Trichorhinophalangeal Syndromes (TRPS I–III and Langer-Giedion)

Autosomal dominant ectodermal and skeletal dysplasias caused by loss of function of the transcription factor TRPS1 (types I and III) or by a contiguous gene deletion at 8q23.3–q24.11 that includes TRPS1, RAD21 and EXT1 (type II, Langer-Giedion syndrome), with sparse hair, a bulbous nose, brachydactyly with cone-shaped epiphyses, early hip dysplasia and, in type II, multiple osteochondromas and cognitive impairment.

Literature and regulatory information updated: 6 November 2026.

0. Initial Reference Table

1. Introduction

The trichorhinophalangeal syndromes form a class of skeletal and ectodermal dysplasias whose name summarises the three most affected territories: the hair (tricho), the nose (rhino) and the phalanges (phalangeal). The common denominator is loss of function of the TRPS1 gene, which encodes a GATA-type zinc finger transcription factor. The clinical forms are distinguished by the genetic mechanism: intragenic TRPS1 variants in types I and III, and a contiguous gene deletion removing TRPS1, RAD21 and EXT1 in type II, or Langer-Giedion syndrome, which adds multiple osteochondromas and a high risk of intellectual disability to the type I phenotype [1, 5]. The article covers the group uniformly, with a common syndromic description, current classifications, a table of types and detailed discussion of each entity, including Langer-Giedion syndrome.

1.1 Historical overview

Klingmüller described in 1956 two sisters with the malformation pattern that would come to be recognised as trichorhinophalangeal syndrome, and Giedion established the entity in 1966, coining the designation «tricho-rhino-phalangeal» [24, 25]. According to the Online Mendelian Inheritance in Man (OMIM) summary, Giedion delineated the picture of fine, slow-growing hair, a pear-shaped nose with a high philtrum, brachyphalangy with finger deformity and wedge-shaped epiphyses, in a girl with two supernumerary incisors, and identified two previous reports of affected sibling pairs, one of them published as pseudo-pseudohypoparathyroidism [16]. Autosomal dominant inheritance was established with the Murdoch family (1969), with an affected grandfather, son and grandson, and was confirmed by Sugiura (1976) in three Japanese families with 19 patients [16].

The form with exostoses was delineated by Hall and colleagues in 1974, who described five new cases and reviewed the initial reports of Giedion and Langer and the older cases collected by Gorlin, naming it Langer-Giedion syndrome [7, 15]. Kozlowski (1977) suggested that the Italian case of Alé and Caló (1961) corresponded to the same entity, and Langer and colleagues (1984) described four patients without severe intellectual disability, reviewed 32 published cases and proposed the designation «trichorhinophalangeal syndrome with exostoses» [6, 7]. The severe form without exostoses was described by Sugio and Kajii (1984) in a family with nine affected members over four generations, initially classified as Ruvalcaba syndrome; Hunter (1985) separated it from that syndrome by the absence of microcephaly and intellectual disability, and Niikawa and Kamei (1986) proposed the designation TRPS III, or Sugio-Kajii syndrome [3, 4].

1.2 Milestones of molecular discovery

The chromosomal hypothesis arose in 1980, when Buhler and colleagues described an adolescent girl with Langer-Giedion syndrome and a terminal 8q deletion removing band q24 [7, 15]. Buhler and Malik (1984) placed the minimal region of overlap of the deletions at 8q24.1 and noted that the exostoses of Langer-Giedion syndrome were radiologically and in their course indistinguishable from hereditary multiple exostoses, which suggested an exostosis locus on 8q [7]. In 1987, Buhler concluded that Langer-Giedion syndrome was due to deletion of 8q24.11 to 8q24.13, whereas TRPS I resulted from a smaller deleted segment, centred on 8q24.12 [7]. Chromosome microdissection by Lüdecke (1989, 1991) mapped the breakpoints of 16 patients and reduced the region of overlap to less than 2 Mb, and the work of Lüdecke and of Hou (1995) showed that the TRPS1 locus lies more than 1000 kb proximal to EXT1 and that both are deleted in Langer-Giedion syndrome, which came to be understood as a true contiguous gene syndrome and not as a pleiotropic effect of a single gene [7].

The gene was cloned by Momeni and colleagues in 2000, by positional cloning: the new gene spanned the chromosomal breakpoint of two patients with TRPS I and was deleted in five patients with an interstitial deletion; it had seven exons, a 3843 base pair open reading frame, two potential nuclear localisation signals and an unusual combination of IKAROS-type and GATA-binding zinc fingers; six different nonsense variants in ten unrelated patients pointed to haploinsufficiency as the mechanism [26]. In 2001, Lüdecke and colleagues found 35 different variants in 44 of 51 unrelated patients with TRPS I or III (detection rate 86%), with no variant in the parents of sporadic cases or in healthy relatives, and showed that four of the five missense variants altered the GATA zinc finger and that six of the seven patients carrying them could be classified as TRPS III, concluding that this type represents the severe end of the TRPS1 spectrum [10]. The largest published cohort, of 103 confirmed patients in an international collaborative study, was assembled by Maas and colleagues in 2015 [11].

1.3 Nomenclature and reclassifications

The classic three-type classification is retained in OMIM (190350, 190351 and 150230) and in the 2021 French PNDS, which defines type I as the classic and most frequent form, type II as the association with the type I phenotype of exostosing disease and, possibly, neurocognitive involvement, and type III as a more severe form of type I, with more pronounced brachydactyly, joint involvement and short stature, without exostoses or intellectual disability [5, 16]. GeneReviews, in its 2024 revision, considers that the designation TRPS III is no longer in use because the phenotype lies within the type I spectrum [1, 11]. The 2023 revision of the nosology of genetic skeletal disorders, which adopted dyadic nomenclature (phenotype associated with the gene), calls the forms due to a heterozygous TRPS1 variant «trichorhinophalangeal dysplasia types 1/3» and the contiguous 8q23.3–q24.11 deletion «Langer-Giedion syndrome (trichorhinophalangeal dysplasia type 2)» [1, 2]. Orphanet groups types I and III under code ORPHA:77258 and type II under ORPHA:502, both within group ORPHA:324764 [17, 18].

1.4 Definition of the entities covered

Isolated hereditary multiple exostoses due to EXT1 or EXT2 and Cornelia de Lange syndrome associated with RAD21 are allelic disorders of genes included in the deletion; here they are of interest as differential diagnoses and as components of the type II phenotype.

2. Molecular Genetics and Pathophysiology

2.1 The TRPS1 gene and the TRPS1 protein

The TRPS1 gene lies at 8q23.3 (OMIM 604386) and the MANE Select reference transcript is NM_014112.5, which encodes the protein NP_054831.2 [8, 9]. The gene has seven coding exons, and the main functional domains are encoded in exons 6 and 7 [5, 26]. The protein is an atypical transcription factor of the GATA family, with nine zinc finger domains (seven classic and two Ikaros-type), a cysteine-rich region and a GATA-type zinc finger; it represses GATA-regulated genes by binding to the consensus sequences, and binding to a dynein light chain reduces this binding and the repressor activity; it can also activate transcription of targets by binding to their promoters [1]. Kaiser and colleagues showed that, of the two basic motifs that are candidate nuclear localisation signals, only RRRTRKR functions as such, and that substitution of arginine by histidine or cysteine at the last residue of this motif prevents the mutant protein from entering the nucleus [30].

TRPS1 is expressed during embryogenesis in cartilage, hair follicles and kidney, and participates in cell cycle regulation [5]. In the growth plate it controls chondrocyte proliferation and differentiation and is involved in bone mineralisation through the osteocalcin, parathyroid hormone-related protein (PTHrP) and Sox9/STAT3/Wnt/β-catenin pathways; in the hair follicle it regulates hair development and the hair cycle [1, 31]. The PNDS adds that TRPS1 promotes differentiation and apoptosis of ATDC5 chondrogenic cells through the MAPK pathway and represses RUNX1 and SOX9, controlling proliferation of cartilage and epithelial follicles [5]. Mouse models confirm these roles: the mouse heterozygous for deletion of the GATA zinc finger reproduces the classic phenotype with progressive kyphoscoliosis, and the homozygote dies in the neonatal period of respiratory failure linked to thoracic and vertebral anomalies; the complete knockout dies in less than 24 hours and has severe renal involvement [5]. Deletion of Trps1 regulatory elements in mice reproduces the postnatal hip anomalies and growth retardation, reinforcing the role of non-coding regulators [32]. A 2026 review of rodent models concluded that there are no established therapeutic strategies and discussed potential targets only at the preclinical level [33].

2.2 Disease mechanism: haploinsufficiency and dominant-negative effect

The predominant mechanism is loss of function through haploinsufficiency, supported by truncating variants and whole-gene deletions; ClinGen dosage curation assigns TRPS1 a haploinsufficiency score of 3 and a triplosensitivity score of 0 [1, 31]. Missense variants of the GATA zinc finger, which are associated with more severe phenotypes, were interpreted by Lüdecke as dominant-negative, through interference with a multimeric protein complex [1, 10]. Missense variants of the nuclear localisation motif, such as p.(Arg965Cys) and p.(Arg965His), act by reducing the nuclear concentration of TRPS1, which is compatible with haploinsufficiency [8, 30]. Biallelic variants have not been described in humans and are lethal in the mouse model [5].

2.3 Spectrum of intragenic variants and nomenclature

The Human Gene Mutation Database (HGMD) listed, according to the 2024 GeneReviews, 166 different pathogenic TRPS1 variants: 94 (56.6%) truncating (nonsense 21.7%, frameshift 32.5% and splicing 2.4%), 31 (18.7%) missense, 30 (18.1%) large deletions, two large insertions and nine complex rearrangements; with four exceptions, all missense variants lie in exons 6 and 7 [1]. In the Maas cohort, the 22 missense variants were exclusively in exons 6 and 7 and the remaining variants were distributed across exons 4 to 7 [11]. In a Korean series of 20 children, 65% had truncating variants, 15% exon 6 missense variants and 20% exonic deletions [21].

