Small Patella Syndrome and TBX4-Related Disorders

A spectrum of disorders of a single developmental gene, the T-box 4 transcription factor: ischiopatellar dysplasia (small patella syndrome), paediatric- or adult-onset pulmonary arterial hypertension, developmental lung diseases of variable severity, 17q23.1q23.2 deletion and duplication syndromes and, in the biallelic form, posterior amelia with pelvic and pulmonary hypoplasia.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From small patella to TBX4 syndrome

Small patella syndrome was described as an entity by Scott and Taor in 1979, in a family with twelve affected members in an autosomal dominant pattern who had small or absent patellae; seven of them also had anomalies of the pelvic girdle and proximal femora, and recurrent dislocation of the patella was a frequent complication [3]. This family had already been studied by Renwick in 1956, during the genetic investigation of nail-patella syndrome, and was distinguished from it by the absence of iliac horns [3]. In 1985, Morin and colleagues published a family with fifteen affected members under the designation coxopodopatellar syndrome, in which all eleven patients whose feet were examined had an increased gap between the first and second toes [2, 3]. Sporadic cases attributed to new mutations followed (Kozlowski and Nelson, 1995), as did the radiological series of Azouz and Kozlowski (1997), which presented the disease as a bone dysplasia to be recognised and distinguished from nail-patella syndrome [2]. In 2001, Bongers and colleagues brought together five new cases from three families and forty-six individuals from the literature and proposed the minimum diagnostic criteria still in use today: aplasia or hypoplasia of the patella associated with absent, delayed or irregular ossification of the ischiopubic junctions or with "hatchet-like" infra-acetabular notches [3, 28].

The molecular basis was identified in 2004. By haplotype analysis in Dutch, Belgian, Czech and Swiss families, Bongers and colleagues defined a critical region of 5.6 cM on 17q22 and found presumed loss-of-function heterozygous variants in the TBX4 gene, which encodes a transcription factor of the T-box family, in five families and in one sporadic patient [28]. The similarity between the human phenotype and that of animals without functional Tbx4 — mice without hindlimb development and chickens without legs and with a hypoplastic pelvis after expression of a dominant negative form — consolidated the causal relationship [28]. The TBX4 gene had been identified in 1996, together with TBX5, as the fourth and fifth members of a family of transcriptional regulators with a domain homologous to that of the murine Brachyury (T) gene [5, 19].

From 2010 the spectrum widened on three fronts. Ballif and colleagues described a recurrent ~2.2 Mb microdeletion at 17q23.1q23.2, flanked by segmental duplications, in seven patients with developmental delay, heart disease and limb anomalies, whose minimal region included TBX2 and TBX4 [12]; in the same year, Alvarado and colleagues associated the reciprocal duplication with familial isolated clubfoot [14]. In 2013, Kerstjens-Frederikse and colleagues found TBX4 variants or deletions in six of twenty Dutch children with pulmonary arterial hypertension (PAH) and found that all living patients and both carrier parents had an SPS that had never been recognised [29]. Between 2016 and 2019, the spectrum extended to developmental lung diseases: a newborn with acinar dysplasia and a de novo variant in the T-box domain (Szafranski, 2016), two infants with congenital alveolar dysplasia and alveolar growth abnormality (Suhrie, 2019), a series of lethal lung diseases with variants in TBX4 or FGF10 (Karolak, 2019) and an international cohort of nineteen children with neonatal and paediatric PH and an often biphasic course (Galambos, 2019) [9, 10, 30, 31]. Also in 2019, Kariminejad and colleagues described fetuses homozygous for TBX4 null alleles, with absence of the lower limbs and pelvic and pulmonary hypoplasia, in families whose heterozygous parents had SPS, and designated the new entity PAPPAS (posterior amelia with pelvic and pulmonary hypoplasia syndrome) [17].

The first large-scale genotype–phenotype study, published by Prapa and colleagues in 2022 with 137 carriers, showed that TBX4 is the second most frequent inherited cause of PAH, especially in the paediatric age group, and that some missense variants increase the activity of the transcription factor rather than reducing it [6]. In 2026, the largest single-centre paediatric series (Morgan and colleagues, United Kingdom) separated the phenotype of multigene deletions from that of variants confined to TBX4 [8].

1.2. Nomenclature and classification

The OMIM entry designates the dominant disease as ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension (ICPPS, 147891) and retains as synonyms small patella syndrome, ischiopatellar dysplasia, coxopodopatellar syndrome, Scott-Taor syndrome and "patellar aplasia, coxa vara and tarsal synostosis" [3]. Orphanet uses coxopodopatellar syndrome (ORPHA:1509) for the skeletal disease and classifies the associated PAH under the aetiological subtype heritable PAH (ORPHA:275777) [1, 32]. The bone dysplasia atlas treats the disease as ischiopubic-patellar dysplasia and includes under this designation mild cases of SOX9-related campomelic dysplasia, which makes it necessary to distinguish the radiological diagnosis from the molecular diagnosis [2]. In the PH literature, "TBX4 syndrome" denotes the set of pulmonary, vascular, skeletal and extrapulmonary manifestations of carriers [4, 6, 33].

The clinical classification of PH places the patient with unexplained PAH and a pathogenic TBX4 variant in group 1 (heritable PAH); the paediatric task force of the 6th World Symposium (2018) created in group 3 the subclass "PH associated with developmental lung diseases", and the 7th Symposium (2024) recognised that, depending on the patient, the same variant may correspond to group 1 (adult with a picture similar to idiopathic PAH and minimal lung abnormalities) or to group 3 (child with significant developmental lung abnormalities), with therapeutic consequences [5, 34]. The 2022 European guideline and the 7th Symposium include TBX4 genetic disease among the developmental lung diseases associated with PH in the paediatric age group [24, 25].

1.3. Definition of the entities in this article

Small patella syndrome is defined by the combination of an aplastic or hypoplastic patella with an ischiopubic ossification anomaly or infra-acetabular notch, sometimes accompanied by changes in the feet, proximal femora and face, in a person heterozygous for a pathogenic TBX4 variant [2, 3]. TBX4-associated PAH is precapillary PH, confirmed by right heart catheterisation (RHC) or, in the newborn and young infant, by echocardiographic and clinical assessment, in a carrier of a pathogenic or likely pathogenic TBX4 variant or of a deletion including it, after other causes have been excluded [4, 25]. TBX4-associated developmental lung diseases cover a histological continuum between acinar dysplasia (arrest at the pseudoglandular stage), congenital alveolar dysplasia (arrest at the canalicular to early saccular stage), pulmonary hypoplasia and milder forms of alveolar simplification and interstitial glycogenosis [31, 33]. The 17q23.1q23.2 deletion and duplication syndromes are reciprocal contiguous rearrangements mediated by non-allelic homologous recombination [12, 14]. PAPPAS is the lethal recessive form due to biallelic loss of TBX4 [17, 18]. Nail-patella syndrome (LMX1B), Meier-Gorlin syndrome, campomelic dysplasia, cleidocranial dysplasia, TAR syndrome and surfactant protein deficiencies appear here only as differential diagnoses.

2. Molecular Genetics and Pathophysiology

2.1. The TBX4 gene and protein

The TBX4 gene is located at 17q23.2 (GRCh38 chr17:61,452,422–61,485,110), has eight coding exons and lies a short distance from its paralogue TBX2; the TBX2/TBX4 pair at 17q23 and the TBX3/TBX5 pair at 12q24 result from evolutionary gene duplications [9, 19, 28]. The MANE Select transcript is NM_001321120.2, which encodes a 546-amino-acid protein (NP_001308049.1); many articles use the NM_018488.3 transcript (NP_060958.2, 545 amino acids), whose numbering coincides with that of MANE up to exon 7 and lags three nucleotides (one amino acid) behind from exon 8 onwards [20]. The protein has a DNA-binding T-box domain (codons 71–251), which contains the first nuclear localisation signal (NLS1, 91–103), a second predicted signal (NLS2, 338–351) and a transactivating region (351–393); it shares 52.6% of its sequence with TBX5 and 93.9% in the T-box domain [6].

2.2. Developmental function

TBX4 is expressed early in the lung mesenchyme and in the hindlimb, and in animal models also in the abdominal wall, genital papilla, allantois, mandible, trachea and tail mesoderm [5, 29]. In the lower limb, it acts downstream of PITX1, a transcription factor exclusive to the hindlimb; the PITX1–TBX4 pathway is relevant to the aetiology of clubfoot [28, 35]. The SPS phenotype suggests that, in humans, TBX4 haploinsufficiency does not prevent limb initiation but disturbs late stages: formation of the patella, the posterior rays of the foot and the ischiopubic junction, the latter being one of the last ossification processes to be completed [28]. In Xenopus, unilateral editing of tbx4 produced hindlimb defects without affecting the forelimb, with dorsal-type skin covering the affected limb [17].

In the lung, TBX4 and TBX5 control the expression of FGF10 in the mesenchyme surrounding the branching epithelial tips and of WNT2, which is required for lung specification; FGF10 acts mainly through the epithelial receptor FGFR2b [5]. Reduction of Tbx4 or Tbx5 decreases branching, disturbs the formation and separation of the lobes and reduces lung size; absence of both completely interrupts branching [5, 9]. Independently of FGF10, TBX4 and TBX5 regulate, through SOX9, the condensation of the cells that form the cartilaginous rings of the trachea and bronchi and the tracheal smooth muscle, which underlies the tracheomalacia, stenosis and airway diverticula described in carriers [4, 5]. The protein is present in pulmonary arteries and veins, which suggests a common mesenchymal origin of the vessels [5]. A mouse with conditional deletion of Tbx4 in the embryonic lung mesenchyme, published in 2025, developed enlarged airspaces (mean linear intercept +24.9% at day 14, +31.5% at day 36 and +49.6% at day 180), 39.3% fewer von Willebrand factor-positive vessels, vascular walls 14.2% thicker and, at six months, right ventricular systolic pressure 15.7% higher and a Fulton index 16.3% greater; these are preclinical data linking early loss of Tbx4 to alveologenesis, angiogenesis and PH [36].

In animal models, the homozygous null mouse dies in mid-gestation through failure of vascularisation and fusion of the allantois, and the heterozygote has no evident phenotype without additional factors; the human fetus without functional TBX4 can reach term, which shows differences in dosage sensitivity between species [17, 28, 33].

