranslated RNA component of RNase MRP.
2. POP1: encodes a protein subunit shared by RNase MRP and RNase P and involved in complex assembly/stability.
3. NEPRO: encodes an RNase-MRP-associated protein; its disease mechanism is incompletely defined. (remmelzwaal2023expandingthephenotype pages 1-2, barrazagarcia2017broadeningthephenotypic pages 1-2, steinbusch2017expressionofrmrp pages 1-2)

Genetic risk

The principal risk factor is inheriting one pathogenic allele from each carrier parent. Consanguinity increases the chance that both parents carry the same rare allele. The recurrent homozygous NEPRO c.280C>T, p.(Arg94Cys) allele was found in several consanguineous Arabic families and was characterized as an apparent founder mutation. (remmelzwaal2023expandingthephenotype pages 4-4)

No validated susceptibility loci, polygenic-risk scores, or modifier genes are established. Variable manifestations with similar RMRP genotypes suggest possible nonallelic modifiers, but these remain unidentified. (thiel2007typeandlevel pages 6-8)

Environmental, infectious, lifestyle, and protective factors

No toxin, infection, radiation exposure, diet, smoking behavior, or other environmental factor is known to cause ANXD. No genetic or environmental protective factor has been validated. Environmental circumstances may modify complications—falls or high-risk neck movement could worsen atlantoaxial instability—but do not cause the disorder. Gene–environment interaction studies specific to ANXD were not identified.

3. Phenotypes

Core phenotype

The common phenotype comprises severe or extreme disproportionate short stature, short limbs, brachydactyly, skin laxity, ligamentous/joint laxity, joint hypermobility or dislocations, and extensive axial and appendicular skeletal dysplasia. (remmelzwaal2023expandingthephenotype pages 1-2)

In an RMRP-related 11-year-old, short limbs were visible by prenatal ultrasound at approximately 17 weeks. Birth length was 39 cm, below −5 SD; height at nine years was 83 cm, approximately −8 SD. She developed progressive scoliosis and lower-limb joint pain but had normal hair and psychomotor development. Radiographs showed shortened tubular bones, widened irregular metaphyses, small epiphyses, premature growth-plate fusion, brachydactyly, coxa vara, and dysplastic femoral heads. (thiel2007typeandlevel pages 2-3, thiel2007typeandlevel pages 3-4)

Historical descriptions place adult height below approximately 85 cm in severe RMRP-associated ANXD, but this is based on very small samples rather than a population estimate. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4)

ANXD3 phenotype expansion in 2023

A seven-year-old homozygous for NEPRO p.Arg94Cys had atlantoaxial subluxation, sagittal-suture craniosynostosis with scaphocephaly, Madelung deformity, and extensive dental abnormalities, including agenesis, microdontia, short roots, taurodontism, enamel hypoplasia, and abnormal crowns. The authors’ abstract states: “Greater awareness of the possibility of atlantoaxial subluxation, dental anomalies, and craniosynostosis may lead to more timely diagnosis and treatment.” (remmelzwaal2023expandingthephenotype pages 4-4, remmelzwaal2023expandingthephenotype pages 3-4)

Motor/cognitive delay and recurrent airway infections occurred in that patient, but congenital ichthyosis was attributable to a separate homozygous ALOX12B variant; therefore, those findings should not automatically be assigned to ANXD3. (remmelzwaal2023expandingthephenotype pages 4-4)

Frequency and quality of life

Reliable percentages are unavailable because cohorts are exceptionally small. Severe short stature and skeletal abnormalities are defining and expected to be common; craniosynostosis, atlantoaxial subluxation, and detailed dental anomalies currently have case-level evidence. No ANXD-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life study was identified. Likely burdens include restricted mobility, pain, spinal and hip deformity, need for adapted environments, dental morbidity, repeated imaging/surgery, and cervical-safety concerns.

