Metaphyseal Dysplasias (Schmid, Jansen, Cartilage–Hair Hypoplasia)

Chondrodysplasias predominantly affecting the metaphyses of the long bones: Schmid metaphyseal chondrodysplasia (COL10A1), Jansen metaphyseal chondrodysplasia (activating PTH1R variants) and the cartilage–hair hypoplasia–anauxetic dysplasia spectrum (RMRP, POP1, NEPRO), with Shwachman–Diamond syndrome as a major differential diagnosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

This article brings together three core, clinically distinct entities that share a metaphyseal location of the growth lesion, and a group of rare phenocopies involving the same biological pathway as the cartilage–hair spectrum. The following table summarises the three main entities; the second table brings together anauxetic dysplasia types 2 and 3 and the allelic PTH1R disorders.

1. Introduction

1.1. Metaphyseal Chondrodysplasias as a Group

Metaphyseal chondrodysplasias are skeletal dysplasias in which the main lesion lies in the metaphysis, the region of a long bone adjacent to the growth plate where hypertrophic cartilage calcifies and is replaced by bone. The epiphyses and spine are little affected or unaffected, distinguishing this group from spondyloepiphyseal and spondylometaphyseal dysplasias. The Oxford Desk Reference describes them as difficult to classify and to distinguish from metabolic disorders such as rickets on radiographs alone, and recommends describing the affected segments, undertaking radiological studies in relatives and seeking support from radiologists experienced in dysplasias [35]. The distinction has practical consequences: before the correct diagnosis, a child with genu varum and irregular metaphyses often receives vitamin D supplements for nutritional rickets that is not present, and vitamin D is contraindicated in these chondrodysplasias [1, 2].

The 2023 revision of the Nosology of genetic skeletal disorders classifies 771 entities associated with 552 genes and adopts dyadic names combining phenotype and gene [3]. In that revision, the Schmid form appears as “metaphyseal dysplasia Schmid (MCS), COL10A1-related”, the cartilage–hair spectrum as RMRP-related “CHH-AD”, and the Jansen form moved into a new group, skeletal disorders of the PTH signalling cascade, which also includes Blomstrand chondrodysplasia, Eiken dysplasia and type E brachydactylies [1, 5, 7]. The three core entities of this article therefore have unrelated mechanisms: a disorder of a structural protein of hypertrophic cartilage (Schmid), an endocrine and paracrine signalling disorder (Jansen), and a ribosomopathy with immunodeficiency (CHH).

1.2. Schmid Metaphyseal Chondrodysplasia

In 1949, Friedrich Schmid described an “enchondral metaphyseal dysostosis” with dominant inheritance, and clinical and radiological delineation was consolidated by Lachman, Rimoin and Spranger in 1988 [2, 36]. Extended pedigrees and the natural history study by Rosenbloom and Smith in 1965 followed [37]. In 1993, Warman and colleagues identified the first pathogenic variant in a large Mormon family with a lod score of 18.2: a 13-base-pair (bp) deletion in COL10A1 that altered the carboxy-terminal non-collagenous (NC1) domain of the α1(X) chain and shortened the polypeptide by 9 residues [38]. “Japanese”-type spondylometaphyseal dysplasia, described by Hasegawa in 1994 and associated with a heterozygous COL10A1 variant by Ikegawa in 1998, was considered identical to the Schmid form by Savarirayan and colleagues in 2000, adding occasional mild platyspondyly to the phenotype [1, 4].

1.3. Jansen Metaphyseal Chondrodysplasia

In 1934, Murk Jansen described a congenital “metaphyseal dysostosis” with severe dwarfism and limb deformities; follow-up of the first patient into adulthood was published by De Haas and colleagues in 1969, and Charrow and Poznanski confirmed dominant inheritance in 1984 [6, 39]. In 1995, Schipani, Kruse and Jüppner demonstrated a heterozygous histidine-to-arginine substitution at residue 223 (H223R) in the first intracellular loop of the PTH/PTHrP receptor, leading to accumulation of cyclic adenosine monophosphate (cAMP) in the absence of ligand; the variant simultaneously explained PTH-independent hypercalcaemia and hypophosphataemia and probably the altered endochondral ossification, in a COS-7 cell assay in which only the mutant receptor accumulated cAMP [40]. Loss-of-function variants in the same gene were subsequently associated with Blomstrand chondrodysplasia and Eiken dysplasia, and heterozygous loss-of-function variants with primary failure of tooth eruption [5, 6, 32].

1.4. Cartilage–Hair Hypoplasia and Anauxetic Dysplasia

Cartilage–hair hypoplasia was described by Maroteaux and colleagues in 1963, and in 1965 McKusick and colleagues published 77 patients from the Old Order Amish community with metaphyseal cartilage hypoplasia, hypoplastic hair, malabsorption, congenital megacolon and fatal varicella [11, 41]. Laboratory defects of cellular immunity were recognised in the 1970s, and the disorder also proved frequent in Finland, where Mäkitie and Kaitila described 107 to 108 patients in the early 1990s [11, 42, 43]. In 2001, Ridanpää and colleagues identified RMRP, an intronless, untranslated nuclear gene encoding the RNA component of the mitochondrial RNA-processing endoribonuclease (RNase MRP) [44]. In 2002, the same group described 36 variants in 135 families and showed that the most common variant, then called “70A>G”, resulted from a single ancient founder event [45].

In 2001, Horn and colleagues described anauxetic dysplasia (from the Greek for “not permitting growth”), a spondylometaepiphyseal dysplasia with extreme dwarfism, and in 2005 Thiel and colleagues showed that it was also caused by biallelic RMRP variants [46, 47]. In 2002, Bonafé and colleagues confirmed a form with skeletal manifestations alone, metaphyseal dysplasia without hypotrichosis [48]. The spectrum was thus described as a continuum of three phenotypes — MDWH, CHH and ANXD1 — and in 2007 Thiel and colleagues related each phenotype's position on the continuum to the type and degree of RNase MRP loss of function [8, 49]. In 2020, follow-up of Finnish patients with MDWH showed that 8 of 10 subsequently developed malignancy or clinically significant immunodeficiency, and the authors proposed that MDWH should cease to be treated as a separate entity and should be managed as CHH [50]. Vakkilainen's 2025 review describes CHH as a syndromic inborn error of immunity [11].

Biallelic POP1 variants, encoding a protein shared by RNase MRP and RNase P, were identified in 2011 in an anauxetic-like dysplasia, later termed anauxetic dysplasia type 2, and biallelic NEPRO variants, whose product interacts with protein subunits of RNase MRP, defined anauxetic dysplasia type 3 in 2019 [26–28]. These forms are functionally rather than allelically related to RMRP, and both appear as subsections of the spectrum.

1.5. Definitions Used in the Article

Schmid metaphyseal chondrodysplasia (SMCD) is defined as metaphyseal dysplasia caused by a heterozygous, or rarely biallelic, COL10A1 variant, with short-limbed short stature, coxa vara and genu varum, normal mineral biochemistry and no extraskeletal manifestations [1]. Jansen metaphyseal chondrodysplasia (JMC) is defined by a heterozygous activating PTH1R variant, with severe metaphyseal dysplasia and PTH-independent mineral metabolism abnormalities [5]. The CHH-AD spectrum is defined by biallelic RMRP variants, with phenotypes ranging from isolated short stature to the extreme dwarfism of ANXD1; Japanese authors have also proposed the term “RMRP-related short stature” for forms without evident skeletal abnormalities or extraskeletal manifestations [8, 51]. Shwachman–Diamond syndrome, in which metaphyseal chondrodysplasia is a consistent feature, is treated as a differential diagnosis [33].

2. Molecular Genetics and Pathophysiology

2.1. COL10A1 and Type X Collagen

Type X collagen is a non-fibrillar homotrimer composed of three α1(X) chains, secreted into the extracellular matrix and expressed exclusively by hypertrophic growth plate chondrocytes during endochondral ossification [1, 37]. Each chain has an amino-terminal signal peptide, a collagenous helical domain and a carboxy-terminal non-collagenous (NC1) domain containing the motifs required for chain recognition and trimer assembly [1]. Pathogenic variants cluster in the NC1 domain; both missense substitutions and truncating variants (frameshift and premature termination) cause misfolding, failed trimerisation and protein aggregation in the endoplasmic reticulum (ER) of hypertrophic chondrocytes [1, 2]. This results in ER stress with activation of the unfolded protein response (UPR), disruption of hypertrophic chondrocyte differentiation and reduced functional collagen X [1, 52]. Metaphyseal cartilage calcification is disrupted and longitudinal growth restricted, with preservation of the epiphyses, explaining the absence of early osteoarthritis [1, 2].

The dominant mechanism has been interpreted in two ways. The first, based on degradation of mutant messenger RNA (mRNA) by nonsense-mediated decay (NMD) in a cartilage biopsy, proposed haploinsufficiency [1, 53]. The second proposes a dominant-negative or neomorphic effect mediated by retained protein [1]. More recent experimental data favour the second: in mice with the Col10a1 p.N617K variant (published designation of the murine model), mutant protein increased ER stress and disrupted hypertrophic differentiation [54]; in an iliac crest biopsy with the p.Y632X variant (published designation; in humans, p.(Tyr632Ter), NM_000493.4:c.1896C>G or c.1896C>A; section 2.2), mutant mRNA was unstable, but in a knock-in mouse with the same variant the mRNA was not degraded, the truncated protein was translated and retained, and the phenotype was relatively severe, with ER stress and UPR [55]. The haploinsufficiency interpretation continues to be cited in clinical reports [56]. This debate has therapeutic significance: if the disorder results from retained misfolded protein, stimulating intracellular degradation of that protein is a rational strategy, and this is the basis for carbamazepine repurposing (section 7.2) [54, 55].

2.2. COL10A1 Variant Spectrum and Genotype–Phenotype Correlations

GeneReviews does not list individual COL10A1 variants; all reported pathogenic variants are missense, truncating or small intragenic deletions, duplications and indels, and no whole-gene deletions or duplications have been described [1]. Penetrance approaches 100%, with substantial inter- and intrafamilial variability; some carriers have normal stature, but radiographic findings are usually present [1]. Manifestations are age-dependent: hand and spinal findings become less pronounced and enlarged capital femoral epiphyses normalise [1, 57].

In the Turkish cohort of 24 patients with metaphyseal dysplasia, 17 had seven different heterozygous COL10A1 variants, and the phenotype was more severe with missense variants (one in the signal peptide, another in NC1) than with truncating variants [57]. Meng and colleagues' analysis of 128 patients (4 Chinese patients and 124 from the literature) showed that NC1-domain variants were associated with earlier onset than variants outside NC1 (median 12 versus 72 months; P = 0.0014), and that patients with missense variants had a lower height Z-score at initial assessment (−3.62 ± 1.95 versus −1.99 ± 1.28 for truncating variants; P = 0.013) and more metaphyseal irregularities in the distal radius and ulna (P = 0.019) [58]. These are group differences and cannot predict an individual patient's course; GeneReviews considers that no genotype–phenotype correlations have been established [1].

Homozygosity or compound heterozygosity produces more severe phenotypes. Ain and colleagues described a recessive chondrodysplasia with severe short stature due to a biallelic variant, the Turkish cohort included a severely affected patient with a biallelic NC1 missense variant, and a seven-generation consanguineous Pakistani family had multiple miscarriages attributed to homozygosity [57, 59, 60]. In 2026, Doğan Arı and Kılıç described a family with the homozygous NM_000493.4:c.1954C>T p.(Leu652Phe) variant whose heterozygous parents were clinically unaffected, showing that some variants cause disease only in the biallelic state and that SMCD may follow a recessive pattern in such families [12]. This variant has conflicting classifications in ClinVar [10]. No allelic phenotypes are known for germline COL10A1 variants [1].

2.3. PTH1R: Receptor Physiology and Constitutive Activation

PTH1R encodes a receptor coupled to stimulatory G protein (Gs) and adenylate cyclase, activated by PTH and PTHrP, and expressed in the kidney, osteoblasts and growth plate chondrocytes [5]. In the proximal tubule, receptor activation causes phosphaturia and stimulates synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), increasing intestinal calcium and phosphate absorption; in the distal tubule it increases calcium reabsorption; in osteoblasts it increases receptor activator of nuclear factor κB ligand (RANKL) and osteoclastogenesis; in prehypertrophic chondrocytes, PTHrP signalling slows differentiation into hypertrophic chondrocytes, thus regulating linear growth [5]. In JMC, activating variants produce constitutive, ligand-independent signalling in all these tissues: delayed chondrocyte differentiation explains the metaphyseal dysplasia, and renal and bone activation explains hypercalcaemia, hypophosphataemia and hypercalciuria with suppressed PTH [5, 6].

Saito and colleagues studied the five known variants in HEK293 cells and demonstrated variable degrees of basal and PTH-stimulated cAMP signalling [18]. In humanised mice, H223R caused early death without reproduction, whereas T410R, associated with a milder phenotype in patients, produced a stable line with near-normal longevity and a profound skeletal phenotype (deformed long bones, expanded metaphyses, disorganised chondrocyte zones and reduced primary spongiosa); genetic ablation of Hdac4 corrected the growth plate abnormalities (human HDAC4 haploinsufficiency causes brachydactyly with intellectual disability), identifying the PTH1R–Gαs–cAMP–protein kinase A–SIK3–HDAC4/5 pathway as the main mediator [63]. In iliac crest biopsies from two siblings with H223R, aged 6 and 8 years, bone architecture was irregular, with increased osteoid and prolonged maturation, normal trabecular volume, increased receptor expression in osteoblasts and fibroblastic cells, cortical areas of intense osteoclastic activity, scattered marrow fibrosis, osteocytes with shorter and fewer canaliculi, increased fibroblast growth factor 23 (FGF23) and reduced sclerostin [64]. The disorder therefore has a bone component extending beyond chondrodysplasia.

2.4. PTH1R Variants and Allelic Disorders

All variants described in JMC are activating missense variants distributed across three residues; H223R is recurrent (18 of 24 patients in Saito's series) [5, 18]. The following table presents current nomenclature, normalised in VariantValidator and ClinVar, and the historical designation.

Sources: [5, 10, 18, 61]. Penetrance is high, with short-limbed dwarfism in almost all individuals; T410R was associated with less reduced adult height [5, 18]. H223R is also annotated in ClinVar for primary failure of tooth eruption [10].

The direction of effect and zygosity determine the PTH1R phenotype. Heterozygous activating variants cause JMC; biallelic loss-of-function variants cause lethal Blomstrand chondrodysplasia, with accelerated chondrocyte differentiation, increased bone density and advanced skeletal maturation; biallelic hypomorphic variants cause Eiken dysplasia, with markedly delayed ossification; and heterozygous loss-of-function variants cause primary failure of tooth eruption [5, 31, 32]. Tsujioka and colleagues' radiological review organises the PTH cascade group by degree of signalling: increased signalling produces osteolysis, focal osteosclerosis and delayed growth plate ossification (JMC); partial loss produces type E brachydactyly, as in pseudohypoparathyroidism; complete loss produces Blomstrand dysplasia [7]. Eiken syndrome with PTH resistance due to a novel PTH1R variant was published in 2024, and a type E brachydactyly syndrome due to receptor helix 8 variants in 2026 [65, 66]. A report stating only “PTH1R variant”, without specifying whether it is activating or inactivating and heterozygous or biallelic, does not allow phenotype assignment or recurrence risk calculation [5].

