Severe and Lethal Skeletal Dysplasias Diagnosed Prenatally: General Approach

Ultrasound recognition, prediction of lethality, nosological classification, molecular diagnosis and counselling when a fetus has a severe skeletal dysplasia.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Skeletal dysplasias, or osteochondrodysplasias, are generalised disorders of skeletal modelling, growth or homeostasis, and the term is distinguished from dysostosis, which denotes an abnormality of a single bone or group of bones, although this boundary has become less clear-cut as the molecular mechanisms have come to be understood [1, 16]. The general diagnostic approach to skeletal dysplasias, particularly after birth, provides the background. In the prenatal setting, the main interest lies in the subset that manifests before birth with marked limb shortening, a narrow thorax or hypomineralisation, because many of these entities are associated with perinatal death from pulmonary insufficiency or from concomitant visceral anomalies [1]. This article addresses that subset as a clinical problem: recognising the ultrasound pattern, estimating the likelihood of lethality, directing the genetic work-up, planning the pregnancy and delivery, and counselling the couple on the recurrence risk. Thanatophoric dysplasia, osteogenesis imperfecta and hypophosphatasia are covered here as far as the prenatal differential diagnosis is concerned.

The history of these entities parallels that of paediatric radiology. In 1925, Donath and Vogl described a lethal disorder that Fraccaro named achondrogenesis ("not producing cartilage") in 1952, after observing a stillborn infant with severe micromelia and marked histological cartilage abnormalities [17, 18]. Langer and colleagues and Saldino subsequently distinguished the type of achondrogenesis now associated with COL2A1 (Langer-Saldino), and hypochondrogenesis came to be understood as the less severe end of the same continuum [19]. In 1967, Maroteaux, Lamy and Robert proposed the term thanatophoric ("death-bearing") for the dysplasia in which patients died shortly after birth, and Langer distinguished types 1 and 2 [20]. In the 1970s, Spranger, Langer and Maroteaux popularised the designation campomelic dysplasia ("bent limb"), and Saldino and Noonan (1972) and Majewski (1971) described the first short-rib–polydactyly syndromes [21, 22].

Classification followed the same trajectory, from radiology to molecular genetics. The Nosology of genetic skeletal disorders, initiated in 1970, has been revised eleven times; the 2023 revision contains 771 entries associated with 552 genes, reduced the number of groups from 42 to 41 and adopted dyadic nomenclature, linking each phenotype to its causative gene (for example, "achondrogenesis, SLC26A2-related" instead of "achondrogenesis type 1B") [4, 8]. This nomenclature is useful prenatally because the same phenotypic name may correspond to opposing recurrence risks depending on the gene [2]. The very concept of lethality is being reconsidered: Japanese series of thanatophoric dysplasia and a North American OI series with a "lethal" prenatal prognosis documented survival with respiratory support, and a 2026 review proposes abandoning the dichotomous "lethal/non-lethal" classification in favour of counselling that reflects the range of possible outcomes with current neonatal care [8, 23, 24]. In this article, "lethal" is used in the historical sense of usual death in the perinatal period without intensive support, rather than as an individual certainty.

In clinical care, the first contact almost always occurs at the second-trimester anomaly scan, when the routinely measured femur length proves short relative to head and abdominal circumference; the geneticist is consulted when a chromosomal disorder, skeletal dysplasia or malformation syndrome is suspected, sometimes after 20 weeks, when the femoral growth curve diverges from the percentiles [25]. The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines for second-trimester ultrasound state that a suspected deviation from normality in the limbs should prompt a more detailed examination, specialist assessment and counselling about possible skeletal dysplasia and genetic and non-genetic syndromes [26].

2. Molecular Genetics and Pathophysiology

2.1. General principles

The appendicular skeleton forms through endochondral ossification, in which a cartilage template is replaced by bone, whereas the cranial vault and parts of the clavicle and pubis ossify through the membranous pathway [1, 8]. The chronology is early: the clavicle and mandible ossify at 8 weeks, the appendicular skeleton, ilium and scapula at around 12 weeks, the metacarpals and metatarsals between 12 and 16 weeks, and secondary epiphyseal centres become visible at around 20 weeks [1]. This chronology explains why the most severe forms may be suspected at the end of the first trimester and why absent ossification of a segment (for example, the vertebral bodies or pubis) has diagnostic value. It also explains the association of some dysplasias with cardiac and renal malformations, since the skeleton, cardiovascular system and genitourinary system derive from the mesoderm [8].

Perinatal death mainly results from pulmonary hypoplasia secondary to a small rib cage, but there are important mechanistic exceptions: in campomelic dysplasia, the cause is airway instability (tracheobronchomalacia) or cervical spine instability, rather than thoracic hypoplasia [14]; in SLC26A2 forms, pulmonary hypoplasia, tracheobronchomalacia and laryngeal malformations contribute [27]; in thanatophoric dysplasia, narrowing of the foramen magnum with brainstem compression is an additional factor [28].

2.2. Mechanisms by nosological group

Group 1, FGFR3 chondrodysplasias. Thanatophoric dysplasia results from gain-of-function variants in fibroblast growth factor receptor 3, all de novo, with a paternal age effect [29]. Type 1 is caused by variants that introduce a new cysteine into the extramembranous segment of the receptor (e.g. p.Arg248Cys, p.Tyr373Cys) or by stop codon variants; type 2 is almost always due to p.Lys650Glu in the tyrosine kinase domain [28, 29]. The former San Diego type of lethal platyspondylic dysplasia is now regarded as the same entity [4, 29].

Group 2, type II collagen. COL2A1-related achondrogenesis and hypochondrogenesis form an autosomal dominant phenotypic continuum; they correlate with glycine missense substitutions by bulky amino acids along the triple-helical region, with a dominant-negative effect on helix formation [30, 31]. In Torrance type platyspondylic dysplasia, variants lie in the C-propeptide or adjacent helical domain [30]. Affected siblings born to unaffected parents have been described and attributed to parental mosaicism [19, 30].

Group 3, type XI collagen. Fibrochondrogenesis results from biallelic COL11A1 variants or biallelic or heterozygous COL11A2 variants; the name reflects the histology, with fibroblast-like chondrocytes and a fibrous cartilage matrix [32, 33].

Group 4, sulphation disorders. SLC26A2 encodes the chondrocyte membrane sulphate transporter; its inactivation causes intracellular sulphate depletion and synthesis of undersulphated proteoglycans, altering the extracellular matrix required for endochondral ossification [27]. Severity depends on residual transporter activity: in descending order, SLC26A2 achondrogenesis (formerly 1B), SLC26A2 atelosteogenesis (formerly AO2), diastrophic dysplasia and recessive multiple epiphyseal dysplasia [18, 34]. Variants predicting stop codons or structural changes in transmembrane domains, in homozygous or compound heterozygous form, are associated with achondrogenesis; the combination of a severe allele and an allele situated in extracellular loops, the cytoplasmic tail or the 5' regulatory region produces milder phenotypes because residual activity partially "rescues" the effect of the null allele [18, 27].

TRIP11 achondrogenesis (formerly 1A). Biallelic TRIP11 variants cause deficiency of GMAP-210 (Golgi microtubule-associated protein 210), with disruption and fragmentation of Golgi apparatus architecture; odontochondrodysplasia is the milder allelic form of the same spectrum [35]. In the 2023 nosology, this entity was placed in group 14 (severe spondylodysplastic dysplasias) [4].

Group 6, filamins. Heterozygous gain-of-function variants in FLNB (filamin B, 3p14.3) cause a continuum of decreasing severity: Piepkorn dysplasia, boomerang dysplasia, atelosteogenesis type 1 (AO1), atelosteogenesis type 3 (AO3) and autosomal dominant Larsen syndrome [36, 37]. Variants associated with the most severe phenotypes are almost invariably located in exons 2 to 5 [38]. Filamin B participates in vertebral segmentation, joint formation and endochondral ossification, and histology may show giant multinucleated chondrocytes, giving rise to the name "giant-cell chondrodysplasia" [36, 39].

Group 10, skeletal ciliopathies. The short rib–polydactyly syndromes (SRPS) and short-rib thoracic dysplasia (formerly Jeune asphyxiating thoracic dystrophy) result from biallelic variants in genes involved in the production, function and maintenance of the primary cilium, including intraflagellar transport and the dynein-2 retrograde motor (DYNC2H1, WDR34, WDR60, DYNC2LI1, IFT80, IFT81, IFT122, NEK1, WDR19, INTU, TRAF3IP1, among others) [4, 40]. The primary cilium transduces hedgehog signalling, which is essential for skeletal development [22]. Allelic variants of the same gene can produce different phenotypes and variants in distinct genes can produce the same phenotype, which makes the clinical classification (Saldino-Noonan, Verma-Naumoff, Majewski, Beemer-Langer) a poor predictor of the gene [4, 40]. The short-rib thoracic dysplasias, the SRPS and Ellis-van Creveld syndrome enter the differential diagnosis.

Group 20, bent bones. Campomelic dysplasia results from haploinsufficiency of SOX9 (17q24.3), a transcription factor essential for chondrocyte differentiation and cartilage formation, which regulates COL2A1 expression and participates in testicular determination [21, 41]. Around 90% of patients have an intragenic pathogenic variant and 5% an interstitial deletion or reciprocal translocation of 17q24.3-q25.1 involving the gene or its regulatory region; rearrangements with upstream breakpoints, sometimes up to around 1 Mb away, cause milder phenotypes, including the acampomelic form [14]. Sex reversal in 46,XY individuals is explained by the role of SOX9 in testicular differentiation [41]. FGFR2-related bent bone dysplasia results from two specific heterozygous variants, c.1141T>G (p.Tyr381Asp) and c.1172T>G (p.Met391Arg) [42].