4. Genetic and molecular information

Genes and representative variants

• RMRP: noncoding RNA gene on chromosome 9p13. Representative severe alleles include g.111_112insACTGTAGACATTCCT, g.90_91AG>GC, g.254C>G, and the null deletion g.254_263delCTCAGCGCGG. A severe patient was compound heterozygous for g.195C>T and g.254_263delCTCAGCGCGG; both were absent from 378 control chromosomes. (thiel2007typeandlevel pages 5-6, thiel2007typeandlevel pages 3-4, thiel2007typeandlevel pages 1-2)
• POP1: reported ANXD-spectrum variants include compound-heterozygous p.Pro582Ser/p.Glu870fs*5 and homozygous p.Asp511Tyr. The former combines a missense and frameshift allele; the latter is missense. (barrazagarcia2017broadeningthephenotypic pages 1-2)
• NEPRO: homozygous NM_015412.4:c.280C>T, p.(Arg94Cys) is the best-documented recurrent ANXD3 allele. (remmelzwaal2023expandingthephenotype pages 4-4)

These are germline variants. There is no evidence that somatic mutation is relevant. Current population allele frequencies were not available in the retrieved papers and should be queried directly in gnomAD by transcript/build before ingestion. Given recessive severe disease and very small case numbers, causal alleles are expected to be rare, but absence from a population database alone is not proof of pathogenicity.

Functional consequences

The RMRP deletion g.254_263delCTCAGCGCGG was undetectable by RT-PCR and interpreted as an unstable-RNA/null allele. Disease-causing RMRP changes cluster in conserved nucleotides or disrupt stem pairing, affecting RNA structure, protein binding, RNA stability, or transcription. (thiel2007typeandlevel pages 5-6, thiel2007typeandlevel pages 6-8)

In POP1-associated disease, p.Pro582Ser/p.Glu870fs*5 was associated with markedly reduced RMRP abundance and increased pre-5.8S rRNA, supporting impaired RNase-MRP function. (barrazagarcia2017broadeningthephenotypic pages 1-2)

ClinVar classifications must be checked at accession level and date of use. The retrieved literature describes the RMRP and recurrent NEPRO alleles as pathogenic/disease-causing, while a 2024 broader CHH-spectrum case illustrates that WES can return a pathogenic allele paired with a VUS; such combinations require phenotype, segregation, and functional review rather than automatic confirmation. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4)

No validated ANXD modifier gene, disease-specific epigenetic signature, recurrent chromosomal abnormality, methylation abnormality, or structural-variant mechanism was established.

5. Environmental information

ANXD is not an infectious, toxic, occupational, lifestyle, or nutritional disease. No causal infectious agent or preventable exposure is known. Standard nutrition and activity adapted to orthopedic limitations support general health but do not reverse the molecular defect. Cervical instability warrants avoidance of unassessed high-impact activities and careful airway/neck positioning, especially during anesthesia. (remmelzwaal2023expandingthephenotype pages 3-4)

6. Mechanism and pathophysiology

Upstream molecular defect

RNase MRP is a ribonucleoprotein endoribonuclease containing RMRP lncRNA and protein subunits including POP1. It participates in ITS1 pre-rRNA cleavage and has reported roles in cyclin-B2 mRNA cleavage and cell-cycle regulation. (steinbusch2017expressionofrmrp pages 1-2)

For RMRP disease, functional testing of 13 variants found a strong negative correlation between bone-dysplasia severity and rRNA-cleavage activity (R = −0.8346, P = .0008). Impaired mRNA cleavage correlated with immunologic/hematologic abnormalities (R = −0.8429, P = .0007) and hair hypoplasia (R = −0.8115, P = .001). Thus, severe impairment of rRNA processing primarily predicts ANXD’s skeletal phenotype, whereas impaired mRNA/cell-cycle regulation better predicts CHH-like extraskeletal findings. (thiel2007typeandlevel pages 5-6, thiel2007typeandlevel pages 1-2)

A key direct statement from the landmark paper is: “the impairment of rRNA cleavage by RMRP mutations is the leading cause of bone dysplasia in patients with features in the CHH-AD spectrum.” (thiel2007typeandlevel pages 6-8)

Cellular and tissue cascade

1. Biallelic RMRP/POP1/NEPRO dysfunction alters RNase-MRP-associated biology.
2. Pre-rRNA processing and ribosome production become abnormal; RMRP instability or reduced abundance may worsen the defect.
3. Highly proliferative growth-plate chondrocytes fail to execute normal proliferative-to-hypertrophic differentiation.
4. Columnization, matrix production/mineralization, and endochondral ossification are disrupted.
5. Longitudinal bone growth fails, producing severe metaphyseal, epiphyseal, vertebral, pelvic, and digital abnormalities.