2.5. RMRP and RNase MRP

RMRP is a nuclear gene without introns or exons whose transcript is untranslated; the 2025 review describes a 269-nucleotide gene encoding a long non-coding RNA [8, 11]. GeneReviews gives 267 bp in one section and 268 bp in another, and RefSeq versions differ (NR_003051.3 with 277 nucleotides, replaced in 2022; NR_003051.4 with 270 nucleotides), contributing to differences in variant numbering [8, 10, 11]. The promoter is type 3, with a proximal sequence element, TATA box and upstream transcription factor-binding sites [8]. The RNA folds into a complex secondary structure and associates with at least ten proteins (Rpp14, Rpp20, Rpp25, Rpp29, Rpp30, Rpp38, Rpp40, Pop1 and Pop5, shared with RNase P, and the human-specific subunits Rmp24 and Rmp64) to form RNase MRP, present in the nucleolus and mitochondria [8, 11].

RNase MRP cleaves precursor ribosomal RNA (pre-rRNA) within internal transcribed spacer 1, a step required for 5.8S rRNA maturation and ribosome assembly, and cleaves cyclin B mRNA, linking it to cell cycle regulation; other reported substrates are the mitochondrial replication primer and viperin mRNA [8, 11, 30]. The complex also associates with telomerase reverse transcriptase (TERT) [8]. In 2005, Thiel and colleagues showed that anauxetic dysplasia variants severely impair pre-rRNA cleavage without affecting cyclin B mRNA levels, whereas the CHH founder variant affects both pathways to an intermediate degree [47]. In 2007, using 13 variants, they demonstrated that reduced rRNA cleavage (ribosome assembly) correlates with the degree of bone dysplasia and that reduced mRNA cleavage (cell cycle) predicts hair hypoplasia, immunodeficiency, haematological abnormalities and cancer risk [49]. GeneReviews attributes these extraskeletal features to disrupted rRNA cleavage, contradicting the primary source; this article follows Thiel 2007 [8, 49].

RMRP-deficient cells accumulate in the G2 phase of the cell cycle, with altered cyclins and kinases and increased apoptosis in peripheral blood mononuclear cells; defective lymphocyte proliferation is the clearest mechanism underlying infections, autoimmunity and malignancies [11]. Eleven of 15 individuals homozygous for the founder variant had short lymphocyte telomeres, 7 also in granulocytes, and in the Finnish cohort of 48 patients telomeres were short for age in 52% of patients and 89% of children, without association with clinical findings [11]. In mice, Rmrp and RNase MRP subunits concentrate in hypertrophic-zone chondrocytes, and in zebrafish lacking rmrp, chondrogenesis is disrupted by Wnt/β-catenin pathway activation, partially attenuated by the inhibitor XAV939 in a preclinical model [11]. Complete RMRP knockout has not been achieved in yeast or mice, and an upstream insertion was lethal before embryonic day 6.5, suggesting that total absence of function is incompatible with life [11].

2.6. RMRP Variants, Nomenclature and Founder Effect

Pathogenic variants in the transcribed region mainly affect highly conserved nucleotides, altering secondary structure through stem mismatching or RNA–protein interaction; benign variants cluster in non-conserved nucleotides [8, 11]. Promoter variants are insertions, duplications or triplications between the TATA box and transcription start site; increasing this distance by 24–26 bp renders the promoter inefficient and reduces the transcript [8, 44]. In the 2002 series, the nucleolar localisation signal region (nucleotides 23–62) had no variants [45].

The same variant has three designations in the literature. The Finnish and Amish founder variant was called “70A>G” in the studies by Ridanpää and Rider, corresponds to NR_003051.3:n.71A>G in the 2025 review and GeneReviews (NG_017041.1:g.71A>G), and to NR_003051.4:n.72A>G in ClinVar and recent studies; all three designations correspond to the same genomic nucleotide, NC_000009.12:g.35657948T>C, confirmed in VariantValidator [8, 10, 11, 45, 61, 67]. This article uses the NR_003051.4 designation and provides the historical designation in parentheses.

Sources: [8, 10, 11, 45, 49, 51, 61, 68, 69]. VariantValidator does not accept “n.-” notation for a non-coding transcript and returns the genomic form shown in the table [61]. The NR_003051:n.35C>A variant in the Omenn syndrome overlap case published in 2026 was reported without a transcript version, and its correspondence in the current version could not be confirmed [70].

Haplotype analysis places the introduction of the founder variant into Finland approximately 3900–4800 years ago; a common haplotype of more than 60 kilobases in 23 of 27 non-Finnish chromosomes indicates a single ancient founder event [45]. Carrier frequency is 1:76 in Finland; for the Amish, GeneReviews gives 1:10 and the 2025 review gives 1:19 [8, 11]. Two founders have been described in Japan, a 17-bp promoter duplication and n.220A>G [11]. In Brazil, Gomes and colleagues genotyped four single-nucleotide polymorphisms in 32 patients and their parents and found a common haplotype among n.197C>T carriers, consistent with a single founder, probably European, in a sample with 58% European, 24% African and 18% Native American ancestry [68].

2.7. Genotype–Phenotype Correlations in the CHH-AD Spectrum

GeneReviews describes correlations dependent on the variant's position in the transcript and its effect on folding and RNA–protein interaction. Milder phenotypes are associated with compound heterozygosity or homozygosity for transcript variants with a small to intermediate effect, or a combination of a transcript variant and a promoter variant; ANXD1 is associated with combinations of variants severely affecting function, or a severe variant with a hypomorphic allele [8]. In practice, correlation is inconsistent: siblings with the same genotype may have different immunological courses, and intrafamilial variability occurs [9, 11]. The three known patients with two promoter variants had severe immunodeficiency, suggesting a dose-dependent effect; of 36 transplanted patients with a published genotype, only 9 were homozygous for n.72A>G, suggesting that this genotype is less frequent among severe cases [11]. Reported patients with normal stature are predominantly compound heterozygotes with promoter duplications or triplications [11]. Heterozygotes are asymptomatic, have no lymphocyte proliferation defect and no increased cancer risk [8, 11].

The allelic RMRP spectrum includes patients with immunodeficiency without skeletal findings, patients with Omenn syndrome and patients with normal childhood growth [8]. In 2026, a neonate with skeletal dysplasia, immunodeficiency and neonatal erythroderma, with CHH–Omenn syndrome overlap, was described with a homozygous RMRP variant [70]. The 2024 Japanese series described six patients with moderate short stature and mild metaphyseal dysplasia or brachydactyly alone, and siblings affected only by mild short stature [51]. ClinGen has RMRP-specific specifications of the ACMG/AMP (American College of Medical Genetics and Genomics / Association for Molecular Pathology) guidelines, version 1.0.0, developed by the severe combined immunodeficiency expert panel, and a dedicated curation group [8, 11].

2.8. POP1 and NEPRO: Anauxetic Dysplasia Types 2 and 3

POP1 encodes a protein shared by RNase MRP and RNase P that interacts with the RMRP RNA domains affected in ANXD1; in patients' cells, RMRP RNA is markedly reduced and 5.8S pre-rRNA increased [11, 26, 27]. Glazov and colleagues identified the first variants by exome sequencing in one family, and Elalaoui and colleagues described a 5-year-old Moroccan boy born to consanguineous parents, homozygous for NM_001145860.2:c.1744C>T p.(Pro582Ser), proposing the designation anauxetic dysplasia type 2 [26, 27]. The 2025 review describes POP1 deficiency as a severe anauxetic-like skeletal dysplasia without extraskeletal manifestations, placing it among the skeletal ribosomopathies alongside RPL13, SBDS and NEPRO [11].

NEPRO (formerly C3orf17) encodes a protein interacting with RNase MRP protein subunits. Narayanan and colleagues identified the biallelic NM_015412.4:c.435G>C p.(Leu145Phe) variant by trio exome sequencing in a 6-year-old girl with CHH features and no RMRP or POP1 variants, and assembled two families from the literature with four affected individuals homozygous for NM_015412.4:c.280C>T p.(Arg94Cys) [28]. All five had severe short stature, brachydactyly, skin laxity, joint hypermobility and dislocations, short metacarpals, broad middle phalanges and metaphyseal irregularities [28]. In 2026, three new cases in a consanguineous Iranian family homozygous for c.280C>T added microcephaly, clubfoot, cataracts, urolithiasis and hearing impairment to the phenotype; the authors describe ANXD3 as a form without immune or gastrointestinal involvement [29]. The POP1 and NEPRO variants are written on the MANE Select transcripts, with the same c. and p. numbering as in the publications.

3. Clinical Spectrum and Systemic Manifestations

3.1. Schmid Metaphyseal Chondrodysplasia

Growth and Age-Related Course

Most neonates with SMCD have normal length and weight; growth deficiency develops progressively from the second year of life, and presentation is usually after 2 years because of short-limbed short stature and bowed legs [1, 2, 71]. In the Turkish cohort, short stature became apparent after 3 years and coxa vara after 5 years [57]. Adult height is usually below −3 to −3.5 standard deviations (SD), between 130 and 160 cm, but the range is broad and overlaps normal stature; it rarely falls below −7 SD, and no specific growth charts exist [1, 2, 37]. Intelligence is normal and early motor milestones are preserved; mild motor delays accompany orthopaedic complications [1].

Musculoskeletal System

Genu varum with a waddling gait is usually the first sign, with tibial bowing most pronounced near the ankle, coxa vara, lumbar hyperlordosis and flaring of the lower rib cage [1, 37]. Knee and hip pain is common in children and adults and may limit activity; reduced mobility promotes obesity [1]. Smith describes childhood leg pain, symptomatic and radiographic improvement from 3 years and absence of osteoarthritic symptoms because the epiphyses are unaffected; Spranger's atlas states that genu varum persists into adulthood, generally without impairing joint function [2, 37]. A Turkish family with p.(Tyr582Asp) had Wormian bones in 6 of 6 examined members, a previously unreported finding, and platyspondyly in all 7 patients from the two families [12]. Frequencies of findings, compiled by GeneReviews from more than 150 published individuals and the authors' experience, are shown below.

Source: [1, 57, 72]. The two GeneReviews frequency columns differ for three findings, and both are retained in the table.

Other Manifestations

Craniofacial appearance is normal and there are no extraskeletal manifestations [1]. Hypothyroidism, growth hormone deficiency, coeliac disease, hypospadias and mild microcephaly have rarely been reported, possibly coincidentally [1, 56]. Life expectancy is unaffected [37].

3.2. Jansen Metaphyseal Chondrodysplasia

Skeleton and Growth

Children may be born with or without visible abnormalities; wide sutures, prominent eyes, choanal stenosis, micrognathia and a high-arched palate may already be detectable at birth, and rickets-like radiological changes may be prenatal [5, 6, 73]. Postnatal growth delay and skeletal deformities develop in early childhood, with delayed motor milestones (standing, walking), waddling gait, crouched posture, enlarged joints with bony restriction of mobility and ligamentous hyperlaxity, genu varum, clinodactyly, short clubbed fingers and scoliosis of variable severity [5, 6, 74]. Adult height ranges from 105 to 130 cm and was far below the third percentile in all patients in Saito's series except T410R carriers [6, 18]. Most of the 24 patients in that series underwent orthopaedic surgery [18]. The National Institutes of Health (NIH) trial registry adds frequent fractures, bone pain, multiple operations and reduced mobility requiring walking aids [22].

Mineral Metabolism and Kidney

Hypercalcaemia with low-normal or suppressed PTH, mild hypophosphataemia and hypercalciuria are the biochemical features; alkaline phosphatase, osteocalcin, urinary hydroxyproline and urinary cAMP are elevated [5, 6]. Saito and colleagues described age-related changes in 24 patients: postnatal calcium was normal in most, rose between 0.15 and 10 years (11.8 ± 1.37 mg/dL) and tended to normalise in adults (10.0 ± 1.03 mg/dL); mean phosphate remained at the lower limit of normal for age; the urinary calcium/creatinine ratio (mg/mg) remained elevated at all ages (0.80 ± 0.40 in children; 0.28 ± 0.19 in adults) [18]. Most had nephrocalcinosis and 2 had advanced chronic kidney disease (CKD); end-stage kidney disease requiring renal replacement therapy has been described [5, 18]. Not all patients have hypercalcaemia: in a family with H223R, both children had overt hypercalcaemia and suppressed PTH, but their 38-year-old mother had never had documented hypercalcaemia and was diagnosed only after her children [74]. Normal serum calcium in an adult does not exclude the diagnosis [5, 18].

Skull, Face, Teeth and Airway

The craniofacial phenotype includes scaphocephaly, prominent forehead and supraorbital ridges, downslanting palpebral fissures, hypertelorism, telecanthus, a broad nasal bridge, maxillary hypoplasia or hyperplasia, low-set ears and retrognathia; older individuals have frontonasal hyperostosis and skull base sclerosis [5, 6]. In the NIH study of 6 patients, sagittal craniosynostosis was present in 5, one of whom had undergone cranial reconstruction for pansynostosis in childhood; computed tomography (CT) showed bilaterally symmetrical expansile lesions, predominantly in neural crest-derived bones, paranasal sinus obliteration in 5 of 6 and bilateral narrowing of the labyrinthine segment of the facial nerve canal in 5 of 6, with progressive facial paralysis in one patient [19]. [18F]-sodium fluoride positron emission tomography showed increased uptake in the skull base and gnathic bones in all patients [19]. Dental findings include a flat shallow palate, delayed eruption with retained or impacted teeth, crowding, malocclusion, multiple extractions and sometimes enamel hypoplasia [5, 19]. Upper airway stenosis with anterior displacement of the hyoid bone was present in all NIH patients, with obstructive sleep apnoea in 2 [19].

Hearing and Vision

Hearing impairment may be conductive (ossicular abnormalities, tympanic membrane stiffness, epitympanic crowding), sensorineural (internal auditory canal narrowing) or mixed, and may progress; at the NIH it was subclinical or mild, predominantly conductive, in 4 of 5 tested patients [5, 19]. Optic canal narrowing causes optic nerve compression and progressive optic neuropathy [5]. In the NIH ophthalmological series, visual acuity was good in 5 of 6; one patient had advanced optic atrophy, with retinal nerve fibre layer thinning on optical coherence tomography (OCT), bilateral optic canal narrowing, central visual field defects and abnormal colour vision; another had subtle temporal pallor; and ganglion cell complex thickness was reduced in 4 of 6, indicating subclinical optic atrophy [75]. Findings became more frequent and pronounced with age, without glaucoma or high myopia [75].

Blood Pressure

Elevated blood pressure is frequent and may develop in infancy, with an unknown cause; severe childhood hypertension has been described [5, 76]. Intelligence is normal, and longevity data are unavailable [5, 6].