Variant numbering has changed: OMIM documents that, after renumbering of the reference sequence, historical protein designations advanced by 13 codons (for example, T901P became T914P, R908Q became R921Q, A919V became A932V, R952C became R965C, R952H became R965H and Y1092X became Y1105X), and ClinVar still lists alternative isoform numberings [8, 34]. Designations follow Human Genome Variation Society (HGVS) nomenclature, and the conversions in the following table were confirmed in ClinVar and VariantValidator, on transcript NM_014112.5 and the GRCh38 genome.

In case publications, variants are often reported in the article's own nomenclature, which does not always match the MANE transcript: this is the case for c.2735G>A p.Cys912Tyr in the family with maternal mosaicism described by Corsini, the two nonsense variants c.1198C>T p.(Gln400*) and c.2086C>T p.(Arg696*) in a patient with growth hormone deficiency, and c.880_882delAAG in a three-generation Chinese family [14, 36, 37]. These designations are reproduced here as published, without conversion.

2.4 Structural rearrangements, position effects and regulation

About 3% of pathogenic variants in TRPS I correspond to structural rearrangements detectable on karyotype, including the inversions inv(8)(q13;q24.1) and inv(8)(q21.1;q24.1) and translocations [1]. The Portuguese family described by David and colleagues was the first familial TRPS I due to a t(8;13)(q23.3;q21.31) translocation, with the breakpoint 87 kb from the 5' end of TRPS1 and no lesion in the gene; the translocation placed a conserved enhancer from 13q21.31 next to the 5' region of TRPS1, and three independent methods showed increased expression of the gene, which led the authors to propose a cis-disruption mechanism with overexpression; the proband had an expanded phenotype with brain malformations and intellectual disability [38]. A de novo t(2;8)(p16.1;q23.3) translocation that does not disrupt TRPS1 produced a similar phenotype [1]. Congenital hypertrichosis universalis of the Ambras type (MIM 145701) has been attributed to a position effect on TRPS1: a pericentric inversion with a breakpoint 7.3 Mb downstream reduced expression of the gene, and other patients had a 6.7 Mb deletion including TRPS1 or a 1.5 Mb upstream deletion [8]. These cases show that reduced and increased TRPS1 expression have distinct clinical consequences and that normal sequencing does not exclude a regulatory defect.

2.5 The contiguous gene deletion of Langer-Giedion syndrome

The TRPS1, RAD21 and EXT1 genes lie at 8q23.3–q24.11 within an interval of approximately 2.8 Mb; the syndrome results from simultaneous haploinsufficiency of TRPS1 and EXT1, and OMIM classifies it with mapping key 4, used for contiguous deletion syndromes [1, 7]. EXT1 encodes exostosin-1, which forms with exostosin-2 the heparan sulfate polymerase heterodimer; loss of one copy reduces heparan sulfate chain elongation and underlies the osteochondromas [39, 40]. RAD21 encodes the kleisin subunit that closes the cohesin ring, and its heterozygous variants cause the mild form of Cornelia de Lange syndrome (type 4, MIM 614701); RAD21 haploinsufficiency probably contributes to the more severe cognitive involvement of type II [1, 11, 41].

The minimal critical region for the typical presentation was estimated at 3.2 Mb from two Brazilian patients characterised by cytogenomic techniques, one of them with the smallest deletion described in classic Langer-Giedion syndrome, and includes TRPS1, RAD21 and EXT1; the authors suggested that deletion of CSMD3 contributes to the central nervous system anomalies [12]. The Turkish cohort of Güneş proposed including EXT1 only partially in the critical region, because a patient with a deletion of EXT1 from exon 2 onwards had exostoses [42]. The PNDS reports deletions up to 20.4 Mb, with variable breakpoints that explain the phenotypic variability, and associates large deletions with a worse prognosis because of the number of genes involved [5]. Deletions extending beyond the critical region may include KCNQ3 and CSMD3, broadening the phenotype to epilepsy and central nervous system anomalies, and a deletion of 8q23.3–q24.22 was associated with Langer-Giedion syndrome, Cornelia de Lange syndrome and epilepsy [27, 28]. Nardmann (1997) found a deletion of approximately 5 Mb in a patient with TRPS I of normal intelligence, which placed the genes for intellectual disability outside this interval, and determined paternal origin in six and maternal origin in three deletions [16].

The relationship between deletion size and cognition is controversial. Smith's and OMIM describe a relationship between size and cognitive outcome, and the Güneş cohort observed severe intellectual disability in patients with larger deletions; Favilla found no correlation between size and the severity of intellectual disability [1, 15, 16, 42]. The most consistent explanation is that the gene content of the deletion, rather than its absolute size, determines the phenotype, which justifies the PNDS recommendation to specify the genes included in the interval [5].

2.6 Mosaicism

Mosaicism has two consequences. In counselling, Corsini described a patient with TRPS I whose healthy mother had the same variant in 10% of blood cells, detected by pyrosequencing, which explains recurrences in sibships of unaffected parents and led the authors to propose a recurrence risk of 5–10% for healthy parents with an affected child [3, 14]. In the phenotype, mosaic type II deletion attenuates expression depending on tissue distribution: Shanske (2008) described a 19.79 Mb deletion present in 7% of lymphocytes and 97% of fibroblasts, with a mild facial phenotype and mild intellectual disability, and Valientes (2026) described a 13.01 Mb deletion in approximately 75% of nucleated blood cells, with a severe skeletal phenotype and relatively preserved neurodevelopment [27]. Buhler (1987) and Naritomi (1989) also described mosaicism for 8q deletions in mild forms of TRPS I [16].

2.7 Penetrance, expressivity and genotype-phenotype correlations

Penetrance is considered complete: Lüdecke found no variants in the parents of sporadic cases or in clinically healthy relatives [1, 10]. Expressivity is highly variable, between and within families, and unrelated patients of the same age and sex with the same variant may have different phenotypes [10, 11]. Genotype-phenotype correlations are limited to missense variants in exons 6 and 7, associated with more marked brachydactyly and short stature; in the Korean series, exon 6 missense variants were always associated with severe brachydactyly, but stature did not correlate with genotype [1, 21]. In the Maas cohort, exon 6 variants were associated with more marked facial features and shorter hands and feet, but with numbers insufficient for firm conclusions; the Danish series of Herlin identified no correlation [11, 20]. The PNDS stresses that it is not possible to predict the course from the genotype alone [5].

2.8 Allelic disorders and modifiers

Apart from the TRPS forms, no germline phenotypes associated with TRPS1 are known; the position effect in Ambras-type hypertrichosis is a regulatory association and not allelic in the strict sense [1, 8]. EXT1 causes hereditary multiple osteochondromas, without intellectual disability or the craniofacial, ectodermal and digital features of TRPS, and RAD21 causes Cornelia de Lange syndrome with growth restriction and minor skeletal anomalies, also without the craniofacial and ectodermal features of TRPS [1, 19]. In Cornelia de Lange syndrome associated with RAD21, 10% of patients have normal cognition and 45% mild impairment, with no severe or profound cases, and there is a DNA methylation signature that aids diagnosis [41, 43]. A homozygous missense variant of RAD21 was associated, in a single consanguineous Turkish family, with Mungan syndrome (MIM 611376, provisional association in OMIM), with chronic intestinal pseudo-obstruction, megaduodenum, long-segment Barrett oesophagus and cardiac anomalies, of autosomal recessive inheritance; Orphanet links this OMIM entry to the TRPS II code (ORPHA:502), but it is a distinct disorder, phenotypically unrelated to Langer-Giedion syndrome [18, 44]. Common variation in TRPS1 has been associated with hip geometry and bone mineral density in the general population, according to the PNDS bibliography [5].

2.9 TRPS1 in oncology: somatic, not constitutional, alteration

Tumour expression of TRPS1 is used as an immunohistochemical marker, particularly in triple-negative breast carcinoma, and has been studied as a prognostic marker in other tumours; the protein behaves mainly as a tumour suppressor, inhibiting epithelial-mesenchymal transition, but may have oncogenic effects in some contexts [5, 45]. These alterations are acquired in the tumour and do not apply to patients with constitutional TRPS; no increased cancer risk has been demonstrated in these patients, and the PNDS recommends general population cancer screening [5].

3. Clinical Spectrum and Manifestations by Organ System

3.1 Sources of clinical data and what each cohort measures

The clinical description of the trichorhinophalangeal syndromes rests on small series and case reports, almost always of patients referred to genetics centres, which biases frequencies towards the more marked phenotypes. The largest published cohort brought together 103 molecularly confirmed patients in a European-based international collaborative study: 85 with TRPS I (22 with missense variants and 62 with other variants), 14 with TRPS II and 5 of uncertain classification [11]. The 2024 GeneReviews pooled trait frequencies for 155 patients (133 with TRPS I and 22 with TRPS II) from several European and Asian series published between 2010 and 2023 [1]. To these are added a Turkish series of 22 patients from 17 families, aged 0.9 to 45 years (19 with TRPS I and 3 with TRPS II), a Danish series of 15 patients with TRPS I followed for a median of 10 years, a Korean series of 20 unrelated children with TRPS I/III seen between 2012 and 2024 at a single centre, an orthopaedic systematic review of 26 patients published up to June 2022 and a series of four adults with Langer-Giedion syndrome followed for decades [20, 21, 42, 45, 46]. The evidence base of the French PNDS, based on a literature search from 1999 to 2019, retained 27 studies, mostly case reports [5]. None of these sources measures trait frequency in the population of unselected carriers, and the absence of a sign in a small series does not mean it is absent in the disease.

3.2 Craniofacial phenotype

The face is the most constant element, described in practically all patients with types I and II, and does not differ significantly between the two types [1, 11]. The most distinctive, possibly unique, feature is the large nose, with a broad, bulbous dorsum and tip, with underdeveloped alae nasi that contrast with the volume of the tip, a columella that is sometimes broad or protrudes below the alae and, occasionally, a broad nasal septum; the appearance is classically described as a «pear-shaped nose» [1, 5, 24]. These are associated with eyebrows that are thick and broad medially, almost always denser than the lateral portion, which may be sparse; a long philtrum, sometimes flat and broad; a thin upper lip vermilion; large, prominent ears; a high forehead; a horizontal smile; a narrow, high palate; inconstant micrognathia or retrognathia; and a horizontal groove of the chin [1, 3, 24]. In Langer-Giedion syndrome, the face overlaps with that of type I and includes deep-set eyes, large anteverted ears of simple configuration, a broad nasal root, thickened alae nasi, tented nostrils and a receding mandible [6, 15]. The PNDS also describes very long mandibular condylar necks and cases of micro-retrognathism or, more rarely, prognathism with malocclusion [5].