Group 26, OI and bone fragility. Around 90% of OI cases result from COL1A1 and COL1A2 variants; recessive forms (for example, CRTAP, P3H1 — formerly LEPRE1 — and PPIB) affect proteins that interact with type I procollagen during post-translational modification or folding [43, 44]. The severe perinatal form almost always results from variants altering the structure of the pro-α1(I) or pro-α2(I) chains with a dominant-negative effect; substitutions in the pro-α1(I) chain by arginine, valine, glutamic acid, aspartic acid or tryptophan in the carboxy-terminal 70% of the triple helix are almost always lethal, as is exon skipping beyond exon 14 of COL1A1 and exon 25 of COL1A2 [45]. The 2023 nosology replaced "perinatal lethal" with "severe perinatal form (Sillence type 2)" [4].

Group 27, mineralisation. Hypophosphatasia is due to variants in ALPL (formerly TNSALP, 1p36), which encodes tissue-nonspecific alkaline phosphatase; enzyme deficiency leads to inorganic pyrophosphate accumulation, which inhibits mineralisation and promotes ectopic calcification, and causes secondary pyridoxine deficiency, lowering the seizure threshold through deficient gamma-aminobutyric acid (GABA) synthesis [46]. Severe forms are almost exclusively recessive, and compound heterozygosity for mild dominant alleles may also be lethal [46].

Other rare entities with usual perinatal death. Greenberg dysplasia (LBR, 3β-hydroxysterol-Δ14-reductase deficiency), Blomstrand chondrodysplasia (PTH1R, loss of function of the parathyroid hormone/PTHrP receptor), Schneckenbecken dysplasia (SLC35D1, nucleotide sugar transporter), Silverman-Handmaker type dyssegmental dysplasia (HSPG2, perlecan) and Stüve-Wiedemann syndrome (LIFR) complete the differential diagnosis [47–51]. In Greenberg dysplasia, biallelic LBR variants affect the domain of the lamin B receptor with sterol-Δ14-reductase activity; other variants of the same gene, particularly those affecting the chromatin-organising domain, cause the Pelger-Huët anomaly (hyposegmentation of neutrophil nuclei in the heterozygous state and absent segmentation in the homozygous state, usually without clinical consequence and identifiable on the blood film) or a regressive spondylometaphyseal dysplasia associated with Pelger-Huët (PHASK), and heterozygous carriers of the lethal form may have Pelger-Huët anomaly [47, 52]. Astley-Kendall dysplasia and dappled diaphyseal dysplasia have been linked to Greenberg dysplasia as possible allelic forms [47, 52].

2.3. Reference variants, transcripts and nomenclature

The following table brings together the variants mentioned in this article, normalised using VariantValidator against the indicated MANE Select transcript [53]. Historical FGFR3 protein nomenclature is identical to current nomenclature; for SLC26A2, the designation IVS1+2T>C corresponds to the normalised form c.-26+2T>C [27].

The MANE Select transcripts of the remaining core genes, confirmed in VariantValidator, are SOX9 NM_000346.4, COL2A1 NM_001844.5, TRIP11 NM_004239.4, COL1A1 NM_000088.4, COL1A2 NM_000089.4, DYNC2H1 NM_001377.3 and FLNB NM_001457.4 [53]. A fetal test report should state the gene, versioned transcript, HGVS nomenclature, zygosity, ACMG/AMP classification and technical limitations; a variant of uncertain significance neither establishes nor excludes the diagnosis, nor does the combination of a pathogenic variant and a variant of uncertain significance in a recessive gene [11, 18].

3. Clinical Spectrum and Manifestations by System

3.1. Manifestations common to the group

The phenotype shared by severe forms is prenatal-onset short-limb dwarfism, with a relatively large head, a narrow thorax due to short ribs, a prominent abdomen and, in several entities, a hydropic appearance due to disproportion between abundant soft tissues and the short skeleton [18, 30]. Polyhydramnios is frequent and may complicate pregnancy with maternal dyspnoea and preterm delivery; breech presentation is common in SLC26A2 achondrogenesis [18]. Fetal movements may be reduced, as described in thanatophoric dysplasia [20]. In the respiratory system, pulmonary hypoplasia secondary to the small rib cage is the main cause of death, with additional contributions, depending on the entity, from tracheobronchomalacia, laryngeal stenosis and cervical instability [14, 27, 39]. Beyond the skeleton, ciliopathies are associated with heart defects, cystic renal dysplasia, pancreatic fibrosis and cysts, cloacal developmental anomalies and ambiguous genitalia [40, 59]; campomelic dysplasia is associated with sex reversal in 46,XY individuals [41]; thanatophoric dysplasia is associated with temporal lobe malformations, megalencephaly, hydrocephalus and neuronal heterotopias [28, 29].

3.2. Main entities

Odontochondrodysplasia (TRIP11): the non-lethal extreme of the spectrum

Odontochondrodysplasia (OMIM 184260; ORPHA:166272), also called Goldblatt syndrome or spondylometaphyseal dysplasia with dentinogenesis imperfecta, is the non-lethal allelic form of TRIP11 achondrogenesis and belongs, in the 2023 nosology, to the spondylometaphyseal dysplasia group [4, 63]. Wehrle and colleagues showed in 2019 that the disease results from hypomorphic TRIP11 variants: residual GMAP-210, although present in reduced amounts, partially preserves the integrity of the Golgi apparatus, global protein secretion and the subcellular distribution of IFT20, functions that are lost in TRIP11 achondrogenesis, in which the protein is absent [64]. In both diseases, chondrocyte maturation is compromised by abnormal glycan processing and deficient secretion of extracellular matrix proteoglycans, which points to a Golgi-dependent rather than a primary cilium-dependent mechanism [64].

Short-limbed dwarfism is present at birth and short stature is often detected on prenatal ultrasound; mesomelia becomes more pronounced during childhood, and it is accompanied by dentinogenesis imperfecta, joint laxity, genu varum and a narrow thorax, which is occasionally lethal [63]. At birth, radiographs show platyspondyly with coronal clefts, marked metaphyseal irregularities of the long bones and phalanges, and mesomelia with a relatively long fibula; in childhood, the disproportion worsens, the cupped metaphyses evolve into enchondroma-like lesions, and coxa valga with an elongated femoral neck, brachydactyly, a trident pelvis with lace-like iliac crests and progressive scoliosis appear [63]. Severity is variable: some patients died shortly after birth or in early childhood, presumably because of the thoracic changes, and others reached adulthood without respiratory compromise; platyspondyly becomes less marked with age, but all published patients had marked short stature [63]. Translucent dentine is visible in the primary dentition, and dentinogenesis imperfecta is usually more pronounced in the primary than in the permanent dentition [63].

In the review by Del Pino and colleagues, which added four new patients to those published, 12 of 14 patients had one null allele and one splicing variant, and one was homozygous for an in-frame splicing variant; an adult woman with two potentially null alleles had the mildest phenotype described, without explanation [65]. The variant NM_004239.4:c.586C>T p.(Gln196Ter), which in messenger RNA studies gives rise to p.Val105_Gln196del, was the most frequent (seven patients from four families, three of them from different regions of the world), and c.2993_2994del p.(Lys998SerfsTer5) was found in two patients with a possible common ancestor [65]. In Brazil, Medina and colleagues (Brasília and the UNICAMP Skeletal Dysplasia Group) described a child with odontochondrodysplasia homozygous for an in-frame splicing variant in intron 9, which appears to give rise to an alternative transcript, and a fetus with classical TRIP11 achondrogenesis caused by a frameshift variant in exon 11, which supports a genotype–phenotype correlation dependent on residual activity [66]. An overlapping picture has been described with biallelic MIA3 (TANGO1) variants: in two unrelated Egyptian patients, homozygous variants in the luminal domain caused short stature with very short limbs, metaphyseal dysplasia, joint laxity and dentinogenesis imperfecta, in a spectrum ranging from forms with extraskeletal manifestations (insulin-dependent diabetes, deafness, obesity and intellectual disability in one sibship) to a lethal dysplasia with fetal hydrops [67].

In the fetus and newborn, platyspondyly with coronal clefts and mesomelia with a long fibula distinguish odontochondrodysplasia from TRIP11 achondrogenesis, which has much more deficient ossification and rib fractures. Sedaghatian type spondylometaphyseal dysplasia presents with severe neurological and cardiorespiratory disease and has neither coronal clefts nor lace-like iliac crests; Torrance type spondyloepiphyseal dysplasia has deficient ossification of the vertebral bodies and pubis, without coronal clefts, lace-like crests or marked mesomelia; and osteogenesis imperfecta with dentinogenesis imperfecta is distinguished by osteopenia, fractures and wormian bones [63]. Treatment is symptomatic, with surgery for progressive scoliosis and angular deformities of the lower limbs and dental care; inheritance is autosomal recessive, with a 25% recurrence risk for siblings and the possibility of prenatal or preimplantation diagnosis when both familial variants are known [63, 65].

3.3. Reconsidering the concept of lethality

The natural course data above concern historical series, mostly without targeted intensive care. In a Japanese national series of 51 liveborn infants with thanatophoric dysplasia, 27 died by 7 days (early neonatal mortality of 56%); the 25 who received no respiratory support died within 48 hours, whereas all 24 who survived the early neonatal period had received respiratory support and 16 lived for at least one year [23]. All long-term survivors described in the literature required mechanical ventilation and continued to have severe developmental delay [28]. In OI, older data indicated that more than 60% of newborns with the perinatal form died on the first day and 80% in the first week; however, at a North American quaternary centre, all 18 newborns with a prenatal diagnosis of moderate to severe OI (12 predicted to be lethal) survived to neonatal discharge, 7 with respiratory support and 9 with feeding support, without correlation between prenatal prediction and support requirements [24, 45]. These data do not make survival the rule for every entity — achondrogenesis, atelosteogenesis type 1 and SRPS remain described as lethal at or shortly after birth [34, 36, 40] — but show that the designation "lethal" depends on the entity, individual severity and care decisions.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

A short femur on routine ultrasound has several non-skeletal explanations that the geneticist should first exclude: incorrect dating, a normally small fetus, intrauterine growth restriction (which would need to be very severe to be detected at 20 weeks), a chromosomal disorder, and malformation syndromes with growth restriction or limb reduction defects [25]. A Spanish series of 75 pregnancies with long bones below the 3rd percentile illustrates the importance of context: with isolated shortening, 23% of newborns were healthy, 45% were small for gestational age or had growth restriction, and 32% had skeletal dysplasia; when other skeletal anomalies were present, 85% had dysplasia [68].