2.3. Pathogenic mechanisms

The predominant mechanism is haploinsufficiency: the ClinGen dosage curation assigns TBX4 a score of 3 (sufficient evidence) for haploinsufficiency and 0 for triplosensitivity, and the 7th World Symposium classifies the gene as definitive for PAH, with a mechanism of haploinsufficiency and expression in the lung mesenchyme [21, 23]. Nonsense and frameshift variants, intragenic deletions, whole-gene deletions and splicing variants (the recurrent c.702+1G>A and c.1021+1G>A cause exon skipping) produce loss of function [6, 9]. In the luciferase assay with T-box motifs of Prapa and colleagues, all indels and 23 of 42 missense variants reduced activity, 11 were neutral and 8 approximately doubled it (gain of function); null variants were concentrated in the T-box domain and hypomorphs were distributed throughout the gene [6]. Gain-of-function variants were associated with later diagnosis of lung disease (median 57 years, versus 14 years for loss-of-function variants), but six of the eight are present in gnomAD and several remain classified as of uncertain significance or likely benign [6].

The variability of the severe pulmonary forms led to a compound inheritance model: Karolak and colleagues found, in all patients with lethal lung disease and a coding variant or deletion of TBX4 or FGF10, at least one non-coding variant in a predicted lung enhancer, located in an intron of BCAS3 about 70 kb upstream of TBX4, and these variants were absent in thirteen controls with the same deletion and normal lungs [9, 33]. In a three-generation family with the variant c.1112dup p.(Pro372Serfs*14) (NM_018488.3), only the two newborns who died had in trans the non-coding allele rs62069651-C, which reduced promoter activity by 63% in vitro [33]. This gene dosage model through compound inheritance explains how the same coding variant can produce isolated SPS, PAH or lethal lung disease, but it has not been validated for predictive use [9, 33].

Biallelic loss causes PAPPAS: in family 1 of Kariminejad, the c.339T>A p.(Tyr113Ter) variant in homozygosity led to complete absence of transcripts through nonsense-mediated decay, the first human null allele described [17]. A biallelic nonsense variant, p.(Trp134Ter), in a consanguineous Indian family with three affected fetuses, extended the phenotype to sacrococcygeal agenesis, hypoplastic left heart and hydrops [3, 37].

2.4. Inheritance patterns

The same gene follows two patterns. SPS, PAH and developmental lung diseases are autosomal dominant, with high penetrance for the skeletal phenotype and incomplete penetrance and variable expressivity for the pulmonary phenotype [6, 33]. PAPPAS is autosomal recessive and the heterozygous parents have SPS, which led the authors to describe heterozygosity as incompletely dominant (semidominant) [17]. Digenic combinations of variants in TBX4 and BMPR2 (one Lebanese patient and one from the PAH Biobank) and in TBX4 and ACVRL1 have also been described [33]. In two sisters with isolated pulmonary hypoplasia, an intragenic TBX4 deletion inherited from the mother coexisted with a missense TBX5 variant inherited from the father, p.(Asp111Tyr), which is consistent with dimerisation of the two proteins [38].

2.5. Variant spectrum and nomenclature

Up to 2021, the literature had gathered 108 distinct sequence variants: 43 missense, 39 frameshift, 15 nonsense, 6 indels (including a deletion of exon 5) and 3 splicing, plus one promoter variant; most are private [6]. Application of the functional criterion PS3 reclassified 32 of 48 variants, which moved from uncertain significance to pathogenic or likely pathogenic [6]. Because articles use different transcripts, the conversions below were confirmed in VariantValidator; the GenBank AF188703 numbering of Bongers 2004 coincides with NM_018488.3 for the three variants checked [20, 28].

Two nomenclature notes arise from this table. The first is that, from exon 8 onwards, the same variant has different numbers depending on the transcript, and OMIM retains the old numbering (p.Gln531Arg, entry .0003) [19, 20]. The second is that some variants in the older literature could not be normalised, such as the c.1112_1113insC insertion in family E of Bongers (AF188703 numbering) [28].

2.6. Genotype–phenotype correlations

Variants in the T-box domain are associated with earlier diagnosis of lung disease (median 7.5 years, interquartile range [IQR] 1–18.5, versus 18 years, IQR 3–51.5), more frequent interstitial lung disease (75% versus 21%) and more developmental lung diseases (15.4% versus 3.8%); the association holds when variants in the nuclear localisation signals are added [6]. SPS as a secondary phenotype was more frequent with variants outside the T-box and NLS2 (29.7% versus 11.4%) and with truncating variants than with missense variants (27.8% versus 7.1%) [6]. The authors propose extending the ACMG critical functional domain criterion (PM1) to the T-box and the two nuclear localisation signals [6].

The variant class distinguishes phenotypes. 17q23 deletions are more frequent in lethal lung diseases and in PAH with parenchymal abnormalities, and developmental delay is more prevalent in their carriers [33]. In the British paediatric cohort, children with a deletion (n=10) were referred earlier (1.5 ± 1.9 versus 3.5 ± 2.0 years), were dependent on oxygen for more than four weeks more often (80% versus 18%) and had more lung disease, cyanosis, congenital heart disease (70% versus 18%), sensorineural deafness (50% versus 0%) and developmental delay (100% versus 27%) than children with variants confined to TBX4 (n=11), and worse survival free of transplantation or Potts shunt [8]. Some of these differences may result from other genes in the deletion, especially TBX2, whose isolated contribution to lung disease is not established [8, 31]. In the Galambos cohort, developmental disability was more frequent in children with a 17q23 deletion (n=6) than in carriers of a TBX4 sequence variant (n=13) (100% versus 33% of children with data; p=0.029), and heart disease and foot anomalies were numerically more frequent with deletions, without statistical significance; children with a sequence variant tended to have more severe haemodynamics, possibly because they were catheterised later [10]. In comparison with published 17q22–q23.2 deletions, those that included TBX2 and TBX4 were more associated with congenital heart disease (57% versus 0%; p=0.02) and, without statistical significance, with PH (57% versus 17%; p=0.16) than those that spared them, whereas developmental disability, deafness and skeletal anomalies were similar in the two groups [10]. The severity of PH does not follow the predicted gene dosage: some children with whole-gene deletion had less severe PH than others with less disruptive variants, which the authors attribute to a dominant negative effect or to interaction with genetic and environmental factors, and which limits genotype-based prognosis [10].

2.7. Penetrance and modifiers

The estimate of pulmonary penetrance remains imprecise. In the original series, none of the 23 patients with SPS (11 families, aged 11 to 67 years, 22 adults) had PAH on echocardiographic screening, and in more than half of the children with PAH the variant had been inherited from an unaffected parent [29, 31]. In the 2026 British series, however, two carrier parents and one carrier sibling developed PH during follow-up [8]. The recurrent variant c.1021+1G>A illustrates intrafamilial variability, with adult-onset index cases and first-degree relatives who died of PAH in childhood or who had only absent patellae; "leaky" splicing may reduce penetrance [6]. To apply the BS1 criterion, Prapa and colleagues used a maximum tolerated allele frequency of 5.00 × 10⁻⁸, based on a generous estimate of 50% penetrance of lung disease [6]. The pLI of TBX4 (0.41–0.5) indicates partial tolerance to loss of function [9, 33]. The proposed modifiers include non-coding variants in trans, variants in other lung development genes and environmental and pregnancy factors, and the lower pulmonary reserve of carriers may increase susceptibility to external insults [5, 6]. In the eight Galambos families in which the origin could be determined, three variants were de novo (37%) and five familial (62%), with carrier siblings or mothers with SPS, with PAH or asymptomatic [10]. In the North American family with the c.1021+1G>A variant, the father had absent patellae and PAH and died at 64 years, a sister died of PAH at 3 years, the proband had PAH diagnosed at 54 years, and two siblings, two children and a nephew had absent patellae without known PAH; two grandchildren aged 3 and 5 years were asymptomatic carriers [40].

2.8. 17q23.1q23.2 rearrangements and relationship to other small patella disorders

The recurrent ~2.2 Mb deletions result from non-allelic homologous recombination between segmental duplications with more than 98% identity in the same orientation; there are also non-recurrent deletions, such as one of ~2.12 Mb at 17q23.2q23.3 and another at 17q22q23.2 that includes TBX2 and TBX4 but not NOG [9, 12, 41]. The minimal region of overlap of the three deletions in the Dutch cohort measured 1 Mb and contained TBX2, TBX4, NACA2, BRIP1, INTS2 and MED13 [29]. In the Galambos cohort there were two deletion sizes: the recurrent ~2.2 Mb deletion (four children) and a larger one, of ~3.6–3.7 Mb (two children), recorded only once in ClinVar; the common minimal region included MED13, INTS2, BRIP1, BCAS3, TBX4, TBX2, PPM1D, APPBP2 and USP32, of which only TBX4, TBX2 and PPM1D have rare variants described in human disease [10]. The reciprocal duplication segregates with autosomal dominant clubfoot of reduced penetrance, and a non-recurrent ~350 kb duplication at 17q23.2 has also been described [14, 33]. From a developmental point of view, Bongers and colleagues noted that LMX1B (nail-patella) cooperates with PTX genes and that Pitx1 acts upstream of Tbx4, which places the two syndromes with abnormal patellae in a common pathway [28]. Isolated familial patellar aplasia-hypoplasia (PTLAH) was mapped nearby, to 17q22, but TBX4 lies outside its critical region and had no variant in one family studied [28]. Radiological ischiopatellar dysplasia is genetically heterogeneous, because mild SOX9-related campomelic dysplasia (17q24.3–q25.1) can reproduce it [2].

3. Clinical Spectrum and Manifestations by System

3.1. Small patella syndrome: lower limbs and pelvis

The main clinical findings are hypoplasia of the patella with recurrent patellar dislocation, mild foot deformities (wide gap between the first and second toes, short fourth and fifth toes, flat foot), brachymesophalangy in some patients, generalised hypotonia that may contribute to the foot deformities and mild facial dysmorphism, with micrognathia and a high-arched palate or cleft palate [2]. The facial changes were described in four sporadic cases and in one family, and in the Bongers series TBX4 variants explained both a family with a characteristic face and families without facial features [28]. According to the 2001 Bongers series, cited by Oda and colleagues, patellar hypoplasia is present in 100% of patients, radiological pelvic anomalies in 89% and the gap between the first and second toes in 76% [42].