3.3 Ectodermal manifestations

The hair is fine, sparse, brittle and slow-growing from the first weeks of life, with thinning mainly frontotemporal and a high hairline, and is often light in colour [1, 5]. About one third of men lose all or almost all their hair a few years after puberty; women tend to retain more hair, with a high anterior hairline, and in some patients the hair is almost normal or improves with time [1, 24]. A retrospective multicentre study of six patients followed at Brazilian and Italian centres, with a median age of 12 years at diagnosis, described on trichoscopy a very low to average hair density, exclusively non-terminal hairs, reduced density due to an increase in single-hair follicular units rather than greater distance between follicles, and a high occipital hairline in all women, proposed as a diagnostic clue [47]. The nails are thin, fragile, dystrophic or racquet-shaped in about half of patients, more on the feet than on the hands [1, 5].

Dental anomalies are frequent. The PNDS reports supernumerary teeth in 69% of patients with TRPS I, as well as malpositions, malocclusion, delayed eruption of the primary dentition and microdontia [5]. The dentition may be the first reason for consultation: a 2024 report described a 13-year-old girl with 11 supernumerary teeth, retained deciduous teeth and delayed eruption of the permanent dentition, whose investigation led to the diagnosis of TRPS I; she was treated with a surgical-orthodontic plan and followed for 6 months to monitor eruption [48]. In type II, Smith's and the Brazilian textbook of genetic syndromes report oligodontia, hypodontia and microdontia [15, 40]. Small breasts have been described in four of 15 women in one series [1]. Premature skin ageing has been described in some patients with TRPS I [5]. In type II, the skin is redundant and lax in infancy, to the point of suggesting a connective tissue disorder, and this laxity regresses with age; maculopapular naevi appear on the scalp, face, neck, upper trunk and upper limbs [6, 15].

3.4 Growth and the endocrine axis

Birth length is generally normal, and growth retardation is mainly postnatal: the PNDS reports retardation from birth in 25% of patients and short stature (below −2 standard deviations) in half to two thirds of adults, with mean heights of approximately 150 cm in women and 160 cm in men [1, 5]. GeneReviews estimates short stature in 40–50% of patients with TRPS I and approximately 80% of patients with TRPS II; among carriers of TRPS1 variants published between 1999 and 2023, 45.3% had short stature, with a mean height z-score of −3.27 in short patients and −0.87 in the others [1]. In the Lüdecke series, the height z-score of 28 adults with TRPS I was −1.29, against −0.96 in 34 children, indicating a progressive deficit [1]. Bone Dysplasias describes adult heights generally below the 10th centile in type I, occasionally approximately 150 cm in men and 140 cm in women, and below the 3rd centile in most patients with type II [3, 6]. In type III, short stature may reach −3 to −4 standard deviations; in type II, it also depends on the exostosing disease [5].

Skeletal maturation has its own dynamics. Bone age is delayed until puberty and then advances beyond chronological age [1, 5]. In the Korean series, bone age was delayed before 12 years and advanced rapidly thereafter, with a significant fall in height standard deviation in adolescence (p = 0.017); short stature (below −2 standard deviations) was present in 21% of children and did not correlate with genotype [21]. GeneReviews notes that bone age can be estimated from the unaffected epiphyses [1]. This pattern explains the reduced pubertal growth spurt, particularly in boys, described by the PNDS [5].

Growth hormone deficiency has been documented in several reports, sometimes partial: two patients with TRPS I with partial deficiency and decreased bone mass and quality, a 3.5-year-old boy at −3.2 standard deviations with deficiency confirmed on two tests, a 10-year-old girl with a growth velocity of 1.5 cm/year (−4.07 standard deviations), a bone age of 4.5 years and no response to stimulation tests, and a girl with TRPS II, a 12–15 Mb deletion and height at −4.8 standard deviations [7, 36, 49, 50]. A review of 12 cases of TRPS I treated with somatropin concluded that classic deficiency is uncommon and that five had elevated insulin-like growth factor 1 (IGF-1) [51]. Outside the somatotrophic axis, the PNDS recognises no other endocrine particularities in TRPS; Schinzel described thyrotrophin deficiency in an adult with TRPS II and Smith's hypothyroidism [5, 15, 46]. Puberty is generally normal in type I; in type II, premature thelarche and pubarche, delayed sexual development and, in the follow-up of adults, reduced puberty and fertility have been described [15, 46].

3.5 Appendicular and axial skeleton

The hands and feet are short, with unequal shortening of the metacarpals and metatarsals (mainly the fourth and fifth), brachyphalangy and swelling of the proximal interphalangeal joints, which progresses to clinobrachydactyly with ulnar or radial deviation of the fingers [1, 24]. The finger deformities develop from mid-childhood, and the reduced mobility of the small joints may be mistaken for rheumatoid arthritis [1, 52]. Cone-shaped epiphyses are present in more than 95% of patients, become detectable after 2 years, when the epiphyseal centres form, and predominate in the middle phalanges of the hands, though they may involve any phalanx of the hands and feet; Bone Dysplasias classifies them as Giedion type 12 epiphyses, deeply invaginated, with premature epiphyseal fusion [1, 3]. The first radiological sign may be a slight metaphyseal convexity, and the distal radial epiphyses may be cleft [5, 24].

The hip is the main source of morbidity. The PNDS describes hip anomalies (coxa plana, coxa vara, coxa magna and dysplasia) in approximately 70% of patients, unilateral or bilateral, whereas GeneReviews estimates hip dysplasia at approximately 25% in type I and 60% in type II, and Bone Dysplasias reports small femoral epiphyses with Perthes-like changes in approximately 65% of patients with TRPS II [1, 5, 6]. The difference reflects different criteria (radiological change versus clinical dysplasia). In children, flattening of the femoral head mimics Legg-Calvé-Perthes disease, but progresses without the sclerotic plaques of that disease; the changes appear mainly in preadolescence and early adulthood and lead to early coxarthrosis, sometimes with hip replacement at around 30 years [1, 3, 5]. In the orthopaedic systematic review, 15 of 26 patients (57.7%) had Perthes-like changes, 11 (42.3%) coxa magna and 10 (38.5%) clinodactyly; the mean age at diagnosis was 14.1 years [45].

In adults, pseudarthrosis-like lesions and early osteoarthritis of multiple joints appear, mainly fingers and hips, but also the cervical spine, knees and ankles, with chronic pain and stiffness that may wrongly suggest an inflammatory rheumatic disease; the PNDS places the onset of early osteopenia at around 30 years [5]. Izumi described a 31-year-old man with chronic joint pain of adult onset in the neck, back, hips, knees and ankles, spondylosis, scoliosis, spondylolisthesis, osteophytes and osteopenia, with no cone-shaped epiphyses visible in adulthood; his mother had alopecia and joint pain [16, 53]. In the Danish series, all patients had joint complaints, often preceding diagnosis [20]. Delayed skeletal maturation was described in a Brazilian report of skeletal anomalies in TRPS I [54].

The axial skeleton may be involved: scoliosis, kyphosis, pectus carinatum, winged scapulae and vertebral segmentation defects [5, 15]. At the craniovertebral junction, a 39-year-old man with genetically confirmed TRPS presented with basilar invagination with platybasia and occipitalisation of the atlas, with severe ventral cervicomedullary compression [55]. A longitudinal syringomyelia with cervical dystonia and action tremor has also been described in a patient with TRPS I [56].

Osteopenia is described in approximately 20% of patients with TRPS I and 25–30% of patients with TRPS II; the PNDS considers it to carry no major increase in fracture risk, but a minority have repeated fractures and some patients have severe osteoporosis [1, 5, 11]. Macchiaiolo described a 7-year-old boy with a lumbar bone mineral density of 0.331 g/cm² and four spontaneous femoral fractures in one year [57]. Mild to moderate joint hypermobility is described in both types and is more marked in type II, in which childhood stiffness may give way to laxity with instability [5, 46].

3.6 Osteochondromas in Langer-Giedion syndrome

Osteochondromas (exostoses) are specific to type II, present in more than 85% of patients, and result from loss of one copy of EXT1; the frequency may be underestimated in series with many young children [1]. They appear between 1 month and 6 years, first on the scapulae and around the elbows and knees, and may involve the ribs, vertebrae, pelvis and metacarpals; they are metaphyseal, sessile or pedunculated, directed away from the joint, and cone-shaped epiphyses usually precede them [1, 5, 6]. Their natural history is that of hereditary multiple osteochondromas: they grow with the skeleton, stop progressing after puberty and may cause axial deviations, limb length discrepancy and neurovascular compressions [1, 5]. A cervical osteochondroma caused spinal cord compression with tetraparesis, and in two patients compression of the internal carotid artery caused a stroke; Schinzel described osteomas of the processes of the cervical vertebrae that compressed nerve roots or caused cerebral artery dissection [15, 46]. In a 21-year-old woman, bilateral osteochondromas of the distal clavicle caused subacromial impingement [58].

The risk of malignant transformation is the most controversial issue. The PNDS reports progression to sarcoma in 2–5% of cases, mainly in adults [5]. The 2023 American Association for Cancer Research (AACR) consensus, published in 2025, records few reports of secondary chondrosarcoma in TRPS II and two cases of primary osteosarcoma, distant from an osteochondroma, in one family, and concludes that the specific risk is unknown, since the cohort of 103 patients (mostly type I, without EXT1 deletion) had no bone neoplasms [59]. Smith's, Bone Dysplasias and the Schinzel series observed no malignant transformation, without being able to exclude it [6, 15, 46]. In isolated hereditary exostosing disease, transformation to chondrosarcoma occurs in 0.2–5.9% of patients, 75% between 20 and 40 years, more in men and in carriers of EXT1 variants; in a series of 529 patients, the frequency was approximately 5% [19, 59, 60]. The PNDS estimate of 2–5% is therefore an extrapolation from exostosing disease and not a figure measured in Langer-Giedion syndrome.