Prenatal medical genetics guidelines recommend referring fetuses with a femur or humerus below the 5th percentile or more than 2 SD below the mean before 24 weeks to a centre experienced in dysplasias, and regard shortening exceeding 3 SD as strongly suggestive of dysplasia, particularly with a head circumference above the 75th percentile [1]. The 2018 Delphi consensus endorsed further assessment for a femur at the 5th percentile on the 18–22-week scan and referral of pregnancies with suspected dysplasia to centres providing advanced ultrasound and maternal–fetal medicine specialists [2]. For second-trimester ultrasound, the ISUOG generally considers measurement of one femur sufficient, but recommends measuring all long bones and comparing them with standardised charts when concerns arise [26].

4.2. Warning signs of severity

4.3. Clues from the bowing pattern and history

The bowing pattern helps guide assessment: symmetrically bowed femora are most often due to campomelic dysplasia or progressively deforming OI; short "crumpled" limbs suggest perinatal OI; very short limbs and ribs with predominantly femoral bowing suggest thanatophoric dysplasia; beaded ribs indicate fractures from perinatal OI; maximal tibial bowing points towards campomelic dysplasia, OI or Beemer-Langer syndrome [44]. When femora are bowed, the spine and kidneys should be examined [44]. Relevant elements of the family and obstetric history include consanguinity (recessive forms), advanced paternal age, short stature of the parents (including the father), a history of easy fractures, stillbirths or neonatal deaths, insulin-dependent maternal diabetes (femoral hypoplasia–unusual facies, sacral agenesis) and drug exposure — warfarin may produce a chondrodysplasia punctata phenotype, and alcohol, phenytoin and carbamazepine may cause limb reduction defects [25, 44]. Fluconazole in utero causes an Antley-Bixler syndrome phenocopy [44]. The 2026 review adds maternal height, ancestry and a history of termination for fetal anomaly to the initial assessment, and recommends examining both parents to identify mild forms or mosaicism [8].

5. Diagnosis: Criteria, Tests and Algorithms

There are no consensus diagnostic criteria for "lethal skeletal dysplasia" as a category; diagnosis rests on integration of ultrasound, molecular genetics and, after birth or fetal loss, radiology, pathology and histology [1, 8]. The process successively answers three questions: whether a skeletal dysplasia is present, what the likelihood of a lethal course is, and which molecular entity is involved, on which recurrence risk depends [1, 8].

5.1. Ultrasound: dating, systematic assessment and follow-up

Interpretation of measurements requires reliable dating, ideally using crown–rump length between 8 and 12 weeks [71]. When dysplasia is suspected, the biparietal diameter, head circumference, abdominal circumference, mandible, clavicle, scapula, thoracic circumference and all long bones should be measured and compared with reference values to determine whether shortening is rhizomelic, mesomelic or generalised; the femur/foot ratio remains close to 1.0 throughout gestation and decreases in rhizomelic forms [1]. The standardised approach also includes long bone shape (straight, bowed, unilateral or bilateral), metaphyseal appearance, echogenicity (mineralisation), skull and vertebral shape and mineralisation, hands and feet, the presence of secondary epiphyses (calcaneus after 20 weeks and knee after 28), facial profile, limb posture, other anomalies, amniotic fluid and hydrops [1]. The Oxford Desk Reference protocol additionally assesses epiphyseal stippling, fractures, cloverleaf skull, scoliosis and hemivertebrae, cardiothoracic ratio and rib length, trident hand (detectable from 25 weeks), club foot, polydactyly, "hitchhiker" thumb, facial clefts, micrognathia and external genitalia [25].

The 2026 review recommends measuring at least one femur — ideally both — at the 11–14-week scan as a baseline for growth velocity, and defines triggers for extended assessment: increased nuchal translucency, hygroma or hydrops, femur < 5th percentile, fractured, short or bowed bones, small thorax, abnormal skull, digit or spinal abnormalities, a "no-call" or abnormal non-invasive prenatal screening result, and a relevant family history [8]. Extended assessment includes transvaginal ultrasound in the first trimester, 3D ultrasound when available, fetal echocardiography (particularly with polydactyly), referral to a tertiary centre and reassessment every 2–4 weeks to document growth velocity [8]. The ISUOG recommends expressing biometric results as percentiles or z-scores, specifying the reference chart, and repeating incomplete examinations or referring the patient [26].

Ultrasound performance has improved but remains limited. The 2009 guideline estimated specific diagnostic accuracy of routine ultrasound at around 40% [1], and the 2018 consensus reports sensitivities of 40–60% for 2D ultrasound [2]. At a German tertiary centre with 162 fetuses with dysplasia (1985–2007), the specific ultrasound diagnosis was correct in 67.9% and partially correct in 30.9%, with 88% and 89% completely correct diagnoses for thanatophoric dysplasia and OI, but 0 of 2 hypophosphatasia cases and 1 of 6 hypochondrogenesis cases [72]. In an ISDR registry of 1,500 cases, 15% of referred cases were not well-defined dysplasias but genetic syndromes or early-onset growth restriction [7].

5.2. Prediction of lethality

FL/AC < 0.16 is the most extensively studied predictor. In Vancouver (around 35,000 fetuses screened, 18 suspected cases), a ratio < 0.16 was associated with a lethal course in 9 of 9 cases and a ratio ≥ 0.16 with non-lethal dysplasia or no dysplasia in 9 of 9 [69]. In Dallas (44,020 ultrasound examinations, 1990–1995, 27 known outcomes), all 12 fetuses with lethal dysplasia had a ratio < 0.16, the mean was 0.106 ± 0.026 in lethal cases and 0.187 ± 0.020 in non-lethal cases, and the only fetus with a ratio < 0.16 who survived had extreme bowing, illustrating the limitation of the ratio when the femur is curved [2, 70]. In a magnetic resonance imaging (MRI) study of 23 fetuses, lethality was associated with observed/expected lung volume (p = 0.002) and FL/AC (p = 0.0476), with suggested cut-offs of 47.9% and 0.124 [9].

The most recent cohort, from Philadelphia (96 fetuses, 2013–2023, 51% with life-limiting dysplasia), assessed three markers: FL/AC < 0.16 and thoracic circumference < 2.5th percentile were associated with lethality (p < 0.001), whereas TC/AC < 0.6 was rare and did not reach significance (p = 0.056) [10]. PPV increased from 50% with one marker to 78% with two and 100% with three; absence of markers had an NPV of 91%; the PPV of two markers was 90% before 28 weeks and 43% from 28 weeks onwards, with few late cases [10]. The authors concluded that isolated markers have poor predictive value [10]. The 2018 Delphi consensus unanimously endorsed thorax/abdomen ratio < 0.6, FL/AC < 0.16, femur/biparietal diameter ratio, micromelia > 3 SD below the mean, hydrops and severe axial hypomineralisation as predictors at 18–20 weeks, but rejected isolated micromelia as the best indicator and did not reach consensus on the best single marker [2]. The Oxford Desk Reference, drawing on Parilla and colleagues (2003), lists early severe shortening, FL/AC < 0.16, a small thorax with short ribs and increased cardiothoracic ratio, and marked bowing or fractures as predictors, stressing that none is particularly accurate [25].

5.3. Adjunctive imaging

5.4. Genetic tests

Sample and test sequence. When dysplasia is suspected, diagnostic testing by chorionic villus sampling (CVS) or amniocentesis should be offered, depending on gestational age; CVS allows earlier diagnosis, but confined placental mosaicism may complicate interpretation [8]. Karyotyping and microarray identify aneuploidies and copy-number variants, which matter in the differential diagnosis (trisomies 21, 13 and 18 and triploidy may present with short bones) and in entities such as campomelic dysplasia due to a 17q24 rearrangement [14, 25], but have limited capacity for specific molecular diagnosis [8]. In a Chinese cohort of 147 fetuses with ultrasound-detected dysplasia, microarray was abnormal in 15.6% (7.7% in isolated forms and 28.6% with anomalies in other systems), and exome sequencing in 58 cases with normal microarray identified pathogenic or likely pathogenic variants in 36.2% [77].

Exome, genome and panels. The 2022 position of the International Society for Prenatal Diagnosis (ISPD) considers prenatal sequencing beneficial in fetuses with an isolated major anomaly or multiple anomalies when microarray is normal and a genetics specialist considers a genetic cause likely, or when the pattern strongly suggests monogenic disease — in which case microarray should be performed beforehand or in parallel; the ISPD yield table attributes an additional yield of 53% (424 fetuses) to isolated skeletal anomalies [11]. In the English PAGE study (610 fetuses with structural anomalies), overall yield was 8.5% and 15.4% (10 of 65) in skeletal anomalies [78]. Dysplasia-focused series show higher yields: 58.0% in 88 fetal samples tested with a panel (versus 38.9% in postnatal samples) [79]; 72% (23 of 32) with singleton genome sequencing and an in silico panel in Stockholm, 2015–2022 [80]; and 52 molecular diagnoses among 99 fetuses tested in a North American multicentre series, in which panels and exome sequencing would detect 96% of diagnosed syndromes and the ultrasound suspicion was incorrect in 7.69% of confirmed cases [81]. The 2026 review recommends the broadest available coverage test (ES or GS, or a comprehensive dysplasia panel), with phenotype-directed analysis to limit variants of uncertain significance, and targeted tests only for known familial variants or strong suspicion of FGFR3 or COL1A1/COL1A2 conditions [8]. A 2025 international survey showed that in 90.3% of responding countries, selection for prenatal exome sequencing is case-by-case, and that predefined phenotypic criteria perform modestly [82]. In 2018, the Delphi panel did not reach consensus on offering prenatal sequencing because of turnaround time, demonstrating the recent evolution of this recommendation [2].