3.3. Cartilage–Hair Hypoplasia

Growth and the Perinatal Period

Short stature in CHH begins before birth. In the Finnish cohort of 35 children born between 2000 and 2023, prenatal ultrasonography showed abnormal growth in 26 of 30 (87%), predominantly short humeri and femora and a small chest, with most findings in the second trimester; median term birth length was 44.5 cm in boys and 44.0 cm in girls, with a median adjusted Z-score of −3.9 and values below −2.0 in 84% [17]. The 2025 review gives birth length of −2.9 SD in boys and −3.0 SD in girls, with 70% of Finnish patients and 64% of an ethnically heterogeneous cohort born short, but none of the 9 Japanese patients with data [11]. Smith reports short stature evident neonatally in 76% and by one year in 98% [77]. The deficit progresses predominantly in the first year and at puberty, with a reduced or absent pubertal growth spurt; median adult height is 131 cm in men and 122–123 cm in women, ranging from 104 to 151 cm, with some patients of normal stature [8, 11, 77]. Adult obesity is frequent [77].

Musculoskeletal System

In the Finnish cohort, incomplete elbow extension (92%) coexisted with ligamentous laxity (95%), particularly in the hands and feet; lumbar hyperlordosis occurred in 85%, chest deformity in 68%, lower limb varus in 63% and scoliosis in 21% [11]. In a series of 135 North American patients, approximately 43% required surgical lower limb realignment [11]. Laxity of the lateral knee ligaments contributes to varus [8].

Hair, Skin and Mucosae

Hair is fine, sparse, light and fragile, with reduced shaft diameter and absence of the central pigmented core; eyebrows, eyelashes and body hair are also affected, approximately 15% have complete alopecia and 7–25% have normal hair [8, 11, 77]. A study of 23 Finnish patients found more oral mucosal lesions and deep periodontal pockets [11].

Immunodeficiency and Infections

Immunodeficiency is combined, variable in severity and sometimes progressive. In vitro cellular immunity is impaired in most patients (88%), but only 35–65% have increased infections, predominantly in infancy and childhood [8, 9]. In the prospective Finnish cohort of 80 patients followed from 1985–1991 to 2016, 57% had no immunodeficiency symptoms, 19% had symptomatic humoral immunodeficiency and 24% combined immunodeficiency, with adult onset in 6; immunodeficiency progressed clinically in 22% [78]. Susceptibility may begin in the first months or only in the third decade [9]. Among 32 Finnish children followed for a median of 8.2 years, none had classical severe combined immunodeficiency (SCID), but 14 had respiratory or severe infections; reduced naïve T cells and abnormal lymphocyte proliferation were the most predictive parameters, all patients with absent T-cell receptor excision circles (TRECs) had severe infections, and opportunistic infections occurred only in those with SCID-level lymphopenia [79].

The infectious spectrum includes severe varicella, pneumonia due to Pneumocystis jirovecii, Aspergillus and cytomegalovirus, adenovirus and bocavirus hepatitis, disseminated viral infections, Haemophilus influenzae meningitis despite vaccination, chronic norovirus gastroenteritis, lethal enteroviral meningoencephalitis, refractory warts and cutaneous granulomas due to vaccine-strain rubella virus [8, 11]. Fatal varicella in the 1965 Amish description was not repeated in later series, in which varicella was predominantly uncomplicated; Finland recorded at least 7 varicella hospitalisations, 2 for varicella pneumonia [8, 11]. Responses to protein vaccines and live viral vaccines are generally normal, but 7 of 8 evaluated patients had specific antibody deficiency against polysaccharides, a marker of more severe clinical immunodeficiency [11]. Laboratory findings include lymphopenia in 36–83% of non-transplanted patients, with reductions in all subsets except NK cells, neutropenia in approximately 27%, and rare hypogammaglobulinaemia [9, 11].

Lung

Bronchiectasis, sometimes of limited clinical significance and progression, occurs in 29–52% of patients [8]. It was present in 8 of 15 symptomatic patients (53%), and on high-resolution CT in 10 of an unselected cohort of 34 adults and adolescents (29%), without hypogammaglobulinaemia and with specific antibody deficiency in several; pulmonary magnetic resonance imaging (MRI) correlated well with CT, and scores remained stable or improved in 14 patients reassessed by MRI after 6.8 years [11, 80, 81]. Progressive lung disease is a leading cause of adult death, and immunoglobulin replacement is often insufficient to halt it [11].

Autoimmunity and Granulomas

Autoimmune disease affected 11% of 104 Finnish patients, compared with 5% in the general population; autoimmune haemolytic anaemia is most common, followed by thrombocytopenia and juvenile idiopathic arthritis, with isolated reports of neutropenia, coeliac disease, thyroid disease, multifocal motor neuropathy, narcolepsy, psoriasis and ulcerative colitis [11]. Asymptomatic autoantibodies are frequent (18% of adults) [11]. Cutaneous and visceral granulomatous lesions occur predominantly in severe immunodeficiency, sometimes with vaccine-strain rubella virus [11, 82].

Anaemia

Macrocytic anaemia results from deficient erythropoiesis. In the Finnish cohort, haemoglobin was low in 73% of children and macrocytosis present in 47%, both absent in adults, with normal reticulocytes, iron, vitamin B12 and folate [11]. Mild anaemia resolves spontaneously during childhood in most patients [8]. Severe anaemia (haemoglobin <30 g/L or repeated transfusions) developed within the first 4 months in 11 of 12 patients, with marrow erythroid hypoplasia in all who underwent biopsy; the cohort's three deaths from pneumonia or sepsis occurred in infants with profound anaemia [11]. Transfusion-dependent anaemia was described in 6% (7 of 114) in older reports and 31% (10 of 32) of those born in the 2000s [11, 83]. The course is variable, with spontaneous resolution or remissions lasting up to 5 years followed by relapse [11].

Gastrointestinal Tract

Hirschsprung disease, involving a short segment or the entire colon, affected 7–10% of patients in twentieth-century series and 25% (8 of 32) of those born in the 2000s, suggesting underdiagnosis of early fatal cases in older series [8, 9, 11]. Historically it was associated with more severe growth deficiency, total alopecia and severe anaemia, and 5 of 13 historical cases died, 4 from enterocolitis-associated septicaemia; Smith gives postoperative mortality up to 38% [11, 77]. In the recent cohort, there was no association with birth length or anaemia, and infectious complications were less severe [11]. Prolonged or recurrent diarrhoea affected 31% of 104 patients, with chronic gastritis, peptic ulceration, villous atrophy and, in some, enteropathy requiring parenteral nutrition; post-infectious malabsorption in the first 2 years may mimic coeliac disease [8, 11].

Malignancies

Malignancy incidence is increased. In 1999, among 122 Finnish patients, the standardised incidence ratio (SIR) was 6.9 for all malignancies and 90 for non-Hodgkin lymphoma, without an increase in siblings or parents; the 2008 update gave an SIR of 33 for basal cell carcinoma and 130 for non-Hodgkin lymphoma between 15 and 29 years [11, 84]. During 39 years of follow-up, 14 of 123 patients developed malignancies, 9 of the 14 between 15 and 44 years, with a Kaplan–Meier probability of 41% by 65 years (excluding basal cell carcinoma); 9 died, a median of 3 months after diagnosis, and neither variant nor prior immunodeficiency severity predicted risk [8, 84]. Among 160 patients in Finnish national registries (1953–2016), there were 16 lymphomas, at a median age of 26.4 years, predominantly advanced-stage; diffuse large B-cell lymphoma was most common (38%), 11 of 16 (69%) died from lymphoma, and survivors were almost all diagnosed during routine visits or because of mild nonspecific symptoms [85]. Three of these patients had no prior signs of immunodeficiency, nor did 8 of 15 patients with non-cutaneous cancer in the prospective cohort [78, 85]. Thyroid, laryngeal, vocal cord, biliary tract and lip carcinomas, leukaemia, Hodgkin lymphoma (including Epstein–Barr virus-positive forms), plasmacytoma and myelodysplasia have been described; basal cell carcinoma occurs only in sun-exposed areas [11, 86, 87].

Puberty, Fertility and Reproductive Health

Boys have smaller-than-expected testes, and all 11 studied had abnormal semen analyses (concentration, motility or morphology), with normal testosterone, inhibin B and gonadotropins [8, 11]. Hypogonadotropic or normogonadotropic hypogonadism without spontaneous puberty has been described in girls, and human papillomavirus (HPV) was detected in cervical samples from 8 of 18 women (44%), with atypia in 3; reduced female fertility has not been described [8, 11]. Cases of autoimmune hypoparathyroidism occur [77].

Mortality

The prospective cohort recorded 20 deaths, with a standardised mortality ratio (SMR) of 7.0 (95% confidence interval [95% CI] 4.3–11), due to malignancy (SMR 10) and lung disease (SMR 46) [78]. Factors associated with mortality were birth length below −4 SD, combined immunodeficiency symptoms, Hirschsprung disease, pneumonia in the first year or recurrent adult pneumonia, and adult autoimmunity (section 11.1) [78].

3.4. Metaphyseal Dysplasia without Hypotrichosis and Mild Forms

MDWH presents with the skeletal phenotype of CHH, normal hair and initial absence of anaemia, intestinal manifestations and immunodeficiency [8, 48]. In the Finnish cohort of 80 patients followed for more than 30 years, 10 had only skeletal findings at preschool age; 8 of those 10 developed malignancy or clinically significant immunodeficiency, with the first extraskeletal manifestation at school age or at 20, 43 and 50 years, and 2 died during chemotherapy [50]. Lymphocyte proliferation was abnormal in 4 before symptoms, and a patient outside the cohort with normal hair developed severe agranulocytosis at 18 years and underwent transplantation [50]. MDWH is therefore now managed as CHH [11, 50]. The Japanese forms described in 2024 are even milder: compared with Finnish patients, none had birth length below −2 SD (versus 70%), 84% had metaphyseal dysplasia (versus 100%) and 26% hair hypoplasia (versus 88%) [51]. In a Turkish series, 3 patients with biallelic variants had typical CHH without immunodeficiency or recurrent infections, one with refractory congenital anaemia [57].

3.5. Anauxetic Dysplasias

ANXD1 is the most severe form of the RMRP spectrum, with fewer than 10 patients described: extreme prenatal-onset short-limbed short stature, barrel chest, hyperlordosis and kyphoscoliosis, hip dislocation, atlantoaxial subluxation with cervical cord compression (fatal in some), midface hypoplasia, macroglossia, hypodontia and mild intellectual disability, features not belonging to CHH [8, 11, 14]. Final height is below 85 cm; the tallest patient measured 83 cm at 19 years [8, 11]. Immunology was assessed in one case and was normal at 11 years, and lethal recurrent pneumonias in one patient were attributed to chest deformity [11]. ANXD2 (POP1) has a similar skeletal phenotype, with adult height below 1 m, hypodontia, midface hypoplasia and mild intellectual disability, and reduced peripheral mononuclear cell proliferation without immunodeficiency symptoms [8, 26, 27]. ANXD3 (NEPRO) was described in section 2.8 [28, 29].

3.6. Natural History and Treated Disease

Growth and orthopaedic complication data for all three entities describe patients without disease-modifying treatment, because none exists. In CHH, mortality and malignancy series predominantly concern non-transplanted patients; HSCT normalises immunity and anaemia but not the skeleton, and recent cohorts with newborn screening and early transplantation in the United States are not directly comparable with historical Finnish cohorts (section 7.3) [11, 23].

4. Clinical Recognition and Warning Signs

4.1. Prenatal and Neonatal Period

In CHH, obstetric ultrasonography shows shortened humeri and femora and a small chest in almost nine out of ten fetuses, predominantly in the second trimester, but prenatal genetic diagnosis was made in only 18% (6 of 34) of the recent Finnish cohort; median postnatal age at diagnosis was 1 month [17]. Ultrasound findings overlap those of other dysplasias, including lethal forms, and the Portuguese review by Portela Carvalho and colleagues proposes a structured prenatal approach with timely genetic counselling [88]. Neonatally, short limbs, widened metaphyses, long fibulae and anterior sternal angulation should raise suspicion [8, 77]. In JMC, wide sutures, prominent eyes, choanal stenosis, micrognathia and a high-arched palate may be present at birth, and rickets-like radiological changes may be prenatal [6, 73]. SMCD usually has no prenatal clinical expression, although a short femur was noted at 38 weeks in the Brazilian case in section 10.2 [1, 56].

4.2. Newborn Screening

There is no newborn screening directed at these dysplasias. SCID newborn screening by TREC quantification identifies some neonates with CHH before any skeletal sign [8, 11]. In the United States, 8 patients with abnormal screening, all homozygous for n.72A>G, had reduced (4) or absent (4) TRECs; transfusion-requiring anaemia and Hirschsprung disease occurred only with absent TRECs, and all were alive at a median of 19 months, including 2 who had undergone transplantation [11]. In Finland, where screening has been available since 2019, some neonates with CHH had reduced but not absent TRECs, others normal TRECs, and TRECs may change from normal to undetectable; only absent TRECs were associated with opportunistic infections [11]. The German programme identified 77 patients with syndromic inborn errors of immunity between 2019 and 2024, predominantly 22q11.2 deletion; the number of CHH cases is not provided in the abstract consulted [89]. A normal TREC result does not exclude CHH.

4.3. Infants and Young Children

4.4. Warning Signs and Emergencies

In CHH, varicella, pneumonia, fever with lymphopenia or neutropenia, and diarrhoea with failure to thrive require immediate assessment because immunodeficiency is unpredictable and varicella may be severe [8, 11]. Profound anaemia in the first 4 months is the presenting feature of severe anaemias and was associated with death from sepsis [11]. In adolescents and adults, new severe anaemia, lymphadenopathy, hepatomegaly, splenomegaly or mild nonspecific symptoms should prompt investigation for lymphoma, because advanced-stage diagnosis accounts for much of the mortality [8, 85]. In ANXD1, neck pain, signs of myelopathy or cervical manipulation during anaesthesia pose risks because of atlantoaxial subluxation [8]. In JMC, visual loss, visual field changes, facial paralysis, new hearing impairment, progressive cranial deformity due to craniosynostosis, snoring with apnoeas, hypertension and nephrolithiasis are warning signs [5, 19, 75]. In SMCD, persistent joint pain, progressive varus and functional limitation are reasons for orthopaedic referral [1].

4.5. Diagnostic Delay

Diagnosis of these dysplasias is often delayed. In the Greek case published in 2026, diagnostic changes were already present on radiographs at 2 years, but genetic testing was not performed until 12 years, after growth hormone stimulation tests, coeliac serology, karyotyping and pituitary MRI [69]. CHH metaphyseal abnormalities may be absent before 2 years, and a normal radiograph at that age does not exclude the diagnosis [9, 11]. In SMCD, many patients are initially diagnosed with nutritional rickets [1]. In JMC, absence of hypercalcaemia in an affected parent delays recognition of familial disease [74].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

None of the three entities has formal or consensus diagnostic criteria [1, 5, 8]. SMCD is established by characteristic clinical and radiographic findings and/or a heterozygous pathogenic or likely pathogenic COL10A1 variant [1]. JMC is strongly suggested by short-limbed short stature, metaphyseal widening and hypercalcaemia with low PTH, and is confirmed by an activating PTH1R variant [5]. The CHH-AD spectrum is established by clinical and radiographic findings and, when these are inconclusive, identification of biallelic pathogenic or likely pathogenic RMRP variants [8]. The 2025 review notes the lack of a specific functional test for RMRP deficiency (cell proliferation is neither sensitive nor specific) and proposes developing a diagnostic scoring system [11].