Histologic description in ANXD includes few dispersed chondrocytes, almost absent columnization, and irregular osteochondral ossification. (thiel2007typeandlevel pages 1-2)

In ATDC5 chondrocytes, Rmrp knockdown increased RNase-MRP substrates and an ITS1 processing intermediate, reduced 18S and 5.8S rRNA, and decreased Sox9, Col2a1, Runx2, Col10a1, and Alpl, with particularly strong effects on hypertrophic differentiation. (steinbusch2017expressionofrmrp pages 7-9)

Rmrp promoter activity responded experimentally to developmental mediators: PTHrP −18%, FGF2 −35%, TGF-β3 +40%, BMP2 +105%, dorsomorphin −76%, WNT3A +45%, and WNT5A +26%. These data show pathway responsiveness, not that any of these factors is an established therapy. (steinbusch2017expressionofrmrp pages 7-9)

Suggested ontology annotations

• GO biological process: rRNA processing (GO:0006364); ribosome biogenesis (GO:0042254); chondrocyte differentiation (GO:0002062); chondrocyte hypertrophy (GO:0003415); endochondral ossification (GO:0001958); regulation of cell cycle (GO:0051726).
• GO cellular component: RNase MRP complex (GO:0000172); nucleolus (GO:0005730); nucleus (GO:0005634).
• Cell Ontology: chondrocyte (CL:0000138); hypertrophic chondrocyte and osteoblast should be mapped to the current CL release.

No ANXD-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, epigenomic, organoid, or multi-omics atlas was found. The available molecular profiling is targeted and preclinical.

7. Anatomical structures affected

Primary system: musculoskeletal/connective-tissue system, particularly growth plates and endochondrally formed skeleton.

Primary sites: vertebral column, metaphyses and epiphyses of long bones, pelvis/ilia/acetabula, proximal femur and femoral neck, knees, ankles, radius/ulna, metacarpals, phalanges, hips, and craniovertebral junction. Dentition and cranial sutures can be involved, especially in reported ANXD3. (remmelzwaal2023expandingthephenotype pages 1-2, remmelzwaal2023expandingthephenotype pages 3-4, thiel2007typeandlevel pages 3-4)

Suggested UBERON mappings include growth plate cartilage (UBERON:0003986), cartilage tissue (UBERON:0002418), vertebral column (UBERON:0001130), pelvis (UBERON:0001270), femur (UBERON:0000981), hand skeleton, tooth, and cranial suture; exact release-specific identifiers should be validated.

At tissue level, proliferative and hypertrophic growth-plate chondrocytes and their extracellular matrix are central. Downstream osteoblast/osteoclast remodeling is likely affected through abnormal cartilage scaffolding, but direct ANXD cell-specific evidence is limited. At subcellular level, the nucleolus/nucleus and RNase-MRP ribonucleoprotein complex are implicated. Findings are generally bilateral/generalized rather than unilateral; leg-length discrepancy can be asymmetric in individual patients. (remmelzwaal2023expandingthephenotype pages 3-4, steinbusch2017expressionofrmrp pages 1-2)

8. Temporal development

ANXD begins prenatally or congenitally and follows a chronic lifelong course. Short limbs may be recognized on second-trimester ultrasound, and extreme short length is present at birth. Skeletal disproportionality, scoliosis, joint pain, deformity, and premature growth-plate fusion become more apparent during childhood. (thiel2007typeandlevel pages 2-3, thiel2007typeandlevel pages 3-4)

There is no validated stage system. A practical clinical framework is:

• Prenatal/neonatal: short limbs and marked birth-length deficit.
• Early childhood: progressive growth failure, metaphyseal/epiphyseal changes, brachydactyly and laxity.
• Later childhood/adolescence: increasing scoliosis/kyphosis, hip and limb deformity, joint pain, premature physeal fusion, and possible cervical instability.
• Adulthood: lifelong extreme short stature and orthopedic disability; robust adult natural-history data are lacking.

There is no spontaneous remission. Growth-plate development is the key vulnerability window, but no proven molecular intervention exists during that period.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele.

Penetrance is presumed high for individuals with two severe pathogenic alleles, but it has not been quantified. Expressivity is variable, especially across RMRP and POP1 allelic combinations. Anticipation is not expected. Germline mosaicism has not been established; standard counseling should acknowledge a small residual recurrence risk after an apparently de novo result, although true de novo biallelic ANXD would be unusual.