Radiology shows hypoplasia to aplasia of the patella; hypoplasia or aplasia of the ischial rami or delayed ossification of the ischiopubic synchondroses; infra-acetabular notches; narrow, elongated proximal femora, with hypoplastic lesser trochanters and flat, relatively wide proximal femoral epiphyses; and, in some patients, shortening of the middle phalanges of the hand and of the fourth and fifth metatarsals [2, 28]. Magnetic resonance imaging of the knee shows thin, eccentric, non-ossified patellar cartilage, an elongated patellofemoral ligament and hypoplasia of the medial femoral condyle and trochlea [2]. In the Azouz and Kozlowski series reproduced in the atlas, four children aged 6 to 12 years had absent ischial rami or wide ischiopubic synchondroses, narrow femoral necks in all, absent, slightly hypoplastic or well-formed patellae and, in two, genu valgum; the authors of the atlas attribute two of them, with wide vertical ischia and scapular hypoplasia, to SOX9 rather than TBX4 [2]. In adults with symptomatic SPS, a hypoplastic femoral trochlea and tibial tuberosity and an increased tibial tuberosity–trochlear groove distance have also been described [42].

Intrafamilial variability is the rule: in the Bongers families, the phenotype ranged from small patellae with irregular ischiopubic ossification to absent patellae with severe pelvic and femoral anomalies, without correlation with the variant type [28]. In the Japanese family of Oda, the father carrying the same variant had no signs or functional limitation [42]. With a TBX4 variant, the skeletal course is benign, except for recurrent patellar dislocation or instability; ossification of the ischiopubic synchondroses may be completed in adulthood and make the radiological diagnosis more difficult after childhood [2].

3.2. Pulmonary hypertension of neonatal and paediatric onset

In the 2013 Dutch series, the six children with a TBX4 variant or deletion were diagnosed between 2.2 and 15.4 years of age, with mean pulmonary arterial pressure (mPAP) of 26 to 84 mmHg and indexed pulmonary vascular resistance (PVRi) of 6 to 27 WU·m²; the three with a deletion had mild intellectual disability and the three with an intragenic variant had normal intelligence; one of six died, versus six of fourteen among the other children, numbers too small for comparison [29]. In one patient with a TBX4 variant, autopsy showed pulmonary veno-occlusive disease [29].

The international Galambos cohort (nineteen children, including two siblings: six with a 17q23 deletion encompassing the whole of TBX4 and thirteen with a TBX4 sequence variant; the thirteen children had twelve distinct variants, because the two siblings shared p.(Arg340*), for a total of eighteen different variants, all classified as pathogenic or likely pathogenic) defined the neonatal phenotype. Ten infants had neonatal hypoxaemic respiratory failure and PPHN, were discharged, and PH was diagnosed later in infancy or childhood; three patients died and two received a transplant; patent ductus arteriosus, septal defects, foot anomalies and developmental disability were associated, the latter more prevalent with deletions [10]. All children were born at term or late preterm (median 40 weeks), with a median birth weight of 3075 g (three small for gestational age) and a female:male ratio of 2.16:1; eleven required invasive respiratory support, PPHN was severe in eight of the ten (oxygenation index >25 or ECMO), four had transient respiratory distress without PH and five had an uneventful neonatal period [10]. All survived neonatal intensive care and were discharged at a median of 37 days (7–180), six on home oxygen and two on sildenafil; two with PPHN maintained raised right ventricular systolic pressure and died at 5 and 8 months, one from hypoxaemic respiratory failure and the other from a PH crisis during abdominal surgery (Meckel diverticulectomy), and in the other eight PH appeared to improve or resolve in the first months [10]. The seventeen survivors were reassessed later, often because of new hypoxaemia or cardiorespiratory symptoms, and PH was diagnosed at a median of 1.5 years; with a median follow-up of 10 years, three progressed to end-stage lung disease despite several vasodilators (one death at 29 years and two heart–lung transplants, at 11 and 18 years, described as lung transplantation in the abstract and in one table of the article), eleven had chronic PH (seven on several targeted therapies, one on monotherapy and three on oxygen only) and in three PH had resolved (one without medication and two on one vasodilator) [10]. In the neonatal period, ten children (53%) had systemic or suprasystemic right ventricular systolic pressure [10]. In the twelve catheterised (median 1.5 years), median mPAP was 60 mmHg and median PVRi 16.6 WU·m², but only six met all the strict criteria for PAH; in the six with serial catheterisations, values remained stable or rose; eight of ten tested (80%) did not respond to the acute vasodilator test, six had a reduced pulmonary-to-systemic flow ratio (Qp/Qs) due to right-to-left shunting, and angiography showed tortuous arterioles, abnormal capillary perfusion, small pulmonary veins and venules and, in one patient, pulmonary venous obstruction [10]. The authors considered the haemodynamics more severe and the diagnosis earlier than in the REVEAL paediatric reference cohort [10]. In Haarman's reading, 63% of these children had a biphasic course, with PPHN that appeared to resolve at about one month, followed by chronic PH [5].

The series from the British national paediatric PH service (Great Ormond Street, 2001–2025; 21 children, 48% girls) added natural history and treated disease data [8]. All were born at term and without growth restriction; 67% were admitted to neonatal intensive care, 57% had PPHN (half required extracorporeal membrane oxygenation, ECMO), 43% had neonatal pneumothorax and three had initially been diagnosed with PPHN due to meconium aspiration; PH resolved in six of the children with PPHN (four by the first month and two at seven and nine months) [8]. At referral, at a mean age of 2.5 ± 2.2 years, 86% were symptomatic, exertional dyspnoea was the most frequent symptom (29%), cyanosis at rest occurred only with deletions (5 of 10) and syncope only with variants confined to TBX4 (4 of 11); there was somatic growth retardation (weight z −0.90 ± 1.19) [8]. At catheterisation (14 children, median 2.9 years), mPAP was 46 ± 16 mmHg, PVRi 11.2 ± 6.3 WU·m², and 4 of 11 children tested responded to the acute vasodilator test [8]. The frequency of syncope (19%) and of vasodilator response suggests a dynamic pulmonary vascular tone [8].

In all recent paediatric series, the skeletal phenotype was present when looked for: 19 of 19 British children with data had musculoskeletal anomalies of the lower limbs consistent with ICPPS, including a 6-year-old girl with patellar hypoplasia and ischiopubic synchondroses wide for her age [8]. Galambos recorded skeletal anomalies, including SPS with the typical foot anomaly, in 10 of the 13 patients with information available (77%) [10].

3.3. Pulmonary arterial hypertension in adults

TBX4-associated PAH can arise at any age. In the French network, twenty patients from seventeen families had a median age of 29 years at diagnosis (0–76), a female:male ratio of 3, 70% were in New York Heart Association functional class III or IV and median PVR was 13.6 WU (6.2–41.8); there were skeletal signs of SPS in 80%, mild restrictive or obstructive ventilatory limitation in half and reduced carbon monoxide diffusing capacity (DLCO) in all [7]. High-resolution computed tomography (CT) showed bronchial abnormalities, peribronchial cysts, mosaic distribution and mediastinal lymphadenopathy, and the explants revealed alveolar growth abnormalities, vascular remodelling similar to that of idiopathic PAH and cholesterol crystals in the parenchyma [7]. In the Spanish registry (579 adults and 45 children), the eight patients from seven families with TBX4 variants had heterogeneous presentations — suspected veno-occlusive disease, interstitial lung disease, pulmonary vascular anomalies and congenital heart disease — and all adults had moderate to severe reduction in DLCO [43]. A 34-year-old woman with unexplained PAH and right heart failure had SPS on radiographs of the feet and pelvis and, on CT, peripheral reticular lines, centrilobular nodules, thin-walled cysts and a diverticular appearance of the trachea and large bronchi [5]. The GeneReviews overview summarises the clues in adults: patellar irregularities, tracheal or bronchial diverticulosis, developmental delay and congenital heart disease [4]. The Spanish cases illustrate the radiological and histological diversity in adults: interlobular septal thickening with peripheral emphysema, subtle emphysema, subtle ground glass with septal thickening, the radiological triad of veno-occlusive disease in a man diagnosed at 62 years and, in a 31-year-old man initially suspected of having hereditary haemorrhagic telangiectasia, marked systemic collateral circulation, with hypertrophy of the mammary, phrenic and bronchial arteries; on histology, one biopsy showed fibrosing non-specific interstitial pneumonia with peribronchial and perivascular granulomas, and one explant typical PAH lesions, with glomeruloid structures and no venous lesions [43]. Adult PAH may also be purely vascular: a man diagnosed at 54 years and a woman with PAH from the age of 15 had no parenchymal disease on CT, with mildly to moderately reduced DLCO (56% in the woman) [40, 44].

The study by Prapa and colleagues compares TBX4-associated lung disease with the other forms. Among 137 carriers, 93% were sporadic cases; 21 had SPS as the primary phenotype and 116 had lung disease, of whom 45% had onset in adulthood, 36% in childhood and 19% in the perinatal period, with a female predominance of 62% [6]. In the comparison subset, the 98 TBX4 carriers were diagnosed earlier (median 14 years, IQR 2–48) than the 162 BMPR2 carriers (39 years) and the 741 without an identified variant (51 years), walked more metres in the six-minute walk test (371 m versus 350 and 330 m) and had worse baseline lung function, with forced expiratory volume in 1 second of 82% predicted and forced vital capacity of 88% [6]. The carriers' diagnoses included idiopathic PAH (59.2%), heritable PAH (17.3%), PAH associated with congenital heart disease (11.2%), developmental lung disease (9.2%), PAH associated with connective tissue disease (2.0%) and veno-occlusive disease or capillary haemangiomatosis (1.0%); 10.2% were vasodilator responders, versus 1.3% for BMPR2 [6]. In the CT substudy, 87.5% of TBX4 carriers (7 of 8) had airway or acinar abnormalities, versus about one third in the other groups, mainly emphysema, air trapping, bronchial and septal thickening [6]. These data come mostly from published cases, with a bias towards severe forms, and only 25% of patients with lung disease had a reported skeletal assessment [6].