5.2. Radiology

Sources: [1, 2, 5, 6, 8, 9, 11, 19, 37, 57, 77]. Coxa vara distinguishes SMCD from other metaphyseal dysplasias and rickets, in which distal femoral metaphyses are more affected and coxa vara is rare [1]. In JMC, radiological evolution is characteristic: demineralisation, subperiosteal erosions and rickets-like changes predominate in infants; in childhood the metaphyses become markedly widened and fragmented; in adults, tubular bones are short and malaligned, with bulbous ends and skull base sclerosis [6]. Cranial CT shows bilateral expansile bone lesions of the skull base and facial bones, sinus obliteration and irregularity of the atlanto-occipital and temporomandibular joints [5, 19]. In CHH, brachydactyly with cone-shaped epiphyses is visible on a simple hand radiograph for bone age [69]. After physeal closure, CHH metaphyses may remain abnormal or normalise [11].

5.3. Biochemistry

Sources: [1, 5, 6, 18]. In CHH, mineral biochemistry is not among the reported abnormalities; calcium, phosphate and PTH were normal in the Greek case in section 10.1 [69]. Bone turnover markers (bone alkaline phosphatase, osteocalcin, type I collagen N-telopeptide) are also increased in JMC [5]. In X-linked hypophosphataemia, elevated FGF23 maintains low or normal 1,25(OH)2D, unlike JMC [5].

5.4. Immunological and Haematological Assessment in Suspected CHH

The initial assessment proposed by GeneReviews and the 2025 review includes IgG, IgA and IgM immunoglobulins and IgG subclasses; lymphocyte immunophenotyping (CD3, CD4, CD8, CD19, CD16/56), naïve and memory T-cell subsets, TRECs and T-cell repertoire; lymphocyte proliferation to phytohaemagglutinin (PHA) and anti-CD3; post-vaccination antibody titres, including against polysaccharides; and a complete blood count with differential [8, 11, 67]. Reduced naïve T cells, abnormal proliferation and absent TRECs are markers associated with severe infections [79]. Lymphopenia occurs in 36–83% of patients, class-switched memory B cells are reduced in 67%, and CD21low CD38low B cells are increased in all studied patients; hypogammaglobulinaemia is rare [11]. RMRP expression can be assessed by reverse transcription polymerase chain reaction (RT-PCR), but is confounded by lymphopenia and has not been shown to be specific [11].

5.5. Genetic Tests and Their Limitations

The 100% figures refer to the proportion of reported pathogenic variants detectable by the method, not clinical sensitivity: a patient with a typical phenotype and negative sequencing may have a variant in an unanalysed regulatory element, mosaicism undetected in blood, a variant not recognised as pathogenic or another diagnosis [1, 5, 8]. Apparent homozygosity for an RMRP variant may be false, reflecting deletion of the other allele, or result from uniparental isodisomy, warranting parental testing [8]. When interpreting RMRP variants, none of the four strong pathogenicity criteria PS1–PS4 of the ACMG/AMP guidelines applies to a non-coding gene, and classification relies on segregation, population frequency, conservation, RNA secondary structure and ClinGen specifications [8, 11, 69]. Patients of Finnish or Amish ancestry may first be tested for n.72A>G [8].

The molecular report should state the gene, versioned transcript (NM_000493.4, NM_000316.3 or NR_003051.4), HGVS designation, zygosity, ACMG/AMP classification and, for RMRP, correspondence with historical nomenclature, because the same variant appears in the literature with three different numbers (section 2.6) [10, 11, 61]. An isolated VUS, two biallelic VUSs, or a pathogenic variant with a VUS neither establishes nor excludes CHH; segregation analysis and clinical and radiological reassessment are the next steps [8]. Ridanpää and colleagues found 2 individuals homozygous for the RMRP founder variant among 20 patients with a clinical SMCD diagnosis but no COL10A1 variant; when SMCD is unconfirmed and the family history is compatible with recessive inheritance, RMRP should be investigated [90].

5.6. Algorithm

1. Child with short-limbed short stature and metaphyseal abnormalities: radiographic survey (pelvis and weight-bearing lower limbs, knees, hands, lateral spine, skull), calcium, phosphate, PTH, 25-hydroxyvitamin D, 1,25(OH)2D, alkaline phosphatase and urinary calcium/creatinine [1, 5, 35].
2. Rickets biochemistry: follow the rickets algorithm. Hypercalcaemia or high-normal calcium with low PTH and hypercalciuria: sequence PTH1R [5].
3. Normal biochemistry with coxa vara, large capital femoral epiphyses and dominant inheritance or an isolated case: sequence COL10A1 or use a panel [1].
4. Normal biochemistry with prenatal-onset short stature, short hands with cone-shaped epiphyses, fine hair, infections, anaemia or Hirschsprung disease, or recessive inheritance: complete blood count, immunological assessment and RMRP sequencing including the promoter [8, 11].
5. Negative targeted sequencing or overlapping phenotype: expanded skeletal dysplasia panel or genome sequencing, confirming RMRP coverage; consider POP1, NEPRO, MMP13, MMP9, LBR, Shwachman–Diamond syndrome genes and RUNX2 [1, 8, 57].
6. Variant identified: parental testing (segregation, detection of de novo cases or carriers), genetic counselling and testing of at-risk siblings in CHH [1, 5, 8].

5.7. Prenatal and Preimplantation Diagnosis

When familial variants are known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible for all three entities [1, 5, 8, 35]. Without known variants, fetal ultrasonography at 16–18 weeks may allow prenatal CHH diagnosis; in mild dysplasia forms, ultrasonography is often normal [8, 35]. In a Chinese family with SMCD, Ye and colleagues developed a non-invasive prenatal diagnostic method using high-depth sequencing of cell-free fetal DNA in maternal plasma; the variant was detected in the fetus and confirmed by amniocentesis, but validation is limited to one case [62].

6. Differential Diagnosis

6.1. Comparative Table

6.2. Schmid Chondrodysplasia versus Rickets and Other Metaphyseal Dysplasias

The most frequent SMCD differential diagnosis is nutritional rickets, sharing age at onset and genu varum. Normal biochemistry and coxa vara point towards SMCD; in rickets, coxa vara is usually absent and distal femoral metaphyses are most affected [1]. Familial hypophosphataemic rickets has undermineralisation, and biochemistry establishes the diagnosis [2]. Metaphyseal anadysplasia causes a 1–2 SD height deficit, with lesions arising in the first months and regressing by approximately 6 years, and should be actively sought because prognosis is good; distinction from SMCD may require molecular testing, and final height is more reduced in SMCD [92]. In Spahr dysplasia, metaphyseal fraying is fine and “comb-toothed”, coarser in SMCD, and the distal radius, which may be affected in infants with SMCD, is usually spared; inheritance pattern helps when several individuals are affected [93]. JMC is distinguished by much more severe lesions and hypercalcaemia, hypochondroplasia by short pedicles and absence of coxa vara, and hypophosphatasia by low alkaline phosphatase [2]. Occasional mild platyspondyly in SMCD may require molecular analysis to distinguish it from spondylometaphyseal dysplasias [2].

6.3. The Cartilage–Hair Spectrum versus Shwachman–Diamond Syndrome and Syndromic Immunodeficiencies

Shwachman–Diamond syndrome (SDS) is the second most common cause of hereditary pancreatic insufficiency after cystic fibrosis, combining exocrine pancreatic insufficiency with fatty replacement, intermittent or persistent neutropenia, other cytopenias and predisposition to myelodysplasia and acute myeloid leukaemia [30, 33, 91]. Metaphyseal chondrodysplasia, described in 1967, is present in all affected children according to Levin and colleagues, although Spranger's atlas reports radiological abnormalities in approximately half [33, 91]. Metaphyseal lesions are generally milder than in CHH and SMCD, most pronounced in the proximal femora and ribs, and short ribs in infants may mimic asphyxiating thoracic dystrophy [1, 30, 91]. CHH is distinguished by fine hair, joint hyperextensibility, lymphopenia with cellular immune deficiency and the absence of pancreatic insufficiency and granulocytopenia [91]. Absence of one of the three components (malabsorption, metaphyseal abnormalities, neutropenia) does not exclude SDS [91]. The 2011 SDS diagnostic and treatment consensus, the 2022 European Society for Blood and Marrow Transplantation (EBMT) working group recommendations for HSCT, the 2025 European chronic neutropenia guidelines and the 2024 American Association for Cancer Research (AACR) recommendations for surveillance of haematological malignancy predisposition are the management references [34, 95–97].

EXTL3 deficiency combines early-onset dysplasia with marked platyspondyly and severe immunodeficiency potentially reaching Omenn syndrome, with ichthyosiform skin, failure to thrive and septicaemia; in CHH, infant skeletal abnormalities are less marked and vertebral abnormalities usually absent [9, 94]. Schimke immuno-osseous dysplasia has short-trunk short stature, unlike the short limbs of CHH, glomerulopathy and characteristic facies; mild forms with recurrent infections may be confused with CHH [8]. CHH–Omenn syndrome overlap has been described with RMRP variants [8, 70]. A Turkish cohort showed that biallelic LBR variants can produce CHH-like ectodermal findings [57]. In an infant with sparse hair or alopecia, the differential diagnosis includes multiple carboxylase deficiency (holocarboxylase synthetase and biotinidase deficiencies), biotin deficiency, hypohidrotic ectodermal dysplasia, the trichorrhexis nodosa of argininosuccinic aciduria and vitamin D receptor abnormalities [98].

6.4. Jansen Chondrodysplasia versus Hyperparathyroidism, Rickets and Hypophosphatasia

In infants, demineralisation, subperiosteal erosions and hypercalcaemia in JMC resemble infantile hyperparathyroidism, but PTH is low or suppressed, and rickets-like metaphyseal lesions, excessive subperiosteal new bone formation and cranial abnormalities are unusual in hyperparathyroidism; progressive disappearance of erosions with increasingly disorganised metaphyseal formation is characteristic of JMC [6]. Rickets lacks the distinctive metacarpal and phalangeal involvement, cranial sclerosis and hypercalcaemia; infantile hypophosphatasia has no cortical erosion, has metaphyses with lytic “bites” rather than bulbous expansion and low alkaline phosphatase, whereas it is elevated in JMC [6]. In a child with hypercalcaemia, suppressed PTH and metaphyseal dysplasia, JMC is the most likely diagnosis, and absence of hypercalcaemia does not exclude it [5, 74].

7. Treatments and Risk Management Strategies

7.1. General Principles and Status of Recommendations

No medicine is approved by the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA) for SMCD, JMC or the CHH-AD spectrum [8, 20, 22]. Nor were clinical practice guidelines from scientific societies or European networks found for these disorders; the three GeneReviews chapters base recommendations on author experience, and CHH management relies on expert reviews, particularly Vakkilainen and colleagues' 2020 immunodeficiency review and the comprehensive 2025 review [1, 5, 8, 11, 99]. Follow-up is multidisciplinary, involving orthopaedics, rehabilitation, endocrinology, otorhinolaryngology, physiotherapy, occupational therapy and psychology for skeletal dysplasias generally, with immunology, haematology, respiratory medicine and oncology in CHH [8, 35]. Vitamin D, prescribed after an erroneous rickets diagnosis, is contraindicated in metaphyseal chondrodysplasias [2, 93]. Growth hormone may accelerate short-term growth but provides no long-term benefit in most skeletal dysplasias [35]. No off-label drug dose (aciclovir, immunoglobulin, bisphosphonates, prophylactic antibiotics, carbamazepine or sirolimus) is provided in the sources consulted for these disorders, and this article does not specify them; institutional protocols and summaries of product characteristics apply in such cases.

7.2. Schmid Metaphyseal Chondrodysplasia

Initial Assessment

GeneReviews proposes initial growth assessment (with a dietitian if required), a complete radiographic survey including lateral spine views for lordosis and scoliosis, orthopaedic consultation ideally with dysplasia expertise, assessment of function and pain during daily activities with physiotherapy and occupational therapy, psychosocial assessment with adaptations, and genetic counselling [1]. School adaptations include access to steps, low switches, accessible toilets, low desks and foot supports, and the child must be able to evacuate the building independently; adult adaptations include pedal extenders and workplace modifications [1].

Orthopaedic Treatment

Spranger's atlas recommends postponing osteotomies to correct genu varum until physeal closure, potentially combining them with bone lengthening [2]. In Al Kaissi and colleagues' series, 8 of 12 children had a waddling gait due to coxa vara and 3 underwent hemiepiphysiodesis for genu varum [100]. In the 2026 Turkish series, 2 of 7 patients underwent hemiepiphysiodesis [12]; bilateral tibial osteotomy was performed at 4 years in the Brazilian case in section 10.2 [56]. Smith reserves orthopaedic measures for unusual deformities and generally until growth is complete [37]. These positions are not contradictory: guided growth acts during growth, whereas corrective osteotomies are preferably performed after physeal closure.

Growth Hormone

Recombinant growth hormone has not been evaluated in SMCD and was considered contraindicated in the Brazilian case, without detailed justification [1, 56]. A report of 10-year follow-up of SMCD with partial growth hormone deficiency exists only as a non-peer-reviewed preprint [101].

Psychosocial Support

Attention to mood, affect and psychosocial stressors should form part of every visit, with access to a psychologist and support resources [1].

Carbamazepine: Rationale and Status

Carbamazepine, authorised as an antiseizure medication, stimulates autophagy and proteasomal degradation and has been repurposed as a candidate for disorders involving retained misfolded structural proteins [1, 54]. In human cells, it reduced ER stress induced by four mutant collagen X forms; in Col10a1 p.N617K mice it reduced hypertrophic zone expansion, attenuated Bip and Atf4 expression, increased bone growth and reduced dysplasia [54]. In p.Y632X mice, it reduced growth plate ER stress, restored architecture, increased bone growth and corrected hip distortion within 2 weeks, suggesting efficacy in both missense and premature termination codon forms [55]. GeneReviews attributes the mouse model to a 2010 article on alpha-1-antitrypsin deficiency; the correct reference is Mullan and colleagues, 2017 [1, 54]. Carbamazepine received EU orphan medicinal product designation for SMCD (EU/3/16/1746), with a positive Committee for Orphan Medicinal Products opinion on 13 September 2016 and a decision on 14 October 2016, when only experimental model studies existed; orphan designation is not marketing authorisation [20]. The phase I/IIa MCDS-Therapy trial ended in May 2024 without published results (section 7.5) [21]. Clinical use in SMCD is therefore experimental and off-label.

7.3. Jansen Metaphyseal Chondrodysplasia

Initial Assessment

GeneReviews, authored by NIH investigators, proposes initial orthopaedic and physical medicine and rehabilitation consultations, radiographs for surgical planning, growth assessment including head circumference, cranial CT if craniosynostosis is present or maxillofacial surgery or neurosurgery is planned, dental examination with radiographs, otorhinolaryngology with audiometry and tympanometry, ophthalmology with visual fields, OCT and orbital MRI when indicated, endocrinology with serum calcium and phosphorus and 24-hour urinary calcium, renal and urinary tract ultrasound, assessment for respiratory failure with airway evaluation before anaesthesia and polysomnography, blood pressure measurement and genetic counselling [5].

Skeleton, Skull and Teeth

Treatment of skeletal manifestations includes physiotherapy, footwear compensation for limb length discrepancy, mobility aids, alignment and mobility surgery, a balanced diet and low-impact physical activity such as swimming [5]. Severe limb deformities and scoliosis are managed by orthopaedics and may require surgical fixation; craniosynostosis may require cranial vault expansion, and malocclusion orthodontic treatment [5]. NIH investigators recommend close monitoring of hearing, cranial nerve compression, craniosynostosis, malocclusion and the airway [19]. Contact sports and high-risk activities should probably be avoided when skeletal involvement is significant [5].