ANXD-specific prevalence, incidence, carrier frequency, sex ratio, and survival distribution are unknown. ANXD3 had only five published patients before the 2023 case, underscoring its extreme rarity. (remmelzwaal2023expandingthephenotype pages 1-2, remmelzwaal2023expandingthephenotype pages 4-4)

Broader CHH-spectrum statistics must not be misassigned to ANXD: a 2024 review/case report cited CHH-spectrum prevalence of approximately 1:23,000 in Finland with carrier frequency 1:76, and 1–2:1,000 in Amish populations with carrier frequency about 1:10. Those figures reflect RMRP-associated CHH enrichment, not demonstrated ANXD prevalence. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 1-2)

No consistent sex bias exists for an autosomal-recessive disorder. Reported patients occur in multiple ancestries; apparent geographic clustering may reflect founder alleles, consanguinity, ascertainment, and publication bias.

10. Diagnostics

Clinical and radiographic diagnosis

Suspect ANXD in prenatal or congenital extreme short stature with severe disproportion, brachydactyly, joint laxity/dislocation, and a generalized spondylo-epi-metaphyseal radiographic pattern. A skeletal survey should assess the spine, pelvis/hips, long bones, hands/feet, and—given the 2023 ANXD3 findings—the craniovertebral junction when clinically appropriate. (remmelzwaal2023expandingthephenotype pages 1-2, remmelzwaal2023expandingthephenotype pages 3-4)

Characteristic findings include ovoid or foreshortened vertebral bodies/platyspondyly, scoliosis, hypoplastic ilia and acetabula, coxa vara, short femoral necks, small/dysplastic epiphyses, irregular widened metaphyses, shortened tubular bones, short broad metacarpals/phalanges, and premature physeal fusion. (remmelzwaal2023expandingthephenotype pages 1-2, thiel2007typeandlevel pages 3-4)

Suggested baseline assessments are:

• Height, weight, body proportions, head circumference, joint range of motion, neurologic examination, and developmental assessment.
• Skeletal survey and serial targeted radiography; dynamic cervical imaging or MRI if instability is suspected.
• Dental examination and panoramic imaging.
• CBC with differential and immune evaluation to distinguish ANXD from CHH and detect spectrum overlap.
• Gastrointestinal history for Hirschsprung disease/chronic diarrhea; respiratory history and pulmonary assessment if recurrent infection occurs.

No specific serum enzyme assay, metabolite biomarker, electrophysiologic signature, or diagnostic biopsy is established.

Molecular testing

1. Preferred: skeletal-dysplasia panel including RMRP, POP1, and NEPRO, with sequence and copy-number analysis and adequate coverage of the noncoding RMRP transcript and proximal promoter.
2. Phenotype-directed testing: RMRP sequencing for classic severe CHH–AD-spectrum radiology; POP1/NEPRO if RMRP is negative or subtype clues support them.
3. WES: useful for POP1/NEPRO and blended phenotypes, as demonstrated by ANXD3 diagnosis; standard exome pipelines may inadequately capture/promote interpretation of noncoding RMRP variants. (remmelzwaal2023expandingthephenotype pages 4-4, park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4)
4. WGS: potentially advantageous for RMRP promoter/noncoding, copy-number, and structural variants, although ANXD-specific incremental-yield studies are absent.
5. Confirm candidate variants by orthogonal testing and perform parental segregation.

CMA and karyotyping are useful when the phenotype suggests a chromosomal syndrome but are not first-line confirmatory tests for typical ANXD. FISH, mitochondrial-DNA testing, repeat-expansion testing, liquid biopsy, and routine diagnostic transcriptomics/proteomics/metabolomics are not indicated unless another diagnosis is suspected.

Differential diagnosis

Important differentials include cartilage-hair hypoplasia and metaphyseal dysplasia without hypotrichosis; other spondyloepimetaphyseal dysplasias; Schmid metaphyseal chondrodysplasia; achondroplasia/hypochondroplasia; pseudoachondroplasia; diastrophic dysplasia; and severe prenatal skeletal dysplasias. CHH is distinguished by hypotrichosis, anemia, immune deficiency, Hirschsprung disease, and cancer susceptibility; MDWH has milder metaphyseal disease without hair or immune abnormalities. RMRP-associated ANXD has more severe vertebral, pelvic, and epiphyseal involvement. (thiel2007typeandlevel pages 1-2)

No population or newborn screening program exists. Cascade testing is appropriate after familial variants are identified.