3.4. Developmental lung disease

The lethal forms form a histological continuum. Acinar dysplasia corresponds to arrest at the pseudoglandular stage (6–8 to 16 weeks of gestation) and kills in the first hours of life; congenital alveolar dysplasia corresponds to arrest at the canalicular to early saccular stage (16–26 weeks) and causes death within weeks to months; together these diseases have a neonatal mortality of 80–90% [33]. In the Karolak series (26 deceased children from 23 families), there was intrauterine growth restriction in 15%, pulmonary hypoplasia detected before birth in 15% (two pregnancies terminated), recurrence in siblings in four families and survival from minutes to ten weeks; the criteria for pulmonary hypoplasia were met in all 19 with a documented lung weight/body weight ratio, and the TBX4 cases were concentrated in the more severe acinar spectrum, whereas the FGF10 cases had more developed lungs [9]. The first case of acinar dysplasia with a TBX4 variant was that of a newborn girl who died on the first day with the de novo variant p.(Glu86Gln) [30]. OMIM groups these cases under the primary pulmonary hypoplasia entry (265430), defined as quantitative or qualitative underdevelopment of bronchial and lung tissue without underlying disease and still without an assigned gene; this includes a newborn with a 2 Mb deletion of fourteen genes, including TBX4, and acinar dysplasia on biopsy at day eight, and a second patient with a different change at the same codon, p.(Glu86Lys) [38].

The non-lethal forms include diffuse or patchy alveolar simplification, pulmonary interstitial glycogenosis, bronchial abnormalities and interstitial lung disease. In the British series, 71% of children had lung disease at referral (all ten with a deletion and five of eleven with an intragenic variant) and 52% met the European criteria for childhood interstitial lung disease (chILD-EU); spirometry showed forced expiratory volume in 1 second and forced vital capacity of about 60% predicted; CT showed mainly ground glass and bronchial dilatation or thickening [8]. The five histological samples (median 0.9 years) all had abnormal lung growth, with mainly patchy alveolar simplification, bronchial abnormalities in four, interstitial glycogenosis in three, arterial remodelling in three (plexiform lesions only in the explant) and lipid-laden macrophages with cholesterol clefts in four, suggestive of aspiration [8]. In biopsies and explants from older children and adolescents, "back-to-back" bronchioles without intervening alveoli, arterial remodelling with plexiform lesions, expanded bronchial circulation, bronchopulmonary anastomoses, focal metaplastic ossification and fibrosis are described [33]. The pulmonary phenotype does not depend on TBX4 alone: two infants with neonatal lung disease shared the ABCA3 variant p.(Arg288Lys), considered of uncertain significance and enriched in European newborns with respiratory distress syndrome, and one infant with interstitial glycogenosis had variants in TBX4 and CTNNB1 [5, 31].

In the Galambos cohort, neonatal radiography (n=5) showed pulmonary hypoplasia, air leaks or ground glass; radiography in infants and young children (n=4), septal thickening with multifocal areas of dysventilation, bronchial thickening and ground glass; and CT between 1 and 18 years (n=5), multifocal ground glass, honeycombing, focal cystic changes and consolidated areas and nodules suggestive of lobular and lobar fibrosis [10]. The seven histological samples all had diffuse alveolar growth abnormality and remodelling of the pulmonary arterial wall, with or without fibrointimal proliferation, without plexiform lesions or vascular necrosis [10]. In the four neonatal biopsies (1.5–4 months), from children with severe early disease and a worse prognosis, there was arrest of distal lung development at the canalicular or early saccular stage, with immature alveoli without secondary septa, thickened interstitium in all, pale immature mesenchymal cells of the interstitial glycogenosis type in three and patchy interstitial fibrosis in three [10]. In the samples from childhood and adolescence, recruitment of the bronchial circulation, with intrapulmonary bronchopulmonary anastomoses and dilated bronchial veins, alveolar simplification, airway remodelling and macrophages with cholesterol crystals predominated [10]. In one child studied at 2 years (biopsy) and at 18 (explant), the disease progressed, with tortuous "back-to-back" bronchioles similar to those of congenital pulmonary airway malformations, thickening of the media of the pulmonary arteries, of the lymphatics, airways and pleural vessels, fibrosis and bone formation, which led the authors to conclude that the abnormal developmental process continues after birth [10].

3.5. Extrapulmonary manifestations

Congenital heart disease is frequent and generally consists of small defects — patent ductus arteriosus, atrial septal defect and septal defects — without increased pulmonary flow; in the British series it reached 43% (70% with deletions) [8, 10]. In the Galambos cohort, eight children had patent ductus arteriosus, which persisted beyond the neonatal period in four (one closed surgically at 4 years), and eight (42%) an atrial septal defect; neurological disorders included autism, microcephaly, neurosensory deficits and abnormal muscle tone [10]. Sensorineural deafness (24%, all with a deletion, four of five without exposure to ECMO), developmental delay (62%), cognitive impairment (all assessable children with a deletion) and gastro-oesophageal reflux were more frequent with deletions [8]. The airway pulmonary phenotype includes laryngomalacia, subglottic stenosis and abnormal bronchial branching [31].

3.6. 17q23.1q23.2 deletion syndrome

In the seven patients of Ballif (8 months to 16.5 years), all had mild to moderate developmental delay, especially of language, and long thin fingers and toes; five had low birth weight, absolute or relative microcephaly and postnatal growth retardation; six had heart disease (mainly patent ductus arteriosus or atrial septal defect, with PH recorded in some); four had musculoskeletal anomalies (lateralised and delayed patellar ossification centres, small subluxed patellae, hypoplasia of the tibial epiphyses, shallow acetabula, scoliosis); two had aggressive behaviour and two deafness; there was mild facial dysmorphism without a recognisable pattern [12]. Among the eleven deletions including TBX4 and TBX2 reviewed by Suhrie, seven had PH, low birth weight and microcephaly [31]. A non-recurrent deletion at 17q22q23.2 was associated with severe congenital microcephaly, thyroglossal duct cyst, sensorineural deafness, tracheomalacia, abnormal auricles and PH; the oesophageal atresia described in other 17q22q23.2 deletions appears to depend on a more proximal region [41]. The deletion does not always cause lung disease: two siblings with the 2.2 Mb deletion had only clubfoot [45].

3.7. 17q23.1q23.2 duplication syndrome

The recurrent duplication was found in 3 of 66 probands with familial idiopathic clubfoot; of the ten carrier relatives, seven had clubfoot (all boys, bilateral in six), one had developmental dysplasia of the hip and two were normal, and the hands were not affected [14, 15]. The subtle radiological anomalies — wide short metatarsals and calcanei, small distal tibial epiphyses, thickened ischia — are partly the opposite of those of the reciprocal deletion [14].

3.8. Biallelic loss: PAPPAS and caudal regression

The homozygous fetuses described by Kariminejad had complete absence of the lower limbs, absent pelvic bones and a hypoplastic sacrum; the fetus examined at 16 weeks also had anal atresia with rectoperineal fistula, ambiguous genitalia, muscular hypoplasia of the upper limbs, atresia of the external auditory canals, hypoplastic undifferentiated lungs and a lung segmentation defect, with a normal heart and gastrointestinal tract [17]. Absence of the lower limbs was detected by ultrasound at 15 weeks; one fetus in family 1 was stillborn at term, with ambiguous genitalia and no lower limbs [17]. The Indian fetus with a biallelic variant had sacrococcygeal agenesis, bilateral aplasia of the lower limbs, hypoplastic left heart, bilateral pulmonary hypoplasia, hydroureteronephrosis and non-immune hydrops [37].

3.9. Comparative summary

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the prenatal period, ultrasound absence of the lower limbs with pelvic hypoplasia, detectable at 15 weeks, in a consanguineous couple or one with signs of SPS, suggests PAPPAS; pulmonary hypoplasia detected before birth occurred in 15% of the lethal lung diseases in the Karolak series [9, 17].

In the term newborn, the combination of hypoxaemic respiratory failure, severe or refractory PPHN, pneumothorax and need for ECMO, especially when the course is atypical or prolonged, should lead to consideration of TBX4, even when another plausible explanation exists, such as meconium aspiration [8, 39]. Abnormal lung lobation, microcephaly and growth restriction add suspicion of developmental lung disease or a 17q23 deletion [12, 31].

In infants and young children, the warning sign is PH that reappears or persists after apparently resolved PPHN, prolonged oxygen dependence, growth retardation and interstitial lung disease [8, 10]. Syncope, cyanosis and exertional dyspnoea are the most frequent presentations of PH at this age [8]. Galambos and colleagues recommend that infants with severe PPHN, especially idiopathic, have echocardiographic follow-up during infancy and early childhood and TBX4 testing when PH is confirmed or when there is congenital heart disease, foot anomalies or SPS [10].

In older children and adolescents, recurrent patellar dislocation, patellar instability and a wide gap between the first and second toes raise the possibility of SPS; "idiopathic" PAH of paediatric onset should prompt a targeted examination of the knees, pelvis and feet [29, 42].

In adults, PAH with reduced DLCO, bronchial changes, peribronchial cysts or tracheobronchial diverticula on CT, congenital heart disease or small patellae suggests TBX4 [4, 5, 7]. SPS may go unnoticed for decades when patellar instability is mild [42].

4.2. Targeted examination

The skeletal changes are recognised only with targeted examination and radiographs of the pelvis, knees and feet, and were missed in all living patients in the 2013 series until the molecular diagnosis [29]. The 2022 European guideline recommends a complete history and physical examination when syndromic PAH is suspected, and indicates for TBX4 radiographs of the pelvis, knees and feet and chest CT [24]. The Karolak review adds, in patients with PAH, chest imaging targeted at signs of arrested lung growth, screening for congenital heart disease and examination of the hands and feet [33].

4.3. Warning and emergency signs

4.4. Newborn screening

There is no newborn screening for TBX4-related disorders. The European guideline recommends screening for PH in infants with bronchopulmonary dysplasia (class I, level B), a recommendation not specifically directed at TBX4 [24].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria for small patella syndrome

The minimum criteria proposed by Bongers and colleagues in 2001 are aplasia or hypoplasia of the patellae associated with absent, delayed or irregular ossification of the ischiopubic junctions or with infra-acetabular notches; the accessory major signs are an increased gap between the first and second toes, shortening of the fourth and fifth rays of the feet and flat foot [3, 28]. The criteria were derived from five new cases and forty-six from the literature, before molecular diagnosis was available [3]. Because ischiopubic ossification may normalise in adults, absence of the pelvic criterion after childhood does not exclude the disease; Oda's adult patient did not have typical radiological pelvic anomalies [2, 42].