3.7 Neurodevelopment and nervous system

In type I, cognition is generally normal: the PNDS considers the prevalence of intellectual disability comparable to that of the general population, GeneReviews estimates it at approximately 10%, slightly above the general population, and the Turkish series found mild impairment in 3 of 19 patients [1, 5, 42]. Language delay requiring speech therapy affects 20% of patients, and motor delay is generally secondary to hip dysplasia [1, 5]. In type II, estimates of intellectual disability vary with the period and selection of the series: approximately 70% in Smith's (mild to severe), approximately 80% in Bone Dysplasias (mild to moderate in most), two thirds in the PNDS and 50–60% in GeneReviews, with severe impairment in 2 of 3 patients in the Turkish series, carriers of the largest deletions [1, 5, 6, 15, 42]. The Brazilian textbook states that intellectual disability accompanies all cases, which differs from the other sources, and Langer described four patients without severe impairment [7, 40]. In the follow-up of adults, Schinzel found borderline or mildly reduced cognition in most and normal cognition in some, with practical abilities greater than tests suggest, low self-esteem and a tendency to underestimate abilities [15, 46]. The Brazilian textbook describes a sociable and friendly behavioural profile and autistic behaviour in some patients [40].

Microcephaly affects 50–60% of patients with TRPS II and less than 10% of patients with TRPS I [1]. Epilepsy occurs in approximately 30% of patients with TRPS II, with onset at variable ages, and is associated with deletions extending to genes such as KCNQ3 [5, 27, 46]. Brain malformations have been described in a single patient with TRPS II (polymicrogyria, delayed myelination, short corpus callosum and dilated ventricle), which underpin the PNDS recommendation for brain magnetic resonance imaging at diagnosis, as have cerebral vascular lesions with atrophy and white matter involvement [5]. The Portuguese proband with the t(8;13) translocation had brain malformations and intellectual disability [38]. Infantile hypotonia is specific to type II [6].

3.8 Other organs and systems

3.9 Frequency of features by type

Frequencies pooled by the 2024 GeneReviews from series published between 2010 and 2023; the small denominators for type II and referral bias limit precision [1].

3.10 TRPS III: the severe end of the TRPS1 spectrum

Type III is characterised by severe generalised brachydactyly, with shortening of all metacarpals and phalanges, and by marked short stature, with the face and hair of type I, normal intelligence and absence of exostoses [4, 5, 24]. In the Japanese family with the p.(Arg921Gln) variant, the proband measured 138 cm at 59 years and her sister 130 cm at 66 years [8]. The PNDS describes it as a form with more pronounced skeletal involvement and, sometimes, functional disability resulting from multiple bone deteriorations and malformations [5]. The phenotypes of types I and III are close and sometimes difficult to differentiate, which justifies their inclusion in a continuous spectrum in GeneReviews and Bone Dysplasias [1, 3, 5]. The PNDS attributes more frequent intellectual disability to type III in its comorbidities section, which contradicts its own definition of the type and the other sources [4, 5].

3.11 Course by age

3.12 Natural history and treated disease

The frequency and course data described refer mainly to natural history, because there is no therapy that modifies the underlying defect. The available interventions act on complications: somatropin alters the growth trajectory in selected patients, hip and exostosis surgery alters joint function, and bisphosphonates alter bone mineral density in isolated cases; none of these interventions has been evaluated in comparative studies in TRPS, and the known results come from case reports and descriptive series (section 7) [1, 5, 45].

4. Clinical Recognition and Red Flags

4.1 Why diagnosis is late

The trichorhinophalangeal syndromes are underdiagnosed because of lack of awareness and highly variable expressivity, even within the same family; the signs may be subtle and go unnoticed in a consultation, and delayed or missed diagnosis leads to inadequate follow-up and, sometimes, unnecessary surgery [5]. In the Danish series, the median age at diagnosis of type I was 15 years (interquartile range 10–18 years), and the orthopaedic review found a mean age at diagnosis of 14.1 years [20, 45]. The characteristic face allows the experienced clinician to recognise the condition on sight, but confirmation requires genetic testing [5].

4.2 When to suspect, by age and setting

The Oxford Desk Reference groups the clues under the bulbous nose: sparse hair, a bulbous nasal tip and progressively curved fingers suggest TRPS, and the finger deformity develops from mid-childhood [52, 62]. In the presence of multiple exostoses with intellectual disability or behavioural abnormalities, Smith's recommends considering two microdeletion syndromes, Langer-Giedion (8q24, with EXT1 and TRPS1) and Potocki-Shaffer (proximal 11p, with EXT2) [61, 63]. Before 2 years of age, the absence of cone-shaped epiphyses does not exclude the diagnosis, because they only become visible when the epiphyseal centres form [1, 5].

4.3 Warning and emergency signs

4.4 Newborn screening

There is no newborn screening for the trichorhinophalangeal syndromes, and the sources consulted describe no biochemical markers that would allow it [1, 5].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

No published consensus clinical criteria exist [1]. The clinical diagnosis is established in a proband with the characteristic face, the ectodermal and joint manifestations and the skeletal findings, including cone-shaped epiphyses; the molecular diagnosis is established with a heterozygous pathogenic or likely pathogenic variant in TRPS1 (type I) or with a heterozygous 8q23.3–q24.11 deletion spanning the TRPS1–EXT1 interval (type II) [1, 65]. The PNDS considers that the diagnosis is clinical, but that only genetic testing confirms it, and that identification of the molecular alteration helps to estimate prognosis in the case of early diagnosis [5]. A variant of uncertain significance in TRPS1 neither establishes nor excludes the diagnosis [1]. A family history compatible with autosomal dominant inheritance supports the diagnosis, but its absence does not exclude it [1].

5.2 Radiological assessment

Hand radiographs are the key orienting examination and show shortening of phalanges and metacarpals, irregular, widened and short metaphyses and cone-shaped epiphyses of the middle phalanges; the PNDS asks that the patient be referred to the genetics clinic with radiographs of the extremities, spine and pelvis [3, 5]. AP and Lauenstein radiographs of the pelvis assess changes in the femoral head [5]. In type II, Smith's describes, in addition to cone-shaped epiphyses visible at 3–4 years, lack of metaphyseal modelling with «cupping» of the metaphyses over the cone-shaped epiphyses, vertebral segmentation defects, narrow posterior ribs and osteopenia, and Bone Dysplasias illustrates multiple «ivory» epiphyses [6, 15]. Bone age should be interpreted from the unaffected epiphyses, because cone-shaped epiphyses fuse prematurely [1, 3].

5.3 Genetic tests and strategy

In the pooling of 206 patients from seven series, biased towards the more severe cases, sequencing identified approximately 81% of pathogenic alterations, targeted deletion and duplication analysis approximately 7%, karyotype approximately 3% (inversions and translocations) and microarray, in type II, approximately 9% [1]. These figures are proportions of the alterations detected by each method among diagnosed patients and do not measure the clinical sensitivity of each test. In the Lüdecke series, sequencing found variants in 44 of 51 unrelated patients (86%), and the remainder were left without a molecular explanation with the methods of 2001 [10]. The French reference laboratories listed in the PNDS include Montpellier (FISH and NGS bone disease panel), Saint-Étienne (Sanger sequencing of TRPS1) and Caen (brachydactyly panel with NGS, Sanger, MLPA and microsatellites, in the prenatal and postnatal setting) [5].

5.4 Limitations of testing

A negative result does not exclude the diagnosis. Sequencing may fail to detect single-exon, multi-exon or whole-gene deletions, depending on the method [1]. Targeted deletion and duplication analysis detects losses from a single exon to the whole gene, but may not define the breakpoints of large deletions or the inclusion of adjacent genes such as RAD21 and EXT1, which is essential for distinguishing type I due to whole-gene deletion from type II [1]. The ability of the microarray to determine the size of a deletion depends on probe density at 8q24, and the microarray does not detect balanced rearrangements, inversions or most intragenic variants [1, 5]. Rearrangements that do not disrupt the gene, such as the t(8;13) translocation of the Portuguese family or the t(2;8) translocation with a breakpoint outside TRPS1, and position effects on regulatory elements escape sequencing and microarray and require karyotype or long-read methods [1, 8, 38]. Low-grade mosaicism in a parent's blood may not be detected in leucocytes and is not detected when confined to the gonads [1, 14]. In a patient with a mosaic deletion, the fraction of cells with the deletion varied between blood lineages (approximately 75%, mainly granulocytes), and in the Shanske case the deletion was present in 7% of lymphocytes and 97% of fibroblasts, which shows that blood may underestimate mosaicism [27].

5.5 Report content and interpretation

The report should state the gene, the reference transcript with version (NM_014112.5 for TRPS1), the variant in HGVS nomenclature at the coding DNA and protein levels, the zygosity and the classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [9, 65]. For deletions, it should state the genome build, the coordinates, the minimum and maximum size and the list of OMIM genes included, because the presence of EXT1 defines the exostosis risk and the presence of neurodevelopmental genes guides the cognitive prognosis [1, 5]. When comparing with the literature, the 13-codon renumbering of TRPS1 between historical and current nomenclature should be taken into account (for example, R952C corresponds to p.(Arg965Cys)) [8, 34]. For a variant of uncertain significance, family segregation with clinical examination and hand radiographs of relatives is useful, because penetrance is complete, although expressivity varies [1, 10].

5.6 Diagnostic algorithm

Source: synthesis of the GeneReviews and PNDS recommendations [1, 5].

5.7 Prenatal and preimplantation diagnosis

Once the familial alteration has been identified, prenatal diagnosis and preimplantation genetic testing are possible, but the severity of the phenotype cannot be predicted from the result [1]. The PNDS notes that prenatal diagnosis is not generally performed, given the frequency of mildly symptomatic patients and good clinical tolerance, but may be discussed at a genetics clinic and at a meeting of a multidisciplinary prenatal diagnosis centre [5]. The sources consulted describe no characteristic prenatal ultrasound signs of TRPS (section 8.4).