Hypercalcaemia, Hypercalciuria and Kidney

High fluid intake is the basic measure to reduce hypercalcaemia, hypercalciuria, nephrolithiasis and nephrocalcinosis [5]. GeneReviews allows consideration of bisphosphonates for severe hypercalcaemia, with administration intervals determined by symptoms and serum calcium, and asks that long-term effects on the growing skeleton and other organs, such as the eyes, be weighed; it specifies neither a drug nor a dose, and use is off-label [5]. Cinacalcet probably provides no benefit because the defect lies downstream of the calcium-sensing receptor [5]. NIH trial exclusion criteria, requiring discontinuation of bisphosphonates for 6 months, denosumab for 3 months and thiazides for 4 weeks, show that these drugs are used in this population but do not constitute recommendations [22].

Blood Pressure, Airway, Hearing and Vision

For elevated blood pressure, GeneReviews recommends monitoring sodium intake and considering drugs acting on the angiotensin receptor pathway, without specifying a drug or dose [5]. Airway management is overseen by respiratory specialists, with reliever bronchodilators if indicated and continuous positive airway pressure (CPAP) for obstructive sleep apnoea [5]. Hearing impairment and visual deficits are managed by otorhinolaryngology and ophthalmology; NIH investigators recommend regular ophthalmological examination including colour vision, OCT measurement of the ganglion cell complex as a progression biomarker, visual fields and orbital and craniofacial imaging [5, 75].

Pregnancy

Women with JMC can conceive and have children, but possibly with increased perinatal morbidity and mortality [5]. Savarirayan and colleagues' best practice recommendations for prenatal assessment and delivery in skeletal dysplasias apply; preterm delivery risk is increased in women with skeletal dysplasia and short stature, and rib cage and spinal involvement may cause respiratory problems during pregnancy and delivery [5, 102]. Whether the disorder worsens during pregnancy is unknown [5].

Receptor Inverse Agonist (PTH-IA)

The peptide [Leu11,dTrp12,Trp23,Tyr36]-PTHrP(7-36)NH2, designated PTH-IA, is a 30-amino-acid inverse agonist that shifts the mutant receptor equilibrium towards the inactive state and reduces basal cAMP signalling; in cells, it reduced basal cAMP from all five mutant receptors [5, 18]. In transgenic mice with H223R in osteoblasts, twice-daily administration for 2 weeks reduced excessive trabecular mass, marrow fibrosis and turnover markers, providing preclinical proof of concept [103]. An optimised inverse agonist peptide normalised calcium and PTH after acute injection in T410R mice, and a long-acting inhibitor with a modified peptide backbone showed inverse agonism against H223R in vitro and in vivo [63, 104]. The first human phase 1/2 trial has been recruiting since 27 May 2026 (section 7.5) [22]. A method for detecting antibodies against PTH-IA in human plasma, developed for this programme, was published in 2026 [105].

7.4. Cartilage–Hair Hypoplasia–Anauxetic Dysplasia Spectrum

Initial Assessment

Initial assessment includes a complete skeletal survey (in ANXD1 including the cervical spine for abnormalities and atlantoaxial subluxation risk), orthopaedics, the immunological assessment described in section 5.4, immunology consultation if tests are abnormal or recurrent infections occur (to define the vaccination programme and varicella prophylaxis), respiratory medicine, a complete blood count with differential and haematology consultation if abnormal, gastroenterology if signs of megacolon are present, developmental assessment in ANXD1 and genetic counselling [8, 67]. Loid and colleagues, with O. Mäkitie's participation, propose immunological assessment at diagnosis, annual clinical infection assessment and annual malignancy screening with clinical assessment, laboratory tests and abdominal ultrasound [69].

Immunodeficiency and Infections

Infections are treated according to organism, site and severity [8]. For varicella, GeneReviews recommends high-dose intravenous aciclovir started immediately, and Spranger's atlas recommends aciclovir for varicella and herpes zoster; some patients receive post-exposure immunoglobulin or early antiviral treatment [8, 9, 11]. The sources do not specify a dose. Prophylactic antibiotics should be considered for recurrent infections, neutropenia or severe lymphopenia, and intravenous immunoglobulin if immunoglobulins or IgG subclasses are low or vaccine responses inadequate [8]. Immunoglobulin replacement is often insufficient to halt lung disease [11]. Bronchiectasis is treated with respiratory physiotherapy and respiratory specialist care [8]. Anti-tumour necrosis factor α (anti-TNF-α) antibodies have been used successfully for granulomas, but fatal JC virus progressive multifocal leukoencephalopathy during anti-TNF-α treatment has been described; HSCT resolved granulomas in 2 of 3 transplanted patients [8, 11, 82].

Vaccines

Routine inactivated vaccines are safe and should be administered [8]. Sources differ in the degree of restriction placed on live vaccines. Spranger's atlas contraindicates them if in vitro cellular immunity is impaired, GeneReviews calls for careful consideration when immune function is abnormal and exclusion in CHH with SCID, and the 2025 review regards CHH as a combined immunodeficiency in which live vaccines are contraindicated, while acknowledging that vaccination may be safe and effective in selected mildly affected patients [8, 9, 11]. In Finland, 86 of 90 patients (96%) received at least one live vaccine, including smallpox, oral poliomyelitis and yellow fever vaccines, without documented complications; measles, mumps and rubella vaccine was given to 40 of 104 patients and varicella-zoster virus (VZV) vaccine to 10, without serious events, and seropositivity for measles, mumps and rubella was 96%, 75% and 91% a median of 24 years after vaccination [11, 106]. Conversely, lethal vaccine-associated paralytic poliomyelitis in an infant with CHH and vaccine-strain rubella virus granulomas have been described, one in a child vaccinated before immunological assessment [11]. In the phase 4 live VZV vaccine trial (Varilrix®, 0.5 mL subcutaneously, a second dose if there was no response, according to protocol), which excluded patients with CD4 below 15% or 200/mm³, signs of severe immunodeficiency or immunoglobulin replacement, all 5 participants developed a cellular response; one adult developed a rash and knee swelling at 3 weeks, which resolved [106, 107]. The practical consequence is to assess immunity before any live vaccine and decide individually with immunology input.

Haematopoietic Stem Cell Transplantation

HSCT is the only curative treatment for immunodeficiency and severe anaemia: it normalises T-lymphocyte numbers and function, resolves autoimmunity and enables catch-up growth, attributed to fewer infections, but does not correct skeletal dysplasia [8, 11, 23]. Indications used include clinically overt combined immunodeficiency, a preventive decision following abnormal TRECs on newborn screening, severe anaemia without immunodeficiency and agranulocytosis [11]. The European survey recommends considering HSCT in CHH with severe immunodeficiency or autoimmunity before severe infections, organ damage or malignancy develop, if a matched donor is available [23]. Benefit in minimally symptomatic patients is debated because several children with SCID-level lymphopenia remained well for decades without intervention [11, 99]. HSCT is more frequent and earlier in the United States, in association with newborn screening [11].

GeneReviews summarises overall survival as 63% with an unrelated donor and up to 80% with a matched sibling [8]. These series are small and retrospective, from different eras and with different conditioning regimens, and do not permit direct comparison.

Anaemia

Severe anaemia due to depressed erythropoiesis is treated with packed red cell transfusions and iron chelation if transfusions are repeated; chelation was well tolerated [8]. Corticosteroids were effective in some patients, but data are insufficient to recommend them because of immunosuppression and growth impairment [8, 11]. Growth hormone, androgens and erythropoietin were ineffective [11]. Sirolimus, an mTOR inhibitor, restored erythropoiesis and controlled immune dysregulation in one child, with relapse on withdrawal and renewed resolution on restarting; use is off-label and based on one case, without a dose in the sources [8, 11].

Malignancies

There are no specific recommendations for treating malignancies in CHH. Non-Hodgkin lymphoma often has a poor prognosis with conventional cytotoxic protocols [8, 84]. Epstein–Barr virus-associated diffuse large B-cell lymphomas have been treated with rituximab followed by HSCT [11]. In two siblings with relapsed or refractory classical Hodgkin lymphoma, salvage with gemcitabine and vinorelbine, radiotherapy and consolidation with brentuximab vedotin, without HSCT, achieved complete remission at 30 months; this is a case report and is not generalisable [86]. Photoprotection should be reinforced because basal cell carcinoma occurs only in sun-exposed areas [11].

Gastrointestinal Tract, Puberty and Growth

Hirschsprung disease and malabsorption are managed using standard methods, with nutritional assessment for short bowel [8]. Delayed puberty requires hormonal induction; women should have regular gynaecological assessment because of HPV risk [8, 11]. Recombinant growth hormone has no sustained benefit in CHH and is not recommended; in 8 patients in case reports it was ineffective or only temporarily effective, and one patient without deficiency changed from −4.2 SD at 3 years to −2.6 SD at 6 years [8, 11]. It may benefit patients with documented growth hormone deficiency, but malignancy risk must be considered [11, 69].

Skeleton and Anaesthesia

Corrective osteotomies in late childhood or adolescence treat excessive varus, and low bone density may complicate orthopaedic surgery [8]. In ANXD1, malformed cervical vertebrae may require fusion in infancy, and kyphoscoliosis compromising pulmonary function should be corrected or prevented [8]. Any general anaesthetic requires care with the cervical spine if abnormality or instability is present [8].

Pregnancy

In a retrospective cohort of 42 pregnancies in 14 women with CHH, 25 (60%) reached term without complications requiring hospitalisation, and all deliveries were by caesarean section because of cephalopelvic disproportion or previous caesarean section; difficulties with epidural anaesthesia and fetal extraction occurred [11, 108]. Because fetal growth is generally unaffected, planned caesarean section should be considered for term pregnancies [8]. When the fetus had CHH, breech or abnormal presentation occurred in 30% and 37% of neonates required respiratory support (section 8.4) [17].

Developmental Support

In ANXD1, with mild intellectual disability in some patients, educational and developmental support is needed [8].

7.5. Regulatory Status and Clinical Trials

Comparative Regulatory Status

There are no medicines with a specific brand name for these disorders in Portugal or Brazil, and information from INFARMED and the Brazilian National Health Surveillance Agency (ANVISA) does not apply to any specific product.

Clinical Trials

Both therapeutic trials are open-label, single-arm and involve very small populations, inevitable in disorders affecting tens to hundreds of patients worldwide. The MCDS-Therapy efficacy endpoint compares growth velocity during treatment with the same patient's observation period; in a disorder in which growth velocity varies with age and radiological abnormalities improve spontaneously from 3 years, this design requires cautious interpretation [21, 37]. In the PTH-IA trial, secondary endpoints include the optimal dose defined by increasing PTH to 30–40 pg/mL when baseline is ≤20 pg/mL, corrected calcium, fractional calcium excretion, nephrogenous cAMP, phosphate and 1,25(OH)2D; exploratory endpoints include bone markers, [18F]-sodium fluoride uptake, ultrasound nephrocalcinosis, high-resolution peripheral quantitative computed tomography, physical function, pain and quality of life [22]. Exclusion criteria include pregnancy and breastfeeding, 25-hydroxyvitamin D ≤20 ng/mL, estimated glomerular filtration rate ≤45 mL/min/1.73 m², transaminases more than 2 times the upper limit, anaemia and total parathyroidectomy [22]. No negative, suspended or withdrawn trials were found for these disorders; the ClinicalTrials.gov search identified no other therapeutic SMCD trials or RMRP gene therapy trials, which does not prove their absence [11, 22]. The 2025 review considers gene therapy an attractive strategy for CHH because correcting one nucleotide in one allele would suffice, but does not mention ongoing studies [11].

Developments in the Last 12 Months

7.6. Agents and Situations to Avoid

In metaphyseal chondrodysplasias, vitamin D administered for suspected rickets is contraindicated and does not correct deformity [2]. High-impact exercise should be avoided in SMCD and JMC, as should contact sports in JMC with significant skeletal involvement, and obesity should be avoided [1, 5]. In JMC, cinacalcet lacks a rationale, and bisphosphonates require consideration of long-term effects on the growing skeleton [5]. In CHH, live vaccines require prior immunological assessment and are not given in CHH with SCID; anti-TNF-α agents carry a risk of progressive multifocal leukoencephalopathy; prolonged corticosteroids compromise growth and immunity; and growth hormone should be avoided outside documented deficiency [8, 11]. Non-Hodgkin lymphoma in CHH often has a poor prognosis with conventional cytotoxic protocols [8, 84]. MCDS-Therapy exclusion criteria highlight carbamazepine risks, including testing for HLA-B*15:02 in people of Han Chinese, Thai or other Asian ancestry because of severe cutaneous reaction risk [21].

7.7. Perioperative Care, Anaesthesia and Transition

The JMC airway (upper airway stenosis, anteriorly positioned hyoid, obstructive apnoea) and the ANXD1 cervical spine require preanaesthetic assessment [5, 8, 19]. In CHH, Hirschsprung surgery historically had high mortality from enterocolitis and septicaemia, and the transplanted patient with Hirschsprung disease in the American series died after transplantation [11, 77]. Transition to adult medicine is critical in CHH because malignancies cluster between 15 and 44 years, lung disease progresses in adulthood and immunodeficiency may have late onset, and also in JMC, where hypercalciuria persists after serum calcium normalises [18, 78, 84]. In SMCD, transition focuses on joint pain, weight and occupational adaptation [1].

7.8. Summary of Recommendations and Divergences

8. Reproductive Options and Family Counselling

8.1. Schmid Metaphyseal Chondrodysplasia

SMCD is autosomal dominant. Between 45% and 57% of probands inherited the variant from a parent who almost always has signs, sometimes only mild, and 43–55% are isolated cases due to a de novo variant [1]. Parents of an apparently isolated proband should be examined, with body proportion measurements, radiographs (some asymptomatic carriers have radiographic abnormalities alone) and targeted molecular testing [1, 56]. An apparently negative family history may reflect failure to recognise the disorder, reduced penetrance in rare cases or mild radiographic signs [1].

The final row changes counselling for apparently de novo cases: before assuming a recurrence risk near 1%, proband zygosity and parental status must be confirmed [12].

8.2. Jansen Metaphyseal Chondrodysplasia

JMC is autosomal dominant and most cases result from a de novo variant; some patients inherit the variant from a parent with skeletal signs [5, 74]. Because an affected parent may never have had hypercalcaemia or a diagnosis, parents should be examined; parental testing is not mandatory in the absence of signs [5, 74]. Gonadal mosaicism has not been described in JMC, but a parent with somatic and gonadal mosaicism may be mildly affected [5]. Sibling risk is 50% if one parent is a carrier, approximately 1% if the variant is not detected in parental leucocytes, and low but increased if parents are clinically unaffected and untested; offspring risk is 50% [5, 110]. The PTH-IA trial requires highly effective contraception [22].