5.2. Radiological assessment

The assessment includes anteroposterior radiographs of the pelvis (ischiopubic junctions, infra-acetabular notches, femoral necks and lesser trochanters), lateral and axial views of the knees (size and position of the patella, tibial tuberosity) and radiographs of the feet (gap between the first and second toes, fourth and fifth rays) [2, 29, 42]. CT of the knee measures subluxation and the tibial tuberosity–trochlear groove distance, and magnetic resonance imaging shows the non-ossified patellar cartilage and trochlear dysplasia [2, 42]. Wide vertical ischia and scapular hypoplasia point to SOX9 rather than TBX4 [2].

5.3. Definition and confirmation of pulmonary hypertension

In adults, PH is defined by mPAP >20 mmHg at rest, and precapillary PH requires a wedge pressure ≤15 mmHg and PVR >2 WU [24, 34]. In children, the definition is the same for mPAP, and precapillary PH requires a wedge pressure ≤15 mmHg and PVRi >3 WU·m² [24, 25]. RHC is the reference investigation and should precede, whenever possible, the start of therapy (class I, level C); in infants under three months and in preterm infants, the risk of catheterisation may preclude the investigation and assessment is based on echocardiography, with caution in excluding post-capillary mechanisms, such as left ventricular diastolic dysfunction or pulmonary vein stenosis [24, 25]. The initial assessment of PAH includes electrocardiogram, echocardiogram, cardiopulmonary exercise testing, blood tests (full blood count, biochemistry, BNP or NT-proBNP, antinuclear antibodies, HIV serology, coagulation), chest CT and, as appropriate, ventilation-perfusion scintigraphy and pulmonary function tests [4]. Acute vasoreactivity testing is recommended in children with idiopathic or heritable PAH, with the same response criteria as in adults: a fall in mPAP ≥10 mmHg to a value ≤40 mmHg, with increased or unchanged cardiac output (class I, level C) [24].

When developmental lung disease is suspected, classification of PH requires assessment of the parenchymal disease and its causal role; the 7th World Symposium accepts that the same TBX4 variant may correspond to group 1 or group 3, depending on the patient, and that classification depends on systematic genetic testing [5, 34]. Lung biopsy carries a high risk and a low yield in the newborn; genetic diagnosis can avoid it and guide decisions, as happens with FOXF1 in alveolar capillary dysplasia [5].

5.4. Genetic testing: indications and choice of test

The 7th World Symposium recommends offering genetic testing to all children with group 1 PH (idiopathic, heritable PAH, PAH associated with congenital heart disease, with veno-occlusive disease or capillary haemangiomatosis and with drugs or toxins) and group 3 PH due to developmental lung disease or congenital diaphragmatic hernia, with exome or genome sequencing, ideally as a trio with the parents; in group 1 adults, it recommends a panel of genes with a definitive or moderate association, followed by exome or genome when the panel is negative in heritable PAH or PAH associated with congenital heart disease [23]. The earlier 2022 European guideline considers that genetic testing "may be considered" in paediatric PAH, after counselling, and recommends informing all patients with idiopathic or familial PAH of the possibility of a genetic disease [24]. In the 2026 British series, the authors recommend testing in children with idiopathic or familial PAH, PH associated with congenital heart disease or PH with unexplained developmental lung disease, and draw attention to severe PPHN with an apparent cause [8]. Vincent and colleagues proposed testing for TBX4 in infants with acinar dysplasia, congenital alveolar dysplasia or other hypoplasias when there is a family history of PAH [5].

In isolated SPS, TBX4 sequencing identified variants in six of seven families or sporadic patients in the founding series [28]. Because one third to one half of children with TBX4-associated PH have 17q23 deletions (6 of 19 and 10 of 21 in the two largest series), testing must include CNV analysis: chromosomal microarray, targeted deletion and duplication analysis (MLPA, quantitative PCR) or CNV calling from the exome or genome, whose sensitivity may be lower than that of targeted methods [4, 8, 10]. Galambos recommends diagnostic panels including TBX4 combined with a microarray, to capture small and large variants [10]. Commercial PAH panels have not always included TBX4: in the North American case, the variant was only found at 71 years, on a panel customised to include the gene, after a negative BMPR2 study at 58 years [40]. Genome sequencing also detects deep intronic variants and variants in untranslated and non-coding regions, such as those of the lung enhancer upstream of TBX4 [4, 9].

5.5. Limits of the tests

A negative result does not exclude the disease. Promoter and enhancer variants, deep splicing variants and structural rearrangements escape panels without CNV or non-coding region analysis [4, 6]. Parental mosaicism may not be detected in leucocyte DNA [4]. Interpretation of missense variants is difficult: before the functional studies, two thirds were of uncertain significance, and some variants with an in vitro effect are present in the general population [6]. A variant of uncertain significance neither confirms nor excludes the diagnosis and requires family segregation; a variant of uncertain significance that turns out to be de novo may be reclassified as likely pathogenic [4, 23]. The presence of a loss-of-function variant does not by itself predict the pulmonary phenotype [9]. The numbering difference between NM_018488.3 and NM_001321120.2 from exon 8 onwards requires the report to state the transcript [20].

5.6. Report content

The report should identify the gene, the transcript with version (preferably MANE NM_001321120.2), the HGVS c. and p. nomenclature, the genomic coordinate, the zygosity, the classification according to ACMG/AMP standards and, for deletions, the coordinates and the genes included [20, 23]. Only pathogenic and likely pathogenic variants are actionable [23]. Results should be discussed with professionals experienced in genetics, and testing of asymptomatic relatives should be carried out by genetic counsellors or clinical geneticists, with discussion of surveillance, treatment, prognosis and reproductive options [23, 24].

5.7. Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible [4]. PAPPAS was suspected on ultrasound at 15 weeks and the terminations took place at 16 weeks [17]. Prenatal diagnosis is rarely used in heritable PAH [23].

5.8. Practical algorithm

6. Differential Diagnosis

6.1. Small patellae and ischiopubic anomalies

Nail-patella syndrome is the most frequent differential of small patellae and is distinguished by the presence of iliac horns and of nail and elbow anomalies, features absent in SPS and in Meier-Gorlin syndrome [46]. Meier-Gorlin syndrome adds microtia and short stature, and mild campomelic dysplasia adds vertical ischia, scapular hypoplasia and developmental delay; it was this last differential that led the atlas to include SOX9 cases under the designation ischiopubic-patellar dysplasia [2, 47]. Ischiospinal dysostosis shares the lack of ossification of the ischial rami and the elongated femoral necks, but has vertebral malformations that do not occur in SPS [49].

6.2. Pulmonary hypertension and neonatal lung disease

The American Thoracic Society classification of diffuse lung disease in children groups acinar dysplasia, congenital alveolar dysplasia and alveolar capillary dysplasia among the diffuse developmental disorders, and pulmonary hypoplasia among the growth abnormalities; the developmental arrest occurs, respectively, at the pseudoglandular, canalicular and saccular or alveolar stages [5]. In TBX4 cases, autopsy does not show the findings of alveolar capillary dysplasia (veins next to the arteries, marked medial hypertrophy and markedly reduced capillary density) [31]. The OMIM entry for alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) defines it histologically by failure of formation and penetration of the alveolar capillaries, which do not make contact with the epithelium, by muscular thickening of the media of small arterioles, with muscularisation of intra-acinar arterioles, by thickened alveolar walls and by abnormal pulmonary veins accompanying the arterioles in the same adventitial sheath; reduced alveolar number and a patchy distribution of the lesions are less frequent [51]. In a series of 23 patients with histological confirmation, 90% were born at term, 85% had an appropriate weight for gestational age and 82% died in the first month despite intensive treatment; of the 22 autopsies available, 18 (82%) showed at least one other major malformation, cardiovascular, gastrointestinal, genitourinary or musculoskeletal, and 5 of these 18 (28%) had disturbed left-right asymmetry of the thoracic or abdominal organs [51]. The same authors separate it from the congenital alveolar dysplasia described in 1948, in which survival is longer, PH is not constant and the veins are normally positioned [51]. ACDMPV is caused by heterozygous FOXF1 variants or by 16q24.1–q24.2 microdeletions that include it: point variants were associated with intestinal malrotation, and microdeletions, which may include FOXC2 and FOXL1, with hypoplastic left heart syndrome and gastrointestinal atresias [51]. In a compilation of 42 variants, 60% were located in the DNA-binding domain; most cases were sporadic, and three of the four familial cases had maternal inheritance, consistent with paternal imprinting of the gene [51]. De novo deletions on the maternal chromosome located about 270–310 kb upstream of FOXF1, which leave it intact and remove distant enhancers with the non-coding RNAs LINC01081 and LINC01082, caused one lethal neonatal form and another with onset at 7 months, so isolated sequencing of the gene does not exclude the disease [51]. The first families, with affected siblings and, in part, consanguineous parents, led to the proposal of autosomal recessive inheritance, a hypothesis replaced by the current classification of the entry, autosomal dominant due to heterozygous FOXF1 variants; no BMPR2 variants were found in 10 patients [51]. Typical PPHN, classified in group 1, resolves with the postnatal transition; the atypical forms that persist, frequently in group 3, include the developmental lung diseases and require aetiological investigation [52]. In adult PAH, veno-occlusive disease is a relevant differential, because one patient in the Dutch series and another in the Prapa series with a TBX4 variant had veno-occlusive disease on histology or clinically [6, 29].