11. Outcome and prognosis

No reliable five- or ten-year survival, life-expectancy, mortality, hospitalization, or quality-of-life statistics are available. Published RMRP ANXD patients can survive through childhood and likely adulthood; however, the literature is too sparse to define survival distributions.

Major morbidity is orthopedic: profound short stature, scoliosis/kyphosis, hip dysplasia or ankylosis, coxa vara, limb bowing/inequality, pain, dislocations, and restricted mobility. Atlantoaxial instability can cause cervical myelopathy and creates procedural/anesthetic risk. Dental and craniosynostosis morbidity may occur in ANXD3. (remmelzwaal2023expandingthephenotype pages 3-4, remmelzwaal2023expandingthephenotype pages 4-5)

Unlike CHH, classic ANXD is generally not associated with clinically significant immunodeficiency, anemia, gastrointestinal manifestations, or established malignancy predisposition. Nevertheless, because molecular and phenotypic boundaries overlap, baseline CBC/immune assessment is prudent rather than assuming their absence. (remmelzwaal2023expandingthephenotype pages 1-2, thiel2007typeandlevel pages 5-6)

Prognosis is likely influenced by genotype/functional severity, spinal and cervical instability, hip disease, pain and mobility, access to orthopedic care, and any spectrum-overlap features. No validated prognostic biomarker or calculator exists.

12. Treatment

There is no curative or disease-modifying ANXD therapy and no evidence-based pharmacologic algorithm. Growth hormone has not been shown to correct the primary growth-plate ribosome-biogenesis defect; broader CHH-spectrum cases have normal stimulated GH responses, and treatment was not attempted in the 2024 Korean report. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4)

Current management

• Orthopedic/spine care: surveillance for scoliosis, kyphosis, hip dysplasia, coxa vara, limb deformity, contractures, dislocation, and pain; individualized bracing or corrective surgery.
• Cervical care: evaluate suspected atlantoaxial instability; consider immobilization or surgical fixation according to neurosurgical/orthopedic assessment; use cervical and airway precautions during anesthesia. (remmelzwaal2023expandingthephenotype pages 3-4)
• Rehabilitation: physical and occupational therapy, mobility aids, adaptive equipment, environmental modification, and low-impact activity adapted to joint/spine status.
• Dental/craniofacial care: preventive dentistry, orthodontic/prosthodontic planning, and craniofacial/neurosurgical assessment for craniosynostosis.
• Symptomatic care: pain management and monitoring for neurologic compromise.
• Spectrum surveillance: CBC, immune function, infection history, pulmonary status, and gastrointestinal symptoms when indicated.

Suggested NCIT intervention concepts include Physical Therapy, Occupational Therapy, Orthopedic Surgery, Spinal Fusion, Dental Care, Genetic Counseling, Pain Management, and Surveillance; exact NCIT codes should be validated against the current release.

No gene replacement, CRISPR therapy, cell therapy, ASO/siRNA therapy, targeted small molecule, or immunotherapy is clinically available. Modulating BMP/WNT/TGF-β based solely on promoter-reporter findings would be premature and potentially unsafe. (steinbusch2017expressionofrmrp pages 7-9)

The retrieved ClinicalTrials.gov record NCT00001754, “Clinical and Molecular Manifestations of Human Skeletal Dysplasias and Short Stature,” was a completed NIH observational study enrolling 600 participants across many skeletal disorders, including cartilage-hair hypoplasia. It evaluated phenotype, natural history, and genotype–phenotype relationships; it was not an ANXD treatment trial. URL: https://clinicaltrials.gov/study/NCT00001754. (NCT00001754 chunk 1)

13. Prevention

Primary prevention by lifestyle change, vaccination, or environmental control is not possible. Relevant prevention is reproductive and complication-directed:

• Genetic counseling and familial-variant confirmation.
• Carrier testing for adult relatives.
• Prenatal diagnosis by chorionic-villus sampling or amniocentesis once familial variants are known.
• Preimplantation genetic testing for monogenic disease where available.
• Early prenatal ultrasound can detect limb shortening but is not molecularly specific.
• Cascade testing in at-risk relatives.
• Tertiary prevention through early orthopedic, cervical, dental, respiratory, and rehabilitation surveillance.