8.3. Cartilage–Hair Hypoplasia–Anauxetic Dysplasia Spectrum

The spectrum is autosomal recessive. Parents are presumed heterozygotes and parental testing is recommended; if only one is a carrier, with confirmed parentage, the other variant may be de novo in the proband or result from postzygotic mosaicism in a parent, and apparent homozygosity may reflect an undetected deletion (false homozygosity) or uniparental isodisomy [8]. A proband's siblings have a 25% risk of being affected, 50% of being asymptomatic carriers and 25% of being neither affected nor carriers, with intrafamilial variability [8]. Children of an affected individual are obligate carriers unless the partner is a carrier or affected, and the proband's aunts and uncles have a 50% carrier risk [8]. Heterozygotes are asymptomatic and have no increased cancer risk [8, 11].

Partner carrier testing should be considered, particularly with shared ancestry: carrier frequency is 1:10 among Amish according to GeneReviews and 1:19 according to the 2025 review, and 1:76 in Finland [8, 11]. Early identification of at-risk siblings has clinical value (infections, live vaccines, malignancies); they should be tested if signs are present, particularly short stature, by molecular testing when familial variants are known or by radiographs and RMRP analysis when they are not; completely asymptomatic individuals do not require testing according to GeneReviews [8]. This latter position should be weighed against MDWH, in which severe manifestations arose decades after a skeletal-only phenotype, and absence of skeletal findings in some patients with immunodeficiency [8, 50]. DNA banking is recommended when molecular diagnosis has not been confirmed [8]. POP1 and NEPRO disorders are also recessive, with the same risks [27, 28].

8.4. Prenatal and Preimplantation Diagnosis and Delivery

When familial variants are identified, prenatal diagnosis and preimplantation genetic testing are possible for all three entities, and counselling should ideally precede pregnancy and include affected young adults [1, 5, 8]. In CHH, ultrasound at 16–18 weeks may permit diagnosis without known variants [8]. A Portuguese familial case illustrates both pathways: a healthy, non-consanguineous couple with two children whose CHH was confirmed by two pathogenic RMRP variants had signs of an affected fetus on routine ultrasonography in a third pregnancy; they declined invasive diagnosis and the diagnosis was confirmed in cord blood [109]. In SMCD, the cell-free fetal DNA non-invasive method was validated in a single case [62].

When the fetus had CHH, the Finnish cohort showed 82% term and 18% preterm deliveries (30+4 to 36+4 weeks), 46% vaginal deliveries, breech or abnormal presentation in 30% (versus 3–4% in the general population), accounting for 56% of caesarean sections, and postnatal respiratory support in 37% [17]. When the mother had CHH, all deliveries were by caesarean section (section 7.4) [11, 108]. Best practice recommendations for prenatal assessment and delivery in pregnant women with skeletal dysplasia apply to mothers with JMC [5, 102].

8.5. Counselling Minors and Counselling Content

Testing minor siblings in CHH is justified by immediate clinical benefit (vaccines, infection and malignancy surveillance), as in JMC because of renal, auditory and visual surveillance [5, 8]. In SMCD, testing children with clinical signs is diagnostic; predictive testing of asymptomatic children has less clinical justification because the disorder has no extraskeletal complications [1]. Counselling should cover intrafamilial variability, risk of severe double-heterozygous phenotypes when both partners have dysplasia, consequences of each reproductive option and contact with patient associations [1, 8].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What Each Figure Measures

A published case count is not prevalence, and absence of cases in a region does not demonstrate that the disorder is absent there. SMCD and JMC estimates depend on clinical recognition and access to testing and are probably below the true figures [1].

9.2. Founder Populations and CHH Geography

CHH is frequent in two founder populations. Among the Old Order Amish, n.72A>G is present in 100% of patients and carrier frequency is 1:10 or 1:19 depending on the source [8, 11]. In Finland, the same variant accounts for 92% of patient alleles (94% of cases in the recent perinatal cohort) and carrier frequency is 1:76; the variant is thought to have arrived approximately 4000 years ago and belongs to the so-called Finnish disease heritage [11, 17, 45]. Outside these populations, n.72A>G represents 48% of alleles in patients from Europe, North and South America, the Near East and Australia, reflecting a single ancient founder [45]. In Japan, the variant was absent in 13 published patients, two distinct founders exist and the phenotype is milder [11, 51]. Immunodeficiency, malignancy and mortality frequencies in section 3 derive mainly from the Finnish cohort, predominantly homozygous for n.72A>G, and cannot be extrapolated uncritically to populations with other genotypes.

9.3. United States and Europe

In the United States, in addition to the Amish community, a series of 135 patients described realignment surgery requirements, and SCID newborn screening identified CHH patients homozygous for n.72A>G [11]. In Europe, the European Society for Immunodeficiencies (ESID) registry contributed 11 patients to an international registry of 74 (with 16 from the North American USIDNET registry and 47 from the Finnish Skeletal Dysplasia Register), in which 8% died [11]. The European HSCT series included 16 patients from several countries [23]. In Germany, TREC newborn screening since 2019 has identified patients with syndromic inborn errors of immunity [89]. Published SMCD cohorts are Canadian (10 patients), Turkish (17 with COL10A1 among 24), Chinese and from other backgrounds; the principal JMC natural history series included 24 patients [18, 57, 58, 71].

9.4. Portugal and Brazil

In Brazil, Gomes and colleagues demonstrated a founder effect for n.197C>T (historical “195C>T”) in 2024, in a study of 32 CHH patients with mean ancestry of 58% European, 24% African and 18% Native American; the shared haplotype suggests a single event of probable European origin [68]. A Brazilian SMCD case has also been published, described in section 10.2 [56]. In Portugal, a narrative review of prenatal CHH diagnosis and a familial case of three siblings with the same RMRP variants were published in 2026 [88, 109]. The sources consulted provide no Portuguese or Brazilian prevalence data for any of the three entities.

9.5. Special Populations

Women with CHH and JMC have pregnancies carrying obstetric and anaesthetic risks (sections 7.3 and 7.4) [5, 108]. Transplanted CHH patients retain skeletal dysplasia and short stature [23]. Adults with CHH without immunological symptoms remain at risk of late-onset immunodeficiency and malignancy [50, 78]. Adults with JMC may have normal calcium but persistent hypercalciuria and renal risk [18].

9.6. Reference Networks and Patient Associations

ERN BOND (European Reference Network on rare bone diseases) is the reference network for all three dysplasias and enables identification of centres and experts; ERN RITA (rare immunodeficiency, autoinflammatory and autoimmune diseases) is relevant to CHH immunodeficiency [24, 25, 69]. Portugal has ANDO Portugal, Associação Nacional de Displasias Ósseas [112]. In the United States, Little People of America supports people with skeletal short stature, and the Jansen's Foundation, founded in 2017 by an individual with JMC, funds research [113, 114]. GeneReviews also lists the Finnish association Lyhytkasvuiset – Kortväxta ry, the ESID registry, the International Skeletal Dysplasia Registry at the University of California, Los Angeles, and, in the United Kingdom and Australasia, Little People UK and Short Statured People of Australasia [1, 8]. SDS has the Shwachman-Diamond Syndrome Alliance [115].

10. Illustrative Clinical Case

10.1. Cartilage–Hair Hypoplasia with Delayed Diagnosis (Greece, 2026)

In 2026, Loid and colleagues described the first published Greek CHH case [69]. The patient, born to healthy non-consanguineous parents (mother 172 cm, father 187 cm) with three healthy siblings, was delivered by caesarean section at 38 weeks, measuring 50 cm (50th–75th percentile) and weighing 3150 g (25th–50th percentile). At 2.3 years she measured 77.5 cm (below the third percentile) and weighed 11.05 kg (10th–25th percentile), with head circumference 48.5 cm, short arms and brachydactyly. Thyroid function, growth hormone stimulation tests, coeliac serology, karyotype and pituitary MRI were normal. Radiographs at that age showed mild abnormalities of the proximal humeral, femoral and knee metaphyses, multiple unilateral elbow dislocations and bilateral genu varum; her hair was fine and silky [69].

At 8 and 11 years, radiographs showed broad irregular metaphyses, predominantly at the knees and wrists, with less affected hips, metaphyseal abnormalities in metacarpals and phalanges, cone-shaped epiphyses, shortened phalanges and premature distal physeal closure, with a normal spine and skull [69]. At 11.9 years she measured 127.8 cm (−3.0 SD), weighed 37 kg (body mass index 22.7 kg/m², above the 95th percentile), had an arm span of 138 cm and sitting height of 57.7% of total height, Tanner stage P3/M2 without menarche and bone age of 13 years; dual-energy absorptiometry was normal, insulin-like growth factor 1 was 386.5 ng/mL, calcium 10 mg/dL, phosphate 4.6 mg/dL, PTH 28.9 pg/mL and 25-hydroxyvitamin D 20 ng/mL, and there was no infection history [69].

At 12 years, targeted RMRP sequencing identified two compound heterozygous variants, NR_003051.3:n.97_98dup in the transcribed region and a promoter duplication described by the authors as n.-25_-12dup (NC_000009.12:g.35658032_35658045dup), each inherited from one parent [61, 69]. Immunoglobulins and IgG subclasses (IgG 1010 mg/dL), complete blood count and immunophenotyping were normal, and measles, rubella and mumps responses adequate, but VZV IgG was negative despite two vaccine doses and anti-HBs was negative [69]. No specific treatment was instituted; the family received genetic counselling and the patient remained under surveillance [69]. Retrospective review showed that diagnostic features were already present on radiographs at 2 years and that diagnostic delay led to unnecessary endocrine investigations [69].

The article's figures were consulted through their captions: figure 1 shows growth curves (https://pmc.ncbi.nlm.nih.gov/articles/PMC13122024/figure/luag102-F1/); figure 2 shows knees at 8 years with metaphyseal widening and irregularity, hands at 11 years with short metacarpals and phalanges and cone-shaped epiphyses, short broad feet and a hip with very mild irregularity (https://pmc.ncbi.nlm.nih.gov/articles/PMC13122024/figure/luag102-F2/); figure 3 shows the pedigree and variant positions (https://pmc.ncbi.nlm.nih.gov/articles/PMC13122024/figure/luag102-F3/) [69].

This case illustrates four points of this article. CHH may present with normal birth length, minimally abnormal hair and normal laboratory immunity, particularly with promoter variants associated with less impaired growth (section 2.7) [11]. Hand and knee radiography guides diagnosis (section 5.2) [69]. Testing must include the promoter, which a conventional exome would not analyse (section 5.5) [11]. Failure to respond to VZV vaccination is relevant when deciding about exposures and vaccines, and malignancy surveillance also applies to patients without clinical immunodeficiency, as demonstrated by MDWH cases with late manifestations (section 3.4) [50].

10.2. Schmid Metaphyseal Chondrodysplasia with Radiology-Guided Diagnosis (Brazil, 2020)

De França and colleagues described a boy assessed at 2 years at the Federal University of São Paulo, the only child of a non-consanguineous couple [56]. His mother had treated hypothyroidism; ultrasonography at 38 weeks showed a short femur, and delivery was vaginal at 39 weeks, with Apgar score 9/10, weight 3150 g, length 48 cm (10th–25th percentile) and head circumference 34 cm. Distal hypospadias was corrected at 20 months. Bowed legs were noticed at 10 months and worsened. On examination, at 13 kg and 81 cm (below the third percentile), he had disproportionate rhizomelic short stature, mild rectus diastasis, no dysmorphism and normal development [56]. Complete blood count, electrolytes, thyroid and parathyroid function, 25-hydroxyvitamin D, insulin-like growth factor 1 and its binding protein 3, bone age, karyotype, echocardiogram, abdominal ultrasound and retinal mapping were normal [56].

Radiographs showed mild lumbar hyperlordosis, a horizontal sacrum, coxa vara, rhizomelic limb shortening, bilateral femoral and tibial bowing, generalised metaphyseal widening, a broad humerus, short broad middle phalanges and reduced bone density [56]. Sanger sequencing of COL10A1 identified the novel heterozygous NM_000493.4:c.1900del p.(Asp634IlefsTer43) variant in the NC1 domain, classified as pathogenic by ACMG/AMP criteria; transcript notation was published with a typographical error (“NM_00493.4”), and the variant was confirmed in VariantValidator [56, 61]. The patient underwent bilateral tibial osteotomy at 4 years, growth hormone was considered contraindicated, and development remained normal with persistent short stature [56].

Figure captions were consulted: figure 1 shows the pelvis and lower limbs with bowed femora and tibiae, large capital femoral epiphyses, short femoral necks, wide physes, medial metaphyseal beaking and disorganised metaphyseal ossification (https://pmc.ncbi.nlm.nih.gov/articles/PMC7553887/figure/fig0001/); figure 2 shows upper limbs with disorganised humeral metaphyses, short broad tubular bones and mild radial and ulnar irregularities (https://pmc.ncbi.nlm.nih.gov/articles/PMC7553887/figure/fig0002/) [56].

Tibial osteotomy at 4 years differs from the practice recommended by GeneReviews and Spranger's atlas, which reserve corrective osteotomies for late childhood or adolescence and favour guided growth during growth because deformity may recur and improve spontaneously (section 7.2) [1, 2, 100]. Hypospadias and maternal hypothyroidism belong to the rare, possibly coincidental associations mentioned in section 3.1 [1].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In SMCD, life expectancy and intelligence are normal; adult height ranges from 130 to 160 cm, genu varum generally persists without impairing joint function, and absence of epiphyseal damage explains the rarity of osteoarthritis, although chronic joint pain and obesity limit mobility in some adults [1, 2, 37]. Enlarged capital femoral epiphyses normalise between 11 and 14 years, and metaphyseal abnormalities may improve from 3 years [37, 57].

In JMC, adult height is 105–130 cm, with deformities requiring multiple operations; hypercalcaemia tends to normalise in adulthood, but hypercalciuria persists, most patients develop nephrocalcinosis and 2 of 24 had advanced CKD [6, 18]. Hearing impairment and optic neuropathy progress with age [5, 75]. Longevity data are unavailable [5].

In CHH, prognosis depends on immunodeficiency, anaemia, Hirschsprung disease and malignancies. The SMR was 9.3 in 2001 (120 patients, 7 related deaths) and 7.0 in 2019 (80 patients, 15 related deaths), with median age at death of 41 years (24 years for infectious deaths, 41 for malignancies and 53 for lung disease); mortality among siblings and parents matches the general population [11, 78]. In the international registry of 74 patients, 6 (8%) died from infection during adolescence, lymphoma in young adulthood or post-HSCT pulmonary complications, and opportunistic infections, particularly uncontrolled Epstein–Barr virus, were associated with higher mortality [11]. The probability of non-cutaneous malignancy by 65 years is 41%, and lymphoma mortality 69% [84, 85]. In ANXD1, atlantoaxial subluxation and thoracic deformity may be fatal [8, 11].

Source: [11, 78]. Wide confidence intervals reflect the small number of events and preclude precise individual estimates.

11.2. Surveillance

JMC and CHH surveillance intervals derive from the experience of the GeneReviews authors and from reviews, without comparative evidence [5, 8]. The argument for universal oncological surveillance in CHH is that neither the variant, nor the severity of immunodeficiency, nor other manifestations predicted the malignancies, and that lymphoma survivors were diagnosed during routine surveillance or with mild symptoms [84, 85]. For SDS, haematological surveillance follows the 2024 AACR and 2022 EBMT recommendations [95, 97].