6. Differential Diagnosis

6.1 Principles

The differential diagnosis is organised around three associations: short stature with brachydactyly and cone-shaped epiphyses; abnormalities of the hair, nails and teeth with anomalies of the extremities; and multiple exostoses with dysmorphism or intellectual disability [1, 5]. Two clues guide the decision: the calcium-phosphate balance is normal in TRPS, and the face, with the bulbous nose with hypoplastic alae and medially predominant eyebrows, is specific [5]. Cone-shaped epiphyses, although almost constant in TRPS, are not exclusive to it, and only genetic testing confirms the diagnosis [1, 5].

6.2 Comparative table

AD: autosomal dominant; AR: autosomal recessive; CNV: copy number variant; PTH: parathyroid hormone.

6.3 Differential between TRPS types

Types I and II share the face, hair and digital changes; type II is distinguished by osteochondromas, microcephaly, more frequent intellectual disability, lax skin in infancy, epilepsy and hearing loss [1, 6]. Clinical distinction requires radiographs, because exostoses may only appear at 5 years, and only the microarray demonstrates the inclusion of EXT1 [5, 6]. A patient with a whole-gene deletion of TRPS1 without EXT1 has a type I phenotype, and a deletion including EXT1 and RAD21 but sparing TRPS1 produces osteochondromas without the trichorhinophalangeal face [1, 27]. Types I and III are distinguished by the degree of shortening of all metacarpals and phalanges and of short stature, in a continuous transition that led GeneReviews to abandon the type III designation [1, 5]. Two disorders may coexist: the twins described as having Fitzsimmons-Guilbert syndrome had, on reanalysis, a SACS-associated spastic ataxia and TRPS I due to a truncating TRPS1 variant [16].

6.4 Differential of multiple exostoses

In the presence of multiple exostoses, the absence of dysmorphism suggests an isolated disorder due to EXT1 (8q24.11) or EXT2 (11p11.2), whereas a syndromic exostosing disorder suggests Langer-Giedion syndrome or Potocki-Shaffer syndrome, both identifiable by microarray [5]. Potocki-Shaffer syndrome, with just over 30 published patients, is distinguished by bilateral parietal foramina, a normal hairline and genitourinary anomalies [5, 59]. In metachondromatosis, the exostoses are associated with enchondromas and characteristically involve the hands [6].

7. Treatment and Risk Management Strategies

7.1 Objectives, team and initial assessment

There is no therapy targeting the TRPS1 defect or the type II deletion, and treatment is supportive and preventive [1, 33]. The PNDS sets four objectives: to prevent the onset of pain or functional disability, to limit functional impairment when it already exists, to limit the socio-occupational consequences and to limit the psychological impact [5]. The family doctor and the paediatrician guide the patient; the geneticist coordinates and confirms the diagnosis; the paediatric endocrinologist assesses growth and the indication for growth hormone; the rheumatologist intervenes in chronic pain; the orthopaedic surgeon or the physical and rehabilitation medicine physician carries out a first assessment after diagnosis and, in type II, the paediatric orthopaedic surgeon follows the exostosing disease until the end of growth; the school doctor, dermatologist, dentist, orthodontist, maxillofacial surgeon, plastic surgeon (at the adult's request, rarely in childhood), neurologist (neurovascular conflicts, epilepsy and intellectual disability in type II), psychologist, physiotherapist, occupational therapist and psychomotor therapist also take part [5].

7.2 Growth and growth hormone

Indications according to the PNDS. Growth hormone deficiency should be sought when growth velocity slows, with a loss of 1 standard deviation after 2 years; the parental target height is difficult to interpret in the context of bone dysplasia and is often of no use [5]. With confirmed deficiency, somatropin (recombinant human growth hormone) may be proposed within the marketing authorisation; it is effective, re-accelerates growth velocity, and follow-up is the usual one, with doses adapted to the clinical response and IGF-1 [5]. As the pubertal growth spurt may be reduced, particularly in boys, treatment is more effective the earlier it starts before puberty, ideally before 8–10 years [5]. Without deficiency, somatropin may be considered off-label, with moderate efficacy and few data; the efficacy criteria, a significant acceleration of growth velocity at 1 and 2 years, should be explained to the patient and family at the start, and treatment should be stopped if they are not met; off-label prescribing is the responsibility of a paediatric endocrinologist experienced in rare diseases [5]. GeneReviews limits the recommendation to patients with short stature and proven deficiency, suggests stimulation tests when growth is below normal and concerns the family, and stresses the variability of the response [1, 36, 51].

Mechanism, presentation and doses. Somatropin is human growth hormone produced by recombinant DNA technology, administered subcutaneously [64, 76]. The PNDS does not specify doses and refers to the framework of the marketing authorisation for growth hormone deficiency, so the reference dose in proven deficiency is that of the label; in use without deficiency, the dose is derived from published reports and, by declared extrapolation, from the approved indications for short stature without deficiency [5, 64, 77].

The US Genotropin® label contraindicates somatropin in acute critical illness, active neoplasia, hypersensitivity, proliferative or severe non-proliferative diabetic retinopathy, closed epiphyses and Prader-Willi syndrome with severe obesity or respiratory impairment, and warns of slipped capital femoral epiphysis, progression of pre-existing scoliosis, intracranial hypertension, glucose intolerance, hypothyroidism, fluid retention and pancreatitis [64]. Two of these warnings weigh particularly in TRPS, in which the hip and spine are targets of the disease: any limp or hip or knee pain during treatment requires orthopaedic assessment, and scoliosis should be monitored at each visit [5, 64]. The European labels and the Portuguese SmPC include warnings about slipped epiphysis and scoliosis; the Portuguese SmPC adds that cases of slipped capital femoral epiphysis and Legg-Calvé-Perthes disease have been reported in treated children, without it being known whether they are more frequent during treatment, and that the diagnosis should be considered in any child with hip or knee discomfort or pain [76, 77]. In a disease with Perthes-like changes in more than half of published patients, this warning makes radiological assessment of the pelvis relevant before starting and in the presence of any hip or knee complaint [45, 77].

Published results. The evidence is limited to reports and small series. In a boy without deficiency treated from 8 years and 4 months, height standard deviation went from −2.4 to −1.4 and growth velocity from 4.7 to 7.7 cm/year, but bone age advanced 2.5 years in 2 years; his untreated brother grew 5.5 cm/year [78]. The authors cite patients without response to 0.2 mg/kg/week for 10 years and better responses with 0.3–0.5 mg/kg/week [78]. In an 11-year-old boy with the variant c.1957C>T p.(Gln653*), 0.34 mg/kg/week produced a velocity of 1.12 cm/month (+1.1 standard deviations per year) in the first year; in the review of 12 cases of TRPS I, eight had a good response [51]. In a 3.5-year-old boy with confirmed deficiency, growth velocity improved and so did the radiographic appearance of the femoral epiphyses, which the authors interpret with caution [50]. In a three-generation Chinese family, the siblings treated for 2 years improved their linear growth, and earlier start and longer duration were associated with better height [37]. Two patients with partial deficiency had no bone response to growth hormone [49], and in the Korean series responses were variable [21]. No controlled study has assessed adult height, and the advance in bone age observed in some treated patients raises the possibility that the initial gain does not translate into final height.

7.3 Bone health: calcium, vitamin D and bisphosphonates

The PNDS recommends assessing calcium and vitamin D intake and, possibly, bone mass in the presence of clinical or radiological warning signs, supplementing vitamin D according to current recommendations, using the French PNDS for secondary bone fragility in children to guide investigations and discussing bisphosphonate treatment as a team in symptomatic bone fragility [5]. GeneReviews adds recommendations on sun exposure, calcium and vitamin D intake or supplementation, adaptation of activities to prevent fractures and consideration of bisphosphonates [1]. Neither source gives doses, and no bisphosphonate has an approved indication in TRPS; the doses below come from TRPS reports and, by declared extrapolation, from the French PNDS for osteogenesis imperfecta, in which bisphosphonates are also used off-label in children [79].

The precautions of the osteogenesis imperfecta protocol include monitoring temperature during the first cycles (fever treated with paracetamol), oral assessment and hygiene because of the risk of osteonecrosis of the jaw, a pregnancy test before each cycle in adolescent girls because of the risk of fetal osteosclerosis, suspension of the bisphosphonate in the week before a planned osteotomy until bone callus is visible and respiratory monitoring in infants; at each cycle, calcium, phosphate, 25-hydroxyvitamin D, parathyroid hormone, osteocalcin, C-terminal telopeptide and the urinary calcium/creatinine ratio are measured, and lumbar densitometry is annual [79]. In the TRPS reports, neridronate eliminated new fractures and increased lumbar bone mineral density by 45%, and pamidronate was associated with no fractures for 12 months; the pamidronate dose used in the latter case corresponds to approximately one third of the per-cycle dose of the osteogenesis imperfecta protocol [27, 57, 79]. The absence of healing abnormalities after orthopaedic or maxillofacial surgery in TRPS, recorded by the PNDS, refers to patients not on bisphosphonates [5].

7.4 Pain: assessment and analgesia

Pain should be sought at each visit with a validated scale adapted to age and cognitive abilities; non-opioid analgesics, and in particular non-steroidal anti-inflammatory drugs (NSAIDs), are first choice, and chronic pain despite usual analgesics justifies assessment by a pain specialist or at a pain assessment and treatment centre [5]. GeneReviews recommends NSAIDs or other non-opioids, physiotherapy to relieve pain and maintain hip range of motion, and regular exercise [1]. None of the TRPS sources gives doses; the following doses are those of the osteogenesis imperfecta PNDS, used by declared extrapolation [79].

The minimum age for tramadol in the osteogenesis imperfecta PNDS predates the paediatric contraindication introduced by the FDA on 20 April 2017 for codeine and tramadol below 12 years and, up to 18 years, after tonsillectomy or adenoidectomy [79, 81, 82]. The divergence persists: the French SmPC for tramadol drops, updated in 2025, still authorises it from 3 years, with warnings for CYP2D6 ultrarapid metabolisers, use after tonsillectomy and compromised respiratory function [80]. In the EU, analgesic codeine has been restricted since 2013 to moderate acute pain above 12 years and contraindicated below 18 years after tonsillectomy or adenoidectomy for obstructive sleep apnoea, in ultrarapid metabolisers and during breastfeeding [83]. Below 12 years, the choice of opioid follows the national product label.