No vaccine, prophylactic medication, or population screening program prevents ANXD. Standard immunizations remain appropriate unless an individual has immune dysfunction requiring specialist guidance.

14. Other species and natural disease

No naturally occurring veterinary disorder clearly equivalent to human ANXD was established in the retrieved evidence. There is no zoonotic potential or cross-species transmission because ANXD is inherited, not infectious.

Orthologues of RMRP, POP1, and NEPRO are evolutionarily conserved. RMRP sequences were compared across human, mouse, rat, rabbit, dog, armadillo, elephant, opossum, and frog; disease-associated nucleotides frequently mapped to conserved structural regions. (thiel2007typeandlevel pages 4-5, thiel2007typeandlevel pages 1-2)

Suggested taxa for comparative work include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Xenopus tropicalis (8364). Species-specific NCBI Gene IDs and any OMIA/VBO entries should be verified directly before database loading.

15. Model organisms and experimental systems

Cellular and mouse-derived models

• ATDC5 mouse chondrogenic cells: Rmrp RNAi causes accumulation of RNase-MRP substrates and ITS1 pre-rRNA intermediates, reduction of 18S/5.8S rRNA, and impaired chondrocyte differentiation—especially hypertrophy. This recapitulates a plausible cellular mechanism but not the full multisite human skeletal phenotype. (steinbusch2017expressionofrmrp pages 7-9)
• MCT chondrocytes: temperature-induced hypertrophy increases Rmrp expression; PTHrP suppresses both hypertrophy and Rmrp expression. (steinbusch2017expressionofrmrp pages 7-9)
• Murine growth plate: Rmrp and RNase-MRP proteins are expressed during growth-plate differentiation, supporting biological relevance. (steinbusch2017expressionofrmrp pages 1-2)
• Human fibroblast assays: transient expression of mutant RMRP constructs quantified ITS1/5.8S rRNA and cyclin-B2 mRNA cleavage; functional impairment correlated with clinical severity. These are strong genotype-function assays but do not recreate three-dimensional growth-plate architecture. (thiel2007typeandlevel pages 1-2, thiel2007typeandlevel pages 6-8)
• Patient fibroblast chondrogenic transdifferentiation: broader CHH evidence showed impaired hypertrophic differentiation and supports the same disease spectrum mechanism. (steinbusch2017expressionofrmrp pages 1-2)

No validated ANXD-specific knock-in mouse, zebrafish model, patient-derived iPSC growth-plate organoid, or in-vivo therapeutic-rescue model was demonstrated in the retrieved evidence. These constitute important research gaps. Priority applications include defining NEPRO function, resolving subtype-specific mechanisms, testing whether restoration of RNase-MRP activity rescues chondrocyte maturation, and developing preclinical cervical/spinal and growth-plate outcome measures.

Recent developments and expert interpretation

The most consequential recent direct ANXD development was the 2023 expansion of ANXD3 to include atlantoaxial subluxation, extensive dental anomalies, and sagittal craniosynostosis. Its practical implication is that ANXD3 evaluation should extend beyond stature and limb radiographs to the craniovertebral junction, dentition, and cranial sutures. (remmelzwaal2023expandingthephenotype pages 1-2, remmelzwaal2023expandingthephenotype pages 3-4)

The 2023 skeletal-disorder nosology adopted gene–phenotype dyadic naming across 771 entities and 552 genes, an approach especially useful for ANXD because numbered subtypes can obscure distinct causal genes and overlapping phenotypes. URL: https://doi.org/10.1002/ajmg.a.63132; published February 2023. The preferred knowledge-base labels are therefore RMRP-related anauxetic dysplasia, POP1-related anauxetic dysplasia, and NEPRO-related anauxetic dysplasia.

The 2024 Korean report reinforces that extremely short stature from birth should prompt CHH–AD-spectrum testing even without hair or immune abnormalities and that WES plus RMRP-aware analysis can resolve atypical cases. Its cases were MDWH/CHH rather than pure ANXD, so their immune and anemia frequencies must not be generalized to ANXD. URL: https://doi.org/10.1097/MD.0000000000037247; received November 13, 2023, accepted January 23, 2024, published May 2024. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4, park2024cartilagehairhypoplasia–anauxeticdysplasia pages 1-2)