12. Summary and Final Considerations

Schmid and Jansen metaphyseal chondrodysplasias and the cartilage–hair spectrum share a metaphyseal growth lesion but differ in mechanism, severity and prognosis. The Schmid form, autosomal dominant and caused by COL10A1 variants leading to retention of misfolded collagen X in the endoplasmic reticulum of hypertrophic chondrocytes, presents after 2 years with short-limbed short stature, genu varum and coxa vara, normal mineral biochemistry and no extraskeletal manifestations; the main error is diagnosis of nutritional rickets and vitamin D prescription. Treatment is orthopaedic, with guided growth during growth and osteotomies after physeal closure, and carbamazepine, which reduces endoplasmic reticulum stress in animal models and has held European orphan designation since 2016, was studied in a phase I/IIa trial involving 27 children whose results have not been published.

The ultra-rare Jansen form results from five activating PTH1R variants at three residues, most commonly H223R, rendering the receptor constitutively active in chondrocytes, bone and kidney. Metaphyseal dysplasia is severe, hypercalcaemia with suppressed PTH dominates childhood and tends to normalise in adulthood, but hypercalciuria persists, nephrocalcinosis is the rule and skull base sclerosis compresses optic, facial and auditory nerves. Absence of hypercalcaemia in a parent does not exclude disease. Management is symptomatic and multidisciplinary, with annual renal and mineral surveillance and hearing and visual surveillance every 1–2 years, and the inverse agonist PTH-IA entered its first human trial in 2026.

The autosomal recessive cartilage–hair spectrum, caused by biallelic variants in the untranslated RMRP gene, ranges from mild short stature to the extreme dwarfism of anauxetic dysplasia, and the gradient reflects the degree of loss of ribosomal RNA cleavage (skeleton) and cyclin B messenger RNA cleavage (hair, immunity, haematopoiesis, cancer). Cartilage–hair hypoplasia is a syndromic inborn error of immunity, with variable and sometimes adult-onset combined immunodeficiency, anaemia, Hirschsprung disease, bronchiectasis, autoimmunity and high lymphoma risk, accounting for mortality seven to nine times that of the Finnish population. Metaphyseal dysplasia without hypotrichosis is no longer a separate benign entity and is managed as cartilage–hair hypoplasia. Molecular testing must include the promoter and ensure coverage of a gene that exome sequencing may miss, and founder variant nomenclature (n.72A>G, n.71A>G or “70A>G”) requires careful reading. Haematopoietic stem cell transplantation cures immunodeficiency and severe anaemia but not the skeleton, and annual oncological surveillance applies to everyone because no marker predicts malignancies. Anauxetic dysplasia types 2 (POP1) and 3 (NEPRO) reproduce the skeletal phenotype without clinical immunodeficiency, and Shwachman–Diamond syndrome must be excluded when metaphyseal chondrodysplasia accompanies neutropenia and pancreatic insufficiency.

None of the three entities has formal guidelines or approved medicines. Decisions about live vaccines, transplantation in minimally symptomatic patients, growth hormone and surgical timing continue to rely on small series and reference group experience, and referral to ERN BOND centres and, for immunodeficiency, ERN RITA provides a route to coordinated care.