EVENDOL: child pain assessment scale; GED-DI: pain assessment grid for intellectual disability; DESS: San Salvadour child pain scale; EDAAP: assessment of pain expression in adolescents and adults with polyhandicap; EDD: assessment of pain expression in people with communication difficulties; ESDDA: simplified pain assessment scale for people with communication difficulties and autism spectrum disorder; PPP: Pediatric Pain Profile; COMFORT B: behavioural comfort scale in intensive care [5].

7.5 Orthopaedics, rheumatology and rehabilitation

General measures. Physiotherapy and physical exercise improve joint mobility and reduce pain, but activity should be adapted to physical condition, mobility restrictions and pain; contact sports or sports with high joint impact should be avoided [1, 5]. Assessment in physical and rehabilitation medicine, psychomotor therapy and occupational therapy guides adaptations of daily living and physical activity, and assistive devices may be offered; for fine motor difficulties, occupational therapy and simple mechanical aids, such as electric can openers, compensate for digital limitations [1, 5]. Mobility support at school and at work should be ensured [1].

Hands and feet. The PNDS does not consider it appropriate to operate on malformations of the extremities, except in cases of significant discomfort or potentially improvable functional disability [5]. In an isolated report, resection arthrodesis with tension band osteosynthesis stabilised a painful ulnar dislocation of the proximal interphalangeal joints, with no published follow-up [1]. The systematic review described hand surgery for carpal tunnel syndrome, clinodactyly and thumb anomalies [45].

Hip. Hip pain or restricted mobility requires AP and Lauenstein radiographs of the pelvis; Perthes-like changes should not be treated as isolated Legg-Calvé-Perthes disease [5]. In severe dysplasia, arthroplasty should be considered, sometimes in young adults at around 30 years, and 11% of published patients required some form of hip surgery [5]. Prostheses may require multiple revisions because of their limited lifespan, and functional gain is difficult when other joints are damaged by the disease itself or by compensatory overload [1]. In the systematic review, 8 of 26 patients (30.8%) underwent surgery, mainly of the hip for Perthes-like changes or coxa magna; there were complications in 5 (22.7% of patients with data) and surgical revision in 2 (25%) [45].

Spine and thorax. Scoliosis should be screened for at each visit, every 6–12 months depending on age, and followed by a paediatric orthopaedic surgeon, with bracing or surgery according to severity [5]. Pectus carinatum has no functional consequence; if it is aesthetically troublesome, a brace can remodel the chest and should be maintained until the end of growth [5]. In basilar invagination with cervicomedullary compression, endoscopic endonasal odontoidectomy followed by C0–C2 occipitoaxial fixation with C2 translaminar screws has been described, with neurological recovery, in a patient with an aberrant vertebral artery [55].

Type II osteochondromas. Exostoses should be examined once a year to detect axial deviations and neurovascular compressions; radiological assessment is performed when they are symptomatic or painful, and surgical removal is considered if they cause functional discomfort, axial deviation or compression [1, 5]. The PNDS recommends spinal magnetic resonance imaging at the start of the second decade, to exclude intracanal exostoses, and, at the end of growth, mapping of the exostoses, if possible by whole-body EOS radiography (AP and lateral, low radiation and three-dimensional reconstruction) [5]. Surgical management follows that of hereditary multiple osteochondromas.

In a 21-year-old woman with subacromial impingement due to bilateral osteochondromas of the distal clavicle, staged open resection resolved the symptoms without recurrence [58]. In the patient with a mosaic deletion described in the clinical case, surgery included correction of hip dysplasia, excision of a femoral osteochondroma and a proximal femoral osteotomy [27].

7.6 Hair and nails

Hair is the manifestation that weighs most on body image, particularly in men who lose their hair after puberty [1, 5]. The PNDS cites a young man treated with minoxidil and finasteride without efficacy, who later obtained good results with hair transplantation, and concludes that transplantation appears to be the only treatment to offer for early hair loss; a wig may be discussed from an aesthetic point of view [5, 84]. GeneReviews, updated in 2024, is more favourable: it considers that topical minoxidil and hair transplantation may be useful, based on a 9-year-old girl with TRPS I whose hair density and length improved diffusely after 4 months of topical minoxidil, without hypertrichosis, and on a patient with a successful hair transplant; it also records generalised hypertrichosis after 9 months of 5% minoxidil in another patient [1, 84–86]. In the Korean series, the response to minoxidil was variable [21]. GeneReviews also recommends practical advice on hair care and the use of wigs [1].

Topical minoxidil is approved over the counter in the USA as a hair regrowth treatment. None of the TRPS sources states the concentration, dose or frequency used in children. The US over-the-counter label for the 5% solution indicates 1 ml twice a day applied to the scalp in the area of vertex alopecia, warns that larger or more frequent doses do not improve the result and that stopping causes hair loss to resume, and excludes use below 18 years and in children [87]. Paediatric use in TRPS is therefore outside the label conditions, supported by isolated reports, and generalised hypertrichosis is the described adverse effect that justifies monitoring [86, 87]. Dystrophic nails have no specific treatment, and the dermatologist intervenes in disabling nail dysplasia [5].

7.7 Teeth and the maxillofacial region

Annual dental follow-up should begin in early childhood, from the appearance of the primary teeth, and is supplemented by orthodontics when the dentist deems it necessary and by maxillofacial surgery for severe craniofacial anomalies (micro-retrognathism or prognathism with malocclusion), which led to surgery in two published cases [5]. Extraction of supernumerary teeth may be considered, particularly when they prevent eruption of the permanent dentition [1, 48]. In France, the PNDS recommends including dental care and orthodontics in the long-term condition scheme (affection de longue durée, ALD) [5].

7.8 Neurodevelopment, epilepsy, hearing, vision and psychological support

In type II and in patients with a clinical diagnosis without a molecular cause, developmental assessment should be repeated annually during childhood, with developmental support and educational services; the school doctor coordinates schooling adaptations for learning difficulties [1, 5]. In type II, psychological follow-up should be closer, with neuropsychological assessment, and psychomotor therapy and speech therapy are offered according to symptoms [5]. Epilepsy is treated by the neurologist according to the usual rules; the sources consulted describe no pharmacological particularities in TRPS [5]. Hearing loss should be diagnosed and treated as early as possible, with hearing aids when indicated, because it contributes to speech delay [6, 40]. Refractive errors and strabismus are treated by ophthalmology [5].

Psychological support is offered to the patient and family at diagnosis and throughout growth, because short stature, chronic pain, the aesthetic prognosis, early alopecia, dental anomalies and school absenteeism linked to medical care may cause psychological distress [5]. In type I, the patient may need help with self-acceptance, and GeneReviews recommends peer support and psychological counselling for those who feel self-conscious about their physical differences [1, 5]. Facial changes that cause significant psychological distress may be corrected by plastic surgery, generally at the adult's request [5, 6].

7.9 Other manifestations

Cryptorchidism should ideally be operated on between 6 and 12 months [5]. Heart defects are treated by cardiology, and renal and urinary anomalies and vesicoureteric reflux by paediatric nephrology and urology, according to general rules [1, 5]. In adolescent girls with TRPS II, vaginal atresia with hydrometrocolpos requires gynaecological assessment [46].

7.10 Agents and circumstances to avoid

Contact and high-impact sports should be avoided in patients with reduced mobility and hip changes [1, 5]. Surgery of the extremities without significant discomfort or likely functional gain, and surgical procedures prompted by mistaken diagnoses (for example, treating the hip changes as isolated Legg-Calvé-Perthes disease or osteoarthritis as inflammatory disease), should be avoided [5]. Somatropin is contraindicated with closed epiphyses and in active neoplasia, which includes any sarcoma arising on an exostosis [64]. Bisphosphonates should not be given in the week before a planned osteotomy, by analogy with the osteogenesis imperfecta protocol [79].

7.11 Pregnancy, anaesthesia and surgery, transition to adulthood

Pregnancy and lactation. The sources consulted describe no series of pregnancies in women with TRPS and no specific obstetric recommendations. Hip dysplasia, early osteoarthritis and short stature are the manifestations with potential obstetric relevance, and preconception counselling follows section 8 [1]. Bisphosphonates require a pregnancy test before each cycle in adolescent girls, because of the risk of fetal osteosclerosis [79]. Topical minoxidil is sold over the counter in the USA for adults only, and the label consulted excludes women from the 5% presentation [87].

Anaesthesia and surgery. The PNDS found no delay or abnormality of healing after orthopaedic or maxillofacial surgery in the literature [5]. Postoperative pain should be assessed with the scales in the table in section 7.4 [5]. The sources consulted contain no specific anaesthetic recommendations; micrognathia, the basilar invagination described in an adult and the cervical osteochondromas of type II are findings relevant to management of the airway and cervical spine [1, 15, 55].

Transition. The PNDS follow-up schedule extends beyond 25 years, with progressively spaced visits, and transition to adult medicine includes transfer to adult rheumatology and orthopaedics for chronic pain, osteoarthritis and exostosing disease [5]. A survey on paediatric-to-adult transition in multiple osteochondromas and enchondromatoses, registered on ClinicalTrials.gov with a start in November 2025 and already completed, illustrates the growing attention to this phase in the exostosing diseases [88].

7.12 Regulatory status

7.13 Clinical trials and intervention studies

There is no controlled trial in patients with TRPS, and the evidence on somatropin, bisphosphonates, minoxidil and surgery comes from reports and descriptive series, without a comparison group and with selection of published cases; gains in growth velocity do not inform on adult height [1, 5]. The multiple osteochondroma trials include only non-syndromic forms, and any extrapolation to TRPS II is indirect. Palovarotene did not demonstrate efficacy, and roneparstat, a heparin-derived heparanase inhibitor, remains at the preclinical stage [19].