6.3. Amelia and lower limb defects

PAPPAS is distinguished from other amelias by the selective absence of the lower limbs with pelvic aplasia and pulmonary hypoplasia and by SPS in the parents [17]. OMIM entry 601360 retains the old description of a French-Canadian family with amelia of the upper limbs and severe hypoplasia of the lower limbs, a phenotype different from TBX4-related PAPPAS [18]. The Orphanet group of tetra-amelia with multiple malformations (ORPHA:3301) also includes autosomal recessive tetra-amelia (OMIM 273395) [16]. In familial isolated clubfoot, the 17q23.1q23.2 duplication and the PITX1–TBX4 pathway are causes to consider [14, 35].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment targeted at the TBX4 gene, and no trial has tested a therapy specifically in TBX4-associated disease [21]. PAH drugs are approved by clinical PH group and not by genotype, and the available data do not justify treating TBX4-associated heritable PAH differently from other forms of PAH [5, 21]. Management has three components: treatment of PH, which follows the algorithms for group 1 PAH or for group 3 PH associated with lung disease according to the patient's assessment; treatment of the parenchymal and airway lung disease; and orthopaedic treatment of SPS [2, 25, 34]. The European guideline recommends that the diagnosis, including RHC and the vasodilator test, and treatment of children with PH take place in centres with specific experience in paediatric PH (class I, level C) [24]. The 7th World Symposium recommends multidisciplinary assessment and orthopaedic referral of TBX4 carriers, and the 2026 British series proposes that the team include PH, cardiology, respiratory medicine, clinical genetics, orthopaedics and neurodevelopment, with attention to the manifestations of the other genes in 17q23 deletions [8, 23].

7.2. Newborns and infants

In the newborn with PPHN, treatment is that of hypoxaemic respiratory failure and neonatal PH; PPHN algorithms are outside the scope of the European guideline, which recommends for newborns and infants a diagnostic and therapeutic approach distinct from that for older children and adults, given the frequent association with developmental pulmonary vascular and parenchymal disease (class IIa, level C) [24]. In the described TBX4 cases, high-frequency ventilation, inhaled nitric oxide, inhaled epoprostenol, milrinone, prostaglandin E1 to keep the ductus arteriosus patent and ECMO were used, with outcomes ranging from death to discharge on oxygen [31, 39]. In the British series, half of the children with PPHN received ECMO [8]. The European SmPC and the Portuguese SmPC for sildenafil (Revatio®) state that, outside the authorised indications, sildenafil should not be used in newborns with PPHN, because the risks outweigh the benefits, and that safety and efficacy below one year of age have not been established [53, 54].

In infants with PH associated with developmental lung disease, the 7th Symposium and the European guideline recommend treating the lung disease first — hypoxia, aspiration and structural airway disease — and optimising respiratory support before starting PAH therapy (class I, level B recommendation in bronchopulmonary dysplasia); pulmonary vasodilators are frequently used in these infants, but are not approved by the FDA or the EMA for group 3, and their effects on outcomes have not been established [24, 25]. To enter the algorithm arm dedicated to cardiopulmonary comorbidities, the patient must have confirmed precapillary PH and respiratory compromise; without catheterisation, precapillary PH diagnosed by echocardiography alone requires caution and exclusion of post-capillary mechanisms [25].

Systemic corticosteroids have been used in infants and children with interstitial lung disease or interstitial glycogenosis and TBX4-associated PH: in the British series, nine children with interstitial disease received corticosteroids in addition to vasodilators, and one had resolution of PH after corticosteroid therapy; in Tsoi's case, prednisolone was used for interstitial glycogenosis and stopped at one year of age [8, 39]. This is centre practice described in observational series, without a trial and without a standardised dose in the sources; the authors of the case consider the role of glucocorticoids in these patients uncertain [39].

7.3. Children with pulmonary arterial hypertension

Treatment of paediatric PAH is extrapolated from adults and adjusted for age, based on risk stratification, because randomised efficacy trials in children are lacking [24, 25]. The paediatric recommendations of the 2022 European guideline are summarised in the following table.

Source: [24].

The paediatric algorithm of the 7th World Symposium is based on maintaining a lower risk profile as the treatment goal and on the superiority of combination therapy, supported by retrospective paediatric cohorts [25]. In children with idiopathic, heritable or drug-associated PAH who respond to the vasodilator test (Sitbon criteria), initial treatment is a high-dose calcium channel blocker, with close monitoring, because some patients lose the response; if the response is insufficient, PAH therapy is added without stopping the blocker [24, 25]. In lower-risk non-responders, oral combination of an endothelin receptor antagonist (ERA) with a phosphodiesterase 5 inhibitor (PDE5i) is started, simultaneously or sequentially; in high-risk patients, an intravenous or subcutaneous prostacyclin analogue is started, with rapid addition of a PDE5i and/or ERA and early referral for lung transplantation or palliative procedures [25]. General measures (physical activity, vaccination) and oxygen, digoxin and diuretics are individualised; anticoagulation and antiplatelet therapy are generally not indicated without a specific thromboembolic risk [25]. The algorithm applies best to idiopathic and heritable PAH; in children with developmental lung disease, such as TBX4 mutations, mechanisms of several clinical groups coexist, and treatment should be individualised at a specialist centre [25].

Registry data published in 2026 reinforce the initial combination strategy: in the international TOPP-2 registry (445 children with catheter-confirmed group 1 PAH), initial dual therapy was associated with a lower risk of death or transplantation than monotherapy escalated to dual therapy in the first year (hazard ratio [HR] 0.30; 95% CI 0.16–0.56), and initial triple therapy with a parenteral prostanoid with a lower risk than escalation to a parenteral prostanoid in the first year (HR 0.28; 95% CI 0.15–0.50) [55]. This is a severity-adjusted observational study, not specific to TBX4.

7.4. Published experience in TBX4-associated PH

In the British series, 20 of 21 children received long-term pulmonary vasodilators: monotherapy in 43%, dual therapy in 33% and triple therapy in 19%, with resolution without prolonged therapy in one child; in the twelve treatment-naive children, functional class improved in half and stabilised in the other half after a median of 1.9 months [8]. Therapy was escalated in nine children and reduced in two; three families declined intravenous prostacyclin; nine children (43%) received calcium channel blockers, always combined with other vasodilators [8]. In the French network, which included adults and children, PAH therapy was associated with significant clinical improvement [7]. In Tsoi's case, the child received sildenafil, then bosentan, and later tadalafil in combination with bosentan, after sildenafil was stopped because of severe reflux [39]. These data describe disease treated at reference centres, without a comparison group.

In the Galambos paediatric cohort, eleven children had chronic PH despite several targeted therapies in seven, and three reached end-stage disease despite several vasodilators [10]. In adults, published therapeutic experience, apart from the French series, whose regimens the sources consulted do not detail, comes from cases and small series. In the Spanish registry, therapy was goal-oriented: in a woman initially suspected of having veno-occlusive disease, the initial oral combination of a phosphodiesterase 5 inhibitor and an endothelin receptor antagonist was escalated to a systemic prostanoid after six years and was followed by bilateral lung transplantation at nine years of disease; in a woman with fibrosing interstitial pneumonia, azathioprine was added to PAH therapy [43]. At the Mayo Clinic, a man diagnosed at 54 years did not tolerate epoprostenol and sitaxentan and stabilised on sildenafil, inhaled iloprost and ambrisentan; iloprost was stopped after improvement to World Health Organization (WHO) functional class II, ambrisentan was replaced by macitentan because of pruritus, and at 72 years he remained in class II on macitentan and sildenafil [40]. In Rotterdam, a woman with the de novo variant NM_001321120.2:c.401G>C, NP_001308049.1:p.(Trp134Ser) (the same in NM_018488.3; classified as of uncertain significance), severe PAH from the age of 15 treated with initial triple therapy (sildenafil, bosentan and intravenous epoprostenol) and a purely vascular phenotype, progressed despite switching from bosentan to macitentan, increasing epoprostenol, rehabilitation and percutaneous implantation of an interatrial flow regulator, and was on the waiting list for lung transplantation in NYHA class IV, on oxygen [20, 44]. With sotatercept (Winrevair®; 0.3 mg/kg at the first administration and then 0.7 mg/kg every 3 weeks, in an early access programme), the six-minute walk distance rose from 324 to 510 m at 6 months, NT-proBNP fell from 67 to 5 pmol/L and estimated pulmonary systolic pressure from 98 to 51 and then 37 mmHg; the patient stopped oxygen, came off the transplant list and maintained the response at one year, with mild adverse effects (periorbital oedema, headache and fatigue in the week after injection, prevented with 2 days of prednisone) [44]. The authors attribute the response partly to the purely vascular phenotype; the effect of sotatercept in disease with parenchymal abnormalities has not been studied [44]. These are isolated reports, without a comparison group.

7.5. Paediatric dosing of PAH drugs

The following doses apply to paediatric PAH in general; there is no specific dose for TBX4-associated disease, and use in infants with developmental lung disease (group 3) is off-label [24, 25]. The reference is the European guideline dose; the labels are given for comparison.

The most frequent adverse effects of sildenafil in the paediatric trial (234 patients aged 1 to 17 years) were pyrexia and upper respiratory tract infection (11.5% each), vomiting (10.9%) and increased erections (9.0%) [53]. Bosentan requires monthly liver monitoring because of hepatotoxicity, can cause anaemia and systemic vasodilatation and, in the USA, is only dispensed through a risk evaluation and mitigation strategy (REMS); pregnant women should not take or handle ERAs [4, 58]. Intravenous epoprostenol, described as the most effective treatment, has a short half-life, requires a continuous pump and a central venous catheter, with a risk of sepsis, and causes headache, jaw pain and nausea [4]. PDE5i can cause headache, flushing, diarrhoea and nasal congestion, and rarely priapism [4].

7.6. Comparative regulatory status

7.7. Paediatric trials and studies

Paediatric PAH trials have mostly been designed for pharmacokinetics and safety rather than clinical efficacy, because of the lack of consensus on age-appropriate outcomes and insufficient recruitment; none included identified TBX4 subgroups [25]. The results do not allow indirect comparisons between drugs, and registry data, even when adjusted for severity, are subject to confounding by indication [25, 55]. A Pediatric Pulmonary Hypertension Network trial is under way randomising children in groups 1 and 3 to monotherapy or dual therapy at diagnosis (NCT04039464) [25]. A search of ClinicalTrials.gov on 31 October 2026 did not identify trials targeting TBX4-associated disease, which does not exclude studies in other registries [64].

7.8. Rescue procedures and transplantation

When the response to maximal therapy is insufficient or the drugs are not available, a Potts shunt (surgical or percutaneous connection between the left pulmonary artery and the descending aorta), balloon atrial septostomy or lung transplantation may be considered; experience with the Potts shunt is limited to just over 100 patients, mostly children, with a mortality of 12–25% and long-term benefit in a subgroup [24]. In the British series, two children with TBX4-associated PH received a Potts shunt and one received a bilateral lung transplant, 1.6 years after the initial assessment [8]. In the French series, two patients were transplanted, and in the Galambos series two children [7, 10]. A Hispanic woman with the recurrent variant p.(Met144Ile) was transplanted nine years after diagnosis [6].