Non-invasive screening and diagnosis. Cell-free fetal DNA (cffDNA) represents 10–20% of circulating maternal DNA and is easier to analyse when the variant is absent from the mother, as with de novo FGFR3 variants [83]. In London, cffDNA analysis confirmed c.742C>T (p.Arg248Cys) or c.1948A>G (p.Lys650Glu) in three pregnancies with thanatophoric dysplasia [54]. In a commercial 30-gene panel for dominant monogenic diseases (2,208 results), the positive rate was 33.7% (60 of 178) when the indication was a long bone anomaly, without false positives among the 67 cases with follow-up [84]. The 2026 review stresses that non-invasive single-gene testing is screening with limited coverage (in the USA, chiefly achondroplasia, thanatophoric dysplasia and some forms of OI), may detect maternal or placental variants and requires confirmation; in the Houston series, single-gene testing would detect only 51.9% of identified syndromes [8, 81].

Biochemical and parental tests. When hypophosphatasia is suspected, parental alkaline phosphatase may help with counselling, particularly when there is prenatal bowing with possible dominant transmission, maternal in particular [44]. When Smith-Lemli-Opitz syndrome is suspected, the maternal urinary steroid profile (low oestriol) and analysis of fetal sterols guide the diagnosis [25]. Genetic sex by cffDNA is useful when the fetus appears female and campomelic dysplasia is suspected [44]. In Greenberg dysplasia, confirmation is chiefly molecular (LBR): the sterol profile in fibroblasts cultured in cholesterol-poor medium may show accumulation of cholesta-8(9),14-dien-3β-ol and cholesta-8(9),14,24-trien-3β-ol, consistent with 3β-hydroxysterol-Δ14-reductase deficiency, but there is no marker in plasma or in the amniotic fluid supernatant, unlike 8-dehydrocholesterol in EBP disorders, and the 2022 French PNDS (French National Diagnosis and Care Protocol) considers this biochemical route complex to perform [52]. In the presence of fetal epiphyseal stippling, the same protocol proposes microarray on amniotic fluid to exclude copy number variants and, if normal, a targeted panel or prenatal exome or, after termination of pregnancy, genome sequencing; depending on the suspicion, the profile of cholesterol precursors in the supernatant, peroxisomal studies in cultured amniocytes or chorionic villi (plasmalogens, very long-chain fatty acids and dihydroxyacetone phosphate acyltransferase activity) and lysosomal studies in the supernatant and in cultured cells (oligosaccharides, free sialic acid and acid hydrolases) are added [52].

Test limitations. SLC26A2 sequencing detects more than 90% of alleles in related achondrogenesis and atelosteogenesis, with no exon deletions described as causative [18, 27]; in campomelic dysplasia, SOX9 sequencing (including the 3' and 5' UTRs) detects 90–95%, deletion/duplication analysis around 2%, microarray around 1% and karyotyping another 1% (balanced translocations undetected by microarray) [14]; in severe hypophosphatasia, biallelic ALPL variants are found in around 95% of individuals of European ancestry [56]. These figures concern the proportion of detectable variants in individuals with the diagnosis, rather than clinical sensitivity in a fetus with a non-specific phenotype. Failure to identify a COL1A1/COL1A2 variant does not exclude fetal OI [45], and a negative molecular result does not negate ultrasound findings of lethality [1]. Interpretation should be undertaken by a multidisciplinary team and integrate the phenotype; sample storage and reanalysis should be planned [11].

5.5. Postnatal and post-mortem assessment

All prenatal suspicions should be confirmed by specialist clinical and radiological assessment after delivery or fetal loss [1]. Minimum elements are a complete skeletal survey (anteroposterior and lateral skull views, thorax, anteroposterior and lateral spine, pelvis and a segment of each limb, including hands and feet), photographs, measurements (length, arm span, head circumference), autopsy with cartilage and bone histology (ideally femur and humerus), and storage of DNA, fibroblasts or tissue; cord blood, fetal blood, placental tissue and skin biopsy provide DNA sources [1, 12, 16]. Much of the information can be obtained even without autopsy [25]. The Skeletal Dysplasia Group radiological diagnostic table for lethal dysplasias recommends retaining tissues from all severe dysplasias, suggesting cryopreserved fibroblasts [85]. The Delphi consensus endorsed retention of fetal DNA until the correct diagnosis and post-mortem assessment after termination [2].

5.6. Summary algorithm

6. Differential Diagnosis

6.1. Non-skeletal causes of short bones

The first differential diagnosis of a short femur is growth restriction of placental origin, assessed through maternal and fetal Doppler, and incorrect dating [25]. Among chromosomal disorders, a short femur is an ultrasound marker for trisomy 21; trisomies 13 and 18 are associated with other characteristic signs; triploidy (particularly the digynic form, which survives into the second trimester with relative macrocephaly) produces severe growth restriction; bilateral radial defects occur in trisomy 18 and Fanconi anaemia, which conventional karyotyping does not detect [25]. Malformation syndromes include Cornelia de Lange syndrome (growth restriction and asymmetric radial defects), Russell-Silver syndrome (almost normal head circumference and asymmetry), Seckel syndrome and microcephalic primordial dwarfism, and Smith-Lemli-Opitz syndrome [25]. Most malformation syndromes without a family history are not diagnosed prenatally, and ultrasound cannot reliably distinguish a syndrome from a chromosomal disorder, so cytogenetic investigation is indicated [25]. Asymmetric involvement or involvement of a single bone suggests a sporadic, vascular or environmental cause, or a somatic mutation, rather than a genetic syndrome [44]. Finally, some fetuses with isolated short long bones are normal (23% in the Spanish series) [68].

6.2. Dysplasias presenting at birth: a radiographic pattern-based approach

The following table derives from visual reading of Table A15 in the Oxford Desk Reference (Wynne-Davies, Hall and Hurst for the Skeletal Dysplasia Group for Teaching and Research, publication 8c, 2016), which organises dysplasias present at birth by their principal radiographic findings, in approximately descending order of frequency; the table notes that limb shortening can be identified by ultrasound at 20 weeks in lethal conditions and some non-lethal conditions [85].

6.3. Frequent differential diagnosis pairs

A nomenclature note prevents errors: the term "achondrogenesis" was historically applied to Grebe dysplasia, which differs from all forms of achondrogenesis [30]; and the designation "atelosteogenesis type 2" suggested a relationship with AO1 that does not exist — the entity belongs to the SLC26A2 spectrum [27].

The extended differential also includes the linkeropathies of glycosaminoglycan synthesis: B4GALT7 deficiency (B4GALT7-CDG), which prevents attachment of the first galactose to the linkage tetrasaccharide and reduces the synthesis of heparan, dermatan and chondroitin sulfate, usually causes short stature, anomalies of the forearm bones and elbows and limb bowing with Ehlers-Danlos features, but in one family the phenotype included perinatal lethal skeletal dysplasia with cleft palate and radial ray defects [87].

7. Treatments and Risk Management Strategies

7.1. Principles

For most severe skeletal dysplasias diagnosed prenatally, there is no disease-modifying treatment, and management is supportive or palliative; for SLC26A2 achondrogenesis, GeneReviews recommends palliative care for the liveborn infant, and in SLC26A2 atelosteogenesis the choice between supportive and palliative treatment depends on respiratory compromise at birth [18, 27]. Exceptions in which treatment changes the natural history — asfotase alfa for hypophosphatasia, bisphosphonates for severe OI and vosoritide for achondroplasia — reinforce, according to the 2026 review, the need for early molecular diagnosis and counselling beyond a dichotomy [8]. Management involves three levels: maternal, fetal and perinatal [28].

In Greenberg dysplasia, the 2022 French PNDS (French National Diagnosis and Care Protocol) provides for no treatment and focuses management on diagnosis and counselling [52]. There are two discrepancies with the other sources cited. The bone dysplasia atlas includes dappled diaphyseal dysplasia within the entity itself and considers it uncertain whether Astley-Kendall dysplasia is not rather the extreme of severe OI, whereas the PNDS presents both as forms related to Greenberg dysplasia [47, 52]. The PNDS also accepts reference ultrasound surveillance without molecular testing as an alternative to molecular prenatal diagnosis in a subsequent pregnancy, whereas the GeneReviews chapter on SLC26A2 achondrogenesis, another recessive form with ultrasound anomalies in all affected fetuses, warns that ultrasound should not be used to exclude recurrence [18, 52].

7.2. Pregnancy and delivery management

At the maternal level, polyhydramnios, preterm delivery and cephalopelvic disproportion require surveillance, as many fetuses with lethal and non-lethal dysplasias have relative macrocephaly and vaginal delivery may not be feasible [1, 28]. In thanatophoric dysplasia, complications include prematurity, polyhydramnios, abnormal presentation and disproportion due to macrocephaly, hydrocephalus or a stiff flexed neck; GeneReviews states that cephalocentesis and caesarean section may be considered to avoid maternal complications and, citing the 2018 perinatal consensus, includes surveillance for cephalopelvic disproportion, polyhydramnios and preterm labour, and avoidance of emergency caesarean section for fetal distress in the maternal plan [28]. Management of each pregnancy depends on discussion between the team and family about prognosis and the need for prolonged respiratory support, and varies between centres [28]. At the fetal level, surveillance includes presentation, serial head circumference, MRI lung volumetry and assessment of fetal well-being; at the perinatal level, a written plan for assessment, care and possible withdrawal of care after delivery, with postnatal clinical and radiological assessment and discussion of post-mortem assessment and DNA storage [28].

The 2018 Delphi consensus endorsed early discussion of delivery during pregnancy (place, mode, anaesthesia and perinatal care), and avoidance of instrumentation (forceps, vacuum extraction) where possible because of intracranial and cervical complication risks [2]. There was no consensus that all fetuses with suspected dysplasia should be delivered at a tertiary centre; after discussion, the panel agreed on delivery at a tertiary centre with neonatal intensive care when other congenital anomalies or suspected lethal dysplasia are present [2]. In OI, a series of 540 patients showed no difference in fractures at birth between vaginal delivery and caesarean section, so the panel recommended caesarean section only for other maternal or fetal indications [2]. The 2009 guideline recommends antenatal consultations between obstetrics, neonatology, anaesthesia and genetics for viable fetuses, and notes that even non-lethal dysplasias may cause neonatal respiratory compromise [1].