Principal evidence and exact abstract quotations

1. Remmelzwaal et al., 2023, AJMG Part A. DOI: https://doi.org/10.1002/ajmg.a.63316. Abstract: “The cartilage hair hypoplasia and anauxetic dysplasia (CHH-AD) spectrum encompasses a group of rare skeletal disorders, with anauxetic dysplasia (ANXD) at the most severe end of the spectrum.” It also states, “Thus far, only five patients with type 3 anauxetic dysplasia (ANXD3) have been reported.” This is direct human, single-case evidence. (remmelzwaal2023expandingthephenotype pages 1-2)
2. Thiel et al., 2007, American Journal of Human Genetics. DOI: https://doi.org/10.1086/521034. Abstract: “In vitro testing…revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia.” Direct human genotype–phenotype data plus in-vitro functional assays. (thiel2007typeandlevel pages 1-2)
3. Barraza-García et al., 2017, Clinical Genetics. DOI: https://doi.org/10.1111/cge.12964. Human POP1 cases plus molecular assays; reduced RMRP abundance and increased pre-5.8S rRNA supported RNase-MRP dysfunction. (barrazagarcia2017broadeningthephenotypic pages 1-2)
4. Steinbusch et al., 2017, Scientific Reports. DOI: https://doi.org/10.1038/s41598-017-06809-5. Abstract: “Genetic interference with Rmrp RNA expression in ATDC5 cultures caused a deregulation of chondrogenic differentiation, with a prominent impact on hypertrophy and changes in pre-rRNA processing and rRNA levels.” This is preclinical cellular/mouse-derived evidence, not a clinical treatment study. (steinbusch2017expressionofrmrp pages 1-2)

Evidence limitations

ANXD evidence is dominated by individual cases, a few families, and mechanistic studies spanning the broader CHH–AD spectrum. Consequently, phenotype percentages, penetrance, prevalence, life expectancy, treatment-response rates, and genotype-specific prognosis cannot currently be estimated reliably. Recent 2023–2024 reports improve phenotypic recognition but do not provide population-level natural history or therapeutic evidence. Assertions imported from cartilage-hair hypoplasia—especially immunodeficiency, anemia, Hirschsprung disease, and malignancy risk—must be explicitly labeled as spectrum-level evidence rather than assumed characteristics of pure ANXD.

References

1. (remmelzwaal2023expandingthephenotype pages 1-2): P. Christian Remmelzwaal, Martijn V. Verhagen, Jan D. H. Jongbloed, Peter C. van den Akker, Hermine E. Veenstra‐Knol, and Marrit M. Hitzert. Expanding the phenotype of anauxetic dysplasia caused by biallelic nepro mutations: a case report. American Journal of Medical Genetics Part A, 191:2440-2445, Jun 2023. URL: https://doi.org/10.1002/ajmg.a.63316, doi:10.1002/ajmg.a.63316. This article has 5 citations.

2. (thiel2007typeandlevel pages 1-2): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

3. (thiel2007typeandlevel pages 5-6): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

4. (thiel2007typeandlevel pages 3-4): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

5. (thiel2007typeandlevel pages 6-8): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

6. (barrazagarcia2017broadeningthephenotypic pages 1-2): J. Barraza-García, J. Barraza-García, J. Barraza-García, C. I. Rivera-Pedroza, C. I. Rivera-Pedroza, A. Hisado-Oliva, A. Hisado-Oliva, A. Hisado-Oliva, A. Belinchón-Martínez, A. Belinchón-Martínez, A. Belinchón-Martínez, L. Sentchordi-Montané, L. Sentchordi-Montané, Emma L Duncan, G. R. Clark, A. D. Pozo, A. D. Pozo, K. Ibáñez-Garikano, A. Offiah, P. Prieto-Matos, V. Cormier-Daire, K. E. Heath, K. E. Heath, and K. E. Heath. Broadening the phenotypic spectrum of pop1‐skeletal dysplasias: identification of pop1 mutations in a mild and severe skeletal dysplasia. Clinical Genetics, 92:91-98, Feb 2017. URL: https://doi.org/10.1111/cge.12964, doi:10.1111/cge.12964. This article has 24 citations and is from a peer-reviewed journal.

7. (remmelzwaal2023expandingthephenotype pages 4-4): P. Christian Remmelzwaal, Martijn V. Verhagen, Jan D. H. Jongbloed, Peter C. van den Akker, Hermine E. Veenstra‐Knol, and Marrit M. Hitzert. Expanding the phenotype of anauxetic dysplasia caused by biallelic nepro mutations: a case report. American Journal of Medical Genetics Part A, 191:2440-2445, Jun 2023. URL: https://doi.org/10.1002/ajmg.a.63316, doi:10.1002/ajmg.a.63316. This article has 5 citations.