7.14 Developments in the last 12 months and research

No authorisation, regulatory opinion or sponsor announcement relating to TRPS was identified in the recorded searches, which does not demonstrate that none exists. There are no gene therapies or genome editing therapies in clinical development for TRPS. The reasons are structural: in type I, the defect is haploinsufficiency of a transcription factor that acts during chondrogenesis and hair follicle development, so that a postnatal correction would have to reach the growth plates and follicles before the changes become fixed; in type II, the simultaneous loss of several contiguous genes rules out a strategy targeting a single gene [1, 5, 33]. The 2026 review of animal models discusses potential pathways based on rodent models, namely the roles of Trps1 in chondrogenesis and hair follicles and the reproduction of hip anomalies and growth retardation by deletion of regulatory elements, but without efficacy data in humans or classification of any strategy as a clinical candidate [32, 33].

7.15 Organisation of care and social support in France

The PNDS describes the French network: the reference and competence centres of the AnDDI-Rares network (developmental anomalies with or without intellectual disability of rare causes), the reference centres for constitutional bone diseases and calcium and phosphate metabolism of the OSCAR network, and the diagnostic laboratories of Montpellier, Saint-Étienne and Caen [5]. The support of a social worker is essential for preparing applications; applications should be anticipated and renewed 6 months before the end of current support [5]. Before 20 years of age, parents may apply to the Maison Départementale des Personnes Handicapées (MDPH) for the allocation d'éducation de l'enfant handicapé (AEEH) and supplements or the prestation de compensation du handicap (PCH), and to the Caisse d'Allocations Familiales for the allocation journalière de présence parentale (AJPP), which can be combined with the basic AEEH; the carte mobilité inclusion carries the priority, parking and disability (from 80%) endorsements [5]. At 18 years, protective measures are discussed (curatorship, guardianship, family authorisation); from 19 years, the allocation aux adultes handicapés (AAH), the PCH and the medico-social support services for disabled adults (SAMSAH) and social life support services (SAVS) are applied for, and the reconnaissance de la qualité de travailleur handicapé (RQTH) 6–12 months before entering work; the AAH is granted with an incapacity of 80% or of 50–80% with a substantial and lasting restriction of access to employment [5]. Schooling may take place in mainstream settings with a school support assistant, local units for school inclusion (ULIS) or adapted education sections (SEGPA), or in specialised settings [5]. These measures are specific to the French system; the sources consulted do not describe the Portuguese or Brazilian equivalents.

7.16 Divergences between sources

8. Reproductive Options and Family Counselling

8.1 Inheritance and recurrence risks

All types of TRPS are transmitted in an autosomal dominant manner, affect both sexes and give each child of a patient a 50% risk of inheriting the alteration [1, 5]. Penetrance is complete, but expressivity varies widely within the same family, particularly in type I, in which an affected parent may be unaware of their status [5, 10]. In type II, intrafamilial variability is more limited [1].

About one third of patients with TRPS I have a de novo variant, and many have an affected parent; most tested patients with TRPS II have a de novo deletion [1]. Transmission of the type II deletion has been described (father and daughter reported by Murachi in 1981), but Schinzel had found, up to 2013, no case of transmission by a non-mosaic parent, and linked this rarity to the reduced puberty and fertility of these patients [7, 15, 46]. Nardmann determined paternal origin in six and maternal origin in three 8q deletions [16].

8.2 Parental testing and cascade testing

GeneReviews recommends, in an apparently isolated case, complete physical examination of the parents, radiographs of the hands and feet and molecular testing for the proband's alteration; if the proband has a structural rearrangement, such as an inversion of chromosome 8, the parents should be karyotyped [1]. In type II, the parents should be tested by a genomic method that detects the deletion and also for a balanced rearrangement [1]. An apparently negative family history can only be confirmed after clinical and genetic assessment of the parents [1]. The PNDS requires an extended family enquiry, «by medico-legal injunction» (the French legal obligation to inform relatives of a genetic diagnosis), looking for short stature and osteoarticular complaints, because the disease is underdiagnosed and often inherited from a parent in type I [5]. The risk for other relatives depends on the status of the proband's parents [1].

8.3 Mosaicism

Parental mosaicism explains recurrences in sibships of healthy parents and has been documented by pyrosequencing in a mother with 10% carrier blood cells [5, 14]. Testing of leucocyte DNA may not detect all cases of somatic mosaicism and does not detect an alteration confined to the gonads [1]. In the proband, mosaicism for a type II deletion attenuates the phenotype variably and makes the risk for offspring dependent on the presence of the deletion in the germline [16, 27].

8.4 Prenatal and preimplantation diagnosis

Once the familial alteration has been identified, prenatal diagnosis and preimplantation genetic testing are technically possible, and the ideal time to determine the risk and discuss these options is before pregnancy [1]. The PNDS notes that TRPS does not usually give rise to prenatal diagnosis, given the frequency of mildly symptomatic patients and good clinical tolerance; a couple's request should be heard at a genetics clinic and discussed at the multidisciplinary meeting of a prenatal diagnosis centre, considering the type (II or III in particular) and the family context [5]. Preimplantation diagnosis and gamete donation are alternatives for couples who do not wish to transmit the disease but would not consider termination of pregnancy for medical reasons [5]. No result makes it possible to predict the severity of the phenotype [1]. Differences of perspective on the use of prenatal diagnosis for termination of pregnancy should be acknowledged and discussed [1].

8.5 Counselling of young people, DNA banking and disclosure of the diagnosis

Genetic counselling, with discussion of the risks for offspring and of reproductive options, should be offered to affected or at-risk young adults [1]. In patients without molecular confirmation, DNA banking should be considered, because methods and understanding of the mechanisms will improve [1]. Disclosure of the diagnosis follows the principles for any rare disease: by an experienced doctor, in a calm place without interruptions, without urgency, avoiding evenings and the eve of weekends, with consideration of situations such as recent pregnancy, bereavement or family conflict, preferably together with a psychologist and, for a child, with both parents and, when possible, with the child themself [5]. The disclosure consultation ends with the plan of initial investigations, referrals and the contact details of the nearest reference centre [5].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence and what each figure measures

The Danish estimate, approximately 50 times higher than the Orphanet class, shows that the < 1/1,000,000 class derives from the count of published cases and underestimates the true frequency; GeneReviews and the PNDS consider TRPS I underdiagnosed [1, 5, 20]. The Danish figure is a regional minimum and should not be extrapolated as a national or European prevalence [20]. The 3:1 male predominance stated in the Brazilian textbook is not corroborated by series with sex data: 11 of the 15 Danish patients (73%) were women, and the multicentre trichoscopy series included mainly women [20, 40, 47]. The PNDS stresses that the disease affects both sexes [5]. For comparison, hereditary exostosing disease has prevalences of approximately 1/50,000 in North America, 1/100,000 in the United Kingdom and 1/1000 in Guam, and of 3.0/100,000 in Europe according to Orphanet [19, 39, 59].

9.2 Geographical distribution and populations

No founder variants of TRPS1 or populations with increased frequency are known; variants are generally private to each family [1, 10]. The published series come from Europe (collaborative study of 103 patients, Danish cohort, Czech series), Turkey (the Güneş and Öztürk series), China, Korea, Japan (the historical families of Sugiura and Sugio-Kajii), the USA and Brazil [1, 4, 11, 16, 20, 21, 35, 42, 90]. The manifestations described are similar across populations; in the Korean series, short stature below −2 standard deviations was less frequent (21%) than in European estimates of 40–50%, a difference that may reflect the paediatric age of the sample rather than a population difference [1, 21].

Portugal. Two Portuguese families contributed to the genetics of TRPS: the father and daughter with the p.(Arg965Cys) variant (historical designation R952C), who helped define the functional nuclear localisation signal of the protein, and the family with the t(8;13)(q23.3;q21.31) translocation that appears to increase TRPS1 expression [30, 38]. A Portuguese report discussed systematic testing for growth hormone deficiency in a girl with two nonsense variants and very low growth velocity [36]. The sources consulted include no prevalence estimates for Portugal.

Brazil. A São Paulo group delimited in two patients the 3.2 Mb minimal critical region of Langer-Giedion syndrome, a report published in the Brazilian rheumatology journal described the skeletal anomalies of TRPS I, and a Brazilian-Italian multicentre study characterised trichoscopy [12, 47, 54]. The Brazilian textbook of genetic syndromes devotes a chapter to Langer-Giedion syndrome, with ICD-10 code Q87.8 [40]. The sources consulted include no prevalence estimates for Brazil.

9.3 Special populations

In young children, the absence of cone-shaped epiphyses before 2 years and of exostoses before 5 years may delay diagnosis [1, 6]. In adults, the diagnosis may only arise in the context of early osteoarthritis, chronic pain or alopecia, and in type I parents with mild undiagnosed forms are frequently found [5, 53]. In patients with intellectual disability or communication difficulties, pain should be assessed with observer-rated scales [5]. The sources consulted do not describe the course in older people.

9.4 Reference networks and patient associations

In Europe, patients with TRPS fall under the European Reference Network for rare bone diseases (ERN BOND), which includes skeletal dysplasias and exostosing diseases, and the network for rare congenital malformations and rare intellectual disability (ERN ITHACA), relevant in type II [22, 23]. In France, the reference centres of the AnDDI-Rares and OSCAR networks coordinate diagnosis and follow-up [5]. At the time of the PNDS, there was no French association specific to TRPS; the PNDS lists specific associations in the United Kingdom and the USA, accessible in English, and broader French associations: the Association Française des Dysplasies Ectodermiques (AFDE), the Association des Personnes de Petite Taille (APPT), the Valentin APAC association for carriers of chromosomal anomalies and the Association de la Maladie des Exostoses Multiples (AMem), the latter two for type II, as well as the Alliance Maladies Rares and the Maladies Rares Info Services helpline [5]. The MHE Research Foundation supports patients with multiple exostoses [91]. The doctor should systematically offer contact with associations, the choice being left to the patient or family [5].