Perinatal palliative care is a coordinated obstetric and neonatal care strategy focused on comfort and quality of life for the newborn with a life-limiting condition, and may run alongside life-prolonging treatment; the American College of Obstetricians and Gynecologists (ACOG) emphasises that, with a life-limiting prenatal diagnosis, informed consent requires sufficient information for a voluntary choice and shared decision-making [88]. The option of intensive support should account for the survival data with ventilation described in section 3.3 and variability between entities [23, 24].

7.3. Neonatal care

All newborns with suspected dysplasia should be assessed as early as possible, regardless of the previous diagnosis or prognosis, and referred to a specialist centre if the diagnosis is not established [2]. Immediate elements include a complete skeletal survey, respiratory assessment, assessment for cleft palate and, in campomelic dysplasia, a lateral cervical spine radiograph and karyotyping in female phenotypes (risk of gonadoblastoma in 46,XY individuals) [14, 18, 27]. Newborns with thanatophoric dysplasia who survive usually require prolonged ventilation and tracheostomy; anaesthetic guidelines for skeletal dysplasias apply, and ventricular shunting and suboccipital decompression may be necessary [28].

7.4. Specific treatments with authorisation or reported use

Asfotase alfa (Strensiq®) in perinatal hypophosphatasia. This is a bone-targeted recombinant tissue-nonspecific alkaline phosphatase [89]. In the studies in the US label (68 treated patients with the perinatal/infantile form compared with 48 historical controls), 91% of treated patients and 27% of controls were alive at last contact (HR 0.14; 95% CI 0.05–0.39), and survival free of invasive ventilation was 85% versus 25% (HR 0.21; 95% CI 0.09–0.51); among those who required respiratory support, 21 of 26 treated patients (81%) survived versus 1 of 20 controls (5%) [89]. The comparison is with historical controls and not with a randomised trial.

Vosoritide in thanatophoric dysplasia (off-label). Vosoritide (Voxzogo®) is authorised in the EU for achondroplasia from 4 months of age with open epiphyses, and not for thanatophoric dysplasia [93]. A 2025 report described a 9-year-old child with thanatophoric dysplasia type 1 treated with 15 µg/kg/day subcutaneously, increased to 30 µg/kg/day at 16 months; over 28 months, height improved by +1.3 SD, growth velocity by +2.0 cm/year and vital capacity by 65%, with no radiological progression of foramen magnum stenosis and with adverse effects limited to injection-site reactions and mild vasovagal episodes [55]. This is an isolated case, in a long-term survivor, and the doses given are those of the report, not of a label; therapies targeting FGFR3 have been developed for achondroplasia.

OI. Bisphosphonates alter the natural history of severe OI [8].

7.5. Clinical research and recent developments

This trial does not address the severe perinatal form (formerly type 2), but is the first registered fetal stem-cell intervention in bone dysplasia with a prenatal component. Its interpretative limitations are those of a phase I/II study: a primary safety outcome, comparison with historical and prospective untreated controls, a small sample and only three prenatal participants [95]. A 2026 qualitative study involving families and professionals described the difficulty of balancing hope and uncertainty about efficacy, and the regulatory and logistical barriers to an international trial [96]; a 2025 consent analysis showed that in Sweden, the Netherlands, Germany and the United Kingdom, prenatal consent was obtained solely from the pregnant woman, whereas consent for neonatal interventions requires both parents in three of these countries [97]. No registered therapeutic trials for thanatophoric dysplasia, achondrogeneses, SRPS or campomelic dysplasia were identified on ClinicalTrials.gov (search on 6 October 2026), which does not exclude unregistered studies or those using different terminology [98].

A Swedish fetal genome series (72% yield) was published in June 2025, slightly outside the 12-month window, and is used in section 5 [80].

8. Reproductive Options and Family Counselling

8.1. Communicating the prenatal diagnosis

Ultrasound findings of dysplasia are non-specific and difficult to interpret; a specific diagnosis should be suggested to parents only with additional clinical or ultrasound information [16]. For counselling and to inform neonatologists, an estimate of the likelihood of neonatal lethality is needed, communicated as an estimate rather than a certainty [10, 25]. Counselling should cover the differential diagnosis, prognosis with its uncertainties, options for continuation with intensive or comfort care and, where legally permitted, termination of pregnancy, as well as the plan for postnatal or post-mortem sampling [1, 88]. Pemberton and colleagues noted that if the 20–22-week scan is followed by exome sequencing with a 3-week turnaround, choices may become limited in countries with more restrictive termination laws [57]. The ISPD recommends pre-test and post-test counselling by professionals with genetics experience, written information about results and reproductive implications, and discussion of sample storage and reanalysis [11].

The French PNDS (French National Diagnosis and Care Protocol) for chondrodysplasia punctata recommends that the disclosure of a prenatal diagnosis, when the clinician who requested the test is not a geneticist, be made jointly with a medical geneticist and in the presence of a psychologist, and that it include the main features of the disease, the follow-up options, the opportunity to hear from the specialists who would care for the child after birth, the mode of transmission and, when indicated and after discussion at the multidisciplinary prenatal diagnosis centre (CPDPN), information on termination of pregnancy for medical reasons; a second consultation a few weeks later allows the information, which is difficult to absorb at the time of disclosure, to be revisited, and psychological support extends to the parents and siblings [52].

8.2. Recurrence risk by mechanism

In prenatal practice, up to 63% of pathogenic variants associated with fetal structural anomalies identified by exome sequencing are apparently de novo; some are inherited from a mosaic parent, changing recurrence risk and justifying mosaicism-sensitive techniques when available [100]. The 2018 consensus illustrates the importance of molecular diagnosis through achondrogenesis: risk < 1% if the cause is a de novo COL2A1 variant and 25% if recessive due to TRIP11 or SLC26A2 [2].

8.3. Options in a future pregnancy

Once familial variants have been identified, prenatal diagnosis by CVS or amniocentesis and preimplantation genetic testing are available [14, 18, 27, 45]. Ultrasound complements but does not replace molecular testing: in SLC26A2 achondrogenesis, all affected fetuses have ultrasound anomalies, but ultrasound should not be used to exclude recurrence [18]; in SLC26A2 atelosteogenesis, early transvaginal ultrasound is a reasonable adjunct, but reliable diagnosis is possible only at 14–15 weeks and is operator-dependent [27]; in TRIP11 achondrogenesis, ultrasound may identify recurrence earlier than the molecular techniques available when the atlas was published [35]; in perinatal OI, skeletal changes are visible at around 13–14 weeks and, at 16 weeks, the femur is usually delayed by two or more weeks, the cranial vault is almost unmineralised and rib fractures are present [45]; in perinatal hypophosphatasia, recurrence may be identified by ultrasound [56]. For recurrence of a de novo mutation through gonadal mosaicism, cffDNA permits testing for the known variant [83]. Offering invasive testing after a case of de novo dominant dysplasia, with a low gonadal mosaicism risk, was considered controversial by the 2009 guideline [1].

In Greenberg dysplasia, the French PNDS provides, once the index case variants have been identified, for molecular prenatal diagnosis or preimplantation genetic diagnosis for heterozygous couples; because the ultrasound signs are early and severe, it also accepts, as an alternative to be discussed, ultrasound surveillance by a reference sonographer without molecular testing; termination of pregnancy for medical reasons depends on the couple's request and the opinion of the CPDPN [52].

DNA storage from the index case is essential: genetic diagnosis in a future pregnancy may become possible if DNA has been retained and subsequent investigation (skeletal survey and genetic analysis) identifies the cause [44]. GeneReviews recommends DNA banking in probands without a confirmed molecular diagnosis, and the ISPD allows sequencing both parents to look for shared carriage of recessive variants when no index-case sample exists [11, 18]. Preconception counselling is recommended for individuals with dysplasia or increased risk of an affected fetus [2]. When both parents have dominant dysplasias (for example, achondroplasia), the fetus is at risk of homozygosity or compound heterozygosity, usually lethal, and molecular testing should be prepared before pregnancy [1]. In hypophosphatasia, parental alkaline phosphatase and possible dominant transmission of mild forms should be considered before counselling [44, 46].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Overall frequency

The study with the largest denominator comes from the ECLAMC network (Latin American Collaborative Study of Congenital Malformations), with 1,544,496 births examined in 132 South American hospitals between 2000 and 2007: osteochondrodysplasias were diagnosed in 492 newborns, a prevalence of 3.2 per 10,000 (95% CI 2.9–3.5), with 50% perinatal lethality (stillbirths and early neonatal deaths) and prenatal ultrasound diagnosis in 73% [5]. Among the 211 best-documented cases, 33% belonged to the OI group, 29% to the FGFR3 group and 8% to the bent bone group; prevalences per 10,000 were 0.74 for OI, 0.47 for thanatophoric dysplasia and 0.44 for achondroplasia; paternal age, parity and parental consanguinity (5.4%) were higher than in controls [5]. The study, conducted from the Universidade Estadual de Campinas (São Paulo, Brazil), covers South American hospitals and is the principal source of Latin American data among those consulted [5]. In Utah (population-based birth defects network, 1999–2008, 153 cases), prevalence was 3.0 per 10,000 births and 20.0 per 10,000 stillbirths; OI (0.79 per 10,000), thanatophoric dysplasia (0.43) and achondroplasia (0.35) were most frequent; 88% of deceased cases had prenatal suspicion versus 29% of living cases, and the median age at death of liveborn infants was 1 day [6].