13. References

1. Richmond CM, Savarirayan R. Schmid metaphyseal chondrodysplasia. 2019 Oct 21 [updated 2024 May 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547823/
2. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 33–36 (3.1 Metaphyseal chondrodysplasia, Schmid type).
3. Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164-1209. doi:10.1002/ajmg.a.63132. PMID: 36779427. PMC10081954.
4. Savarirayan R, Cormier-Daire V, Lachman RS, Rimoin DL. Schmid type metaphyseal chondrodysplasia: a spondylometaphyseal dysplasia identical to the "Japanese" type. Pediatr Radiol. 2000;30:460–3. doi:10.1007/s002470000181. PMID: 10929364.
5. Obiezu F, Boyce A, Jüppner H, Jha S. PTH1R-related Jansen metaphyseal chondrodysplasia. 2025 Jul 10. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK616087/. PMID: 40638774.
6. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 54–57 (3.6 Metaphyseal chondrodysplasia, Jansen type).
7. Tsujioka Y, Handa A, Calder AD, Cavalcanti DP, Lausch E, Kim OH, et al. Skeletal dysplasias of the parathyroid hormone signaling cascade: radiological manifestations and molecular mechanisms. Pediatr Radiol. 2026. [Epub ahead of print]. doi:10.1007/s00247-026-06763-3. PMID: 42631736.
8. Mäkitie O, Vakkilainen S. Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders. 2012 Mar 15 [updated 2023 May 11; revised 2025 Aug 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK84550/
9. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 37–40 (3.2 Cartilage-hair hypoplasia).
10. National Center for Biotechnology Information. ClinVar [Internet]. Bethesda (MD): National Library of Medicine; variation IDs 13742, 13743, 13747, 13748, 1030731 (PTH1R); 14208, 633393, 465213, 465208, 580378, 533768 (RMRP); 4857751, 4004896, 2656861, 1224366, 17478 (COL10A1) [cited 2026 Oct 10]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
11. Vakkilainen S. Cartilage-hair hypoplasia: A comprehensive review. J Hum Immun. 2025;1(4):e20250142. doi:10.70962/jhi.20250142. PMID: 42170584. PMC13177382.
12. Doğan Arı AB, Kılıç E. Expanding the Clinical and Genetic Spectrum of Schmid Metaphyseal Chondrodysplasia: A Seven-Patient Series Including a Rare Homozygous COL10A1 Case. Am J Med Genet A. 2026. [Epub ahead of print]. doi:10.1002/ajmg.a.70296. PMID: 42678355.
13. Orphanet. Cartilage-hair hypoplasia (ORPHA:175) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/175
14. Orphanet. Anauxetic dysplasia (ORPHA:93347) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/93347
15. Orphanet. Metaphyseal chondrodysplasia, Schmid type (ORPHA:174) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/174
16. Orphanet. Metaphyseal chondrodysplasia, Jansen type (ORPHA:33067) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/33067
17. Kasanen E, Toiviainen-Salo S, Vakkilainen S, Kainulainen L, Tanner L, Makitie O. Perinatal outcomes in 35 children with cartilage hair hypoplasia. Orphanet J Rare Dis. 2026;21(1):230. doi:10.1186/s13023-026-04364-9. PMID: 42063088. PMC13277163.
18. Saito H, Noda H, Gatault P, Bockenhauer D, Loke KY, Hiort O, et al. Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia. J Clin Endocrinol Metab. 2018;103(7):2660-2669. doi:10.1210/jc.2018-00332. PMID: 29788189. PMC6486824.
19. Obiezu F, Almpani K, Kim HJ, Zalewski C, Chu E, Jahanmir G, et al. Jansen metaphyseal chondrodysplasia: analysis of craniofacial manifestations. JBMR Plus. 2025;9(2):ziae156. doi:10.1093/jbmrpl/ziae156. PMID: 39830149. PMC11736719.
20. European Medicines Agency. EU/3/16/1746: orphan designation for the treatment of metaphyseal chondrodysplasia, Schmid type (carbamazepine). Amsterdam: EMA; 2016 Nov 15 [cited 2026 Oct 10]. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1746
21. Newcastle upon Tyne Hospitals NHS Foundation Trust. An open label phase I/IIa trial repurposing carbamazepine (CBZ) for the treatment of skeletal dysplasia in children (MCDS-Therapy). ISRCTN registry: ISRCTN37815869. doi:10.1186/ISRCTN37815869. Registered 2019 May 23; last edited 2024 Nov 15 [cited 2026 Oct 10]. Available from: https://www.isrctn.com/ISRCTN37815869
22. National Institute of Dental and Craniofacial Research (NIDCR). A Phase 1/2 open-label first-in-human dose-escalating safety and efficacy study evaluating subcutaneous administration of PTH-IA in adults and children with Jansen's metaphyseal chondrodysplasia (JMC). ClinicalTrials.gov identifier: NCT07541209. First posted 2026 Apr 21; last update posted 2026 Oct 1 [cited 2026 Oct 10]. Available from: https://clinicaltrials.gov/study/NCT07541209
23. Bordon V, Gennery AR, Slatter MA, Vandecruys E, Laureys G, Veys P, et al. Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation. Blood. 2010;116(1):27-35. doi:10.1182/blood-2010-01-259168. PMID: 20375313.
24. European Reference Network on Rare Bone Diseases (ERN BOND) [Internet]. [cited 2026 Oct 10]. Available from: https://ernbond.eu/
25. European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) [Internet]. [cited 2026 Oct 10]. Available from: https://ern-rita.org/
26. Glazov EA, Zankl A, Donskoi M, et al. Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS Genet. 2011;7:e1002027. doi:10.1371/journal.pgen.1002027. PMID: 21455487.
27. Elalaoui SC, Laarabi FZ, Mansouri M, Mrani NA, Nishimura G, Sefiani A. Further evidence of POP1 mutations as the cause of anauxetic dysplasia. Am J Med Genet A. 2016;170(9):2462-2465. doi:10.1002/ajmg.a.37839. PMID: 27380734.
28. Narayanan DL, Shukla A, Kausthubham N, Bhavani GS, Shah H, Mortier G, et al. An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO. Am J Med Genet A. 2019;179(9):1709-1717. doi:10.1002/ajmg.a.61267. PMID: 31250547.
29. Kian MM, Sheikholeslami S, Feizabadi MK, Roshanaeizadeh AM, Haghi A, Chaleshtori ARS, et al. Expanding the Phenotypic Spectrum of Anauxetic Dysplasia Type 3: Reporting an Iranian Family With Unique Systemic Features and NEPRO Gene Variant. Clin Case Rep. 2026;14(4):e72355. doi:10.1002/ccr3.72355. PMID: 41982866. PMC13070871.
30. Ferreira CR, Darling A, Vockley J. Disorders of nucleic acid metabolism, tRNA metabolism and ribosomal biogenesis. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 39, sections 39.1 (table) and 39.3 (39.3.3 and 39.3.5). doi:10.1007/978-3-662-63123-2_39
31. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 621–622 (17.1 Blomstrand chondrodysplasia).
32. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 58–60 (3.7 Eiken dysplasia).
33. Levin TL, Mäkitie O, Berdon WE, Lachman RS. Shwachman-Bodian-Diamond syndrome: metaphyseal chondrodysplasia in children with pancreatic insufficiency and neutropenia. Pediatr Radiol. 2015;45(7):1066-1071. doi:10.1007/s00247-014-3231-6. PMID: 25416932.
34. Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci. 2011;1242:40-55. doi:10.1111/j.1749-6632.2011.06349.x. PMID: 22191555.
35. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 317–318 (Skeletal dysplasias).
36. Schmid F. Beitrag zur Dysostosis enchondralis metaphysaria. Monatsschr Kinderheilkd. 1949;97:393–7.
37. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 526–527 (Metaphyseal dysplasia, Schmid type).
38. Warman ML, Abbott M, Apte SS, Hefferon T, McIntosh I, Cohn DH, et al. A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet. 1993;5(1):79-82. doi:10.1038/ng0993-79. PMID: 8220429.
39. Jansen M. Über atypische Chondrodystrophie (Achondroplasie) und über eine noch nicht beschriebene angeborene Wachstumsstörung des Knochensystems: Metaphysäre Dysostosis. Z Orthop Chir. 1934;61:253–86.
40. Schipani E, Kruse K, Jüppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995;268(5207):98-100. doi:10.1126/science.7701349. PMID: 7701349.
41. McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA. Dwarfism in the Amish. II. Cartilage-hair hypoplasia. Bull Johns Hopkins Hosp. 1965;116:285–326. PMID: 14284412.
42. Mäkitie O. Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients. J Med Genet. 1992;29:652–5. doi:10.1136/jmg.29.9.652. PMID: 1404295.
43. Mäkitie O, Kaitila I. Cartilage-hair hypoplasia—clinical manifestations in 108 Finnish patients. Eur J Pediatr. 1993;152:211–7. doi:10.1007/bf01956147. PMID: 8444246.
44. Ridanpää M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104(2):195-203. doi:10.1016/s0092-8674(01)00205-7. PMID: 11207361.
45. Ridanpää M, Sistonen P, Rockas S, Rimoin DL, Mäkitie O, Kaitila I. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP. Eur J Hum Genet. 2002;10(7):439-447. doi:10.1038/sj.ejhg.5200824. PMID: 12107819.
46. Horn D, Rupprecht E, Kunze J, Spranger J. Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism. J Med Genet. 2001;38:262–5. doi:10.1136/jmg.38.4.262. PMID: 11370632.
47. Thiel CT, Horn D, Zabel B, Ekici AB, Salinas K, Gebhart E, et al. Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator. Am J Hum Genet. 2005;77(5):795-806. doi:10.1086/497708. PMID: 16252239. PMC1271388.
48. Bonafé L, Schmitt K, Eich G, Giedion A, Superti-Furga A. RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms. Clin Genet. 2002;61:146–51. doi:10.1034/j.1399-0004.2002.610210.x. PMID: 11940090.
49. Thiel CT, Mortier G, Kaitila I, Reis A, Rauch A. Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum. Am J Hum Genet. 2007;81(3):519-529. doi:10.1086/521034. PMID: 17701897. PMC1950841.
50. Vakkilainen S, Costantini A, Taskinen M, Wartiovaara-Kautto U, Mäkitie O. 'Metaphyseal dysplasia without hypotrichosis' can present with late-onset extraskeletal manifestations. J Med Genet. 2020;57(1):18-22. doi:10.1136/jmedgenet-2019-106131. PMID: 31413121. PMC6929920.
51. Uchida N, Ishii T, Nishimura G, Sato T, Kuratsuji G, Nagasaki K, et al. RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review. Am J Med Genet A. 2024;194(6):e63562. doi:10.1002/ajmg.a.63562. PMID: 38337186.
52. Rajpar MH, McDermott B, Kung L, et al. Targeted induction of endoplasmic reticulum stress induces cartilage pathology. PLoS Genet. 2009;5:e1000691. doi:10.1371/journal.pgen.1000691. PMID: 19834559.
53. Bateman JF, Wilson R, Freddi S, Lamandé SR, Savarirayan R. Mutations of COL10A1 in Schmid metaphyseal chondrodysplasia. Hum Mutat. 2005;25:525–34. doi:10.1002/humu.20183. PMID: 15880705.
54. Mullan LA, Mularczyk EJ, Kung LH, Forouhan M, Wragg JM, Goodacre R, et al. Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism. J Clin Invest. 2017;127(10):3861-3865. doi:10.1172/jci93094. PMID: 28920921. PMC5617653.
55. Forouhan M, Sonntag S, Boot-Handford RP. Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene. Hum Mol Genet. 2018;27(22):3840-3853. doi:10.1093/hmg/ddy253. PMID: 30010889. PMC6216233.
56. de França M, de Faria Soares MF, Luce ALP, Perrone E. Schmid metaphyseal chondrodysplasia: an example of radiology guidance to molecular diagnosis. Radiol Case Rep. 2020;15(12):2554-2556. doi:10.1016/j.radcr.2020.08.005. PMID: 33082897. PMC7553887.
57. Tüysüz B, Kasap B, Sarıtaş M, Alkaya DU, Bozlak S, Kıykım A, et al. Natural history and genetic spectrum of the Turkish metaphyseal dysplasia cohort, including rare types caused by biallelic COL10A1, COL2A1, and LBR variants. Bone. 2023;167:116614. doi:10.1016/j.bone.2022.116614. PMID: 36400164.
58. Meng L, Hu J, Sun L, Zhang Q, Wang O, Jiang Y, et al. Clinical, Molecular Characteristics, and Genotype-Phenotype Relationships of Metaphyseal Chondrodysplasia Type Schmid. Calcif Tissue Int. 2025;117(1):5. doi:10.1007/s00223-025-01457-8. PMID: 41454937. PMC12743679.
59. Ain NU, Mäkitie O, Naz S. Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant. J Med Genet. 2018;55:403–7. doi:10.1136/jmedgenet-2017-104885. PMID: 28830906.
60. Zhang C, Liu J, Iqbal F, et al. A missense point mutation in COL10A1 identified with whole-genome deep sequencing in a 7-generation Pakistan dwarf family. Heredity (Edinb). 2018;120:83–9. doi:10.1038/s41437-017-0021-6. PMID: 29234170.
61. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166. PMC5765404.
62. Ye Y, Li W, Wang G, Zhan L, Lin J, Li T, et al. Identification of a novel COL10A1: c.1952 G>T variant in a family with Schmid metaphyseal chondrodysplasia and development of a noninvasive prenatal testing method. Mol Genet Genomic Med. 2021;9(10):e1758. doi:10.1002/mgg3.1758. PMID: 34423584. PMC8580095.
63. Höppner J, Firat D, Parvez-Khan M, Reyes M, Hanna P, Yadav PS, et al. A mouse model of Jansen's metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics. Proc Natl Acad Sci U S A. 2025;122(23):e2500176122. doi:10.1073/pnas.2500176122. PMID: 40455993. PMC12167993.
64. Pereira RC, Delany AM, Reyes M, Gales B, Jüppner H, Salusky IB. Jansen's Disease: Bone Abnormalities Beyond Chondrodysplasia. J Clin Endocrinol Metab. 2025;110(10):2729-2740. doi:10.1210/clinem/dgaf097. PMID: 39950977. PMC12448618.
65. Calder AD, Allgrove J, Höppner J, Cheung M, Alexander S, Garagnani L, et al. Eiken syndrome with parathyroid hormone resistance due to a novel parathyroid hormone receptor type 1 mutation: clinical features and functional analysis. J Bone Miner Res. 2024;39(11):1596-1605. doi:10.1093/jbmr/zjae148. PMID: 39276366. PMC11523111.
66. Monahan G, Höppner J, Jüppner H, Rick A, McNamara E, Tee W, et al. A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R. J Bone Miner Res. 2026;41(5):521-536. doi:10.1093/jbmr/zjaf134. PMID: 41031626. PMC13135085.
67. Rider NL, Morton DH, Puffenberger E, et al. Immunologic and clinical features of 25 Amish patients with RMRP 70 A-->G cartilage hair hypoplasia. Clin Immunol. 2009;131:119–28. doi:10.1016/j.clim.2008.11.001. PMID: 19150606.
68. Gomes ME, Kehdy F, de Neves-Manta FS, Horovitz DDG, Sanseverino MT, Leal GF, et al. Identification of a founder effect involving n.197C>T variant in RMRP gene associated to cartilage-hair hypoplasia syndrome in Brazilian patients. Sci Rep. 2024;14(1):13436. doi:10.1038/s41598-024-64407-8. PMID: 38862721. PMC11166637.
69. Loid P, Kotanidou EP, Tsinopoulou VR, Galli-Tsinopoulou A, Mäkitie O. Delayed diagnosis of skeletal dysplasia in a girl with cartilage-hair hypoplasia. JCEM Case Rep. 2026;4(5):luag102. doi:10.1210/jcemcr/luag102. PMID: 42058700. PMC13122024.
70. Insalaco A, Rossi C, Bertucci E, Fiorentini C, Soresina A, Giliani S, et al. Neonatal erythroderma and immunodysplasia: Overlap of cartilage-hair hypoplasia and Omenn syndrome. Eur J Med Genet. 2026;80:105069. doi:10.1016/j.ejmg.2026.105069. PMID: 41616907.
71. Mäkitie O, Susic M, Ward L, Barclay C, Glorieux FH, Cole WG. Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations—findings in 10 patients. Am J Med Genet A. 2005;137A:241–8. doi:10.1002/ajmg.a.30855. PMID: 16088909.
72. Elliott AM, Field FM, Rimoin DL, Lachman RS. Hand involvement in Schmid metaphyseal chondrodysplasia. Am J Med Genet A. 2005;132A:191–3. doi:10.1002/ajmg.a.30433. PMID: 15578582.
73. Savoldi G, Izzi C, Signorelli M, et al. Prenatal presentation and postnatal evolution of a patient with Jansen metaphyseal dysplasia with a novel missense mutation in PTH1R. Am J Med Genet A. 2013;161A:2614–9. doi:10.1002/ajmg.a.36115. PMID: 23950054.
74. Nampoothiri S, Fernández-Rebollo E, Yesodharan D, Gardella TJ, Rush ET, Langman CB, et al. Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia. J Clin Endocrinol Metab. 2016;101(11):4283-4289. doi:10.1210/jc.2016-2054. PMID: 27410178. PMC5095231.
75. Obiezu F, Magone De Quadros Costa MT, Huryn LA, Pan K, Almpani K, Ninan A, et al. Ocular findings in Jansen metaphyseal chondrodysplasia. JBMR Plus. 2024;8(9):ziae089. doi:10.1093/jbmrpl/ziae089. PMID: 39108358. PMC11299511.
76. Gabbett MT, Jeavons CJ, Gray PH. Severe hypertension—an infantile feature of Jansen metaphyseal chondrodysplasia? Am J Med Genet A. 2020;182:768–72. doi:10.1002/ajmg.a.61494. PMID: 31977144.
77. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 528–529 (Metaphyseal dysplasia, McKusick type).
78. Vakkilainen S, Taskinen M, Klemetti P, Pukkala E, Mäkitie O. A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia. Front Immunol. 2019;10:1581. doi:10.3389/fimmu.2019.01581. PMID: 31379817. PMC6646460.
79. Pello E, Kainulainen L, Vakkilainen M, Klemetti P, Taskinen M, Mäkitie O, et al. Shorter birth length and decreased T-cell production and function predict severe infections in children with non-severe combined immunodeficiency cartilage-hair hypoplasia. J Allergy Clin Immunol Glob. 2024;3(1):100190. doi:10.1016/j.jacig.2023.100190. PMID: 38187867. PMC10770609.
80. Kostjukovits S, Klemetti P, Föhr A, et al. High prevalence of bronchiectasis in patients with cartilage-hair hypoplasia. J Allergy Clin Immunol. 2017;139:375–8. doi:10.1016/j.jaci.2016.07.023. PMID: 27568079.
81. Toiviainen-Salo S, Kajosaari M, Piilonen A, Mäkitie O. Patients with cartilage-hair hypoplasia have an increased risk for bronchiectasis. J Pediatr. 2008;152:422–8. doi:10.1016/j.jpeds.2007.11.040. PMID: 18280853.
82. Moshous D, Meyts I, Fraitag S, et al. Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-α mAbs. J Allergy Clin Immunol. 2011;128:847–53. doi:10.1016/j.jaci.2011.05.024. PMID: 21714993.
83. Williams MS, Ettinger RS, Hermanns P, et al. The natural history of severe anemia in cartilage-hair hypoplasia. Am J Med Genet A. 2005;138:35–40. doi:10.1002/ajmg.a.30902. PMID: 16097009.
84. Taskinen M, Ranki A, Pukkala E, Jeskanen L, Kaitila I, Mäkitie O. Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma. Am J Med Genet A. 2008;146A:2370–5. doi:10.1002/ajmg.a.32478. PMID: 18698627.
85. Kukkola HL, Utriainen P, Huttunen P, Taskinen M, Mäkitie O, Vakkilainen S. Lymphomas in cartilage-hair hypoplasia - A case series of 16 patients reveals advanced stage DLBCL as the most common form. Front Immunol. 2022;13:1004694. doi:10.3389/fimmu.2022.1004694. PMID: 36211439. PMC9541526.
86. Bukhari SI, Yazdani S, Fadoo Z. Refractory/Relapsed Hodgkin Lymphoma in Cartilage Hair Hypoplasia-Anauxetic Dysplasia Spectrum: Long-term HSCT-free Remission in 2 Pediatric Siblings. J Pediatr Hematol Oncol. 2026;48(2):e91-e96. doi:10.1097/mph.0000000000003158. PMID: 41460196.
87. Hills LB, Wang D, Hoffman HM, Wong V, Gloude NJ. Successful Treatment of Isolated Bone Marrow Classic Hodgkin Lymphoma in a Patient With Cartilage Hair Hypoplasia. Pediatr Blood Cancer. 2026;73(7):e70310. doi:10.1002/1545-5017.70310. PMID: 41935966.
88. Portela Carvalho C, Alves I, Lemos C, Guedes-Martins L. Prenatal Diagnosis of Cartilage-Hair Hypoplasia: A Narrative Review. Acta Med Port. 2026;39(5):349-356. doi:10.20344/amp.23497. PMID: 41525162.
89. Graafen L, Speckmann C, Bakhtiar S, Bernuth HV, Lehmberg K, Bader P, et al. Syndromic Inborn Errors of Immunity in TREC-Newborn Screening: 5-year Experience from the German Screening Program. J Clin Immunol. 2026;46(1):35. doi:10.1007/s10875-026-01995-2. PMID: 41831046. PMC13031199.
90. Ridanpää M, Ward LM, Rockas S, Särkioja M, Mäkelä H, Susic M, et al. Genetic changes in the RNA components of RNase MRP and RNase P in Schmid metaphyseal chondrodysplasia. J Med Genet. 2003;40(10):741-746. doi:10.1136/jmg.40.10.741. PMID: 14569119. PMC1735279.
91. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 50–53 (3.5 Shwachman syndrome).
92. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 44–49 (3.4 Metaphyseal anadysplasia).
93. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 41–43 (3.3 Metaphyseal dysplasia, Spahr type).
94. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 240–244 (7.22 SEMD with immune deficiency and developmental disability, EXTL3-deficient type).
95. Cesaro S, Donadieu J, Cipolli M, Dalle JH, Styczynski J, Masetti R, et al. Stem Cell Transplantation in Patients Affected by Shwachman-Diamond Syndrome: Expert Consensus and Recommendations From the EBMT Severe Aplastic Anaemia Working Party. Transplant Cell Ther. 2022;28(10):637-649. doi:10.1016/j.jtct.2022.07.010. PMID: 35870777.
96. Fioredda F, Spanoudakis M, Skokowa J, Tamary H, Farruggia P, Almeida A, et al. European guidelines on treatment and supportive measures in chronic neutropenias: A consensus between the European Hematology Association and the EuNet-INNOCHRON COST Action based on a systematic evidence review. Hemasphere. 2025;9(4):e70113. doi:10.1002/hem3.70113. PMID: 40242664. PMC12001981.
97. Maese LD, Wlodarski MW, Kim SY, Bertuch AA, Bougeard G, Chang VY, et al. Update on Recommendations for Surveillance for Children with Predisposition to Hematopoietic Malignancy. Clin Cancer Res. 2024;30(19):4286-4295. doi:10.1158/1078-0432.ccr-24-0685. PMID: 39078402. PMC11444884.
98. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Multiple carboxylase deficiency – holocarboxylase synthetase deficiency. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 47.
99. Vakkilainen S, Taskinen M, Mäkitie O. Immunodeficiency in cartilage-hair hypoplasia: Pathogenesis, clinical course and management. Scand J Immunol. 2020;92(4):e12913. doi:10.1111/sji.12913. PMID: 32506568.
100. Al Kaissi A, Ghachem MB, Nabil NM, Kenis V, Melchenko E, Morenko E, et al. Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management. Orthop Surg. 2018;10(3):241-246. doi:10.1111/os.12382. PMID: 30027601. PMC6594483.
101. Wang H, Ma Q, Sun C, Fu J, Sun G, Yu Z. A 10-year follow-up of Schmid metaphyseal chondrodysplasia with partial growth hormone deficiency [preprint]. Research Square. 2026. doi:10.21203/rs.3.rs-10287619/v1.
102. Savarirayan R, Rossiter JP, Hoover-Fong JE, et al. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219:545–62. doi:10.1016/j.ajog.2018.07.017. PMID: 30048634.
103. Noda H, Guo J, Khatri A, Dean T, Reyes M, Armanini M, et al. An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia. J Bone Miner Res. 2020;35(3):540-549. doi:10.1002/jbmr.3913. PMID: 31693237. PMC8050614.
104. Liu S, Daley EJ, Tran LM, Yu Z, Reyes M, Dean T, et al. Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants. J Am Chem Soc. 2024;146(10):6522-6529. doi:10.1021/jacs.3c09694. PMID: 38417010. PMC11162201.
105. Nduwumwami AJ, Wagner EJ, Wang AQ, Fang Y, Tao D, Xu X. Development of an electrochemiluminescence-based bridging assay to detect antibodies against a PTH inverse agonist in human plasma. Bioanalysis. 2026;18(10):863-872. doi:10.1080/17576180.2026.2709280. PMID: 42572867. PMC13540131.
106. Vakkilainen S, Kleino I, Honkanen J, Salo H, Kainulainen L, Gräsbeck M, et al. The Safety and Efficacy of Live Viral Vaccines in Patients With Cartilage-Hair Hypoplasia. Front Immunol. 2020;11:2020. doi:10.3389/fimmu.2020.02020. PMID: 32849667. PMC7432140.
107. Helsinki University Central Hospital. Immunodeficiency in cartilage-hair hypoplasia: sub-project on safety of vaccination against chickenpox. ClinicalTrials.gov identifier: NCT02383797. Last update posted 2019 Oct 22 [cited 2026 Oct 10]. Available from: https://clinicaltrials.gov/study/NCT02383797
108. Holopainen E, Vakkilainen S, Mäkitie O. Outcomes of 42 pregnancies in 14 women with cartilage-hair hypoplasia: a retrospective cohort study. Orphanet J Rare Dis. 2020;15:326. doi:10.1186/s13023-020-01614-2. PMID: 33213509.
109. Portela Carvalho C, Martins A, Alves I, Guedes-Martins L. Familial cartilage-hair hypoplasia: prenatal ultrasound features and clinical outcomes in three siblings with identical RMRP variants. BMJ Case Rep. 2026;19(2):e267490. doi:10.1136/bcr-2025-267490. PMID: 41720498.
110. Rahbari R, Wuster A, Lindsay SJ, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. doi:10.1038/ng.3469. PMID: 26656846.
111. Flynn MA, Pauli RM. Double heterozygosity in bone growth disorders: four new observations and review. Am J Med Genet A. 2003;121A:193–208. doi:10.1002/ajmg.a.20143. PMID: 12923858.
112. ANDO Portugal — Associação Nacional de Displasias Ósseas [Internet]. [cited 2026 Oct 10]. Available from: https://www.andoportugal.org/
113. Little People of America [Internet]. [cited 2026 Oct 10]. Available from: https://www.lpaonline.org/
114. Jansen's Foundation [Internet]. Elkhorn (NE): Jansen's Foundation; [cited 2026 Oct 10]. Available from: https://thejansensfoundation.org/
115. Shwachman-Diamond Syndrome Alliance [Internet]. [cited 2026 Oct 10]. Available from: https://sdsalliance.org/