7.9. Orthopaedic treatment of small patella syndrome

Treatment consists of orthopaedic measures for patellar instability and foot deformities [2]. In Oda's Japanese adult patient, conservative treatment (rest, analgesics, physiotherapy, orthosis) failed and arthroscopic lateral retinacular release and medial patellofemoral ligament reconstruction with a semitendinosus graft were performed; because of the small patella, patellar fixation was subperiosteal with sutures, without a bone tunnel, and because of the hypoplastic tibial tuberosity no distal realignment osteotomy was performed, despite a tibial tuberosity–trochlear groove distance of 22 mm; the patella remained reduced and without instability after one year [42]. The authors advocate diagnosis in childhood, to allow soft tissue procedures (such as the Roux-Goldthwait procedure) before skeletal maturity, when remodelling of the trochlear groove is still possible, and careful planning in adults; the long-term outcome of these techniques in SPS is unknown [42].

7.10. General measures and agents to avoid

Supervised exercise training, aerobic and resistance, started at low to moderate intensity and progressed according to tolerance, improves exercise capacity and quality of life; patients with severe haemodynamics or syncope need close monitoring, exercise should stop in the presence of intense dyspnoea, chest pain or presyncope, and activities in which the patient cannot control the effort should be avoided [4]. In 2026, the European Paediatric Pulmonary Vascular Disease Network (EPPVDN) and the Association for European Paediatric and Congenital Cardiology (AEPC) published the first consensus on sport and supervised exercise programmes in children and young adults with PH, including eligibility criteria for competitive sport [65]. Stimulants, cocaine and amphetamines should be avoided, and other cardiopulmonary drugs and interactions reviewed with the PH specialist [4]. Vaccination is part of the general measures in children [25].

7.11. Pregnancy, contraception and lactation

Pregnancy in a woman with PAH is generally discouraged because of high maternal and fetal mortality, although outcomes have improved with multidisciplinary care at specialist centres [4]. The European guideline recommends counselling women of childbearing potential, at diagnosis, about the risks and against pregnancy (class I, level C), giving clear contraceptive advice (I, C), referring women who are considering pregnancy or who become pregnant immediately to an experienced centre, with genetic counselling (I, C), performing termination of pregnancy in PH centres (I, C) and considering adoption or surrogacy with preconception genetic counselling (IIb, C); ERAs and riociguat are not recommended in pregnancy because of teratogenicity in preclinical models (III, B) [24]. Bosentan is contraindicated in pregnancy and the US label advises against breastfeeding during treatment; for sildenafil, the limited data show no clear association with malformations and are insufficient to define the risk during lactation [56, 58]. A woman with SPS without PAH has no contraindication to pregnancy described in the sources consulted, but carries a variant with a risk of PAH and of transmission (section 8).

7.12. Perioperative care and transition

The sources consulted do not describe specific perioperative recommendations for TBX4-associated disease; perioperative management follows that of PAH. The risk is real: in the Galambos cohort, an 8-month-old child with persistent PH after PPHN died of a PH crisis during a Meckel diverticulectomy [10]. To facilitate the transition from paediatric to adult care, the European guideline recommends using the same haemodynamic definition of PH in children (mPAP >20 mmHg) [24].

7.13. Developments in the last 12 months

No regulatory applications, opinions or authorisations targeting TBX4-associated disease were identified in the period.

7.14. Divergences between sources

The 2022 European guideline states that genetic testing "may be considered" in paediatric PAH, whereas the 7th World Symposium (2024) recommends offering it to all children in groups 1 and 3 due to developmental disease, with trio exome or genome [23, 24]. The European guideline did not indicate EMA paediatric approval for tadalafil and suggested a per-kilogram dose, whereas the current SmPC approves a fixed dose by weight band from 2 years of age [24, 59]. Titration of sildenafil up to 40 mg 3×/day above 45 kg appears only in the FDA label; the guideline and the European SmPC limit it to 20 mg 3×/day [24, 53, 56]. The classification of TBX4-associated PH in group 1 or group 3 remains open and may change the algorithm applied [34]. Galambos and colleagues prefer the term PH to PAH, because many children, despite a precapillary profile, do not meet the classic group 1 criteria and could belong to group 3, whereas the authors of the Mayo Clinic case classify disease without parenchymal involvement as heritable PAH of group 1.2 [10, 40]. The acute vasodilator response also differs between series: 2 of 10 children in the Galambos cohort, 4 of 11 in the British cohort and 10.2% of carriers in the Prapa comparison (versus 1.3% for BMPR2) [6, 8, 10].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks in dominant inheritance

SPS, PAH and developmental lung diseases associated with heterozygous TBX4 variants are transmitted in an autosomal dominant manner: each child of a carrier has a 50% probability of inheriting the variant [4, 29]. The probability of inheriting is not the probability of developing PAH. The skeletal phenotype has high penetrance, but PAH has incomplete penetrance and variable expressivity: none of the 23 carriers with SPS in the Dutch series had PAH on screening, more than half of the children with PAH inherited the variant from an unaffected parent, and the same variant can cause absent patellae in one relative and fatal PAH in childhood in another [6, 29, 31, 33]. There is no validated estimate of PAH penetrance by age or sex in TBX4 carriers; the 50% value used by Prapa for lung disease was a deliberately generous approximation for variant classification purposes, not a clinical estimate [6]. The penetrance figures known for BMPR2 (14% in men and 42% in women) do not apply to TBX4 [4].

In a child with an apparently de novo variant, testing of the parents is recommended to confirm the origin, define the risk for siblings and decide on surveillance of a carrier parent [4]. If the parents do not have the variant in blood, the recurrence risk for siblings is estimated at about 1% because of the possibility of gonadal mosaicism [4]. If the parents' genetic status is unknown, 50% is assumed for screening purposes [4]. The 17q23 deletions tested in the parents were all de novo in the British series (6 of 6), which is consistent with non-allelic homologous recombination, and in the Ballif series the origin was apparently de novo in the five cases with parental testing [8, 12]. By contrast, seven of eight intragenic variants studied in the parents in the same British series were inherited, and all carrier relatives assessed had signs of ICPPS [8].

8.2. Recessive inheritance and couples with SPS

PAPPAS occurs when both parents are heterozygous; in the families described, the couples were consanguineous and both had radiological SPS [3, 17]. In a couple in which both members are carriers, each pregnancy has a 25% probability of a homozygous fetus with lethal PAPPAS, 50% of a heterozygous child at risk of SPS and PAH and 25% of a child without the variant. Ultrasound identified absence of the lower limbs at 15 weeks [17].

8.3. Cascade testing and surveillance of relatives

Testing should start, whenever possible, in an affected relative; a negative panel in an unaffected relative, without a known familial variant, is uninformative [23]. When the variant is known, at-risk relatives can have targeted testing; those without the variant have the general population risk, and those with it enter surveillance [4, 24]. The European guideline recommends counselling on PAH risk and annual screening in carriers of PAH-causing variants and in first-degree relatives of patients with heritable PAH (class I, level B) [24]. GeneReviews recommends an echocardiogram every 1–3 years in at-risk relatives of unknown genetic status [4]. Families with SPS should be informed of the association with PAH, and screening for PAH should be considered in young people with SPS [29, 33]. After PPHN in a carrier child, the TBX4 variant predicts the possibility of recurrence of PH, and an annual echocardiogram may be useful [33].

8.4. Genetic counselling and minors

Genetic counselling by professionals trained in PAH or by clinical geneticists should precede testing, to discuss penetrance, at-risk relatives, reproduction, genetic discrimination and psychosocial aspects; testing of asymptomatic relatives should be carried out by genetic counsellors or clinical geneticists [23, 24]. The sources consulted do not specifically address predictive testing in asymptomatic minors; the potential benefit (echocardiographic screening, early orthopaedic guidance) and the absence of pharmacological prevention of PAH are part of that discussion [29, 42]. Guilt associated with transmission and the perception of no medical benefit may reduce uptake of family testing [33].

8.5. Reproductive options

The options include no testing during pregnancy, prenatal diagnosis (rarely used in PAH), preimplantation genetic testing after in vitro fertilisation, use of donor gametes, adoption and the decision not to have children [23]. The ideal time for this discussion is before pregnancy, and affected or at-risk young adults should receive counselling on risks and options [4]. In women with PAH, the contraception and preconception counselling recommendations of section 7.11 apply [24]. When the molecular diagnosis has not been established, DNA from the proband can be stored for future studies [4].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

These proportions measure the frequency of TBX4 among patients already diagnosed with PAH at reference centres and not the frequency of PAH among carriers, nor the population prevalence. Differences between cohorts reflect different recruitment and testing methods [33].

9.2. Sex and age

In TBX4-associated lung disease, Prapa found a female predominance of 62% and diagnosis at all ages (19% perinatal, 36% in childhood, 45% in adulthood) [6]. In the French series, the female:male ratio was 3, and in the British paediatric series 48% were girls, in line with the ratio close to 1:1 in prepubertal PAH [7, 8, 23]. In the Galambos paediatric cohort, the female:male ratio was 2.16:1, similar for deletions and sequence variants, which the authors hypothetically attribute to selective loss of male fetuses or to hormonal factors and modifier genes, as in BMPR2 disease [10]. In the 17q23 duplication, the seven patients with clubfoot were all male [15].

9.3. Ancestry and founder populations

No founder variants of TBX4 have been described. In European cohorts, most carriers are of European ancestry (84.1% in the Prapa study, with 7.9% of African ancestry), and the data come mainly from the Netherlands, United Kingdom, France, Spain and the USA [6]. PAPPAS was described in consanguineous families from Iran and India, which reflects the greater probability of homozygosity in marriages between relatives [17, 37]. The first description of SPS with a TBX4 variant in an Asian population was that of a Japanese family in 2018 [42]. The Spanish cohorts (Navas, Hernandez-Gonzalez) are the available southern European series: in the Navas study, TBX4-associated forms had the longest survival and 37.5% of relatives tested were positive on family screening [43, 69].