These figures measure different things: birth prevalence in a malformations registry, relative frequency in a referral registry and distribution in a hospital series are not interchangeable. In the ISDR, with 1,500 referred cases, perinatal OI, thanatophoric dysplasia and achondrogenesis type 2 accounted for almost 40% [7]; in a German tertiary centre series, thanatophoric dysplasia (25%) and OI (22%) were most frequent [72]. The 2026 review estimates skeletal dysplasias at 2–3 per 10,000 pregnancies and 5–6% of newborns with congenital anomalies [8].

9.2. Entity-specific data and populations with founder effects

Consanguinity increases the proportion of recessive forms — in lethal OI, carrier frequency for recessive forms may, in some ethnic groups, make recessive risk exceed that of parental mosaicism [13, 44]. Biometric reference charts derive from small samples and specific populations, and no validated method exists for integrating constitutional or ancestry-related variation into thresholds for suspected dysplasia, potentially leading to overdiagnosis in shorter families [8]. No prevalence data specific to Portugal for lethal skeletal dysplasias were found in the sources consulted; for South America, including Brazil, the reference is the ECLAMC study [5]. This absence concerns the sources consulted and does not demonstrate that no studies exist.

9.3. Reference networks and family resources

In Europe, the relevant network is ERN BOND (European Reference Network on Rare Bone Diseases), coordinated by the Istituto Ortopedico Rizzoli in Bologna, with an area dedicated to patient representatives (EPAG) [15]. The Orphanet entry for the Rare bone disease group provides access to specialist centres, networks, diagnostic tests and patient associations [3]. The 2009 guideline lists the International Skeletal Dysplasia Registry and European Skeletal Dysplasia Network as diagnostic resources [1]. Associations cited by the sources include Antenatal Results and Choices (ARC) and Contact a Family in the United Kingdom [44], Compassionate Friends and Helping After Neonatal Death (HAND) for perinatal bereavement [18], the Osteogenesis Imperfecta Foundation, Brittle Bone Society and OI Registry [45], and Little People of America [14, 16].

In France, the PNDS (French National Diagnosis and Care Protocol) for chondrodysplasia punctata due to cholesterol biosynthesis defects and arylsulfatase E deficiency, which covers Greenberg dysplasia, was prepared by the competence centre for constitutional bone diseases and the reference centre for developmental anomalies and malformation syndromes of the South-East (Hospices Civils de Lyon) and published by the HAS in December 2022; the organisation relies on the filières de santé AnDDI-Rares (developmental anomalies) and OSCAR (constitutional bone diseases) and, in the prenatal setting, on the CPDPN [52].

10. Illustrative Clinical Case

10.1. Lethal dysplasia unsuspected on ultrasound and clarified by prenatal exome sequencing (osteocraniostenosis)

Pemberton and colleagues, in the United Kingdom, described in 2020 the first prenatal diagnosis of osteocraniostenosis [57]. A non-consanguineous couple, both of whom had healthy children from previous relationships, presented in their first pregnancy together; the first-trimester ultrasound was normal and combined screening showed a low risk of chromosomal abnormality. The 20-week ultrasound showed short long bones and an unusual skull shape with open sutures (Figure 1). Chromosomal analysis by comparative genomic hybridisation was normal and the couple was referred to clinical genetics. A second ultrasound confirmed the abnormal skull shape, without the features of a typical cloverleaf skull; all long bones were 5 SD below the mean and the head and abdominal circumferences 2 SD below. The images did not support diastrophic dysplasia: although they suggested bowing of the radii and bilateral "hitchhiker" thumbs, ear morphology was normal and there was no clubfoot. As there was neither a narrow thorax nor hydrops, a lethal dysplasia was not initially suspected, and the couple was counselled about the uncertain prognosis [57].

Targeted trio exome sequencing was offered, using fetal DNA extracted from amniotic fluid at 21 weeks and parental DNA; analysis took 15 days and identified a de novo FAM111A variant, c.1026_1028del, p.(Ser343del), previously described in two male patients with osteocraniostenosis, both of whom died in their first month of life [57]. On MANE Select transcript NM_001312909.2, VariantValidator confirms the variant as c.1026_1028del, p.(Ser343del), and ClinVar records it with the repeat notation c.1020TTC[2], classified as pathogenic/likely pathogenic for osteocraniostenosis and autosomal dominant Kenny-Caffey syndrome by multiple submitters without conflict [53, 58]. Analysis was restricted to genes associated with skeletal anomalies, and consent explicitly stated that incidental findings would neither be sought nor reported [57]. Following the diagnosis of lethal dysplasia, the couple decided to terminate the pregnancy; postnatal 3D CT confirmed short, thin, gracile bones and an abnormal skull with basal cranial stenosis (Figure 2) [57].

10.2. Lessons

The case illustrates three points in this article. First, absence of the classic lethality markers (narrow thorax, hydrops) does not guarantee a non-lethal course, just as their presence does not guarantee it [10, 57]. Second, phenotype-directed trio exome sequencing, with a turnaround compatible with decision-making, changed prognosis and management; the authors stress that ultrasound phenotyping quality (HPO terms) determines the analysis and that cooperation between genetics and fetal medicine is essential [57]. Third, postnatal imaging confirmation documented the phenotype and enabled counselling of the couple — a de novo variant, with low recurrence risk dependent on excluding parental mosaicism [57, 100]. The management described concerns an individual case in a specific legal framework and is not a routine recommendation.

11. Prognosis and Long-Term Follow-up

Prognosis depends chiefly on the molecular entity, the degree of thoracic and pulmonary hypoplasia and care decisions. Forms of achondrogenesis, atelosteogenesis type 1/boomerang dysplasia, fibrochondrogenesis, SRPS, Greenberg dysplasia, Blomstrand chondrodysplasia and Schneckenbecken dysplasia are described as lethal before or shortly after birth [32, 34–36, 40, 47–49]. In other entities, the course is heterogeneous: in thanatophoric dysplasia, long-term survivors with ventilation exist, one described at 28 years, with estimated final height of 80–90 cm, severe developmental delay, seizures and deafness [20, 28, 29]; in campomelic dysplasia, survivors include cases with intellectual disability and others with normal intelligence, and progressive kyphoscoliosis and cervical instability emerge [14, 41]; in atelosteogenesis type 3, one woman survived into adulthood and had an affected child [39]; in hypochondrogenesis, survival ranges from days to months [31]; in OI with a severe prenatal prognosis, 16 of 18 children were alive at follow-up at a specialist centre [24]; in perinatal hypophosphatasia treated with asfotase alfa, the Kaplan–Meier estimate of survival at 1 year of age was 97% in treated patients versus 42% in historical controls [89]. In Stüve-Wiedemann syndrome, most cases are fatal, but those surviving the first year tend to improve [51].

11.1. Follow-up during the current pregnancy

11.2. Follow-up after birth or fetal loss

In all cases, the prenatal diagnosis should be confirmed by clinical assessment, a radiological survey and, where applicable, autopsy with histology; omitting this step may lead to incorrect information on recurrence and suboptimal management [1]. Genetic follow-up includes communicating the molecular result, testing the parents to estimate recurrence, possible reanalysis of the exome or genome if the diagnosis remains unresolved, and planning the next pregnancy, ideally before conception [11, 18]. Survivors need multidisciplinary, entity-directed follow-up (respiratory, neurological, orthopaedic, auditory), according to the GeneReviews surveillance tables [14, 27, 28]. Perinatal bereavement support is part of follow-up [18, 88]. In Greenberg dysplasia, confirmation is made after fetal death or termination of pregnancy, by autopsy with a radiological survey and histology of cartilage and bone and by molecular study of LBR, supplemented if necessary by the sterol profile in tissue or fibroblasts [52].

12. Summary and Final Considerations

Severe skeletal dysplasias diagnosed prenatally form a heterogeneous group with birth prevalence of around 3 per 10,000 and perinatal lethality close to half of cases in population series [5, 6]. The 2023 nosology, with 771 entries and 552 genes, replaced numbered names with dyadic phenotype–gene designations, which are more useful for recurrence risk [4]. The approach starts with recognition of a femur below the 5th percentile or deviating by more than 2–3 SD, proceeds with systematic skeletal assessment and estimation of lethality — FL/AC < 0.16, TC/AC < 0.6, thoracic circumference < 2.5–5th percentile, observed/expected lung volume < ~48%, hydrops and axial hypomineralisation — and recognises that an isolated marker has poor predictive value and that combining markers before 28 weeks is more reliable [1, 2, 9, 10].

Molecular diagnosis, using microarray and exome or genome sequencing (or an extended panel), reaches yields of around 50% to 72% in dysplasia-focused series, defines recurrence risk — from < 1% to 25% for similar phenotypes — and enables prenatal and preimplantation diagnosis in future pregnancies [2, 11, 79, 80]. Low-dose CT and MRI have adjunctive roles at tertiary centres; radiography, CT and post-mortem autopsy, with DNA storage, remain essential [1, 73, 76]. Pregnancy and delivery planning should be shared, avoid instrumentation, anticipate cephalopelvic disproportion and integrate perinatal palliative care when chosen [2, 28, 88]. Survival data with intensive support in thanatophoric dysplasia and OI, and with asfotase alfa in perinatal hypophosphatasia, require the term "lethal" to be used as a probability dependent on the entity and care, rather than as an individual destiny [8, 23, 24, 89].