8. (remmelzwaal2023expandingthephenotype pages 3-4): P. Christian Remmelzwaal, Martijn V. Verhagen, Jan D. H. Jongbloed, Peter C. van den Akker, Hermine E. Veenstra‐Knol, and Marrit M. Hitzert. Expanding the phenotype of anauxetic dysplasia caused by biallelic nepro mutations: a case report. American Journal of Medical Genetics Part A, 191:2440-2445, Jun 2023. URL: https://doi.org/10.1002/ajmg.a.63316, doi:10.1002/ajmg.a.63316. This article has 5 citations.

9. (thiel2007typeandlevel pages 2-3): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

10. (steinbusch2017expressionofrmrp pages 1-2): Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don A. M. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche L. M. Schroen, Lodewijk W. van Rhijn, Bernhard Zabel, and Tim J. M. Welting. Expression of rmrp rna is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation. Scientific Reports, Jul 2017. URL: https://doi.org/10.1038/s41598-017-06809-5, doi:10.1038/s41598-017-06809-5. This article has 56 citations and is from a peer-reviewed journal.

11. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 2-4): Ju Heon Park, Minji Im, Yae-Jean Kim, Ja-Hyun Jang, Sae-Mi Lee, Min-Sun Kim, and Sung Yoon Cho. Cartilage-hair hypoplasia–anauxetic dysplasia spectrum disorders harboring rmrp mutations in two korean children: a case report. Medicine, 103:e37247, May 2024. URL: https://doi.org/10.1097/md.0000000000037247, doi:10.1097/md.0000000000037247. This article has 4 citations and is from a peer-reviewed journal.

12. (steinbusch2017expressionofrmrp pages 7-9): Mandy M. F. Steinbusch, Marjolein M. J. Caron, Don A. M. Surtel, Franziska Friedrich, Ekkehart Lausch, Ger J. M. Pruijn, Wouter Verhesen, Blanche L. M. Schroen, Lodewijk W. van Rhijn, Bernhard Zabel, and Tim J. M. Welting. Expression of rmrp rna is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation. Scientific Reports, Jul 2017. URL: https://doi.org/10.1038/s41598-017-06809-5, doi:10.1038/s41598-017-06809-5. This article has 56 citations and is from a peer-reviewed journal.

13. (park2024cartilagehairhypoplasia–anauxeticdysplasia pages 1-2): Ju Heon Park, Minji Im, Yae-Jean Kim, Ja-Hyun Jang, Sae-Mi Lee, Min-Sun Kim, and Sung Yoon Cho. Cartilage-hair hypoplasia–anauxetic dysplasia spectrum disorders harboring rmrp mutations in two korean children: a case report. Medicine, 103:e37247, May 2024. URL: https://doi.org/10.1097/md.0000000000037247, doi:10.1097/md.0000000000037247. This article has 4 citations and is from a peer-reviewed journal.

14. (remmelzwaal2023expandingthephenotype pages 4-5): P. Christian Remmelzwaal, Martijn V. Verhagen, Jan D. H. Jongbloed, Peter C. van den Akker, Hermine E. Veenstra‐Knol, and Marrit M. Hitzert. Expanding the phenotype of anauxetic dysplasia caused by biallelic nepro mutations: a case report. American Journal of Medical Genetics Part A, 191:2440-2445, Jun 2023. URL: https://doi.org/10.1002/ajmg.a.63316, doi:10.1002/ajmg.a.63316. This article has 5 citations.

15. (NCT00001754 chunk 1): Study of Skeletal Disorders and Short Stature. National Human Genome Research Institute (NHGRI). 1998. ClinicalTrials.gov Identifier: NCT00001754

16. (thiel2007typeandlevel pages 4-5): Christian T. Thiel, Geert Mortier, Ilkka Kaitila, André Reis, and Anita Rauch. Type and level of rmrp functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. American journal of human genetics, 81 3:519-29, Sep 2007. URL: https://doi.org/10.1086/521034, doi:10.1086/521034. This article has 114 citations and is from a highest quality peer-reviewed journal.

Artifacts

• Edison artifact artifact-00