9.4. Portugal and Brazil

The sources consulted do not include Portuguese or Brazilian series of TBX4-associated disease, which does not demonstrate the absence of published cases. In Portugal, sildenafil (Revatio®) is authorised and bosentan (Tracleer®) is listed in Infomed [54]. Patient resources exist in Portuguese: the portal "Hipertensão Pulmonar: Informação para Doentes e Profissionais", in Portugal, and ABRAF, in Brazil [70, 71].

9.5. Special populations

Young children and preterm infants are at increased risk during catheterisation, and in infants under three months the diagnosis may be based on echocardiography [25]. In women of childbearing potential with PAH, the contraception and pregnancy recommendations of section 7.11 apply [24]. Carriers of a 17q23 deletion need neurodevelopmental, hearing and cardiac assessment, because these manifestations are more frequent than with intragenic variants [8]. Adults with SPS diagnosed late have fewer surgical options for patellar instability [42].

9.6. European networks and patient associations

ERN-LUNG (rare respiratory diseases, including PH) and ERN BOND (rare bone diseases) are the relevant European Reference Networks [26, 27]. Patient associations include PHA Europe, PHA UK and, in the USA, the Pulmonary Hypertension Association, which maintains a list of PH centres, as well as PHAWARE [4, 72, 73]. Research registries include the PAH Biobank and the UK National Cohort Study of Idiopathic and Heritable PAH [4].

10. Illustrative Clinical Case

10.1. Persistent pulmonary hypertension of the newborn that did not resolve

Tsoi and colleagues, from the University of California, San Francisco, published in 2022 the case of a girl born in 2013 at 34 weeks and 6 days of gestation, after antenatal corticosteroids, with cyanosis and respiratory distress [39]. She received surfactant for bilateral opacities on the radiograph and drainage of bilateral pneumothoraces; the echocardiogram showed suprasystemic PH with exclusively right-to-left flow across the ductus arteriosus, without major structural heart disease, and inhaled nitric oxide was started [39]. On the first day she was placed on venovenous ECMO for PPHN, with prostaglandin E1 to keep the ductus arteriosus patent; she was decannulated on day nine and extubated to continuous positive airway pressure on day 27, with modest improvement in PPHN [39].

Because of the atypical and prolonged course, she was investigated. CT showed diffuse ground-glass opacities, mainly central and perihilar, without cysts or air trapping; genetic testing of the surfactant proteins and chromosomal microarray were normal [39]. Catheterisation on day 37, with an inspired oxygen fraction of 40% and nitric oxide, showed PAH with mPAP of 30 mmHg, PVRi of 7.2 WU·m², a pulmonary-to-systemic flow ratio of 1.4:1 through a patent foramen ovale and normal pulmonary veins; angiography showed a pruned distal bed and reduced capillary density [39]. Lung biopsy on day 38 revealed delayed maturation (late saccular stage) with moderate alveolar simplification, pulmonary interstitial glycogenosis and vascular remodelling with medial hypertrophy and focal intimal proliferation (Figure 1 of the original article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9297023/figure/pul212108-fig-0001/) [39].

She started sildenafil for PAH and prednisolone for interstitial glycogenosis, and was discharged on day 67 with a gastrostomy and oxygen; bosentan was started after discharge, following insurance authorisation [39]. At 7.5 months, without improvement (mPAP 38 mmHg, PVRi 8.9 WU·m²), she showed reactivity to nitric oxide (26 mmHg; 5.3 WU·m²); corticosteroids were stopped at one year of age, and at 15 months there was modest improvement (mPAP 23 mmHg, PVRi 6.3 WU·m²), with greater capillary density on angiography and less ground glass on CT [39]. Sildenafil was stopped because of severe reflux, daytime oxygen was withdrawn at 18 months and, in view of slow worsening of PAH on subsequent catheterisations, tadalafil was added to bosentan at 3.5 years; she came off oxygen at 6 years [39]. At 7 years, her mother reported cyanosis and desaturation on exertion: exercise echocardiography was normal, but the six-minute walk distance was 70% of predicted, with saturation of 85–94%, and spirometry showed a restrictive pattern (forced vital capacity 58%); catheterisation showed mPAP of 20 mmHg and PVRi of 4.3 WU·m² [39]. At 8 years, a PH gene panel identified the heterozygous truncating variant TBX4 NM_018488.3:c.576C>A p.(Tyr192Ter) — identical in NM_001321120.2 — classified as likely pathogenic and absent in the parents; physical examination then showed a bilateral gap between the first and second toes, and SPS was diagnosed, with the skeletal survey pending [20, 39].

10.2. What the case teaches

The case brings together the elements of TBX4-associated developmental lung disease: severe PPHN requiring ECMO, pneumothoraces, interstitial glycogenosis and alveolar simplification on biopsy, PH persisting beyond the neonatal period and, years later, restrictive lung disease [10, 39]. The genetic diagnosis came eight years later, in the year in which the association between TBX4 and paediatric PAH had been described, and the skeletal sign was only looked for after the result — a delay that the current recommendation of exome or genome sequencing in children with group 3 PH due to developmental disease aims to prevent [23, 29, 39]. The management described (prednisolone for interstitial glycogenosis, the sequence sildenafil, bosentan and tadalafil) consists of individual decisions by one centre; prednisolone has no controlled evidence in this indication, and sildenafil is not indicated in PPHN according to the European SmPC [39, 53]. The reactivity to nitric oxide, the slow response and the progression to near-normal haemodynamics on dual therapy are in line with the dynamic vascular tone and favourable survival described in the treated paediatric series [8].

Other published cases show the extremes of the spectrum: a newborn girl with congenital alveolar dysplasia and the de novo variant c.524_527del p.(Asn175ThrfsTer52), who died after 19 days of ECMO, and an infant with a 2.2 Mb 17q23.1q23.2 deletion and alveolar growth abnormality, who needed a tracheostomy and ventilation for eight months and, at 15 months, no longer had right ventricular hypertension [31]. At the other extreme, a 19-year-old Japanese woman with SPS and patellar instability since the age of 8, carrying a variant inherited from a father without signs, was treated with medial patellofemoral ligament reconstruction [42].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The prognosis depends on the phenotype. In isolated SPS, the skeletal course is benign, except for recurrent patellar instability [2]. The lethal developmental lung diseases have a neonatal mortality of 80–90% [33]. In TBX4-associated PH, the available data describe disease treated at reference centres: event-free survival (death or transplantation) of 100%, 94% and 83% at 1, 3 and 5 years in the French series of adults and children, with two deaths and two transplants over a median follow-up of 76 months [7]; survival free of transplantation or Potts shunt of 100% (95% CI 100–100) at 1 year and 94.4% (95% CI 84.4–100) at 5 years in the British paediatric series, with a median follow-up of 7.1 years (0.7–17.2), two Potts shunts, one transplant and one death, and a worse course with deletions [8]. This survival compares favourably with that of the historical British cohort of paediatric idiopathic PAH (89% and 75% at 1 and 5 years, transplant-free) [8]. In the Prapa comparison, event-free survival was shorter with T-box domain variants, with an effect independent of age at diagnosis, and male sex and older age were associated with worse survival [6]. In Spain, TBX4-associated forms had the longest survival among the genetic groups studied [69]. In paediatric PAH in general, transplant-free survival at 5 years is 81% [55]. Without treatment, the historical mean survival of heritable PAH after diagnosis was 2.8 years [4]. In the international Galambos cohort, with a median follow-up of 10 years, 5 of 19 children (26%) died or received a transplant, PH resolved in three and remained chronic in eleven; children biopsied in the neonatal period had a worse course than those biopsied in childhood [10]. These estimates come from small series with selection bias; patients with lethal forms do not enter the survival series and asymptomatic carriers are not represented [6, 8].

The high-risk factors of the 7th World Symposium paediatric tool include younger age, right heart failure, progression of symptoms, weight or height with z <−2, functional class III–IV, walk test ≤350 m (above 6 years of age), NT-proBNP >1,200 ng/L, tricuspid annular plane systolic excursion <12 mm, PVRi >11 WU·m², mean right atrial pressure >10 mmHg, cardiac index <2.5 L/min/m² and mPAP/mean systemic arterial pressure ratio >0.75; maintaining a low-risk profile is the treatment goal [25].

11.2. Surveillance

The European guideline notes that echocardiography-only screening of BMPR2 carriers missed the cases detected in the DELPHI-2 study (PAH incidence of 2.3% per year), which also used electrocardiogram, NT-proBNP, DLCO, cardiopulmonary exercise testing and optional RHC; it therefore advocates a multimodal approach, although the optimal strategy has not been defined and no equivalent data exist for TBX4 [24].

12. Summary and Concluding Remarks

TBX4 is a transcription factor in the development of the lower limb, pelvis, lung and its vessels, and its deficiency produces a spectrum ranging from asymptomatic small patella to lethal lung disease in the newborn. Small patella syndrome, autosomal dominant and highly penetrant, is defined by aplastic or hypoplastic patellae with anomalies of ischiopubic ossification and infra-acetabular notches, and is often recognised only after a diagnosis of PAH in a relative. TBX4-associated PAH is the second most frequent genetic cause of PAH, especially in children, is frequently accompanied by airway and parenchymal disease and low DLCO, and may arise in a biphasic pattern after PPHN. 17q23.1q23.2 deletions add heart disease, deafness and developmental delay and are associated with a worse course, whereas the reciprocal duplication causes clubfoot. Biallelic loss causes PAPPAS, which is lethal, so couples in which both members have SPS have a 25% risk in each pregnancy.

Diagnosis rests on targeted examination of the knees, pelvis and feet, chest CT and a genetic test that includes CNV analysis — trio exome or genome in children with group 1 PH or group 3 PH due to developmental disease, a panel with CNV in adults. Interpretation requires attention to the transcript (MANE NM_001321120.2, with numbering shifted from exon 8 onwards relative to NM_018488.3), to the existence of gain-of-function variants and to incomplete penetrance, which precludes using the variant to predict the pulmonary phenotype. There is no gene-targeted treatment: PH is treated according to the algorithms for PAH or PH associated with lung disease, in centres with paediatric experience, lung disease is treated before vasodilation in infants, and patellar instability is preferably treated before skeletal maturity. In the treated series, five-year survival is around 83–94%, but the data come from small selected cohorts. Carriers and first-degree relatives should receive genetic counselling and annual clinical and echocardiographic surveillance, and families with SPS should be aware of the risk of PAH.

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