13. Bibliographical References

1. Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med. 2009;11(2):127–133. doi:10.1097/GIM.0b013e3181971ccb. PMID:19265753.
2. Savarirayan R, Rossiter JP, Hoover-Fong JE, Irving M, Bompadre V, Goldberg MJ, et al.; Skeletal Dysplasia Management Consortium. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219(6):545–562. doi:10.1016/j.ajog.2018.07.017. PMID:30048634.
3. Orphanet. Rare bone disease. ORPHA:93419 [Internet]. Paris: INSERM. Group entry. Accessed 6 October 2026.
4. 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.
5. Barbosa-Buck CO, Orioli IM, da Graça Dutra M, Lopez-Camelo J, Castilla EE, Cavalcanti DP. Clinical epidemiology of skeletal dysplasias in South America. Am J Med Genet A. 2012;158A(5):1038–1045. doi:10.1002/ajmg.a.35246. PMID:22407836.
6. Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp ML. Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A. 2012;158A(5):1046–1054. doi:10.1002/ajmg.a.35327. PMID:22461456.
7. Krakow D, Alanay Y, Rimoin LP, Lin V, Wilcox WR, Lachman RS, et al. Evaluation of prenatal-onset osteochondrodysplasias by ultrasonography: a retrospective and prospective analysis. Am J Med Genet A. 2008;146A(15):1917–1924. doi:10.1002/ajmg.a.32269. PMID:18627037.
8. Wang MJ, Jacobsen C, Arnold J, Wapner RJ, Krakow D. Pathways to enhancing prenatal diagnosis of skeletal dysplasias. Pregnancy (Hoboken). 2026;2(3):e70284. doi:10.1002/pmf2.70284. PMID:42596956.
9. Weaver KN, Johnson J, Kline-Fath B, Zhang X, Lim FY, Tinkle B, et al. Predictive value of fetal lung volume in prenatally diagnosed skeletal dysplasia. Prenat Diagn. 2014;34(13):1326–1331. doi:10.1002/pd.4475. PMID:25102973.
10. Crane HM, Schindewolf E, Burrill N, Debari S, Khalek N, Paidas Teefey C, et al. The reliability of ultrasound markers in identifying fetuses with a life-limiting skeletal dysplasia. Prenat Diagn. 2024;44(11):1318–1326. doi:10.1002/pd.6638. PMID:39078648.
11. Van den Veyver IB, Chandler N, Wilkins-Haug LE, Wapner RJ, Chitty LS; ISPD Board of Directors. International Society for Prenatal Diagnosis updated position statement on the use of genome-wide sequencing for prenatal diagnosis. Prenat Diagn. 2022;42(6):796–803. doi:10.1002/pd.6157. PMID:35583085.
12. Firth HV, Hurst JA. Investigation of lethal metabolic disorder or skeletal dysplasia. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 836. Local chapter.
13. Pyott SM, Pepin MG, Schwarze U, Yang K, Smith G, Byers PH. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet Med. 2011;13(2):125–130. doi:10.1097/GIM.0b013e318202e0f6. PMID:21239989.
14. Unger S, Scherer G, Superti-Furga A. Campomelic Dysplasia. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 31 July 2008; updated on 18 March 2021; revised on 6 April 2023. NBK1760.
15. ERN BOND — European Reference Network on Rare Bone Diseases [Internet]. Bologna: Istituto Ortopedico Rizzoli. Network website. Accessed 6 October 2026.
16. Firth HV, Hurst JA. Skeletal dysplasias. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 316–319. Local chapter.
17. Jones KL, Jones MC, del Campo M. Achondrogenesis types IA and IB. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 460–461. Local chapter.
18. Unger S, Superti-Furga A. Achondrogenesis Type 1B. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 30 August 2002; updated on 9 June 2022; revised on 16 March 2023. NBK1516.
19. Jones KL, Jones MC, del Campo M. Type II achondrogenesis-hypochondrogenesis (Langer-Saldino achondrogenesis, hypochondrogenesis). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 462–463. Local chapter.
20. Jones KL, Jones MC, del Campo M. Thanatophoric dysplasia. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 478–479. Local chapter.
21. Jones KL, Jones MC, del Campo M. Campomelic dysplasia. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 482–483. Local chapter.
22. Jones KL, Jones MC, del Campo M. Short rib–polydactyly syndromes. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 474–477. Local chapter.
23. Sawai H, Oka K, Ushioda M, Nishimura G, Omori T, Numabe H, et al. National survey of prevalence and prognosis of thanatophoric dysplasia in Japan. Pediatr Int. 2019;61(8):748–753. doi:10.1111/ped.13927. PMID:31247124.
24. Carroll RS, Little S, McGreal T, Bonner S, Willis D, Franzone JM, et al. Most infants with prenatal osteogenesis imperfecta diagnosis and poor prognosis survive: experience of a quaternary care osteogenesis imperfecta center. JBMR Plus. 2025;9(4):ziaf022. doi:10.1093/jbmrpl/ziaf022. PMID:40070560.
25. Firth HV, Hurst JA. Short limbs. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 784–787. Local chapter.
26. Salomon LJ, Alfirevic Z, Berghella V, Bilardo CM, Chalouhi GE, Da Silva Costa F, et al. ISUOG Practice Guidelines (updated): performance of the routine mid-trimester fetal ultrasound scan. Ultrasound Obstet Gynecol. 2022;59(6):840–856. doi:10.1002/uog.24888. PMID:35592929.
27. Superti-Furga A, Unger S. SLC26A2-Related Atelosteogenesis. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 30 August 2002; revised on 16 March 2023; updated on 3 September 2026. NBK1317.
28. French T, Savarirayan R. Thanatophoric Dysplasia. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 21 May 2004; revised on 18 May 2023; updated on 15 September 2026. NBK1366.
29. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Thanatophoric dysplasia, types 1 and 2 (MIM 187600, 187601). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 1–4. Local chapter.
30. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Achondrogenesis II, hypochondrogenesis (MIM 200610). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 65–67. Local chapter.
31. Gregersen PA, Savarirayan R. Type II Collagen Disorders Overview. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 25 April 2019; updated on 24 October 2024. NBK540447.
32. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Fibrochondrogenesis (MIM 228520). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 101–102. Local chapter.
33. Jones KL, Jones MC, del Campo M. Fibrochondrogenesis. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 464–465. Local chapter.
34. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Achondrogenesis, type IB (MIM 600972). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 245–246. Local chapter.
35. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Achondrogenesis type 1A (MIM 200600). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 157–159. Local chapter.
36. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Boomerang dysplasia/atelosteogenesis type I (MIM 112310, 108720). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 331–334. Local chapter.
37. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Atelosteogenesis type III (MIM 108721). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 335–338. Local chapter.
38. Jones KL, Jones MC, del Campo M. Boomerang dysplasia. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 472–473. Local chapter.
39. Jones KL, Jones MC, del Campo M. Atelosteogenesis, type I (giant cell chondrodysplasia), type II and type III. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 466–471. Local chapter.
40. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Short rib (±polydactyly) syndrome, Saldino-Noonan and Verma-Naumoff types (MIM 613091). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 390–393. Local chapter.
41. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Campomelic dysplasia (MIM 211990, 114290). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 757–761. Local chapter.
42. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bent bone dysplasia-FGFR2 type (MIM 614592). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 853–856. Local chapter.
43. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteogenesis imperfecta. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 497–500. Local chapter.
44. Firth HV, Hurst JA. Bowed limbs. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 710–711. Local chapter.
45. Rodriguez Celin M, Steiner RD, Basel D. COL1A1- and COL1A2-Related Osteogenesis Imperfecta. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 28 January 2005; revised on 14 March 2024; updated on 29 May 2025. NBK1295.
46. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Hypophosphatasia (MIM 146300, 241500, 251510). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 557–563. Local chapter.
47. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Greenberg dysplasia (MIM 215140). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 351–352. Local chapter.
48. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Blomstrand chondrodysplasia (MIM 215045). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 621–622. Local chapter.
49. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Schneckenbecken dysplasia (MIM 269250). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 163–164. Local chapter.
50. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Dyssegmental dysplasia (MIM 224400, 244110). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 194–198. Local chapter.
51. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Stüve-Wiedemann syndrome (MIM 601559). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 535–539. Local chapter.
52. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Chondrodysplasies ponctuées : déficit de la biosynthèse du cholestérol et déficit en arylsulfatase E. Centre de compétences Maladies osseuses constitutionnelles et Centre de référence Anomalies du développement et syndromes malformatifs Sud-Est, Hospices Civils de Lyon [Internet]. Saint-Denis La Plaine: HAS; 2022 Dec 12 [cited 2026 Nov 6]. Available from: https://www.has-sante.fr/jcms/p_3392235
53. 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. Accessed 6 October 2026 (GRCh38, MANE Select transcripts): variantvalidator.org.
54. Chitty LS, Khalil A, Barrett AN, Pajkrt E, Griffin DR, Cole TJ. Safe, accurate, prenatal diagnosis of thanatophoric dysplasia using ultrasound and free fetal DNA. Prenat Diagn. 2013;33(5):416–423. doi:10.1002/pd.4066. PMID:23408600.
55. Montero-Lopez R, Blaschitz A, Karas K, Fritz T, Laurer E, Naidoo U, et al. Thanatophoric dysplasia type 1 treated with vosoritide: a case report. Horm Res Paediatr. 2025 Oct 10:1–8 (advance publication). doi:10.1159/000548836. PMID:41078071.