10. Illustrative Clinical Case

10.1 Mosaic 8q23.1–q24.12 deletion with Langer-Giedion syndrome, Cornelia de Lange syndrome type 4 and multiple osteochondromas

Valientes and Wang published in 2026 the case of a girl first seen at the genetics clinic at 2 years (21 December 2021), referred for multiple congenital anomalies and an abnormal chromosomal microarray [27]. She was born at 39 weeks and 3 days, to a 25-year-old mother and a 30-year-old father; the pregnancy involved maternal alcohol exposure up to 6–7 weeks. She walked independently at 16 months, language developed at the expected time and she is bilingual. She had microcephaly, plagiocephaly, postaxial polydactyly and overlapping toes on the left foot, and had already undergone surgery for right hip dysplasia and the polydactyly; three months before the first visit she had sustained a fracture of the right femur. On examination she had large ears, a flat nasal root, a bulbous nasal tip, a long philtrum and a thin upper lip. The skeletal survey showed an angulated comminuted fracture of the distal metadiaphysis of the right femur, multiple sessile osteochondromas of several long bones and postoperative changes of a right proximal femoral osteotomy, with no anomalies of the axial skeleton and no cone-shaped epiphyses. The family history included Noonan syndrome in a maternal half-cousin and polydactyly in a paternal great-grandmother [27].

The microarray (13 October 2021) showed a 21.5 Mb mosaic interstitial duplication at 8q21.2–q23.1, a 13.01 Mb mosaic interstitial deletion at 8q23.1–q24.12 (hg19, 8:107,431,257–120,443,762) and a 25.78 Mb mosaic terminal duplication at 8q24.12–q24.3; approximately 10% of nucleated blood cells had the duplications and approximately 75%, mainly granulocytes, the deletion [27]. The deleted interval included, among OMIM genes with a phenotype association, OXR1, ANGPT1, RSPO2, TRHR, PKHD1L1, TRPS1, RAD21, SLC30A8, EXT1, SAMD12, TNFRSF11B and COLEC10. The maternal microarray was normal and the father was not available [27].

At 3 years she fractured her left wrist and at 4 years the left distal radius and right clavicle. At the visit on 24 October 2023, the mother reported distractibility and less clear speech, with no other global developmental concerns; hypotonia and weakness were treated with physiotherapy and occupational therapy, and the overlapping toes, in-toeing gait and bone pain had worsened. A left femoral osteochondroma was then excised. Growth lay between the 10th and 50th centiles of the general population charts and between the 80th and 95th centiles of the Cornelia de Lange syndrome charts. On examination there was also sparse, coarse, thick hair, synophrys with lateral thinning of the eyebrows, a short upturned nose with anteverted nostrils and a low columella, downturned corners of the mouth, thoracic kyphosis, winged scapulae with posterior prominence of the superomedial border of the left scapula and of the acromioclavicular region, flat feet and osteochondromas on the medial aspect of the foot [27]. Magnetic resonance imaging showed non-expansile osteochondromas in the right humeral head and the scapula; radiographs confirmed bilateral hip dysplasia and additional osteochondromas and a new distal fracture of the right clavicle; there was femoral length discrepancy (right femur 28 cm and left 25.5 cm) [27].

Because of the fracture history, an osteogenesis imperfecta and bone fragility panel confirmed the pathogenic deletion of TNFRSF11B within the interval and identified a maternal variant of uncertain significance in LRP5, with no clinical evidence of osteopetrosis. The composite diagnosis was Langer-Giedion syndrome, Cornelia de Lange syndrome type 4 and hereditary multiple osteochondromas due to a mosaic 8q23.1–q24.12 deletion [27]. Calcium, 25-hydroxyvitamin D, osteocalcin, urinary creatinine and the bone turnover marker NTx were normal; lumbar densitometry (L1–L4) showed 0.375 g/cm², with a Z-score of −2.6. With the mother's consent, off-label pamidronate was started, 1 mg/kg every 4 months, with vitamin D3 supplementation, and a plan of annual densitometry, fracture surveillance and orthopaedic follow-up of the osteochondromas; she remained fracture-free for the following 12 months [27].

Figures consulted. Figure 1: photographs at 5 years (microcephaly, large protruding ears, broad nasal root, hypoplastic alae nasi, low and broad columella; flat feet with overlapping toes and osteochondromas; thoracic kyphosis and winged scapulae), available at https://pmc.ncbi.nlm.nih.gov/articles/PMC12940567/figure/genes-17-00175-f001/. Figure 2: Ensembl GRCh37 representation of the deletion and the proximity of TRPS1, RAD21 and EXT1, at https://pmc.ncbi.nlm.nih.gov/articles/PMC12940567/figure/genes-17-00175-f002/. Figure 3: radiographs with sessile osteochondromas and the femoral fracture, and MRI scans of the scapula and humeral head at 5 years, at https://pmc.ncbi.nlm.nih.gov/articles/PMC12940567/figure/genes-17-00175-f003/ [27].

10.2 Lessons from the case

The case illustrates the spectrum of 8q deletions: the combination of TRPS1, RAD21 and EXT1 produced the facial and hair features of TRPS, the osteochondromas and the overlap with Cornelia de Lange syndrome type 4 that led the authors to the composite diagnosis, and the deletion of TNFRSF11B, classified as pathogenic on the bone fragility panel, was the alteration linked by the authors to the fractures [1, 27]. The complex architecture, with a central deletion flanked by two duplications and in mosaic form, was interpreted by the authors as a post-zygotic replicative error, and the contribution of the trisomic regions cannot be excluded [27]. The mosaicism, with 75% of blood cells carrying the deletion, is compatible with relatively preserved neurodevelopment, as in the Shanske case with predominance of the deletion in fibroblasts [27]. The absence of cone-shaped epiphyses on the skeletal survey at 2 years is a reminder that this sign may be absent in early childhood [1, 5]. The bone management should not be read as routine: the PNDS does not establish a bisphosphonate protocol for TRPS and reserves them for symptomatic bone fragility discussed as a team, and the dose used in this case corresponds to approximately one third of the per-cycle dose of the French osteogenesis imperfecta protocol (1 mg/kg/day for 3 days every 4 months from 3 years) [5, 79]. Follow-up of 12 months does not allow conclusions about efficacy.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Life expectancy is not demonstrably reduced: the Brazilian textbook describes a prognosis similar to that of the general population, and Smith's describes, in type II, generally good health after childhood, apart from the tendency to fractures and the problems caused by the exostoses [15, 40]. Morbidity is dominated by the musculoskeletal system: pain, stiffness and early osteoarthritis of the hips, fingers, cervical spine, knees and ankles, with osteopenia from 30 years and hip arthroplasty sometimes at around that age [1, 5, 11]. Mean adult height is around 150 cm in women and 160 cm in men, with lower values in type III and type II [5, 6]. In type II, prognosis depends on the severity of the exostosing disease and of neurodevelopmental involvement, and large deletions are associated with a worse prognosis because of the number of genes involved [5]. Adults with Langer-Giedion syndrome often have practical abilities greater than those measured on tests, but low self-esteem, seizures at variable ages, cervical compressions and joint instability [46]. Cognition in type I is generally normal, and the PNDS recognises no increased cancer risk in TRPS, recommending general population cancer screening; in type II, the risk of transformation of the exostoses is unknown, estimated by the PNDS at 2–5% by extrapolation [5, 59].

11.2 PNDS follow-up schedule

Source: child and adult follow-up schedule of the PNDS [5].

11.3 Surveillance table

Systematic oncological surveillance of type II exostoses is not consensual: the AACR consensus allows surveillance similar to that for hereditary exostosing disease (annual examination from birth, baseline whole-body MRI in early adolescence and regional MRI of pelvic and scapular lesions every 2–3 years), but does not strongly recommend it, and recommends dedicated MRI of symptomatic lesions and follow-up at an experienced academic centre [59]. In isolated exostosing disease, GeneReviews estimates the screening time needed to identify one transformation at 3.9 years and considers imaging of pelvic and scapular lesions every 2–3 years in adults reasonable [19]. Clinical signs of transformation, such as rapid growth and increasing pain after maturity, a cartilage cap greater than 2–3 cm on MRI or CT and increased uptake on serial scintigraphy, remain the main reason for investigation [5, 19].

12. Summary and Concluding Remarks

The trichorhinophalangeal syndromes are autosomal dominant dysplasias in which loss of function of TRPS1 produces a recognisable picture: fine, sparse, slow-growing hair, a bulbous nose with hypoplastic alae, medially predominant eyebrows, a long philtrum, dystrophic nails, supernumerary teeth, brachydactyly with cone-shaped epiphyses from 2 years, progressive short stature and early hip changes. In types I and III, the cause is an intragenic variant or a rearrangement of TRPS1, and type III corresponds to the severe end of the spectrum, with marked brachydactyly and short stature, associated mainly with missense variants of the GATA zinc finger; in type II, Langer-Giedion syndrome, a contiguous gene deletion at 8q23.3–q24.11 removing TRPS1, RAD21 and EXT1 adds multiple osteochondromas, microcephaly, intellectual disability that is generally mild to moderate, lax skin in infancy, hearing loss and epilepsy, with a severity that depends on the gene content of the deletion and any mosaicism.

Diagnosis is clinical and radiological, confirmed by TRPS1 sequencing with deletion and duplication analysis in type I and by chromosomal microarray in type II, which should define the genes included; a negative test does not exclude the disease when there are balanced rearrangements, position effects or mosaicism. The disease is underdiagnosed, and the only population estimate, a minimum of 0.5/100,000 in a Danish region, is much higher than the prevalence class derived from published cases. Treatment is supportive, organised by the 2021 French PNDS: monitoring of growth with somatropin in proven deficiency and, off-label, with efficacy and stopping criteria; annual dental care; surveillance of the spine and hips, analgesia with anti-inflammatory drugs, physiotherapy and arthroplasty when needed; surgical correction of symptomatic exostoses, spinal MRI at the start of the second decade and mapping of exostoses at the end of growth in type II; and psychological, educational and social support. Divergences between sources centre on retention of type III, the role of minoxidil, imaging surveillance of exostoses and quantification of sarcoma risk in type II, for which the 2–5% estimate is an extrapolation from exostosing disease. Genetic counselling should consider the 50% risk for offspring, the variable expressivity that hides affected parents, the parental mosaicism that justifies a recurrence risk above that of the population for healthy parents and the impossibility of predicting severity at prenatal diagnosis.

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