56. Dahir KM, Nunes ME. Hypophosphatasia. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 20 November 2007; revised on 30 March 2023; updated on 27 March 2025. NBK1150.
57. Pemberton L, Barker R, Cockell A, Ramachandran V, Haworth A, Homfray T. Case report: targeted whole exome sequencing enables the first prenatal diagnosis of the lethal skeletal dysplasia osteocraniostenosis. BMC Med Genet. 2020;21(1):7. doi:10.1186/s12881-019-0939-z. PMID:31910817. PMCID:PMC6947839.
58. National Center for Biotechnology Information. ClinVar: VCV000056811, NM_001312909.2(FAM111A):c.1020TTC[2] (p.Ser343del) [Internet]. Bethesda: NCBI. ClinVar record. Accessed 6 October 2026.
59. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Short rib (±polydactyly) syndrome, Majewski type (MIM 263520). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 394–395. Local chapter.
60. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Atelosteogenesis, type 2 (MIM 256050). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 247–249. Local chapter.
61. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Short rib (±polydactyly) syndrome, Beemer-Langer type (MIM 269860). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 396–397. Local chapter.
62. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteogenesis imperfecta, type IIA (MIM 166210). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 506–508. Local chapter.
63. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Odontochondrodysplasia (MIM 184260). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 160–162.
64. Wehrle A, Witkos TM, Unger S, Schneider J, Follit JA, Hermann J, et al. Hypomorphic mutations of TRIP11 cause odontochondrodysplasia. JCI Insight. 2019;4(3):e124701. doi:10.1172/jci.insight.124701. PMID:30728324. PMCID:PMC6413787.
65. Del Pino M, Sanchez-Soler MJ, Parrón-Pajares M, Aza-Carmona M, Heath KE, Fano V. Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants. Eur J Med Genet. 2021;64(5):104198. doi:10.1016/j.ejmg.2021.104198. PMID:33746040.
66. Medina CTN, Sandoval R, Oliveira G, da Costa Silveira K, Cavalcanti DP, Pogue R. Pathogenic variants in the TRIP11 gene cause a skeletal dysplasia spectrum from odontochondrodysplasia to achondrogenesis 1A. Am J Med Genet A. 2020;182(4):681–688. doi:10.1002/ajmg.a.61460. PMID:31903676.
67. Abdel-Hamid MS, Elhossini RM, Abdel-Ghafar SF, Mehrez M, Aglan MS, Hassib NF. Deciphering the phenotypic spectrum associated with MIA3-related odontochondrodysplasia. J Hum Genet. 2025;70(5):257–263. doi:10.1038/s10038-025-01328-y. PMID:40119123. PMCID:PMC11964919.
68. Illescas T, Mansilla E, Herrero B, Rodríguez R, López F, Aza-Carmona M, et al. Prenatal diagnosis of fetal skeletal dysplasias in a tertiary hospital in Spain. Eur J Obstet Gynecol Reprod Biol. 2020;250:209–215. doi:10.1016/j.ejogrb.2020.05.009. PMID:32470698.
69. Rahemtullah A, McGillivray B, Wilson RD. Suspected skeletal dysplasias: femur length to abdominal circumference ratio can be used in ultrasonographic prediction of fetal outcome. Am J Obstet Gynecol. 1997;177(4):864–869. doi:10.1016/s0002-9378(97)70284-9. PMID:9369835.
70. Ramus RM, Martin LB, Twickler DM. Ultrasonographic prediction of fetal outcome in suspected skeletal dysplasias with use of the femur length-to-abdominal circumference ratio. Am J Obstet Gynecol. 1998;179(5):1348–1352. doi:10.1016/s0002-9378(98)70158-9. PMID:9822527.
71. Firth HV, Hurst JA. Imaging in prenatal diagnosis. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 742–743. Local chapter.
72. Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, et al. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009;34(2):160–170. doi:10.1002/uog.6359. PMID:19548204.
73. Macé G, Sonigo P, Cormier-Daire V, Aubry MC, Martinovic J, Elie C, et al. Three-dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia. Ultrasound Obstet Gynecol. 2013;42(2):161–168. doi:10.1002/uog.12298. PMID:22945478.
74. Cassart M, Massez A, Cos T, Tecco L, Thomas D, Van Regemorter N, et al. Contribution of three-dimensional computed tomography in the assessment of fetal skeletal dysplasia. Ultrasound Obstet Gynecol. 2007;29(5):537–543. doi:10.1002/uog.4001. PMID:17444568.
75. Waratani M, Ito F, Tanaka Y, Mabuchi A, Mori T, Kitawaki J. Prenatal diagnosis of fetal skeletal dysplasia using 3-dimensional computed tomography: a prospective study. BMC Musculoskelet Disord. 2020;21(1):662. doi:10.1186/s12891-020-03663-x. PMID:33032557.
76. Rajala K, Toiviainen-Salo S, Mäkitie O, Stefanovic V, Tanner L. The role of prenatal ultrasound and added value of post-mortem radiographic imaging with X-ray and CT in suspected fetal skeletal dysplasia. Prenat Diagn. 2025;45(1):77–88. doi:10.1002/pd.6732. PMID:39674903.
77. Jiang M, Zhang B, Wang J, Qiao W, Mao X, Yu B. Sequential prenatal diagnosis of fetal skeletal dysplasia: a cohort study. Acta Obstet Gynecol Scand. 2025;104(5):860–874. doi:10.1111/aogs.15095. PMID:40035361.
78. Lord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, et al.; Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393(10173):747–757. doi:10.1016/S0140-6736(18)31940-8. PMID:30712880.
79. Scocchia A, Kangas-Kontio T, Irving M, Hero M, Saarinen I, Pelttari L, et al. Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia. Orphanet J Rare Dis. 2021;16:412. doi:10.1186/s13023-021-02025-7. PMID:34627339.
80. Lindelöf H, Hammarsjö A, Voss U, Gaetana Piticchio S, Conner P, Papadogiannakis N, et al. Genome sequencing in a cohort of 32 fetuses with genetic skeletal disorders. Eur J Hum Genet. 2025;33(11):1474–1483. doi:10.1038/s41431-025-01886-x. PMID:40500351.
81. Murphey N, Stevens B, Micke K, Espinoza J, Ashfaq M, Gonzalez Cendejas A, et al. Utility of prenatal screening and diagnostic testing for skeletal dysplasias. Fetal Diagn Ther. 2026;53(3):228–236. doi:10.1159/000548470. PMID:41086120.
82. Reilly K, Rolnik DL, Allen S, Sotiriadis A, Ong S, Sonner S, et al. Performance of international phenotypic criteria for prenatal exome sequencing: systematic review and comparative diagnostic accuracy study using historical individual participant data. Ultrasound Obstet Gynecol. 2025;66(3):282–289. doi:10.1002/uog.29290. PMID:40627867.
83. Firth HV, Hurst JA. Non-invasive prenatal diagnosis/testing (NIPD/T). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 764–767. Local chapter.
84. Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, et al. Clinical experience with non-invasive prenatal screening for single-gene disorders. Ultrasound Obstet Gynecol. 2022;59(1):33–39. doi:10.1002/uog.23756. PMID:34358384.
85. Firth HV, Hurst JA. Skeletal dysplasia charts. Table A15: An approach to the radiological diagnosis of lethal and other skeletal dysplasias presenting at birth (Wynne-Davies R, Hall CM, Hurst J, Skeletal Dysplasia Group for Teaching and Research, Occasional publication no. 8c, 2016). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 853–855. Local chapter.
86. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Dysplastic cortical hyperostosis type Kozlowski-Tsuruta. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 627–628. Local chapter.
87. Jaeken J, Morava E. Congenital disorders of glycosylation, dolichol and glycosylphosphatidylinositol metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 43, section 43.2.1. doi:10.1007/978-3-662-63123-2_43.
88. American College of Obstetricians and Gynecologists. Perinatal palliative care: ACOG Committee Opinion, Number 786. Obstet Gynecol. 2019;134(3):e84–e89. doi:10.1097/AOG.0000000000003425. PMID:31441826.
89. Alexion Pharmaceuticals. STRENSIQ (asfotase alfa) injection, for subcutaneous use. Prescribing information (December 2025 label) [Internet]. Silver Spring (MD): FDA. DailyMed. Accessed 6 October 2026.
90. U.S. Food and Drug Administration. Drugs@FDA: BLA 125513, Strensiq (asfotase alfa) — submission history [Internet]. Silver Spring (MD): FDA. Drugs@FDA. Accessed 6 October 2026.
91. European Medicines Agency. Strensiq (asfotase alfa): EPAR [Internet]. Amsterdam: EMA. Medicine webpage. Accessed 6 October 2026.
92. European Medicines Agency. Strensiq: summary of product characteristics (Annex I of the EPAR) [Internet]. Amsterdam: EMA. Product information. Accessed 6 October 2026.
93. European Medicines Agency. Voxzogo (vosoritide): EPAR [Internet]. Amsterdam: EMA. Medicine webpage. Accessed 6 October 2026.
94. Karolinska Institutet. Boost Brittle Bones Before Birth (BOOSTB4). ClinicalTrials.gov identifier: NCT03706482 [Internet]. Latest update published on 12 September 2025. Record. Accessed 6 October 2026.
95. Sagar RL, Åström E, Chitty LS, Crowe B, David AL, DeVile C, et al. An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol. BMJ Open. 2024;14(6):e079767. doi:10.1136/bmjopen-2023-079767. PMID:38834319.
96. Behera B, Ingvoldstad Malmgren C, Åström E, Chitty LS, Crowe B, David AL, et al. Parent and professional experiences of a clinical trial of prenatal and postnatal stem cell therapy for severe osteogenesis imperfecta. Eur J Hum Genet. 2026;34(8):1176–1184. doi:10.1038/s41431-026-02164-0. PMID:42380257.
97. Oldekamp EJ, de Vries MC, David AL, Semler O, Westgren M, Götherström C, et al. Clinical trials of fetal therapy with continuing neonatal interventions: legal requirements and customary procedures regarding parental consent. The BOOSTB4 trial as a case study. Prenat Diagn. 2025;45(13):1810–1815. doi:10.1002/pd.70012. PMID:41171023.
98. U.S. National Library of Medicine. ClinicalTrials.gov API v2 — searches «thanatophoric», «achondrogenesis OR short rib polydactyly OR campomelic», «skeletal dysplasia AND prenatal» [Internet]. ClinicalTrials.gov. Accessed 6 October 2026.
99. D'Hondt A, Goergen S, Miller E, Gould S, Shelmerdine S, Klein W, et al. Implementation of pediatric and fetal postmortem imaging into clinical practice: a multi-society statement from the ESPR, SPR, SLARP, AOSPR, WFPI, and IAFR. Pediatr Radiol. 2026;56(7):1465–1479. doi:10.1007/s00247-026-06639-6. PMID:42176061.
100. Zemet R, Van den Veyver IB, Stankiewicz P. Parental mosaicism for apparent de novo genetic variants: scope, detection, and counseling challenges. Prenat Diagn. 2022;42(7):811–821. doi:10.1002/pd.6144. PMID:35394072.
101. Sena Filho JIN, Campos IFS, Ribeiro EM, Andrade MDFC. Displasia tanatofórica. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 242–245. Local book.
102. Orphanet. Achondrogenesis. ORPHA:932 [Internet]. Paris: INSERM. Disease entry. Accessed 6 October 2026.